Sleep Disorders Part II: Handbook of Clinical Neurology (Series Editors: Aminoff, Boller and Swaab)

HANDBOOK OF CLINICAL NEUROLOGY Series Editors

MICHAEL J. AMINOFF, FRANC¸OIS BOLLER, AND DICK F. SWAAB VOLUME 99

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2011

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Handbook of Clinical Neurology 3rd Series Available titles Vol. 79, The human hypothalamus: basic and clinical aspects, Part I, D.F. Swaab ISBN 0444513574 Vol. 80, The human hypothalamus: basic and clinical aspects, Part II, D.F. Swaab ISBN 0444514902 Vol. 81, Pain, F. Cervero and T.S. Jensen, eds. ISBN 0444519017 Vol. 82, Motor neurone disorders and related diseases, A.A. Eisen and P.J. Shaw, eds. ISBN 0444518940 Vol. 83, Parkinson’s disease and related disorders, Part I, W.C. Koller and E. Melamed, eds. ISBN 9780444519009 Vol. 84, Parkinson’s disease and related disorders, Part II, W.C. Koller and E. Melamed, eds. ISBN 9780444528933 Vol. 85, HIV/AIDS and the nervous system, P. Portegies and J. Berger, eds. ISBN 9780444520104 Vol. 86, Myopathies, F.L. Mastaglia and D. Hilton Jones, eds. ISBN 9780444518966 Vol. 87, Malformations of the nervous system, H.B. Sarnat and P. Curatolo, eds. ISBN 9780444518965 Vol. 88, Neuropsychology and behavioural neurology, G. Goldenberg and B.C. Miller, eds. ISBN 9780444518972 Vol. 89, Dementias, C. Duyckaerts and I. Litvan, eds. ISBN 9780444518989 Vol. 90, Disorders of Consciousness, G.B. Young and E.F.M. Wijdicks, eds. ISBN 9780444518958 Vol. 91, Neuromuscular Junction Disorders, A.G. Engel, ed. ISBN 9780444520081 Vol. 92, Stroke – Part I: Basic and epidemiological aspects, M. Fisher, ed. ISBN 9780444520036 Vol. 93, Stroke – Part II: Clinical manifestations and pathogenesis, M. Fisher, ed. ISBN 9780444520043 Vol. 94, Stroke – Part III: Investigations and management, M. Fisher, ed. ISBN 9780444520050 Vol. 95, History of Neurology, S. Finger, F. Boller and K.L. Tyler, eds. ISBN 9780444520081 Vol. 96, Bacterial Infections of the Central Nervous System, K.L. Roos and A.R. Tunkel, eds. ISBN 9780444520159 Vol. 97, Headache, G. Nappi and M.A. Moskowitz, eds. ISBN 9780444521392 Vol. 98, Sleep Disorders Part I, P. Montagna and S. Chokroverty, eds. ISBN 9780444520067

Foreword

We spend about one-third of our life either sleeping or attempting to do so. Sleep is not only comforting, but is also essential for our normal cognitive functioning and for our survival. Yet sleep can be disturbed or abnormal in up to one-quarter of the US population. The field of sleep medicine has developed dramatically in the past few years. To reflect these advances, we are proud to introduce the present two volumes, which are a novelty in several respects. It is the first time that two Handbook volumes have been dedicated entirely to sleep and its disorders. Readers will find in these two volumes considerable emphasis on recent developments in the field. There is a new focus on diagnostic techniques, particularly imaging. Fresh attention is given to genetics and clinical aspects of sleep. Finally, there is extensive coverage of management and of new therapeutic strategies for sleep disorders. The volumes were edited by Pasquale Montagna and Sudhansu Chokroverty. As series editors, we reviewed all the chapters and made suggestions for improvement, but we are delighted that the volume editors and chapter authors produced such scholarly and comprehensive accounts of different aspects of sleep and its disorders. Hence we hope that these volumes will appeal to clinicians and neuroscientists alike. Significant new advances, particularly in terms of diagnosis and therapy, lead to new insights that demand a critical appraisal. Our goal is to provide basic researchers with the foundations for new approaches to the study of these disorders, and clinicians with a state-of-the-art reference that summarizes the clinical features and management of the many neurological manifestations of sleep disorders. In addition to the print form, the Handbook series is now available electronically on Elsevier’s Science Direct site. This should make it even more accessible to readers and should facilitate searches for specific information. We are grateful to the two volume editors and to the numerous authors who contributed their time and expertise to summarize developments in their field and helped put together these outstanding volumes. As always, we are grateful to the team at Elsevier and in particular to Mr. Michael Parkinson, Ms. Caroline Cockrell, and Mr. Timothy Horne for their unfailing and expert assistance in the development and production of these volumes. Michael J. Aminoff Franc¸ois Boller Dick F. Swaab

Preface

Sleep has been mentioned in art, literature, religion, and philosophy since antiquity, but a long period of ignorance and a lack of interest paralyzed the scientific community until recently. There has been an explosion of information about sleep medicine and sleep research in the past three decades, making it difficult to keep abreast of progress. There is therefore a need for a comprehensive book on sleep medicine and sleep science. Sleep researchers have made remarkable progress in the last century in unraveling the mysteries of sleep, including its molecular neurobiology and functional neuroanatomy. The 1930s to 1950s was an active period for sleep research, and, since the late 1990s, there has been a resurgence of interest in the neurobiology of sleep. The twenty-first century is witnessing the continuation of such progress. Advances have occurred in basic science, clinical aspects, laboratory techniques, and therapy. Advances in basic science include new understanding of the neurobiology of sleep–wakefulness, including new models of rapid eye movement (REM) sleep mechanisms; controversy about sleep states, stages, and memory consolidations; advances in the understanding of sleep–wake-dependent genes, gene products, and the circadian clock, and the role of sleep duration in mortality and morbidity; and fascinating noninvasive neuroimaging studies (particularly positron emission tomographic and single photon emission computed tomographic scans) visualizing marked changes in function in cortical and subcortical neuronal networks in different sleep states. Advances in clinical science include new understanding of the neurobiology of narcolepsy-cataplexy, restless legs syndrome, REM behavior disorders, and fatal familial insomnia. Further clinical advances have been made in our understanding of sleep apnea and heart failure, and nocturnal paroxysmal dystonia (now known as nocturnal frontal lobe epilepsy), and in describing new parasomnias and acquiring new knowledge about the genetics of sleep disorders. These clinical advances required revision of the International Classification of Sleep Disorders in 2005. New laboratory techniques (e.g., actigraphy, cyclic alternating pattern recognition and scoring in the electroencephalogram, peripheral arterial tonometry, and pulse transit time), in addition to the gold-standard techniques of polysomnography, with advances in ambulatory recordings, multiple sleep latency, and maintenance of wakefulness tests, expanded the horizon of the field of sleep medicine. Publication of the American Academy of Sleep Medicine (AASM) Manual for Scoring of Sleep and Associated Events in 2007 was a step towards standardization of the techniques. Finally, significant advances have been made in therapy, with the addition of new drugs for treating narcolepsycataplexy, insomnia, and restless legs syndrome. Considerable improvement has been made in treating central and upper-airway obstructive sleep apnea syndrome with the addition of bi-level positive airway pressure, flexible positive airway pressure, autotitrating continuous positive airway pressure, assisted servo-ventilation, and intermittent positive pressure ventilation for treating sleep-disordered breathing in neuromuscular disorders. Application of appropriately timed bright light therapy for circadian rhythm sleep disorders is also a significant therapeutic contribution of modern sleep science. It is therefore an opportune moment to produce a comprehensive volume on sleep disorders, addressing all these recent advances in basic, technical, clinical, and therapeutic issues. When we first drafted a preliminary list of topics, it immediately became obvious that a single volume, as originally conceived, would not be enough to cover the topic in the Handbook of Clinical Neurology (HCN) series. This series is widely regarded as the ultimate reference work of clinical neurology and it is found in every medical library. However, the previous two series of the HCN were organized by disease, and neither in the first nor second series was any volume specifically dedicated to sleep disorders. This absence was probably due to inadequate knowledge and awareness about sleep disorders within the context of classic neurological diseases at that time.

x

PREFACE

Despite all the progress, two vexing questions remain: What is sleep and why do we sleep? What happens if we are sleep-deprived? In animal experiments Rechtschaffen’s rats on carousel (“disk over water”), deprived of REM and non-REM sleep, lost weight despite eating excessively and died. REM-deprived rats survived longer than nonREM-deprived rats. In later experiments by other investigators using different sleep deprivation techniques, rats did not show a similar syndrome. Furthermore, adult and newborn dolphins survive with no ill effects after long periods (weeks) without sustained sleep. Awareness of the importance of sleep leads to an acceptance of sleep medicine as an independent specialty. There are new guidelines for practicing sleep medicine developed by the AASM and European Sleep Research Society. Other countries are also in the process of developing guidelines independently or in collaboration with the World Association of Sleep Medicine and other national and international organizations. In these two volumes devoted to sleep disorders, nationally and internationally known scholars, researchers, clinicians, and educators address various aspects of sleep disorders medicine to keep sleep clinicians and researchers, and all those interested in sleep, abreast of recent developments. We, the editors, owe these authors an enormous amount of gratitude for their excellent contributions, which we hope will make these two volumes authoritative reference books. They will be useful to those practicing neurology and internal medicine, especially those in pulmonary, cardiovascular, gastrointestinal, renal and endocrine specialties, and to family physicians, psychiatrists, otolaryngologists, pediatricians, dentists, psychologists, and to neurosurgeons and neuroscientists, as well as technologists, nurses, respiratory therapists, and other paraprofessionals with an interest and curiosity about the mysteries of sleep. Pasquale Montagna Sudhansu Chokroverty

Acknowledgments

We thank all of the authors for their scholarly contributions and patience in waiting to see these two volumes finally in production after a long and protracted period (beyond our control). We also thank all the authors, editors, and publishers who have granted us permission to reproduce illustrations that were published in other books and journals. We must thank Mike Parkinson, development editor for the Handbook of Clinical Neurology, for his dedication and professionalism, and the editorial and production staff at Elsevier B.V. Dr. Montagna would like to express his gratitude and love to his family and in particular to his wife, Flavia Valentini, for her continued support throughout the long time it took to edit the books, and especially for her unfailing assistance in a time of severe personal adversities. Dr. Chokroverty wishes to thank Annabella Drennan, the editorial assistant to the journal Sleep Medicine, for assisting in proofreading and corrections of many of the chapters, and, his wife, Manisha Chokroverty, MD, for her love, patience, tolerance, and continued support throughout the long period of editing and proofreading during the production of these volumes.

List of contributors

K. Adachi Faculte´ de Me´decine Dentaire, Universite´ de Montre´al, Hoˆpital Sacre´ Cur de Montre´al, Montreal, and Faculty of Dentistry, University of Toronto, Toronto, Canada

Michel A. Cramer Bornemann Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA

Richard P. Allen Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

Christopher J. Earley Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

R. Robert Auger Mayo Center for Sleep Medicine, Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA

Stephen Feren Sleep Medicine and Research Center, St. John’s Mercy Medical Center and St. Luke’s Hospital, Chesterfield, MO, USA

Claudio L. Bassetti Department of Neurology, University Hospital Zurich, Zurich, Switzerland

Luigi Ferini-Strambi Sleep Disorders Center, Universita` Vita-Salute San Raffaele, Milan, Italy

Ruth M. Benca University of Wisconsin, Madison, WI, USA

Jean-Franc¸ois Gagnon Centre d’e´tude du sommeil et des rythmes biologiques, Hoˆpital du Sacre´-Coeur de Montre´al, and Department of Psychiatry, Universite´ de Montre´al, Montreal, Canada

Michel Billiard Department of Neurology, Gui de Chauliac Hospital, Montpellier, France Bradley F. Boeve Mayo Center for Sleep Medicine, Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA

Peter J. Hauri Mayo Clinic, Department of Psychiatry and Psychology and Mayo Medical School, Rochester, MN, USA Wayne Hening (deceased) Department of Neurology, UMDNJ-RW Johnson Medical School, New Brunswick, NJ, USA

S. Chokroverty New Jersey Neuroscience Institute, JFK Medical Center, Seton Hall University, Edison, NJ, USA

Dirk M. Hermann Department of Neurology, University Hospital Essen, Essen, Germany

Cynthia L. Comella Department of Neurological Sciences, Section of Movement Disorders, Rush University Medical Center, Chicago, IL, USA

N. Huynh Faculte´ de Me´decine Dentaire, Universite´ de Montre´al, and Hoˆpital Sacre´ Cur de Montre´al, Montreal, Canada

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LIST OF CONTRIBUTORS

Mayumi Kimura Max Planck Institute of Psychiatry, Munich, Germany Clete A. Kushida Stanford University Center of Excellence for Sleep Disorders, Stanford, CA, USA G.J. Lavigne Faculte´ de me´decine dentaire, Universite´ de Montre´al, Hoˆpital Sacre´ Cur de Montre´al, Montreal, and Faculty of Dentistry, University of Toronto, Toronto, Canada Mujahid Mahmood Kaiser Permanente South San Francisco Medical Center, South San Francisco, CA, USA Mark W. Mahowald Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA Emmanuel Mignot Stanford University School of Medicine and Center for Narcolepsy, Stanford Sleep Research Center, Palo Alto, CA, USA Pasquale Montagna Department of Neurological Sciences, University of Bologna Medical School, Bologna, Italy Jacques Montplaisir Centre d’e´tude du sommeil et des rythmes biologiques, Hoˆpital du Sacre´-Coeur de Montre´al, Universite´ de Montre´al, Montreal, Canada Charles M. Morin Centre de recherche, Universite´ Laval, Quebec, Canada Adrian R. Morrison Laboratory for Study of the Brain in Sleep, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA Seiji Nishino Sleep and Circadian Neurobiology Laboratory and Center For Narcolepsy, Stanford University, and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA

K. Okura Faculte´ de me´decine dentaire, Universite´ de Montre´al, and Hoˆpital Sacre´ Cur de Montre´al, Montreal, Canada, and Institute of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan Liborio Parrino Sleep Disorders Center, Department of Neuroscience, University of Parma, Parma, Italy Teresa Paiva EEG/Sleep Laboratory, Centro Estudos Egas Moniz/ IMM, Medical Faculty of Lisbon, Hospital Santa Maria, Lisbon, Portugal Mathieu Pilon Centre d’e´tude du sommeil, Hoˆpital du Sacre´-Cur de Montre´al, Montreal, Canada Ronald B. Postuma Centre d’e´tude du sommeil et des rythmes biologiques, Hoˆpital du Sacre´-Coeur de Montre´al and Department of Neurology, Montreal General Hospital, Montreal, Canada F. Provini Department of Neurological Sciences, University of Bologna Medical School, Bologna, Italy Kathryn J. Reid Department of Neurology, Northwestern University Medical School, Chicago, IL, USA Carlos H. Schenk Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center and Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA Paula K. Schweitzer Department of Psychology, St. Louis University, St. Louis, MO, USA Luigi Ferini-Strambi Sleep Disorders Center, Universita` Vita-Salute San Raffaele, Milan, Italy Mario Giovanni Terzano Sleep Disorders Center, Department of Neuroscience, University of Parma, Parma, Italy

LIST OF CONTRIBUTORS

xv

Fred W. Turek Department of Neurobiology & Physiology, Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL, USA

St. Louis, and Department of Psychiatry, St. Louis University Health Sciences Center, St. Louis, MO, USA

Me´lanie Vendette Centre d’e´tude du sommeil et des rythmes biologiques, Hoˆpital du Sacre´-Coeur de Montre´al, and Department of Psychology, Universite´ de Montre´al, Montreal, Canada

Juliane Winkelmann Department of Neurology, Institute of Human Genetics, Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen and Helmholtz Zentrum Mu¨nchen, German Research Center for Environmental Health, Munich, Germany

R. Vetrugno Department of Neurological Sciences, University of Bologna Medical School, Bologna, Italy

D. Yao Faculty of Dentistry, University of Toronto, Toronto, Canada

Martha Hotz Vitaterna Department of Neurobiology & Physiology, Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL, USA

Antonio Zadra Department of Psychology, Universite´ de Montre´al, Montreal, Canada

Aleksandar Videnovic Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Phyllis C. Zee Department of Neurology, Northwestern University Medical School, Chicago, IL, USA

James K. Walsh Sleep Medicine and Research Center, St. John’s Mercy Medical Center and St. Luke’s Hospital, Chesterfield, Department of Psychology, St. Louis University,

Marco Zucconi Sleep Disorders Center, Department of Clinical Neurosciences, H San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy

Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 42

Classification of sleep disorders PETER J. HAURI * Mayo Clinic, Rochester, Minnesota, USA

THE DEVELOPMENT OF A NEW SLEEP DISORDERS CLASSIFICATION This chapter introduces the Second Edition of the International Classification of Sleep Disorders (ICSD-2), which was published in the summer of 2005 (American Academy of Sleep Medicine, 2005). This revision of ICSD was commissioned and supervised by the Board of the American Academy of Sleep Medicine, but it was an international group of sleep specialists who developed it. I was privileged to be appointed as chairman of this Committee to develop ICSD-2. The committee first struggled to find a common organizing principle along which to sort the many different sleep disorders. We were unable to find one. In part this was because our knowledge about the different sleep disorders varies widely; for some, such as sleep apnea and narcolepsy, we know quite a bit and may be close to understanding the basic pathophysiological mechanisms of the disorder. For other sleep disorders we are still in the discovery phase and know very little about them, except for some of their symptoms. ICSD-2 therefore abandoned the hope for a common framework along which to classify all sleep disorders. Rather, we decided to group these disorders into eight categories that, at present, seemed to make the most pragmatic sense. Some of these eight categories are based on a common complaint such as insomnia or hypersomnia. Others are grouped around the organ system from which the problems arise, such as the sleep-related breathing disorders and the sleep-related movement disorders. Still others are grouped around a presumed common etiology, such as the problems with the biological clock that are thought to underlie circadian rhythm disorders. Hopefully, in the future, a more overarching framework will emerge for classifying the sleep disorders, but we are not there yet.

ICSD-2 distinguishes the following eight categories of sleep disorders, each of which will be discussed in more detail later in this chapter: 1. 2. 3.

4. 5. 6. 7. 8.

Insomnias Sleep-related breathing disorders Hypersomnias of central origin not due to a circadian rhythm sleep disorder, sleep-related breathing disorder, or other cause of disturbed sleep Circadian rhythm sleep disorders Parasomnias Sleep-related movement disorders Isolated symptoms, apparently normal variants, and unresolved issues Other sleep disorders.

Many sleep disorders are multifactorial. In accordance with the rules developed by the World Health Organization (WHO) for the International Classification of Diseases (ICD), these different factors are classified separately. For example, if a case of insomnia is related to anxiety, and to a restless legs syndrome, and to bad sleep habits, these three individual elements would be coded separately. Thus, the above case would carry three diagnoses.

HISTORY OF THE SLEEP DISORDERS CLASSIFICATION SYSTEM The WHO, based in Geneva, Switzerland, maintains a list of all known human diseases. This International Classification of Diseases was published in its 10th revision (ICD-10) in 1992. ICSD-10 contains two sections especially reserved for sleep disorders. The US Public Health Service maintains a standing committee that adapts the WHO’s ICD to the needs and practices of the USA. The one that is currently still used in the USA is ICD-9-CM (International

*Correspondence to: Peter J. Hauri, Ph.D., Mayo Clinic, 422 Seventh Ave, SW, Rochester, MN 55902, USA. Tel: (507) 282-0059, Fax: (507) 266-7772, E-mail: [email protected]

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P.J. HAURI

Classification of Diseases, ninth revision, Clinical Modifications). It is this committee that has authorized the five-digit code numbers that are listed for each of the individual sleep disorders discussed below. In the 1970s, our knowledge about sleep disorders exploded. There was the discovery that sleep apnea was a common disorder, the new understanding that insomnia had many more etiologies than had been anticipated, the finding that periodic limb movements during sleep could significantly disturb sleep, etc. ICD had not foreseen this vast increase in our knowledge of sleep disorders. True, from very early versions onwards, ICD had listed some sleep disorders such as narcolepsy and the restless legs syndrome, but no room was reserved to place all the new sleep disorders that had emerged. Therefore, in the mid-1970s, Dr W. Dement appointed an ad hoc group of interested sleep specialists under the leadership of Dr H. Roffwarg to develop a Diagnostic Classification of Sleep and Arousal Disorders (DCSAD), which was published in the journal Sleep in 1979 (Association of Sleep Disorders Centers, 1979). By the late 1980s, the field had developed beyond DCSAD. A revision and update was needed, carried out by a committee under the leadership of Dr M. Thorpe. This time the process was more formalized and international input was sought. This revision, called The International Classification of Sleep Disorders (ICSD-1), was published in 1990 and revised slightly in 1997 (American Sleep Disorders Association, 1997). There is no question that, in the long run, any classification of sleep disorders needs to be absorbed into the WHO’s International Classification of Diseases. Therefore, when developing ICSD-2, the current committee tried to move towards the goal of such a merger, mainly by adapting the thinking and structure of ICD whenever feasible. However, some significant obstacles for merger remain. Chief among them is the fact that ICD makes a fundamental distinction between the organic and the nonorganic disorders. For sleep disorders, this distinction is often very difficult to make, adds little to our understanding, and may even be counterproductive in our efforts to understand many of the sleep disorders.

THE CONTENT OF ICSD-2 ICSD-2 is published as a book containing about 300 tightly written pages. Obviously, only a minimal amount of that information can be included in a chapter such as this one. The following tries briefly to characterize each of the eight sleep disorders categories and each of the over 80 individual sleep disorders that are included in

ICSD-2. The goal of this chapter is to allow the reader some overview and appreciation of this nosology. No attempt is made in this chapter to provide enough information to make a diagnosis of each of the disorders.

Insomnia Insomnia is defined as a complaint of unsatisfactory sleep. The sleep difficulty may lie in problems with falling asleep, in frequent awakenings during sleep, in waking too early in the morning, or in poor quality, “nonrestorative” sleep. To be called insomnia, according to ICSD-2, there have to be daytime consequences of this poor sleep, such as fatigue, irritability, or cognitive problems (American Academy of Sleep Medicine, 2005). The following 11 subtypes of insomnia are recognized by ICSD-2. Adjustment insomnia (acute insomnia) (307.41). This involves a relatively short-term insomnia (< 3 months) that is caused by an identifiable stressor (Roehrs et al., 2000). Psychophysiological insomnia (307.42). This is characterized by heightened arousal and learned sleep-preventing associations such as trying too hard to fall asleep, or excessive worrying about sleep (Bonnet and Arand, 1995). Paradoxical insomnia (307.42). This used to be called “sleep state misperception syndrome”. However, there is more to paradoxical insomnia than just a marked mismatch between how the patients think they slept and what objective data document about their sleep. During sleep, patients with paradoxical insomnia show either a near-constant awareness of the environment or a near-continuous pattern of conscious thoughts (Edinger and Fins, 1995). Idiopathic insomnia (307.42). This is a form of chronic insomnia that started in infancy or childhood, has no identifiable precipitant, and is chronic and relentless, with no periods of sustained remission. An imbalance in the neurological/neurochemical sleep/ wake system has been postulated (Hauri and Olmstead, 1980). Insomnia due to mental disorder (327.02). This is diagnosed only in patients who have a diagnosed mental disorder. Also, this diagnosis is used only when the insomnia is an unusually predominant complaint of the underlying mental disorder or when insomnia warrants independent, clinical attention (Nofzinger et al., 1993).

CLASSIFICATION OF SLEEP DISORDERS Inadequate sleep hygiene (V69.4). This involves an insomnia that is caused by maladaptive habits that cause poor sleep, such as excessive daytime napping, alcohol or caffeine near bedtime, excessively stimulating activities close to bedtime, etc. (Morin et al., 1999). Behavioral insomnia of childhood (V69.5). This is diagnosed when maladaptive child-rearing techniques are at the base of the insomnia, such as a lack of limit-setting throughout the day, or inadvertently teaching the child to fall asleep only when being rocked (Gaylor et al., 2001). Insomnia due to drug or substance (292.85, or, if alcohol, 291.82). This indicates that the insomnia is based on the use of or withdrawal from prescription or recreational drugs, or it may be caused by food items or toxins such as carbon monoxide poisoning (Schweitzer, 2000). Insomnia due to medical condition (327.01). This is involved when a condition such as asthma is presumed to cause the insomnia (Gislasen and Almquist, 1987). Insomnia not due to substance or known physiological condition, unspecified (304.41). This category is used when a patient has insomnia that is not classifiable into any of the above insomnias, but seems to be related to psychological issues. The unusually cumbersome title for this insomnia has to do with the fact that terms such as “psychiatric” or “psychological” are hard to define nowadays, except by exclusion (nonphysiological, nonsubstance induced). Physiological (organic) insomnia, unspecified (327.00). This is the category to use when a patient has an insomnia that clearly does not fit into any of the above-named insomnias, or when there are not enough data to diagnose the patient into any of the above disorders.

Sleep-related breathing disorders Listed in this category are sleep problems that are characterized by disordered breathing during sleep. Other respiratory disorders that occur both during wakefulness and during sleep, such as asthma, are not classified as sleep disorders.

CENTRAL

SLEEP APNEA SYNDROMES

These are sleep disorders where respiratory drive is repetitively either diminished (central hypopnea) or absent (central apnea) during all or parts of sleep. It appears that the patient simply stops trying to breathe adequately. These syndromes are usually based on either cardiac or neurological dysfunctions.

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Primary central sleep apnea (327.21). This involves the repeated stopping of respiratory effort during sleep. This leads to frequent awakenings (sleep fragmentation) and excessive daytime sleepiness (EDS). A high ventilatory response to carbon dioxide is often found in such patients (Xie et al., 1995). Central sleep apnea due to a Cheyne–Stokes breathing pattern (786.04). This breathing pattern shows repetitive crescendo–decrescendo breathing. Feedback in the respiratory system is slow. The tidal respiratory pattern gradually waxes and wanes. The repetitive hypoxic lows and the increased effort to restart breathing can disturb and fragment sleep (Xie et al., 2002). Central sleep apnea due to high-altitude periodic breathing (327.22). This is found in almost everyone when rapidly brought to altitudes, say over 4000 meters (Anholm et al., 1992). Central sleep apnea due to a medical condition not Cheyne Stokes (327.27). This is usually caused by a brainstem lesion, or by cardiac or renal disease. Central sleep apnea due to a drug or substance (327.29). This is usually related to taking long-acting drugs such as opioids for long periods. Such medications can also cause other sleep-related respiratory disorders such as obstructive hypoventilation or periodic breathing (Farney et al., 2003). Primary sleep apnea of infancy (770.81). This involves prolonged respiratory pauses that may be either central, obstructive, or mixed. This is usually a developmental problem, often caused by immaturity in the brainstem (Kahn et al., 2000).

OBSTRUCTIVE

SLEEP APNEA SYNDROMES

These disorders are based on an obstruction in the upper airway that develops during sleep, e.g. by the relaxing of the muscles that keep the airway open. The patient continues to try to breathe, but during all or parts of sleep the airflow is limited or inhibited by the obstruction, and gas exchange is absent or at least curtailed until the sleeper awakens. Obstructive sleep apnea, Adult (327.23). This is by far the most common problem seen in sleep disorders centers. It involves repetitively either complete collapse of the upper airway during sleep, or at least a narrowing. This results in either apnea or hypopnea, or it may simply require an increased effort to move

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air through the upper airway (upper airway resistance syndrome). In severe obstructive sleep apnea there may be as many as 500 or more respiratory-related arousals during a night. The usual consequence of such a massive disturbance of sleep is excessive daytime somnolence (Flemons, 2002). Obstructive sleep apnea, pediatric (327.23). This is essentially the same condition as adult obstructive sleep apnea, except for different criteria. While an occasional obstructive apnea is acceptable for an adult, even one obstructive apnea per hour may be pathological in a child (Marcus, 2000).

SLEEP-RELATED

HYPOVENTILATION/HYPOXEMIA

SYNDROMES

These disorders show a chronically reduced oxygen and carbon dioxide exchange during sleep. Typically, this causes sleep fragmentation and nonrestorative sleep. Sleep-related nonobstructive alveolar hypoventilation syndrome, idiopathic (327.25). Chronically decreased alveolar ventilation during sleep results in lower arterial oxygen saturation. When this occurs in patients with otherwise normal lung properties it is called idiopathic. The condition is usually based on blunted chemoresponsiveness (Plum and Leigh, 1981). Congenital central alveolar hypoventilation syndrome (327.24). This is present at birth and is lifelong. It involves a failure of the automatic central control of breathing. Sleep aggravates this syndrome, and many patients may need mechanical ventilation during sleep (American Thoracic Society, 1999).

SLEEP-RELATED

HYPOVENTILATION/HYPOXEMIA DUE

TO MEDICAL CONDITION

(327.26)

This occurs in such problems as lower airway obstructions, neuromuscular and chest wall disorders. (PerezPadilla et al., 1985).

SLEEP

APNEA/SLEEP-RELATED BREATHING DISORDER,

UNSPECIFIED

(327.20)

This is classified when the sleep-related breathing disorder cannot be classified into any of the above categories.

Hypersomnias of central origin not due to a circadian rhythm sleep disorder, sleep-related breathing disorder, or other cause of disturbed nocturnal sleep The tortured title of this category tries to indicate that many sleep disturbances that are dealt with in other

parts of ICSD-2 may also cause excessive daytime somnolence (EDS), but that the disorders discussed here are different. In them, EDS is a primary, not a secondary, symptom.

NARCOLEPSY This group of sleep disorders has been recognized for over 100 years. Characterizing features of narcolepsy are: (1) EDS, usually associated with markedly disrupted sleep; (2) daytime naps that are refreshing for a short time only; (3) an unusual tendency to transition rapidly from wakefulness to rapid eye movement (REM) sleep without intervening nonREM sleep. This fast transition into REM sleep gives rise to cataplexy, hypnagogic hallucinations, and sleep-onset paralysis, features that are characteristic of narcolepsy but not invariably present. Narcolepsy with cataplexy (347.01). This is the pure form of narcolepsy, involving almost daily excessive sleepiness, combined with a history of cataplexy (sudden, transient loss of muscle tone usually triggered by emotions). This form of narcolepsy is closely associated with sleep-onset REM periods, with a genetic abnormality, and 90% of these patients have abnormally low hypocretin levels (Overeem et al., 2001). Narcolepsy without cataplexy (347.00). This is a somewhat more heterogeneous, less clearcut group that may involve some patients whose cataplexy has not yet emerged and others who may have a milder or atypical form of the disease. In the majority of these patients, hypocretin levels are normal. Sleep-onset REM periods may or may not be present (Krahn et al., 2002). Narcolepsy due to a medical condition. This is secondary to medical conditions such as a hypothalamic tumor or a blow to the brainstem (Scammell et al., 2001). Distinguish narcolepsy with cataplexy (347.11) from narcolepsy without cataplexy (347.10). Narcolepsy, unspecified (347.11). This is the category to use if enough is known about a patient to diagnose narcolepsy, but not enough to classify them into one of the other narcolepsy categories.

HYPERSOMNIAS This group combines the various hypersomnias that are not dealt with elsewhere in ICSD-2. Recurrent hypersomnia (327.13). This consists of episodic hypersomnolence alternating with periods of normal sleep, such as is typical in menstrual-related hypersomnia or in the Kleine–Levin syndrome. This

CLASSIFICATION OF SLEEP DISORDERS

673

latter disorder involves episodes of 16–18 hours of sleep per day for a few days or weeks, alternating with long stretches of normal sleep (Dauvilliers et al., 2003).

it may have a periodicity that is significantly longer than 24 hours or it may be misaligned with local clock time, such as in jet lag.

Idiopathic hypersomnia with long sleep time (327.11). This is diagnosed when the patient typically sleeps longer than 10 hours per night but still is excessively sleepy during the day (Billiard and Dauvilliers, 2001).

Circadian rhythm sleep disorder, delayed sleep phase type (327.31). In this disorder, also called the “night owl syndrome”, the internal clock of the individual lags behind the local clock time. For example, when the clock on the wall indicates midnight, the internal clock may indicate only 9 pm, and the individual is biologically not yet ready to sleep. Then, when the clock on the wall indicates 8 am, the internal clock may show only 5 am, not yet time to get up. Now, if the biological clock were running in a time-free environment, the individual would go to bed and get up progressively later each day. However, in the real world, there are countervailing forces to free running, such as bright light during the day, or social pressures requesting a steady sleep time. The result is a delayed sleep phase syndrome – an uneasy balance is reached between internal and external clock: the individual goes to bed very late and gets up late, but still much earlier than is comfortable (Baker and Zee, 2000).

Idiopathic hypersomnia without long sleep time (327.12). This is diagnosed when the patient sleeps a normal 6–10 hours per night but is excessively sleepy during the day. Behaviorally induced insufficient sleep syndrome (307.44). Some patients are required by circumstances (e.g. jobs) to get by with less sleep than needed, others believe that sleep is an unnecessary waste of time, and many consistently obtain less sleep than they require, for social, cultural, financial, or other reasons. When they then show excessive somnolence during the day from lack of sleep, they often do not recognize what causes their EDS (Von Dongen et al., 2003). Hypersomnia due to a medical condition (327.14). This occurs when EDS is secondary to a disease such as Parkinson’s disease, a brain tumor, or an endocrine disorder.

Circadian rhythm sleep disorder, advanced sleep phase type (327.32). This is the opposite of the delayed sleep phase disorder: The patient has an internal clock that is ahead of local time. This results in the “early bird” behavior pattern (Jones et al., 1999).

Hypersomnia due to drug or substance (292.85, 291.82 if alcohol). This may be based on substance abuse (e.g. abuse of sedatives, withdrawal from excessive use of stimulants) or it may be related to the use of medically required drugs such as a high dose of sedative antiepileptic medication required for seizure control (Young-McCaughan and Miaskowski, 2001).

Circadian rhythm sleep disorder, irregular sleep– wake type (327.33). This disorder is characterized by a relative weakness or total lack of a circadian rhythm, with sleeping and waking being spread almost evenly over a 24-hour period. It appears as if the internal clock has stopped altogether (Pollack and Stokes, 1997).

Hypersomnia not due to substance or known physiological condition (327.15). Nonorganic hypersomnia, not otherwise specified, may be found in certain psychiatric diseases such as atypical depression, bipolar disorder, seasonal affective disorder, or conversion disorder (Overeem et al., 2002).

Circadian rhythm sleep disorder, free-running (non-entrained) type (327.34). This usually occurs when there are not enough stimuli to synchronize the internal clock to local time. It is like the delayed or the advanced sleep phase syndrome, except that the countervailing forces discussed under delayed sleep phase are absent. This problem is most often found in totally blind people (Sack et al., 1992).

Physiological (organic) hypersomnia, unspecified (327.10). Patients in this group satisfy the diagnosis of hypersomnia but do not fit any of the above types of hypersomnia.

Circadian rhythm sleep disorders Human functioning is regulated by an internal “clock” that is located in the suprachiasmatic nucleus. This clock dictates when we become sleepy and when we become alert. It may be malfunctioning. For example,

Circadian rhythm sleep disorder, jet lag type (327.35). This is a temporary complaint of insomnia or EDS after an individual has crossed many time zones and the body clock has not yet caught up to the new local time (Spitzer et al., 1999). Circadian rhythm sleep disorder, shift work type (327.36). Complaints of either insomnia or EDS occur in individuals who have difficulties adjusting to shift

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work. The problem is aggravated by the fact that during their time off work such individuals try to sleep on a “normal” day/night cycle, so that the clock can never adjust to any regular 24-hour periodicity (Akerstedt, 2003). Circadian rhythm sleep disorder due to a medical condition (327.37). This may occur in patients with dementia, Parkinson’s disease, hepatic encephalopathy, etc. (Bliwise et al., 1995). Circadian rhythm disturbance due to drug or substance (292.85) or, if alcohol induced (291.82). This occurs when substances such as some antidepressants affect the circadian rhythm. Circadian rhythm sleep disorder, other (327.39). Classified here are patients who have problems with the circadian rhythm but cannot be diagnosed into any of the above categories.

Parasomnias Parasomnias are undesirable events that accompany sleep. Often they seem to be purposeful and goal directed. They may result in injuries, disturb sleep (of the patient as well as of others), and they may cause untoward psychosocial developments.

DISORDERS

OF AROUSAL (FROM NONREM SLEEP)

Confusional arousals (327.41). Such patients are mentally or behaviorally more confused than others when awakening, usually from deep (slow-wave) sleep (Ohayon et al., 2000). Sleepwalking (307.67). This involves walking or other complex behaviors that are started when awakening, usually from slow-wave sleep. The person may be difficult to awaken, coordination is often impaired, and behavior is often inappropriate (Kavey et al., 1990). Sleep terrors (307.67). These involve sudden terrified arousals, usually with a piercing scream, usually from slow-wave sleep. There is evidence of intense autonomic activation and panic. The person is difficult to awaken and usually shows amnesia for the episode (Ohayon et al., 1999a).

PARASOMNIAS REM SLEEP

USUALLY ASSOCIATED WITH

REM sleep behavior disorder (327.42). During REM (dreaming) sleep, most of our voluntary muscles are paralyzed. This keeps us from acting out our dreams. When this paralysis is weak or fails altogether,

we start enacting parts of our dreams. Shouting, grabbing, punching, and leaping are often seen, but walking is rare. Injuries to self or bed partner are of concern (Olson et al., 2000). Recurrent isolated sleep paralysis (327.43). This involves the inability to speak or move, either when falling asleep or when waking up. Consciousness is preserved during the paralysis, which may last up to minutes (Ohayon et al., 1999b). Nightmare disorder (307.47). This consists of increasingly disturbing dream sequences that are highly emotional, involving fear, panic, and anger. However, in contrast to sleep terrors, autonomic arousal is minimal and patients often retain considerable recall of their dream (Levin and Fireman, 2002).

OTHER

PARASOMNIAS

Sleep-related dissociative disorders (300.15). These arise out of wakefulness during the sleep period. These events are similar to waking dissociative disorders, except that they are often associated with other parasomnias (Mahowald and Schenck, 2001). Sleep-related enuresis (788.36). While bedwetting in young children is expected, it becomes pathological if it occurs frequently after the age of about 5 years or so (Fritz and Rockney, 2004). Sleep-related groaning (catathrenia, 327.49). Chronic expiratory moaning and groaning during sleep usually occurs nightly and mainly during the later REM episodes of the night (Vetrugno et al., 2001b). Exploding head syndrome (327.49). This occurs at the transition between waking and sleeping. The person experiences either a sudden loud noise or a violent explosion in the head. Although very frightening, there is no pain, and, as far as known, the experience is benign (Pearce, 1989). Sleep-related hallucinations (368.16). These occur either when falling asleep or waking up. They are primarily visual and may be hard to distinguish from dreams (Silber et al., 2002), except that they occur when the patient is awake. Sleep-related eating disorder (327.49). In these patients there are recurrent episodes of involuntary eating and drinking during sleep. Some patients may be fully asleep during these episodes, others only partially so, or they may gradually awaken to full consciousness during the episode. Patients often consume

CLASSIFICATION OF SLEEP DISORDERS peculiar “foods” such as a peanut butter/cigarette sandwich. Many patients realize that they have had an eating episode only when they enter the kitchen in the morning, finding food items displaced or missing (Winkelman, 1998). Parasomnias due to drug or substance (292.85, if alcohol 291.82). There are many possibilities, such as a REM behavior disorder (RBD) triggered by antidepressants or sleep-related hallucinations triggered by b-adrenergic receptor blocking agents. Parasomnias due to a medical condition (327.44). These may involve such parasomnias as sleep-related visual hallucinations associated with Parkinson’s disease or RBD related to dementia. Parasomnia, other or unspecified (327.40). This is diagnosed when a given parasomnia cannot be classified into any of the above disorders.

Sleep-related movement disorders Except for restless legs, this category of sleep disorders involves relatively simple, stereotyped movements during sleep or on the threshold between sleeping and waking. These movements cause fragmented sleep, insomnia and/or EDS. Restless legs syndrome (333.94). In this disorder there are very strong urges to move the legs (occasionally arms as well), often accompanied by paresthesias such as a “creepy/crawly” feeling in the legs. Restless legs occur mainly when resting or lying down. There is a circadian rhythm to them (nights are worst) and there is temporary relief when the extremities are moved (Allen and Earley, 2001). Periodic limb movement sleep disorder (327.51). This involves episodes during sleep of highly stereotyped, periodic limb movements. Such movements can also occur in good sleepers. A sleep disorder is diagnosed only when these limb twitches cause arousals and lead to a complaint of either insomnia or EDS (Coleman, 1982). Sleep-related leg cramps (327.52). These may arise from either sleep or wakefulness during the night, may last up to a few painful minutes and then abate spontaneously (Saskin et al., 1988). Sleep-related bruxism (327.53). This indicates that the patient is grinding or clenching the teeth during sleep. Considerable tooth damage may occur and sleep may become disturbed (Kato et al., 2001).

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Sleep-related rhythmic movement disorders (327.59). These may involve body rocking, head banging, head rolling, etc. during sleep. Quite normal in young children, the rhythmic movements may become a problem when they disturb sleep either in the patient or in a bed partner (Dyken et al., 1997). Sleep-related movement disorder due to a drug or substance (327.59). An example might be disturbed sleep secondary to tardive dyskinesia caused by dopamine receptor blocking agents. Sleep-related movement disorder due to a medical condition (327.59). This is diagnosed when such movements disturb sleep, an underlying condition such as Parkinson’s disease is suspected, but has not yet been properly identified as the reason for the sleep disturbance. Sleep-related movement disorder, unspecified (327.59). This is used when there is clearly a sleep disturbance caused by muscle movements that does not fit into any of the above disorders, or when not enough is known to assign it to any of the above categories.

Isolated symptoms, apparently normal variants, and unresolved issues Sleep clinicians frequently deal with issues that lie at the borderline between normal and abnormal sleep. Some may occur in many people without causing difficulties, but may become abnormal in excess or in highly sensitive sleepers. 1.

2.

3.

4. 5.

Long sleeper is a term reserved for adults who sleep more than 10 hours per night (or for children who sleep more than 2 hours longer than age-adjusted norms). When they do not get that amount of sleep, long sleepers show signs of sleep deprivation (Aeschbach et al., 1996). Short sleeper is an adult who regularly sleeps fewer than 5 hours per night, or a child who sleeps 3 hours less than age-appropriate norms, without showing daytime signs of sleep deprivation. Snoring is diagnosed when there is audible, often very loud, snoring without disruption of the snorer’s sleep. Sleep talking is usually disruptive to a bed partner, but not to the talker. Sleep starts (hypnic jerks) usually occur around sleep onset and may delay the beginning of sleep, especially when they occur frequently. A subjective feeling of falling, a sensory flash, or a dream fragment often accompanies them (Sander et al., 1998).

676 6.

7.

8.

9.

P.J. HAURI Benign sleep myoclonus of infancy involves repetitive large jerks that occur only during sleep, usually in children less than 6 months of age. Hypnagogic foot tremors and alternating leg muscle activation involves benign movements in the legs and feet during sleep. Propriospinal myoclonus at sleep onset consists of sudden muscular jerks occurring at sleep onset, mainly in the abdomen, trunk, or neck (Vetrugno et al., 2001a). Excessive fragmentary myoclonus involves small movements or fasciculations in fingers, toes, or corners of the mouth that may disturb the relaxing patient. (Vetrugno et al., 2002).

Other sleep disorders It seems likely that in the near future other sleep disorders will be found that do not fit into the framework of ICSD-2. The category of “other sleep disorders” is reserved for them. However, environmental sleep disorder is also classified here, mainly because it overlaps with so many other categories (insomnia, EDS, parasomnia). Environmental sleep disorder (307.48). This is diagnosed when the sleep disorder is caused by environmental factors such as noise, temperature, a bed partner, etc. It may manifest itself as insomnia, EDS, parasomnia or the patient may simply show daytime signs of sleep deprivation (Thiessen and Lapointe, 1983). Other or unspecified sleep disorder (327.8). This is diagnosed when there is a sleep disorder that does not fit into any of the other ICSD-2 diagnoses.

CONCLUDING REMARKS The above outline of the recognized sleep disorders gives a cursory glance at what is involved in the field of sleep disorders medicine. Clearly this field is multidisciplinary. Among others, knowledge of pulmonary medicine is needed to deal with the respiratory sleep disorders, knowledge from neurology to deal with the hypersomnias and some parasomnias, from psychiatry and psychology to deal with the insomnias. Obviously, the field of sleep medicine is still young and evolving. It will be different in a decade or so. For more information, the reader might contact the central office of the American Academy of Sleep Medicine, One Westbrook Corporate Center, Suite 920, Westchester, IL 60154, USA (Tel: 708 492-0930; www.aasmnet.org).

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 43

Genetics of sleep disorders JULIANE WINKELMANN 1 * AND MAYUMI KIMURA 2 Department of Neurology, Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München and Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany

1

2

Max Planck Institute of Psychiatry, Munich, Germany

INTRODUCTION In recent years, genetic approaches have became very popular in many fields of science. Finding causative genes specific for disorders and a variety of quantitative phenotypes is the hottest target in biomedical sciences, and such effort has also been made in the field of sleep research (Franken and Tafti, 2003; Lavie, 2005; Cirelli, 2009). One of the most successful findings in terms of sleep genetics so far is the discovery of the hypocretins/orexins, internal ligands of G-coupled orphan receptors in the hypothalamus. Hypocretins/orexins, when first discovered, were thought to function as appetite promoters (Sakurai et al., 1998), and it was then found that their impaired system initiates narcoleptic symptoms (Chemelli et al., 1999; Lin et al., 1999; Mieda and Yanagisawa, 2002; Sutcliffe and de Lecea, 2002; Sakurai, 2005; Nishino, 2007). However, as familial clustering had been observed in narcolepsy with a close association of human leukocyte antigens (e.g., HLA-DQB1 and HLA-DQA1), the discovery of gene products triggering or blocking narcolepsy was expected earlier (Peyron et al., 2000; Miyagawa et al., 2008). Thus, identifying a gene or its products responsible for sleep disorders will be difficult because of the complexity of these conditions. However, there is an increasing demand for the discovery of genetic factors in sleep pathology (Taheri and Mignot, 2002; Dauvilliers et al., 2005; Dauvilliers and Tafti, 2008; Kimura and Winkelmann, 2007). It is known that several sleep problems can be inherited. Further, twin studies have demonstrated that sleep components are influenced significantly by genetic background. Thus, sleep regulation or dysregulation must

be closely linked to genetic control. To prescreen a risk factor, find an adequate cure, or even classify the complexity of sleep phenotypes for further treatments, genetic information contributes to an in-depth understanding of the pathophysiology of major sleep disorders. Indeed, several mutations in particular genes are reported to be involved in certain sleep disorders. These “sleep-related” genes or mutations have mostly been demonstrated in animal models (Andretic et al., 2008), but, with the help of advanced molecular genetic approaches, sleep genetics will soon expand into a search among human models and lead to pharmacogenomic development for individualized sleep medicine. In this chapter, we first describe the genetic influence on normal sleep and its regulatory mechanism, and then discuss recent clinical discoveries regarding the role of genetic factors in selected sleep disorders.

A GENETIC INFLUENCE ON NORMAL SLEEP AND SLEEP^WAKE REGULATION Evidence for genes The various genetic aspects in normal sleep of healthy subjects are evident from earlier studies employing twin pairs (Linkowski, 1999). Under visual inspection, monozygotic (MZ) twins show a very similar hypnogram if they have not been exposed to similar environmental factors. The similarities of their sleep patterns are observed particularly in sleep latency, duration of sleep cycles, and appearance of rapid eye movement (REM) sleep (Webb and Campbell, 1983). The majority of twin studies have been based on questionnaire analyses, comparing sleep habits, subjective mood

*Correspondence to: Dr Juliane Winkelmann, Klinik fu¨r Neurologie und Institut fu¨r Humangenetik, Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen (TUM), Ismaninger Strasse 22, 81675 Mu¨nchen, Germany. Tel: þ49-89-4140-4688, E-mail: [email protected]

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after night sleep, etc., and most demonstrate higher concordance for sleep characteristics in MZ than in dizygotic (DZ) twins (Partinen et al., 1983; Heath et al., 1990). However, more advanced polygraphic analyses show a stronger impact of the influence on genes in sleep regulation of twins (van Beijsterveldt and van Baal, 2002). In a previous study, alpha rhythms during waking were reported to be similar only in MZ twin pairs (Davis and Davis, 1936; Lennox et al., 1945). Recently, quantitative EEG measures revealed that spectral power during nonREM sleep showed significantly higher concordance than in DZ twin pairs, especially in the range of alpha and sigma bands (Ambrosius et al., 2008; De Gennaro et al., 2008). Furthermore, even MZ twins who were discordant for schizophrenia demonstrated almost identical spectra profiles (Brunner et al., 2001) (Figure 43.1). Apart from the strong evidence of similarity between MZ twins, more general findings of similarities in siblings suggest broader genetic heredity in sleep architecture (de Castro, 2002). Genetic factors do affect sleep architecture. Whether sleep disorders can be transmitted within mV 10

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families is a moot question. In the case of insomnia, familial occurrence is common (Bastien and Morin, 2000). Although not every sibling experiences insomniac symptoms, they show similar power spectral distribution in their EEGs (Brunner et al., 2001). Therefore, genetic vulnerability to insomnia would be hidden even in normal sleep cycles, and the signs for potential sleep problems could be assessed by polysomnography. According to our local survey, vulnerability has been found in healthy probands who have family members diagnosed with insomnia associated with anxiety or depression (Modell et al., 2002; Friess et al., 2008); affected and nonaffected family members all showed higher REM density. However, this is controversial because insomnia begins prior to the onset of affective disorders, which are also inheritable. We cannot really separate which genomic factor influences the most or primarily, but it is worth recalling that sleep is a complex of phenotypes. Many gene factors may be involved in sleep, and balancing or counterbalancing their functions maintains homeostasis of sleep–wake regulation. Thus, there must be many possible genetic avenues for sleep disturbances.

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Fig. 43.1. Comparison of spectral profiles in nonREM and REM sleep (A) and temporal dynamics of delta and sigma EEG activity during nonREM sleep (B) in five monozygotic twin pairs who were discordant for schizophrenia (black line, affected twin; grey line, unaffected twin) (Brunner et al., 2001). (Reprinted with permission from Kimura and Winkelmann, 2007. # Birkhauser.)

GENETICS OF SLEEP DISORDERS

Genetic aspects of the human and animal EEG HUMANS EEG is the most useful and convenient tool available at present to examine genetic influences on individual differences in CNS functioning and human behaviors. EEG records reflect rhythmic electrical activity of the brain and provide a direct measure of the functional state of the brain and its different levels of arousal. EEGs are described by various parameters, such as amplitude (power in mV2) and rhythm (frequency in Hz). These EEG variants can reflect genetic traits. From the EEG recordings for three consecutive nights in 26 twin pairs living apart, Linkowski and associates (1989, 1991) found heritable signs in stages 2 and 4 of nonREM sleep, but not in REM sleep. In their study, variance in REM sleep appeared to be influenced substantially by environmental rather than genetic components. However, when heritability of EEGs was investigated in 213 twin pairs across four main frequency bands, van Beijsterveldt et al. (1996) reported that all delta, theta, alpha, and beta frequencies showed significantly high heritability. However, Vogel (1970) performed extensive earlier studies and, in the 1970s, had already proposed a hypothesis that the normal EEG rhythm is influenced by many genes. His group focused on the low-voltage EEG (lack of a waves) in 17 families with 191 individuals, and identified a linkage region for a putative gene underlying the normal human EEG variant to chromosome 20q (Steinlein et al., 1992). Their results indicate strong evidence for close linkage with the high polymorphic marker CMM6 (D20S19) and for genetic heterogeneity to the low-voltage EEG. Recently, Re´tey et al. (2005) demonstrated a functional polymorphism of the gene encoding adenosine deaminase on chromosome 20, revealing an association with interindividual variability in sleep architecture and the sleep EEG. Their healthy young subjects, who possess a G to A transition at nucleoside 22 (G/A genotype compared with G/G), were characterized by more slow-wave sleep (SWS) and of greater intensity, indicating a direct role for a single gene in homeostatic human sleep regulation. Furthermore, recently Viloa, Archer and their collaborators have reported the significance of a variablenumber tandem-repeat polymorphism in the PERIOD3 (PER3) gene on individual differences in sleep structure (Viola et al., 2007; Archer et al., 2008). This polymorphism was found earlier in association with diurnal preferences and delayed sleep phase syndrome (Ebisawa et al., 2001; Archer et al., 2003). The later studies have revealed that individuals with the longer PER35 allele than the others who are homozygous for

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the PER34 allele show higher delta power during nonREM sleep, and also higher theta and alpha power during REM sleep and wakefulness. Taken together, PER3 polymorphism seems to affect susceptibility to sleep loss, resulting from its influences on sleep homeostasis. Regarding polymorphisms, it is known that a cause of fatal familial insomnia (FFI; see below for details) is a mutation at codon 178 of the prion protein gene, located on human chromosome 20, cosegregating with the methionine polymorphism at codon 129 (129M) of the mutated allele (Goldfarb et al., 1992; Montagna et al., 1998). These mutations are also found in another prion disease, Creutzfeldt–Jakob disease (CJD), in which a valine residue segregates at codon 129 (129V). Although the polymorphism at codon 129 is critical in distinguishing between FFI and CJD, the 129 polymorphism without the mutation at codon 178 occurs commonly in the general population, and does not result in prion disease. One study recently conducted EEG recordings and insomnia questionnaires in 884 middle-aged men and women to examine whether the 129V/M polymorphism influences sleep, with special emphasis on items related to insomnia complaints and any sleep disruption (Pedrazzoli et al., 2002). The results failed to clarify any differences in polysomnographic measures among three genotypes (129VV, 129MV, and 129MM), indicating that the prion 129 polymorphism does not really affect normal sleep. Other pathogenic mechanisms, implicating the normal allele of prion protein gene, need to be considered.

ANIMALS A role for the prion protein in sleep regulation has been also investigated in a genetically modified animal model, the prion protein null mouse (Tobler et al., 1996). Involvement of the prion protein in the neuropathogenesis of human and animal transmissible spongiform encephalopathies has been well documented (Prusiner, 1997); the normal function of this protein is still unknown. Compared with wild-types (129/Ola mice or 129/Sv and C57BL/6J mixture, Prn-pþ/þ), prion gene-disrupted homozygous mice (Prn-p0/0) display abnormalities in circadian activity rhythm and sleep structure; none of the mice differed particularly in their behavior or sleeping time. EEG studies have revealed that Prn-p0/0 mice exhibit a larger degree of sleep fragmentation and a larger response to sleep deprivation. The response to sleep deprivation is often indicated by the magnitude of EEG slow-wave activity (SWA, power density in the delta band) during and after sleep deprivation (Tobler and Borbe´ly, 1986; Dijk et al., 1987). SWA in Prn-p0/0 mice during recovery

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sleep is twice than that in Prn-pþ/þ mice after 6 hours of sleep deprivation. Data from the gene-knockout model suggest that the prion protein may participate in maintaining sleep continuity and regulating sleep intensity (Huber et al., 1999). More recently, a study by Dossena et al. (2008) confirmed its impact on sleep regulation, characterizing EEG abnormalities (e.g., sawtooth waves in the range of 3–4 Hz), and showed significantly reduced REM sleep in transgenic mice expressing the mouse homolog of the D178N/V129 mutation in the prion protein gene. In mouse strains, systematic and quantitative studies of sleep EEG can also distinguish a genetic background that influences particular rhythmic brain activity (Valatx et al., 1972; Friedmann, 1974), as described above in the determination of zygosity in twins. Franken and Tafti’s group screened many inbred mice and categorized them according to spectral dynamics of their EEG activity (Franken et al., 1998). First, time spent in each vigilance state was compared across six commonly used inbred strains (Figure 43.2). There were slight but significant differences in the amount of sleep and wakefulness, in which the relative amount of wakefulness appeared to be counterbalanced by that of SWS (¼ nonREM sleep). Among these six strains, AKR/J (AK) mice had most SWS (least wakefulness), whereas DBA/2J (D2) mice had least SWS (most wakefulness) per day. When spectral profiles were compared, delta power (c. 1.5–4.0 Hz) typical for SWS was highest in AK and lowest in D2 mice respectively, whereas the distribution of peak delta frequencies was similar among the six strains. However, the peak frequency for theta band (c. 5.5– 8.5 Hz) during paradoxical sleep (PS ¼ REM sleep) was distributed in a strain-dependent manner, which did not coincide proportionally with relative power or episode duration of PS (Figure 43.3). Therefore, it is plausible that the theta peak frequency (TPF) associated with PS varies with genotype. Based on these findings, Tafti and colleagues (2003) performed quantitative trait loci (QTL) analysis, crossing a slow-theta strain (BALB/cByJ, C) with a fast-theta strain (C57BL/6J, B6), and demonstrated a chromosomal region that segregates with TPF. Finally, a single autosomal recessive gene, which contributes to controlling theta oscillations during REM sleep, was identified as the acylcoenzyme-A dehydrogenase for short-chain fatty acids (encoded by Acads). Demonstrating this gene with reference to TPF suggests also that brain fatty acid metabolism is important for cognitive function, and sleep represents a condition favoring or requiring b-oxidation. Furthermore, with recombinant inbred mice, changes in the accumulation of EEG delta power can

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Fig. 43.2. Comparison of time spent in each vigilance state across six inbred mouse strains: (A) Wake; (B) slow-wave sleep (SWS); (C) paradoxical sleep (PS). AK, AKR/J; C, BALB/cByJ; B6, C57BL/6J; BR, C57BR/6J; D2, DBA/2J; 129, 129/Ola mice. Hatched bars represent significant differences from other strains. (Redrawn from Franken et al., 1998. Reprinted with permission from Kimura and Winkelmann, 2007. # Birkhauser.)

be used to detect a trace of genetic factors. As described above, and in other chapters in this volume, delta power increases proportionally over the course of recovery sleep after a certain period of sleep loss (or prior wakefulness). Therefore, requirement of SWS is predictive through the magnitude of delta power that indicates SWS intensity, i.e., homeostatic drive for nonREM sleep. Using QTL analysis, Franken et al. (1999) examined 25 BXD (B6  D2 mice) recombinant inbred strains and looked for genomic regions that might affect the increase of delta power after 6 hours of sleep deprivation. One significant locus was identified on chromosome 13 that accounted for

GENETICS OF SLEEP DISORDERS 15

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Fig. 43.3. Distributions of peak frequency in paradoxical sleep of six inbred mouse strains. AK, AKR/J; C, BALB/ cByJ; B6, C57BL/6J; BR, C57BR/6J; D2, DBA/2J; 129, 129/Ola mice. Curves illustrate changes in maximum power spectra for each frequency bin. (Modified from Franken et al., 1998. Reprinted with permission from Kimura and Winkelmann, 2007. # Birkhauser.)

49% of the genetic variance in this trait. In contrast, the decrease in delta power afterwards did not vary with genotype. These results indicate that the homeostatic regulation of SWS need is under genetic control (Franken et al., 2001). In addition, QTL analysis has also demonstrated PS-related loci on chromosome 7 during the light period, chromosome 5 during the dark period, and chromosomes 2, 17, and 19 across the 24-hour period from CXB (C  B6 recombinant mice) lines (Tafti et al., 1997). Differences in the level of delta power during nonREM sleep can also indicate a sign of gene mutation when compared with respective wild-types. For example, double knockout mice lacking both cryptochromes 1 and 2 (cry1,2/) show greater delta power during nonREM sleep across 24 hours (Wisor et al., 2002). The cryptochrome genes, as well as period genes (per), are mainly involved in circadian rhythm generation under the control of transcriptional factors such as CLOCK and BMAL1; therefore, genetic inactivation of cryptochromes results in circadian arrhythmicity (for details see Chapter 60). Although cryptochromes

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are clock-related genes, the experimental data from cry1,2/ mice suggest their noncircadian role in the homeostatic regulation of sleep (Dudley et al., 2003; Franken et al., 2007). In this mutant mouse, per 1 and 2 genes are overexpressed reversely; therefore, it is not yet clear which genes or gene products are responsible for high nonREM sleep drive. However, their more recent study demonstrates increased gene expression of both per 1 and 2 in the mouse forebrain after 6 hours of sleep deprivation (Franken et al., 2007). Although upregulation of these genes does not show a linear parallel with the accumulation of process S (see below) among different strains, the results further support the hypothesis that clock-related genes participate in controlling sleep homeostasis. On the other hand, low nonREM sleep drive is seen in mouse mutants with T-type calcium channel deficiency (Lee et al., 2004; Cueni et al., 2008). In a model (a1G/), low-threshold spikes in the thalamocortical relay neurons are absent, suggesting that the a1G subunit of T-type calcium channels is critical for the genesis of sleep spindles and delta oscillations (Kim et al., 2001). In fact, Lee et al. (2004) reported lack of delta waves with much lower power density during nonREM sleep in a1G/ mice compared with wild-types, and sleep disturbances were significantly characterized by brief awakening interrupting nonREM but not REM stages. Similar sleep fragmentation was also observed in potassium channel-related mutant mice that do not have functional Kv3 potassium channels (double knockout of Kv3.1 and Kv3.3 encoding genes) (Espinosa et al., 2004). In this Kv3.1- and Kv3.3-deficient mouse model, significant sleep loss of nearly 40% was detected during the light period owing to a reduced mean duration of SWS episodes (Joho et al., 2006). Furthermore, the double mutant mice displayed dramatically reduced spectral power in the delta band and fewer sleep spindles (Espinosa et al., 2008), resembling the sleep phenotypes of the above-mentioned calcium channel-related mutants. According to these studies, genes related to influx–efflux ion channels in brain regions implicated in the modulation of the sleep–wake cycle appear to influence thalamocortical oscillations and contribute to the stabilization of nonREM sleep. Regarding REM sleep regulation, using a genemodified (transgenic) mouse model in which corticotropin-releasing hormone (CRH) was site-specifically overexpressed in the brain, we demonstrated that CNS-restricted CRH overexpression produces a strong drive towards REM sleep (Kimura et al., 2010). In this model, theta power during REM sleep is not particularly affected under baseline conditions. However, in response to sleep deprivation, even heterozygous

686 J. WINKELMANN AND M. KIMURA CRH-overexpressing mice that fail to show increased lead to the development of personalized sleep medibaseline REM sleep demonstrate more REM sleep cine. As QTL analysis reveals, a small difference in rebound than is seen in respective control and wildgenotypes may result in a large difference in phenotype animals. The results indicate that homeostatic contypes in terms of the characteristics of sleep patterns, trol in REM sleep can be detected in a particular model including EEG modulation. cDNA array studies will and only a single gene manipulation could possibly provide a novel direction for searching for a central contribute to changes in REM sleep. alteration that causes sleep disorders, and suggest a sleep cure on an individual basis. At present, gene hunting for human sleep disorders is not yet estabMicroarrays lished; however, the microarray technique has been During the past several years, microarray technology used to demonstrate gene traits in selectively bred anihas become a significant trend in the genetics of sleep mals for short or long sleepers (Xu et al., 2001). In the research and opens up an opportunity for new discovnear future, perhaps using this gene technology, differeries in this field. Most of the related studies so far have ences in sleep architecture seen in different ethnic been done under conditions of sleep deprivation, and groups may also be explained (Profant et al., 2002; then cDNA arrays are applied to find genes in the whole Stepnowsky et al., 2003). brain that are upregulated or downregulated, particuFAMILIAL SLEEP DISORDERS larly during the process of sleep loss (Tononi and Cirelli, 2001; O’Hara et al., 2007). In the past, “sleep-inducing Restless legs syndrome factors” were hypothesized to accumulate in the brain The restless legs syndrome (RLS) is probably one of during prolonged wakefulness, and some of the putathe prime examples of a sleep disorder demonstrating tive sleep-promoting substances were isolated from a strong genetic component. RLS is characterized by the brain of sleep-deprived animals. When “sleep presunpleasant sensation and an urge to move the lower sure” (power densities in delta waves ¼ process S) is limbs, occurring exclusively at rest in the evening or enhanced, the expression of related mRNAs either at night. Moving the affected extremity improves the increases or decreases. cDNA microarrays would be symptoms. The diagnosis is based on the clinical able to detect such an intensified transcription of particdescription of the symptoms by the patient and the ular genes in relation to sleep needs. Earlier studies in presence of four essential diagnostic criteria, including rats (Cirelli and Tononi, 2000) and fruit flies (Cirelli the core clinical features of the disease (Allen et al., et al., 2005; Zimmerman et al., 2006) showed that either 2003). It has been reported that 40–60% of patients 3, 6, or 8 hours of sleep deprivation increases the with RLS have a positive family history (Montplaisir expression of several genes that can be categorized as: et al., 1997; Winkelmann et al., 2000). Similar figures immediate early genes/transcription factors, energy with heritability estimates of 0.6 derived from twin balance-related genes, growth factors, heat shock prostudies further support the importance of a genetic teins (chaperons), neurotransmitter/hormone receptors, contribution to the disease (Ondo et al., 2000; Xiong kinases, etc. (Terao et al., 2003; Cirelli et al., 2004). et al., 2007). Comparing all clinical characteristics in Most of the properties and functions of these molefamilial and nonfamilial RLS, it has been consistently cules have not yet been clearly defined in association demonstrated that patients with a positive family hiswith sleep regulation. However, amongst these encodtory have an earlier age at onset of the disease coming genes, Homer1a is the most promising candidate pared with patients with a negative family history that reflects sleep need, depending on the duration of (Ondo and Jancovic, 1996; Montplaisir et al., 1997; sleep loss (Maret et al., 2007). The expression of Winkelmann et al., 2000). Several families with RLS Homer1a can be induced in the brain of D2, B6, and have been described, showing a large phenotypic variaAK mice by sleep deprivation in a dose-dependent bility. Within a single family there are family members manner. It has been hypothesized that sleep plays a with very severe symptoms and sleep disturbances key role in synaptic plasticity (Krueger and Oba´l, owing to the dysesthesias at night, as well as family 1993; Tononi and Cirelli, 2006). As the Homer1 gene members with only mild symptoms on a few occasions contributes to recovery from glutamate-induced neuroin their lives. nal hyperactivity, its involvement in sleep homeostasis Linkage studies are family based and analyze a posis quite reasonable, suggesting that sleep has a funcsible cosegregation with a genetic marker and a specific tion in protecting neurons from the consistent activaphenotype. A prerequisite is an accurate assumption tion imposed by wakefulness. of the underlying genetic model and knowledge about In any case, such transcriptome profilings have the the disease penetrance and phenocopy rate. Several loci potential to identify a gene or gene product that may

GENETICS OF SLEEP DISORDERS 687 for RLS have been published on chromosomes 12q the nitric oxide/arginine pathway in the pathogenesis (RLS1), 14q (RLS2), 9p (RLS3), 2q (RLS4), and 20p of RLS. (RLS5) (Winkelmann, 2008). In a French Canadian famCurrent technology has made large-scale, highily, linkage to chromosome 12q was identified based on density, genome-wide association studies a reality. a recessive mode of inheritance and was confirmed These studies combine the power of association studies in further five French Canadian families (Desautels with the systematic nature of a genome-wide search. et al., 2001). Possible phenocopies and nonpenetrants Three studies have taken advantage of this new methmade it difficult to detect a common segregating haploodology. In a study conducted in up to 2600 patients type in these families and it is not clear whether a with RLS and up to 5000 controls in the German, founder effect of the French Canadian population plays Canadian, and Czech populations, four genomic a role (Desautels et al., 2005). Based on an autosomal regions have been identified encoding the genes dominant mode of inheritance, a second locus was idenMEIS1, BTBD9, a region that encodes the genes tified on chromosome 14q13-21 (RLS2) in a northern MAP2K5 and LBXCOR1 (Winkelmann et al., 2007) Italian RLS family (Bonati et al., 2003), and confirmed and PRPRD (Schormair et al., 2008). The association in an independent family of French Canadian origin was identified within intronic variants, suggesting a (Levchenko et al., 2004). Investigating 15 extended functional role in the expression or alternative splicing American families including 134 RLS-affected indiviof the gene. Carriers of one risk allele had a 50% duals, a third RLS locus on chromosome 9p24-23 increased risk of developing RLS. In a similar study (RLS3) was identified using a model-free multipoint conducted in Icelandic and US populations, an associaanalysis with a multipoint nonparametric linkage score tion was found with the identical variant in BTBD9 of 3.22 (Chen et al., 2004). Although the statistical anal(Stefansson et al., 2007). The studies used different assessments of the phenotype. In the latter study, the ysis was criticized (Ray and Weeks, 2005), this locus association of BTBD9 was based on individuals with was confirmed within a RLS family (Liebetanz et al., periodic leg movements (PLM), suggesting that 2006; Lohmann-Hedrich et al., 2008) under the assumpBTBD9 is associated more with PLM than with RLS. tion of intrafamilial heterogeneity and stratification Furthermore, an analysis of parameters involved in according to an early age at onset phenotype (Liebetanz iron metabolism revealed that the risk allele was assoet al., 2006), and possibly further defined to the centrociated with a 13% decrease in the serum ferritin level meric part of chromosome 9p (Lohmann-Hedrich et al., (Stefansson et al., 2007). 2008). Defining the exact candidate region in RLS is A closer inspection of the known function of the difficult owing to intrafamilial, allelic, and nonallelic genes identified is surprising because some of them heterogeneity. This suggests locus heterogeneity and it are developmental factors and challenge our previous appears likely that several genes contain several dispathophysiological concept of RLS. MEIS1 is a memease-associated variants contributing different effects ber of a family of highly conserved TALE homeobox (Desautels et al., 2005). transcription factors. Heterodimers of MEIS1 with Association studies analyze the frequencies of PBX and HOX proteins augment the affinity and specalleles or genotypes at the site of interest and compare ificity of DNA binding by HOX proteins. HOX genes these in a case and control sample (although familyare organized in clusters and are expressed along the based designs can also be used). A higher frequency body axis in a manner corresponding to their position in cases is taken as evidence that the allele or genotype along the chromosome. Mutation in HOX genes results is associated with an increased risk for the disease. in morphological transformation of the segmental A systematic, hypothesis-free approach was perstructures in which a specific gene is normally formed in a case–control study of 918 independent expressed (Capecchi, 1997). MEIS1 is part of a trancases and controls of European ancestry. The RLS1 scriptional regulatory network that specifies spinal locus on chromosome 12q was analyzed and significant motor neuron pool identity and connectivity (Dasen association with the neuronal nitric oxide synthase et al., 2005), and therefore may have a function in (NOS1) identified. Different allele frequencies with the motor part of RLS or PLM. A study in Xenopus opposite directions were found after analyzing singleshowed that MEIS1 was also involved in neural crest associated single nucleotide polymorphisms (SNPs) development (Maeda et al., 2001). within the NOS1 gene (Winkelmann et al., 2008). This The third region encoded the MAP2K5 gene, a implies that the same allele is a risk allele in one but member of the mitogen-activated protein kinase fama protective allele in the other sample. Further studies ily, and the adjacent LBXCOR1 gene. LBXCOR1 is in independent populations are needed to replicate annotated downstream of MAP2K5 and acts as a and confirm this finding. The association of variants transcriptional corepressor of LBX1. This homeobox in NOS1 and RLS, however, suggests involvement of

688 J. WINKELMANN AND M. KIMURA gene plays a critical role in the development of sensory specific HLA haplotypes suggested an autoimmune pathways in the dorsal horn of the spinal cord, which process in the etiology. Therefore, DRB1 and DQB1 relays pain and touch (Gross et al., 2002). Based on genes have been sequenced in narcoleptic patients, but its function, it is more likely that LBX1 is involved in no mutation has been found (Tafti et al., 2005). Further RLS. Both genome-wide association studies showed alleles contributing to the risk are DQB1*0301 and association with BTBD9. Little is known about BTBD9 DQB1*0407, whereas the DQB1*0501 or DQB1*0601 other than that it belongs to the BTB (POZ) domainalleles are likely protective (Mignot et al., 2001). containing proteins, making assignment of a specific Families with narcolepsy–cataplexy over several function difficult at present (Stogios et al., 2005). generations show a variable phenotype and individuals Analysis of endophenotypes can give a better with and without cataplexy within a single family have understanding about the genes involved in association complicated the clinical classification within these with a specific symptom of RLS. It is very likely that studies. So far, only a few linkage studies of narcoinvestigations in a larger sample size will identify leptic families have been performed. In eight narcolepfurther variants associated with RLS. Analysis of tic families of Japanese origin, suggestive evidence pooled data will also provide the basis for a comfor linkage was found on chromosome 4p13-21q bined analysis of several thousand samples. This will (Nakayama et al., 2000). A second locus was identified allow researchers to identify further common variants on chromosome 21q in a French family, based on an contributing to the phenotype with even smaller autosomal dominant mode of inheritance (Dauvilliers effects. Finally, it is of course also possible that rare et al., 2004). Interestingly, the authors were able to variants with large effects on the phenotype will be show that the primary excessive daytime sleepiness in identified using the second-generation sequencing individuals of the narcolepsy family was a reliable mintechnology. imal clinical condition for the affected phenotype in multiplex families (Dauvilliers et al., 2004). Today, a causal relationship between narcolepsy and Narcolepsy hypocretin, a neuropeptide of the lateral hypothalaNarcolepsy is characterized by excessive daytime sleepmus, is well established. It has been shown repeatedly iness, cataplexy (sudden loss of muscle tone triggered that most narcoleptics have undetectable levels of by emotions), hypnagogic hallucinations, and sleep hypocretin in the CSF. Originally, a mutation in the paralysis (Taheri and Mignot, 2002). The disease is gene encoding the type 2 hypocretin/orexin receptor mainly sporadic, and pathophysiological studies point was found to be responsible for narcolepsy in canines, to an involvement of both environmental and genetic where the disease follows an autosomal recessive mode susceptibility factors interacting with one another. of inheritance (Lin et al., 1999). Further behavioral Familial cases of narcolepsy are rare and first-degree assessments of transgenic mice with a null mutation relatives have a risk of 2% to develop narcolepsy, of the prepro-hypocretin/orexin gene showed sympwhich is up to 10–40% times higher than the prevalence toms like behavioral arrests and EEG patterns similar (0.02–0.06%) in the general population of western to those in human narcolepsy (Chemelli et al., 1999). European countries and the USA (Mignot, 1998). Up However, no association of single nucleotide polyto one-third of monozygotic twins are concordant for morphisms (SNPs) in the prepro-hypocretin gene or narcolepsy, demonstrating that nongenetic factors in the hypocretin 1 and hypocretin 2 genes have been must also play a role in the etiology of the disorder identified in humans. So far, only a single patient (Taheri and Mignot, 2002). with a mutation in the prepro-hypocretin gene has Narcolepsy has a high association to a specific been identified (Peyron et al., 2000). This patient human leukocyte antigen (HLA) allele. Some 88–98% was DQBq*01602 negative, had undetectable levels of of patients with narcolepsy–cataplexy are positive for hypocretin 1 in the CSF, and showed the first sympthe HLA class II allele, DQB1*0602, most often in toms of cataplexy at the age of 6 months. combination with DR2 (Mignot et al., 2001). Even up Altogether these findings indicate that, although to 60% of patients with milder symptoms or without hypocretin deficiency constitutes the best biological catalepsy show this haplotype, in comparison to only marker of sporadic narcolepsy, the molecular cause 12–38% of the general population. However, patients remains elusive and mutations of the three hypocretiwith narcolepsy can also be negative for the nergic genes are exceptional in human narcolepsy DQB1*0602 allele, and familial cases cannot be (Tafti et al., 2005). Genome-wide association studies explained by a shared HLA haplotype (Dauvilliers identified polymorphisms in the T-cell receptor alpha et al., 2004), pointing to the involvement of further (TRA-a) locus. Thus, narcolepsy is the first documensusceptibility genes. The strong association with ted disease with a genetic involvement of the TRA-a

GENETICS OF SLEEP DISORDERS 689 locus, encoding the major receptor for HLA peptide A biometric genetic study based on data from presentation. It is still unclear how specific HLA alleles 68 MZ and 54 DZ twin pairs demonstrated that sleepconfer susceptibility to over 100 HLA-associated disordisordered breathing, even in old age, is determined, ders; thus, narcolepsy will provide new insights into in part, by genetic factors. Differences in age of presenhow HLA–TCR interactions contribute to organtation and anatomic risk factors for obstructive sleep specific autoimmune targeting and may serve as a apnea (OSA) in Caucasians and African Americans model for HLA-associated disorders (Hallmayer suggest possible racial differences in the genetic underet al., 2009). Furthermore, an association with a genetic pinnings of the disorder. Performing a segregation analvariant between CPT1B and CHKB was identified ysis, Buxbaum et al. (2002) assessed the transmission (Miyagawa et al., 2008). The involvement and function patterns in 177 Caucasian and 125 African American of the variant is still unknown. CPT1B regulates families for the AHI, adjusted for age, and for age b-oxidation, a pathway involved in regulating theta and body mass index (BMI). Analysis of the Caucasian frequency during REM sleep, and CHKB is an enzyme sample showed that the transmission pattern was consisinvolved in the metabolism of choline, a precursor tent with a major gene that was stronger with the of the REM- and wake-regulating neurotransmitter age-adjusted than with the age- and BMI-adjusted acetylcholine (Miyagawa et al., 2008). variable. In the African American families, adjusting for BMI gave strong evidence for the segregation of a codominant gene. These results provide support Sleep apnea syndrome for an underlying genetic basis for OSA in African Obstructive sleep apnea syndrome (OSAS) is a comAmericans independent of the contribution of BMI mon disorder affecting up to 2–4% of middle-aged (Buxbaum et al., 2002). adults (Young et al., 1993). It is characterized by recurTo identify susceptibility loci for OSA, Palmer and rent episodes of apnea (no airflow) and hypopnea (parcoworkers (2004) performed a genome-wide model tially obstructed airflow) that occur during sleep, and free linkage analysis on AHI and BMI in 59 African is followed by oxygen desaturation, sleep fragmentaAmerican OSA pedigrees. A region on chromosome tion, and symptoms of disruptive snoring, all leading 8q gave the only evidence for linkage to the AHI, to daytime sleepiness (Flemons et al., 1999). The diagwhereas the BMI was linked to multiple regions, most nosis is based on standard clinical criteria, and is gensignificantly to markers on chromosomes 4q and 8q, erally validated by an overnight sleep study with suggesting that there are both shared and unshared measurement of the apnea–hypopnea index (AHI), genetic factors underlying susceptibility to OSA and the number of apneas and hypopneas per hour of sleep obesity (Palmer et al, 2004). (Flemons et al., 1999). It is a complex phenotype and is Furthermore, at the central level there may also be associated with other conditions such as regional obean associated genetic factor. Congenital central hyposity, alteration of craniofacial morphology, and ventilation syndrome (CCHS; OMIM 209880) is a enlargement of critical upper airway soft tissue, as life-threatening disorder involving an impaired ventilawell as significant cardiovascular morbidity and daytory response to hypercarbia and hypoxemia. This phetime sleepiness. Moreover, OSAS is an independent notype is associated with lower-penetrance anomalies risk factor for hypertension, myocardial infarction, of the autonomic nervous system (ANS), including and insulin resistance. Hirschsprung disease and tumors such as ganglioneurA number of studies have shown that a familial omas and neuroblastomas. In mice, the development of aggregation of some associated conditions is involved ANS reflex circuits is dependent on the paired-like in the pathogenesis of sleep apnea. An extensive homeobox gene Phox2b. Amiel and colleagues (2003) family study was performed by Guillminault and identified the human ortholog PHOX2B as a candidate colleagues (1995), who investigated 157 patients with gene in CCHS heterozygous de novo mutations in 18 of OSAS using a detailed assessment of clinical symp29 CCHS patients. This indicates an essential role for toms, physical evaluation, cephalometric X-ray films, PHOX2B in the normal patterning of the autonomous and polysomnography. In addition, 531 living firstventilation system in humans (Amiel et al., 2003). degree relatives and 189 age-matched controls were Further investigation of candidate genes suggested investigated. Interestingly, this study demonstrated a polymorphism in angiotensin-converting enzyme in that none of the very obese patients had any familial association with hypertension in moderate OSAS aggregate of OSAS, whereas patients with specific (Zhang et al., 2000). A possible association of an allele craniofacial features, mostly involving maxilloin the apolipoprotein E e4 gene to OSAS was not mandibular growth, did have a familial aggregate found consistently in independent populations (Taheri (Guillminault et al., 1995). and Mignot, 2002).

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Circadian sleep disorders Advanced sleep phase syndrome (APS) is characterized by consistently advanced sleep onset and awakenings that are earlier than desired. It is a rare disorder and only a few families have been described. It is suggested that the phenotype is transmitted in a classic mendelian autosomal dominant mode of inheritance. A mutation responsible for the disorder was identified in the PER2 gene on chromosome 2q (Toh et al., 2001). However, further cases of familial APS are not caused by a mutation in the PER2 gene, suggesting genetic heterogeneity of the disorder. Delayed phase syndrome (DPS) is characterized by persistent delayed sleep– waking timing. Although DPS seems to be heterogeneous, an association with HLA-DR1 and a PER gene polymorphism has been suggested (Hohjoh et al., 1999; Satoh et al., 2003).

Kleine–Levin syndrome Kleine–Levin syndrome (KLS) is a very rare disorder with the cardinal clinical features of recurring spells of hypersomnia, cognitive and mood disturbances, accompanied by altered behavior such as hyperphagia, hypersexuality, and autonomic alterations (Katz and Ropper, 2002). The pathophysiological hypotheses suggest dysfunction of the hypothalamus. KLS is usually sporadic, but recently two siblings with the syndrome have been described (Katz and Ropper, 2002). An analysis of polymorphism in candidate genes in 30 unrelated patients with KLS showed that the human leukocyte antigen HLS-DQB1*0201 allele frequency is significantly increased in these patients. The authors therefore suggested a possibility of an autoimmune etiology for the disorder (Dauvilliers et al., 2002).

SUMMARY AND PERSPECTIVES The first sleep-related genes have been identified in monogenic disorders. Most of the sleep disorders in this review, however, have complex phenotypes. Using array technologies and performing genome-wide association studies and investigating thousands of patients and controls, we were able to identify common genetic susceptibility factors for sleep phenotypes. Genomewide sequencing with second-generation sequencers will allow us to detect further rare genetic variants with a large effect on the phenotype. Finally, to explore further the genetics of sleep disorders, epigenetic factors should be also considered that might explain the complexity of phenotypes.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 44

Neurological perspectives in insomnia and hyperarousal syndromes MARIO GIOVANNI TERZANO * AND LIBORIO PARRINO Sleep Disorders Center, Department of Neuroscience, University of Parma, Italy

INSOMNIA: SYMPTOM OR DISEASE? Soon I ceased to sleep altogether, an acute attack of insomnia set in, so terrible that it nearly made me go off my head. Insomnia does not kill its man unless he kills himself – sleeplessness is the most common cause of suicide. But it kills his joie de vivre, it saps his strength, it sucks the blood from his brain and from his heart like a vampire. It makes him remember during the night what he was meant to forget in blissful sleep. It makes him forget during the day what he was meant to remember. Memory is the first to go overboard, soon friendship, love, sense of duty, even pity itself are one after another washed away. Despondency alone sticks to the doomed ship to sheer it on the rocks to total destruction. Voltaire was right when he placed sleep on the same level of hope. . . Beware of a doctor who suffers from insomnia! My patients began to complain that I was rough and impatient with them, many of them left me. . . Only when they were about to die did I seem to wake up from my torpor, for I continued to take keen interest in Death long after I had lost all interest in Life. (Axel Munthe, The Story of San Michele)

Definition of insomnia According to the International Classification of Sleep Disorders (American Academy of Sleep Medicine, 2005) insomnia is defined as: 1. A complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early,

or sleep that is chronically nonrestorative or poor in quality. 2. Sleep difficulty occurs despite adequate opportunity and circumstances for sleep. 3. At least one of the following forms of daytime impairment related to the nighttime sleep difficulty is reported by the patient: ● Fatigue or malaise ● Attention, concentration, or memory impairment ● Social or vocational dysfunction, or poor school performance ● Mood disturbance or irritability ● Daytime sleepiness ● Motivation, energy, or initiative reduction ● Proneness for errors or accidents at work or while driving ● Tension, headaches, or gastrointestinal symptoms in response to sleep loss ● Concerns or worries about sleep. Diagnosis of insomnia is based on the identification of one or more symptoms which also include nonrestorative or poor quality of sleep. This implies that classification criteria have definitely accepted the pivotal issue that sleep can be unrefreshing independent of its duration. Another important consideration is that the sleep-related symptoms must be associated with a diurnal complaint. Among daytime dysfunction, sleepiness is not the most frequent impairment and may not be always reported by the insomniac patient. Other more common disturbances are psychosomatic manifestations or mood disorders. In particular, the complaint of fatigue is almost always associated with insomnia. However, if insomnia is associated with daytime complaints, is it still correct to define it as a

*Correspondence to: Professor Mario Giovanni Terzano, Centro di Medicina del Sonno, Clinica Neurologica, Universita` di Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail: [email protected]

698 M.G. TERZANO AND L. PARRINO symptom or would it more correctly be indicated as disorders that are, in fact, associated with an increased a syndrome with global implications throughout the risk of morbidity. 24-hour period? Some authors consider insomnia to Epidemiological studies of both clinical and general be a symptom with numerous possible causes. Others samples of population have demonstrated an associaconsider insomnia as a syndrome or a disease. This tion between insomnia and depression (Nowell et al., seems particularly appropriate for primary insomnia, 1997; Bixler et al., 2002), whereas cardiovascular illwhich is unrelated to any physical or mental comorbidnesses and chronic pain are the most frequent comorbid ity, but is characterized by a set of symptoms, a medical conditions in patients with insomnia (Hatoum defined disease course, and, in most cases, a predictet al., 1998; Terzano et al., 2004). Insomnia is also often able response to treatment. associated with an increased metabolic rate 24 hours per day, and increased heart rate, sympathetic tone, and plasma cortisol concentrations, indicating a heightened Diagnosis of insomnia activation of the nervous system or “hyperarousal” Insomnia is the most common sleep complaint in the (Bonnet and Arand, 1995; Vgontzas et al., 2001a; general population around the world (Soldatos et al., Nofzinger et al., 2004). A statement from the National 2005). Recent research has addressed a wide range Institutes of Health State of the Science Conference on of issues related to this condition, including epidemiManifestations and Management of Chronic Insomnia ology, consequences, pathophysiology, and treatment. in Adults (2005) proposed to use the term comorbid An updated review of epidemiological studies showed insomnia, suggesting the presence of one or more disthat the reported prevalence of insomnia in the general orders in addition to insomnia as a distinct disorder. population ranges from 6% to about 33%, depending This proposal indicates a revision of the cause–effect on the definition of insomnia (Ohayon, 2002). Studies relationship. For instance, despite the clinical evidence examining the clinical and physiological characteristics that emotional stress or depression precedes the onset of insomnia have used definitions ranging from the of insomnia and that insomnia is a risk factor for very broad (e.g., self-defined “good vs. poor sleepers”), depression, there is growing evidence that insomnia is to the very narrow (e.g., individuals with “sleep state not simply a byproduct of depression and the complex misperception”, which can be defined only with polyassociation of these two disorders needs independent somnography). The term insomnia symptom refers to research and clinical efforts. Clinicians have long the sleep-specific insomnia definition, i.e., difficulty recognized that insomnia is often maintained despite falling asleep, difficulty staying asleep, early awakenthe remission of the accompanying depression and ing, or unrefreshing nonrestorative sleep in an individmay require separate therapeutic interventions from ual who has adequate circumstances and opportunity depression. for sleep (American Psychiatric Association, 2000). The separation criteria between insomnia and other The following quantitative criteria have been suggested medical or psychiatric disorders have inspired the secto define insomnia symptoms: sleep-onset latency or ond edition of the International Classification of Sleep wakefulness after sleep onset of more than 30 minutes, Disorders (American Academy of Sleep Medicine, frequency of at least three times a week, and duration 2005), where specific insomnia diagnostic subtypes of at least 6 months. In contrast, the term insomnia are identified (Table 44.1) and where the term insomdisorder, or simply insomnia, denotes a broader clininia finally reappears after a 15-year blackout (in the cal condition with both sleep and waking symptoms International Classification of Sleep Disorders pub(Billiard and Bentley, 2004). lished in 1990, the term insomnia was omitted and secInsomnia symptoms, considered in isolation, confer ondarily incorporated in the definition of dyssomnia). limited morbidity and thus are of questionable cliniWhat remains to be clarified is the objective nature cal significance. Therefore, reliance solely on insomnia of poor sleep quality. While insomnia symptoms of symptoms for sample selection appears a suboptidifficulty initiating asleep, difficulty maintaining sleep, mal research practice. Arguably, a more defensible and early morning awakening correlate with practical research practice is that of defining insomnia as a dispolysomnographic (PSG) measures (sleep latency, order with impairment of sleep and waking functions. wake after sleep onset, and wake after final awakenTypically such definitions include complaints of insoming, respectively), conventional quantitative criteria nia symptoms coupled with waking symptoms such do not address unrefreshing or nonrestorative sleep as functional impairments, sleep-related distress, or (Guilleminault et al., 2006), one of the cardinal sympgeneral sleep dissatisfaction. Insomnia definitions that toms of insomnia. An individual under PSG monitoring combine sleep-specific complaints with daytime sympcan report a sleep period of several hours with a contoms appear to represent clinically significant insomnia comitant high sleep efficiency and still wake up feeling

NEUROLOGICAL PERSPECTIVES IN INSOMNIA AND HYPERAROUSAL SYNDROMES Table 44.1 Classification of adult insomnia Type of insomnia Primary insomnia Idiopathic

Psychophysiological

Paradoxical (sleep-state misperception)

Secondary insomnia Adjustment Inadequate sleep hygiene

Insomnia due to a psychiatric disorder Insomnia due to a medical condition

Insomnia due to a drug or substance

Description

Arising in infancy or childhood with a persistent, unremitting course Insomnia due to maladaptive conditioned response in which the patient learns to associate the bed environment with heightened arousal rather than sleep; onset often associated with an event causing acute insomnia, with the sleep disturbance persisting despite resolution of the precipitating factor Insomnia characterized by a marked mismatch between the patient’s description of sleep duration and objective polysomnographic findings Insomnia associated with active psychosocial stressors Insomnia associated with lifestyle habits that impair sleep Insomnia due to an active psychiatric disorder, such as anxiety or depression Insomnia due to a condition such as restless legs syndrome, chronic pain, nocturnal cough or dyspnea, or hot flashes Insomnia due to consumption or discontinuation of medication, drugs of abuse, alcohol, or caffeine

Modified from the International Classification of Sleep Disorders (American Academy of Sleep Medicine, 2005).

tired and sleepy throughout the day. The lack of objective criteria for the identification of normal sleepers vs. insomniac patients can also determine underestimation of treatment effects in clinical and research trials (Cortoos et al., 2006). Collectively, these observations suggest that a more accurate neurophysiological approach to insomnia is deemed necessary. This chapter reviews the mechanisms that regulate the sleep process and describes the quantitative criteria that support the restoring properties of sleep.

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THE NEUROPHYSIOLOGICAL BASES OF INSOMNIA The sleeping process Sleep is a spontaneous active process, consisting of cyclic changes in many aspects of body chemistry and function, that must occur periodically to restore and maintain health. The control mechanisms of sleep are manifested at every level of biological organization, from genes and intracellular mechanisms to networks of cell populations and to all neuronal systems, including those that control movement, arousal, autonomic functions, behavior, and cognition. During sleep, the brain controls the sequence of a number of states that follow some general rules. We fall asleep in nonrapid eye movement (NREM) sleep, we reach slow-wave sleep (SWS) in approximately 20–25 minutes, we remain in this state for approximately 30–40 minutes, and then we shift within 10–15 minutes into an episode of rapid eye movement (REM) sleep. This process is regulated by an ultradian oscillator in the brainstem that controls the regular alternation of NREM and REM sleep. Once the first period of REM sleep has been completed, the cycle starts again, although it tends to change from cycle to cycle. As sleep goes on, the amount of SWS decreases, leaving progressive space for stage 2 and REM sleep, which become the dominant features of the second part of the night (Carskadon and Dement, 2000). The nocturnal sleep chronogram is depicted by the conventional histogram (Figure 44.1). The onset and offset of sleep are regulated by the circadian process (closely related to thermoregulation), whereas the intensity of SWS depends on the amount of previous wakefulness (homeostatic process). However, the skeleton of sleep (i.e., macrostructure) can be manipulated within certain limits. If we prolong the time of previous wakefulness, we will have an enhancement of SWS and a contraction of stages 2 and REM, but the general architecture will be maintained. Things can change only when disturbing factors heavily interfere with the sleep process. Clinical conditions such as severe insomnia and sleep apnea syndrome can determine a drastic curtailment of SWS and an increase of light sleep, but as soon as the disturbing factor is removed or counteracted (hypnotic treatment in insomnia or nasal continuous positive airway pressure in breathing disorders), the sleeping brain tends to recover the original program. Even after sleep deprivation there is an immediate powerful rebound of SWS, the values of which, however, return to normal in the following nights. These findings suggest that the software governing sleep is powerful and resistant. You can influence it with several pressures

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Fig. 44.1. Comparison between histograms based on the sleep staging rules of Rechtschaffen and Kales (A) and on the new criteria of the American Academy of Sleep Medicine (B). REM, rapid eye movement sleep. R, REM sleep; stage N1, nonREM stage 1; stage N2, nonREM stage 2; stage N3, non-REM stage 3.

but it tends to recover its core trait once the perturbing factor is withdrawn.

Reactivity and arousal during sleep Both robustness and sensitivity are necessary for complex systems to function effectively in the context of changing environments. Sleep is based on a solid program, which is under the influence of interacting regulatory processes: genetic constraints (Dauvilliers and Tafti, 2008; De Gennaro et al., 2008), the circadian sleep–wake alternation (Czeisler et al., 1980), the homeostatic balance between wakefulness and sleep (Borbely, 1982), and the ultradian NREM–REM interaction (McCarley and Massaquoi, 1992). Performing this program, the brain seeks internal stability and at the same time follows the dynamics of the sleep trajectory. This is achieved through control mechanisms, involving the arousal systems, that pace the state progression of the NREM/REM sleep cycle and protect sleep architecture against destabilizing stimulation. A stimulus is an interference that affects the system’s operations and may arise from within or outside

the system. Once the stimulus has registered itself in some way, the system measures its own internal tendency to depart from stability, and uses the responses either by evolving back to its initial condition or by switching to another state (Bar-Yam and Epstein, 2004). Within complex systems, such as the sleeping brain, control can be obtained only if the variety of the controller is at least as great as the variety of the situation to be controlled (Ashby, 1957). This implies that the sleeping brain must be endowed with a number of hierarchically graded arousal responses which guarantee a rapid and flexible adaptation to the interfering stimulus as a buffer system. This task is achieved through a graded activation of the brain expressed by EEG frequency shifts. The EEG responses elicited during sleep are not limited to a single pattern but are part of a continuous spectrum of EEG modifications ranging from high-voltage slow rhythms (K-complexes and delta bursts) to low-amplitude fast rhythms (conventional arousals) (American Sleep Disorders Association, 1992). The EEG responses play a special role in the sleep program, ensuring on the one hand enough stability to the sleeping brain and on the other enough flexibility to provide the necessary arousability from sleep. The sleep-promoting and wake-promoting neurons play a complementary role, both protecting and tailoring the length and depth of sleep according to the individual’s internal and external demands. In other words, the arousal system is the bridge that connects the internal sleep program to the environment and reacts to the signals with a variety of responses. Besides their buffering role against perturbing factors, arousals are natural EEG features of sleep, endowed within the texture of the physiological sleep process. In other words, brief awakenings from sleep are not simply random disruptions of the sleep process but rather are related to the underlying mechanisms of sleep control. Recent studies have also ascertained that brief awakenings exhibit robust scaleinvariant features across different mammalian species (Lo et al., 2004). The term arousal is commonly related to the concept of awakening. In the field of classic neurophysiology, the behavior of wakefulness is associated with the occurrence of EEG desynchronization (low-amplitude fast rhythms). Indeed, according to the conventional criteria, an arousal is identified by a rapid shift towards faster frequencies preceded by at least 10 seconds of continuous sleep (Figure 44.2). Thus, it is not surprising that slow phasic activities such as K-complexes and delta bursts are excluded from the definition of arousal. However, these slow phasic activities, although different in morphology from conventional arousals, are endowed with properties of cerebral, motor, and

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Fig. 44.2. EEG arousal according to the conventional rules. Only the fast EEG rhythms (right-hand box) are included in the phasic event. The slow waves preceding the shift to the rapid frequencies are excluded (left-hand box).

vegetative activation, i.e., vasoconstriction, increased blood pressure, heart rate acceleration, increased ventilation (Hornyak et al., 1991; Sforza et al., 2000). Consequently, the concept of activation is much more extensive than the term arousal, which is the tip of an iceberg with manifold EEG features including also delta bursts, K-complexes, and K–alpha complexes (De Carli et al., 2004). This does not mean that all the activation complexes exert the same impact upon the vital functions. The activation complexes dominated by EEG synchronization (sequences of K-complexes, delta bursts) are associated with milder variations of motor and autonomic activities, whereas the forms with more rapid rhythms (i.e., conventional arousals) are combined with stronger modifications (Figure 44.3). In a spectrum of continuity, a hierarchy of activation samples can be defined and classified according to the relative amount of EEG synchrony and desynchrony (Halasz et al, 2004).

The cyclic nature of arousal The pattern of long-term EEG activity is generated by a time-averaged and smoothed collection of multiple, discrete frequencies of rhythm generation. Once NREM sleep has been initiated by the combined influence of homeostatic pressure and circadian propensity, there is a progressive inhibition of the arousal–waking system accompanied by alpha-rhythm fragmentation. The progression to the slower activities induces the rising of the slow (<1 Hz) oscillations, which are seminal for the implementation of slow wave activities (1–4 Hz) of deep NREM sleep (Steriade et al., 1993). K-complexes and delta bursts are the most relevant EEG manifestations of the slow (<1 Hz) rhythm regulated by intracortical loops (Amzica and Steriade,

1997). During this slow rhythm, the membrane potential of all cortical neurons oscillates, with a periodicity of about 1 second, between depolarized (up-state) and hyperpolarized (down-state) levels. This pattern of alternating states is associated with the continuous fluctuation of the synaptic release at the cortical level and powerfully entrains thalamic neurons (Massimini et al., 2003). In the state progression of different NREM stages the balance between wake-promoting cortical arousals and sleep-promoting (<1 Hz) slow oscillations is regulated by an infraslow oscillation (0.002–0.02 Hz) expressed in the scalp electrocortical activities by the cyclic alternating pattern (CAP) (Terzano et al, 1985; Ferri et al., 2006). CAP is an EEG periodic activity of NREM sleep organized in sequences of repetitive cycles that recur with a periodicity of 20–40 seconds (Terzano et al., 2001). Each CAP cycle is composed of a phase A (specific, repetitive, and transient EEG pattern) and a phase B (the interval between two consecutive A phases). Phase A of CAP is the EEG marker of cerebral activation, and phase B is an EEG indicator of rebound deactivation (Figure 44.4). CAP is the EEG translation of unstable sleep that accompanies the dynamic evolution of the sleep process, such as falling asleep, stage shifts, NREM/REM transition and intrasleep awakenings. The absence of CAP for more than 60 seconds is scored as nonCAP and reflects a condition of stable consolidated sleep (Terzano et al., 1988d; Smerieri et al., 2007). In the transition from light to deep stages, the <1 Hz oscillations become increasingly more frequent and tend to cluster in transient packages of approximately 10 seconds, similar to the mean duration of a CAP phase A. In consolidated deep sleep, the intermittent clusters of high-voltage slow EEG waves progressively

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Fig. 44.3. An example of muscle and autonomic activation linked with a sequence of K-complexes which induces a jerk on the right tibialis muscle and an initial recovery of airflow. The rise in pulse rate starts at the end of the K-complex cluster and accompanies the waxing of chin muscle tone (Milo channel) and breathing restoration. The black box containing EEG features is artificially split into two portions by a dotted vertical line: the slow-wave component of activation (left side) followed by a conventional arousal (right side).

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Fig. 44.4. A sequence of cyclic alternating pattern (CAP) in stage 2. Three complete CAP cycles are visible with the A phases coupled with transient heart rate acceleration and the B phases with a pulse deceleration.

NEUROLOGICAL PERSPECTIVES IN INSOMNIA AND HYPERAROUSAL SYNDROMES merge into a continuous nonalternating pattern in which the phases A and B of CAP are no longer distinguishable (nonCAP), being gradually replaced by sustained slowwave activity (Figure 44.5). By contrast, the shift from deep NREM sleep to REM stage is accompanied by the intrusion of cortical arousals, slow-wave fragmentation, and reappearance of the CAP rhythm (Ferrillo et al., 1996; Terzano and Parrino, 2000). Scoring rules, classification of phase A subtypes, and distribution of CAP parameters are detailed in the Appendix.

Homeostatic regulation of the sleeping brain Physiological regulation of the living organism varies according to the different conditions of vigilance. During wakefulness, the homeostatic control is achieved by means of highly dissipative metabolic processes, whereas motor quiescence and decreased sympathetic activity make sleep a condition of low energy expenditure (Parmeggiani, 1990). Although characterized by a low rate of energy transformation, sleep is, nevertheless, an active phenomenon maintained by means of a twofold homeostatic regulation (Moore-Ede, 1986): 1. Predictive homeostasis that warrants, under the control of intrinsic chronobiological systems, an endogenously programmed development of the sleep profile.

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2. Reactive homeostasis that encompasses the continuous adjustments in response to all changes arising in the organism and in the environment. Therefore, the final architecture of a night of sleep emerges from the dynamic interaction between the internal constraints and the functional adaptability of the sleeping brain to the ongoing events. Owing to the time-related coupling between vigilance and autonomic functions, an adequate and simultaneous regulation of both sleep and neurovegetative systems is assured. Predictive homeostasis controls the tonic development of the NREM/REM cyclic alternation associated with a progressive decline of muscle tone, arterial pressure, body temperature, cardiorespiratory rate, and oxygen consumption. Reactive homeostasis intervenes through corrective responses to the phasic variations of vigilance level and physiological functions induced by the ever-changing environment. In the two-process model proposed by Borbely (1982), the homeostasis of sleep is related to the process-S curve that reflects the damping decline of EEG synchronization from sleep onset to final arousal. The slope of the process-S curve depends on sleep intensity and is linked to the duration of previous wakefulness, whereas its beginning and interruption are related to the process-C curve that undergoes the circadian constraints of internal clocks. This model supplies predictive information on the development and duration of

Fig. 44.5. A 60-second stretch of nonCAP in stage 2, characterized by a sustained homogeneous EEG trace (with intermittent spindles) and stable heart rate and SaO2 values.

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sleep based on the interaction between a single oscillator (process C) and a homeostatic process (process S). However, it neglects the occurrence and role of microstructural phenomena that partake in the accomplishment of process S and permit continuous adjustments of the sleeping brain to the unpredictable conditions of reality (Halasz, 1993, 1998; Terzano and Parrino, 2000). The different phase A subtypes of CAP represent a wide spectrum of short-lived graduated homeostatic reactions, which appear to be superimposed on the background rhythms of the single NREM stages and restrain the variability of biological functions within compatible ranges. From this perspective, sleep dynamics reflect a predefined plot implemented by ceaseless surprises. Every night, sleep onset is followed by a chain of regular and predictable events (the prevalence of SWS in the first part of the night, the 90–120-minute alternation between NREM and REM sleep, the intrinsic structure of sleep cycles, the duration of the single stages). On the other hand, it is a common experience that even in the same individual no two sleep recordings are exactly identical, as a series of random factors (eating, environment, worries, tiredness) vary from night to night. In other words, the sleeping brain can be considered as a kind of computer with certain inherited programs that receive and code input information from the world and guide adaptive action accordingly. This means that the sleeping brain must be able to process information and predict instability in the external milieu. Normative studies (Parrino et al., 1998; Bruni et al., 2002, 2005) have ascertained that normal sleep contains certain amounts of CAP rate, with age-related differences along the natural lifespan (Figure 44.6). Within compatible ranges, the sleeping brain can incorporate a supply of perturbation (increase in CAP rate) in the absence of relevant alterations of sleep stages. However, an excessive enhancement of instability drags sleep into becoming shallower and fragmented, as shown by a curtailment of the deeper stages and an increase of nocturnal awakenings (Terzano et al., 1990). Thus, the oscillating instability of CAP acts both as a protective mechanism for architectural stability and as a preparatory device for macrostructural alterations (Terzano and Parrino, 1993). Through the profile of sleep architecture and the magnitude of CAP-related changes it is possible to reconstruct the brain’s nocturnal experience.

Acoustic perturbation: an experimental model of insomnia The sleeping brain continuously explores the external world, especially by means of the hearing function. Macrostructural changes such as stage shifts and

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Fig. 44.6. Distribution of the single CAP rate values across the different ages in normal healthy sleepers. Notice that across the lifespan physiological CAP rate tends to remain above 20% (horizontal black line), the minimum dynamic effort exerted by the brain to maintain a proper sleep structure.

awakenings are generally determined by strong acoustic stimuli (Terzano et al., 1993). However, noise can impinge upon sleep even when macrostructural alterations are lacking. An isolated stimulus (250 milliseconds; 1000 Hz; 60 dB) delivered during nonCAP in stage 2 immediately evokes a CAP sequence that persists in stage 2 (Terzano et al., 1986). In other words, arousal stability can be compromised despite an unmodified macrostructural background. The possibility of converting nonCAP into CAP by means of acoustic perturbation has been exploited in experimental studies based on continuous white noise administered throughout the night. The increases in CAP rate correlate positively with the increases of sound pressure level and with the impairment of subjective appreciation of sleep quality. In healthy young adults, values of CAP rate between 25% and 45% emerge when the subjective report is essentially satisfactory. For values of CAP rate between 45% and 60%, subjects generally refer to a moderate nocturnal discomfort, whereas a CAP rate above 60% corresponds to a severe complaint (Terzano et al., 1990). From the macrostructural viewpoint, no remarkable alterations of the conventional PSG parameters emerge at 45 dB, where CAP rate already shows a significant increase compared with the baseline condition (<30 dB). More relevant macrostructural changes, such as reduced slow-wave sleep and more frequent and longer awakenings, occur only at higher noise intensities (55, 65, and 75 dB respectively). Thus, in the chain of events from normal to pathological sleep, the expansion of CAP rate is a first-aid response for maintaining the physiological organization of sleep. Under the thrust of increasing

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of zolpidem against noise reverberated especially upon stages 3 and 4, where the disruptive effects of acoustic perturbation were more prominent (Terzano et al., 1988c).

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Fig. 44.7. Escalating values of CAP rate in healthy volunteers undergoing increasing levels of controlled acoustic perturbation during different nights.

sound pressure level, CAP operates as a “buffer” mechanism that counteracts, within compatible ranges, the disruptive effects of noise on the macrostructure of sleep (Figure 44.7). However, when adaptive thresholds are crossed, the destabilizing effects of noise also reverberate on the macrostructural level (Terzano and Parrino, 1993).

PHARMACOLOGICAL MANAGEMENT OF INSOMNIA Effects of zolpidem on CAP rate The sensitivity of CAP rate to noise has enabled the use of an “active” technique for exploring the effects of hypnotic drugs on the organization of sleep under strictly controlled conditions. In a group of healthy young adults with normal habits and no sleep complaints, an experimental trial was carried out on the basis of the aforementioned premises of microstructural manipulation by means of continuous noise (Terzano et al., 1988a, b). After an adaptation night, treatments (either placebo or 10 mg zolpidem) and conditions (presence or absence of continuous 45 dB white noise automatically delivered and controlled during the entire sleep recordings) were administered four times at 48-hour intervals, according to a completely randomized crossover factorial design. Despite the lack of significant macrostructural change when placebo was associated with noise, this condition provided a model of acute situational insomnia as disclosed by the complaint of a poor sleep quality. The subjective judgment was, however, supported by the microstructural data. Compared with baseline values (25%), white noise induced a significant increase of CAP rate during the noisy placebo nights (55%). Under unperturbed conditions, zolpidem preserved the regular organization of sleep at both the macrostructural and the microstructural level (CAP rate 26%), but the drug drastically reduced the increased values of CAP rate induced by acoustic perturbation (CAP rate 38%). The protective effects

In a long-term study (Terzano et al., 1997), zolpidem 10 mg was used for 5 weeks in patients with transient or short-term insomnia. After adaptation to the sleep laboratory, nocturnal PSG recordings were accomplished on: night 1 (baseline), night 2 (first day of drug administration), night 3 (seventh day of drug administration), night 4 (28th day of drug administration), night 5 (third day after the end of drug tapering). At the macrostructural level, significant overall modifications emerged only for SWS. For this parameter, a significant difference was found only between the baseline night (10%) and the first night of drug administration (20%), but the amounts of SWS remained enhanced during the remaining drug period. Highly significant and persistent differences did emerge, instead, at the microstructural level. In particular, CAP rate was significantly reduced throughout the entire drug period, decreasing from 59% (baseline night) to 32–38% (zolpidem nights). The variations in CAP rate correlated with the subjective appreciation of sleep quality. There was no PSG evidence of rebound insomnia when active medication was discontinued. Efficacy of zolpidem was also confirmed when the drug was administered according to an intermittent regimen (Parrino et al., 2008).

Hypnotic drugs in situational insomnia The model of situational insomnia based on continuous noise and CAP analysis has been used to compare the effectiveness of different hypnotic compounds against a common background (Terzano et al., 1995). Comparative multidrug studies have been carried out on a number of benzodiazepine (brotizolam, triazolam, lorazepam) and nonbenzodiazepine (zolpidem, zopiclone) drugs in healthy subjects both under basal (silent baseline night at a sound pressure of 30 dB) and acoustically perturbed conditions (noise-disturbed night at a sound pressure level of 55 dB). This model of situational insomnia allows discrimination between hypnotic drugs and placebo, between nonbenzodiazepine compounds and benzodiazepine agents, and between zolpidem and zopiclone (Parrino et al., 1997).

Antidepressant drugs and insomnia The close relationship between sleep and depression can justify the extensive use of antidepressant drugs in several forms of insomnia. However, the hypnotic

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M.G. TERZANO AND L. PARRINO impairment in social, occupational, or other important areas of functioning. 3. The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, or a parasomnia. 4. The disturbance does not occur exclusively during the course of another mental disorder (e.g., major depressive disorder, generalized anxiety disorder, delirium). 5. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

efficacy of an antidepressant agent does not necessarily imply that the sleep disorder is determined by a mood disturbance. The beneficial action of sedating antidepressant medication in primary insomnia has been reported (Curry et al., 2006). In addition, not all effective antidepressants exert the same hypnotic action. In a study carried out blind for 8 weeks in 125 patients with major depression and insomnia, 61 individuals were treated with fluoxetine and 64 with nefazodone (Gillin et al., 1997). PSG recordings were accomplished in the second, fourth, and eighth weeks of treatment. Both compounds proved effective in improving the symptoms of depression. However, in the fluoxetine group sleep appeared severely altered (decreased sleep efficiency and shallower sleep depth), whereas patients using nefazodone also presented subjective (self-report) and objective (PSG measures) improvement of sleep quality. Thus, the wake-promoting effect of fluoxetine and other selective serotonin reuptake inhibitors with activating properties suggests that the improvement in depressive symptoms may not be associated with a simultaneous improvement of insomnia. In support of this separation between antidepressant and hypnotic action, it is interesting to note that the effects on mood tend to appear after several days of treatment (generally weeks), whereas the effects on sleep commonly occur a few days after introduction of the medication. In a clinical–PSG study conducted on adult dysthymic patients with chronic insomnia, administration of trazodone CR (controlled release) reduced the excessive values of pretreatment CAP rate (65%) and improved subjective sleep quality in 4 days. Significant improvement of the mood-related symptoms occurred only after 3 weeks of medication (Parrino et al., 1994).

PRIMARY INSOMNIA Does primary insomnia exist? Primary insomnia generally refers to a situation where underlying causes of secondary insomnia have been ruled out. In primary insomnia, sleeplessness is not attributable to a medical, psychiatric, or environmental cause. The diagnostic criteria for primary insomnia from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (American Psychiatric Association, 2000) are as follows: 1. The predominant complaint is difficulty initiating or maintaining sleep or nonrestorative sleep for at least 1 month. 2. The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or

Primary insomnia subsumes a number of insomnia diagnoses in the International Classification of Sleep Disorders (American Academy of Sleep Medicine, 2005) including psychophysiological insomnia, paradoxical insomnia, idiopathic insomnia, and some cases of inadequate sleep hygiene. Primary insomnia is sometimes referred to as “pure” insomnia and in this case difficulty sleeping is at the core of the disorder. In other cases, primary insomnia and other disorders are independent, but cooccurring (Vgontzas, 2005). Computer-aided methods of sleep EEG, such as power spectral analysis, have revealed significantly increased fast activity in primary insomnia compared with that in good sleepers (Merica et al., 1998; Perlis et al., 2001). Studies assessing a wide range of physiological aspects in primary insomnia have also measured vital signs, temperature and metabolic rate, neuroendocrine function (e.g., cortisol and plasma melatonin), immune function (cellular and humoral immune components), cortical/neurological function (using functional neuroimaging and cognitive assessments), and psychological aspects (e.g., depressive tendencies and mood states). Through such investigations, a distinct profile involving endocrine, neurological, cognitive, and behavioral factors has been identified that suggests a pivotal role for psychophysiological hyperarousal in the disease etiology (Roth et al., 2007). Studies have shown significantly increased heart rate and core body temperature, and a raised metabolic rate in patients with insomnia (Bonnet and Arand, 1997). Evening and nocturnal plasma cortisol concentrations have exhibited alterations in the circadian cortisol rhythm (Rodenbeck and Hajak, 2001; Vgontzas et al., 2001a). In both young and elderly individuals with primary insomnia, nocturnal plasma melatonin levels tend to be lower than those in healthy controls (PandiPerumal et al., 2007). Patients with insomnia have also been shown to exhibit lower levels of cellular immunity (CD3þ, CD4þ, CD8þ cells) compared with normal sleepers (Savard et al., 2003).

NEUROLOGICAL PERSPECTIVES IN INSOMNIA AND HYPERAROUSAL SYNDROMES 707 Functional neuroimaging evidence of increased metamount of time they have slept, little is known about abolic and neuronal activity in primary insomnia has the mechanisms that underpin this phenomenon. In a also emerged recently, showing significant increases study carried out on 20 individuals with insomnia and in whole-brain metabolism and greater activity in brain 20 individuals who did not have insomnia, all subjects arousal systems in patients with insomnia compared were asked to perform two time estimation tasks, one with healthy subjects (Nofzinger et al., 2006). If, on in the laboratory during the day and one in the particithe one hand, insomniacs have globally increased brain pant’s own bedroom during the night. The results indimetabolism during both waking and sleep, possibly a cated that the performance of the insomnia group was reflection of hyperarousal (Nofzinger et al., 2004), on no different from that of the no-insomnia group, the other they show relative reductions in glucose regardless of the context in which the time estimates metabolism in the prefrontal cortex, possibly due to were made. Time overestimation correlated positively insufficient sleep restoration. with cognitive and physiological arousal experienced Under normal circumstances, sustained wakefulness during the time estimation tasks. These findings argue should produce an easy transition into sleep, consoliagainst the hypothesis that individuals with insomnia dated sleep, deep sleep, and sustained sleep. Given that misperceive their sleep simply because they are poor the latter phenomena do not occur with insomnia, and estimators of time (Tang and Harvey, 2005). Candidate the duration of wakefulness appears to be normal, it is mechanisms that underpin misperception can be sought plausible that the “sleep homeostat” itself is dysreguin the investigation of sleep microstructure. lated (Tononi and Cirelli, 2006). What happens during At the Parma Sleep Disorders Center, data were colthe night somehow reflects the diurnal neurophysiologlected from all-night PSG recordings of 20 patients ical experiences of the sleeping brain. In particular, with a diagnosis of sleep state misperception or parawakefulness is accompanied by synaptic potentiation in doxical insomnia (International Classification of Sleep a large fraction of cortical circuits, resulting in a net Disorders; American Academy of Sleep Medicine, increase in synaptic weight. In contrast, sleep (in particu2005). Recruitment of misperceptors without coexistlar SWS) is associated with synaptic downscaling. Under ing neurological, medical, or psychiatric disorders was normal conditions, the total synaptic strength increases based on objective total sleep time (TST) of at least during wakefulness and reaches a maximum just before 6.5 hours, objective sleep latency (SL) shorter than going to sleep. At sleep onset, total synaptic strength 30 minutes, underestimated difference between objecstarts to decline, and reaches a baseline level by the time tive and subjective TST of at least 120 minutes, and sleep ends (Tononi and Cirelli, 2007). subjective estimation of sleep latency >20% of objecSleep deprivation and sleep restriction produce two tive sleep latency. PSG data from misperceptors were kinds of symptoms: (1) “sleepiness” and related sympcompared with those from 20 normal sex- and agetoms, due to increased sleep pressure mediated by central matched subjects (controls). Patients and controls prehomeostatic mechanisms; and (2) cognitive impairment, sented nonsignificant differences in the amounts of irritability, difficulty concentrating, and fatigue, due to objective sleep time (464 vs. 447 minutes) and objective synaptic overload of cortical and limbic circuits caused sleep latency (9 vs. 8 minutes). However, compared by local sleep loss. Symptoms resulting from dysregulato controls, misperceptors reported a significantly tion of synaptic homeostasis are prominent in primary shorter time of perceived sleep (285 vs. 461 minutes; insomnia and in syndromes characterized by subjective P < 0.0001), and a significantly longer duration of perfeeling of nonrestorative sleep (Tononi and Cirelli, 2006). ceived sleep latency (51 vs. 22 minutes; P < 0.0001). At Whatever the underlying cause, primary insomnia the microstructural level, arousal index (32 vs. 19 per is the outcome of an internal dysregulation of sleephour; P < 0.0001) and total CAP rate (58% vs. 35%; promoting and arousal-promoting mechanisms. The P < 0.0001) were significantly higher in insomniacs. sleeping brain can articulate a number of graded In the sleep period between objective and subjective arousal responses that guarantee a quick and flexible sleep onset, CAP rate was 64.4% in misperceptors adaptation to the interfering stimulus as a buffer sysand 45.1% in controls (P < 0.002). Insomniacs showed tem. However, when the internal buffer systems are significantly higher amounts of CAP rate in stage 1 unable to control the stability of internal environment, (62.7% vs. 37.5%; P < 0.0001) and in stage 2 (53.3% sleep becomes fragile, fragmented, and nonrestorative. vs. 33.2%; P < 0.0001), but not in SWS. The percentage of subtypes A2, which include both sleep-promoting and Paradoxical insomnia wake-promoting EEG features, was significantly higher (P < 0.001) in misperceptors (31%) compared with conAlthough it is an established finding that people with trols (24%). It is interesting to notice that misperceptors insomnia characteristically overestimate the time they reported a limited amount of subjective awakenings have taken to get to sleep, and underestimate the total

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(mean 4) in contrast to objective findings (mean 11). The mismatch could be in part explained by the high amounts of CAP between successive awakenings that were merged together in a single experience. In other words, if sleep between two successive awakenings is disturbed, as reflected by increased amounts of CAP, time separating the two events is perceived as continuous wake. These findings suggest that in misperceptors difficulty to maintain consolidated sleep is interpreted as wakefulness (Mercer et al., 2002). In particular, if sleep between two successive awakenings is excessively fragmented (i.e., increased arousal index and CAP rate), the interval separating the two events is globally combined and perceived as waking time (Ozone et al., 2007; Parrino et al., 2009).

CAP and arousals in primary insomnia In a study of 50 patients with a diagnosis of primary insomnia (Parrino et al., 2004), the PSG findings were compared with those of age- and sex-matched healthy subjects with sleep complaints (controls). After an adaptation night, each patient had two randomized double-blind PSG recordings. Twenty-five patients followed a placebo–drug sequence and 25 a drug–placebo succession. Active medication consisted of widely used hypnotic drugs at therapeutic nighttime doses: zolpidem (17 patients), triazolam (13 patients), zopiclone (10 patients), brotizolam (7 patients), and flurazepam (3 patients). Compared with controls, primary insomnia appeared to be associated with significantly increased amounts of CAP and EEG arousals (Figure 44.8). When sleep quality was improved by active medication, most

CAP variables appeared highly sensitive to hypnotic treatment, whereas EEG arousals were poorly affected by sleep-promoting drugs (Figure 44.8). Hypnotic treatment improved total sleep time, nocturnal awakenings, stage 1 and SWS. However, the most significant correlation between sleep quality and PSG variables was found for CAP rate (Figure 44.9). The PSG variables with the greatest difference in mean value between placebo and medication are shown in Table 44.2 (Terzano et al., 2003). In a placebo-controlled randomized crossover study, 17 Japanese patients with psychophysiological insomnia were evaluated. During the first period, patients were administered the placebo on the first night, followed by either zolpidem or the placebo on the second night (treatment night). The second crossover period was conducted after a minimum 3-day observation. Zolpidem significantly decreased the overnight CAP rate values (57.6% vs. 39.0%; P ¼ 0.009) and improved “sleep depth” (P ¼ 0.044) and “sleep quality” (P ¼ 0.023) subjective questionnaire scores. The amount of time spent in SWS was significantly increased by zolpidem without affecting the amounts of stage 2 and REM sleep. Significant negative correlations (P ¼ 0.022) were found when the sleep quality score was matched to the CAP rate (Ozone et al., 2008).

The autonomic costs of insomnia If insomnia is not only a subjective compliant but also a disorder supported by objective disturbances, a biological price must be paid by patients afflicted by this sleep disorder.

500

placebo drug

100

444 405

253 262

250

222 182

65

83

87 99

209

111

VAS (mm)

(min.)

80 60 40 20

r = −0,51 p < 0,0001

0 TST*

S1+S2

S3+S4*

REM

CAP* AROUSALS

Fig. 44.8. Impact of placebo (white bars) and active hypnotic medication (black bars) on sleep variables in patients with primary insomnia. The sequence of administration (placebo/drug or drug/placebo) was completely randomized. Compared with placebo, active medication significantly increased total sleep time (TST) and slow-wave sleep (stages 3 þ 4) and reduced CAP time (marked by an asterisk (all P<0.0001). Note that the acute action of hypnotic agents had no particular effect on superficial sleep, REM sleep, and the total number of arousals.

0

10

20

30

40 50 CAP rate (%)

60

70

80

Fig. 44.9. CAP rate values plotted against subjective sleep quality, measured by means of a visual analog scale (VAS). The higher the VAS score, the better the restorative properties of the previous night’s sleep. Note the concentration of drug nights (black squares) on the left side of the graph, associated with lower CAP rate values and higher VAS scores. In contrast, placebo nights (white squares) prevail on the right side of the chart.

NEUROLOGICAL PERSPECTIVES IN INSOMNIA AND HYPERAROUSAL SYNDROMES Table 44.2 Polysomnographic variables with the greatest difference in mean values between placebo and hypnotic medication Discriminant analysis* CAP rate A1 subtypes A2 subtypes WASO Total sleep time Slow-wave sleep Arousal index A3 subtypes

0.881 0.524 0.513 0.248 0.233 0.216 0.199 0.154

*Placebo vs. hypnotic drug. CAP, cyclic alternating pattern; WASO, wake-time after sleep onset.

In normal subjects, increases in low-frequency and decreases in high-frequency R–R interval oscillations have been described during CAP, indicating a relative dominance of the sympathetic tone during the states of unstable NREM sleep. Accordingly, reverse autonomic findings are associated with the nonCAP condition (Ferini-Strambi et al., 2000; Ferri et al., 2000). Further studies have ascertained that, during CAP, blood pressure increases significantly in comparison with that for nonCAP, reaching the same levels as those found in REM sleep and wakefulness (Iellamo et al., 2004). The low-frequency component of blood pressure variability and the baroreflex sensitivity are significantly higher during CAP than nonCAP. In particular, baroreflex sensitivity is no different during CAP and REM and is greater during both in comparison with the awake state. A novel ECG-based analysis technique has been developed that combines heart rate variability and respiratory modulation of R-wave amplitude to generate sleep spectrograms of high- and low-frequency coupling states that correlate more closely with CAP scoring but not with conventional NREM stages (Thomas et al., 2005). Spontaneous switches are seen in health and disease and are not dependent on delta power or stage. The low-frequency coupled (unstable) state is characterized by phasic EEG, fluctuating arousal thresholds, cyclic respiratory volume/flow change and autonomic outflow, cyclic variation in heart rate, and blood pressure close to REM/wake levels. Conventional stage is generally superficial NREM sleep. The highfrequency coupled (stable) state usually is associated with nonCAP EEG, stable arousal threshold, stable respiration and autonomic outflow, sinus arrhythmia, and blood pressure dipping. Conventional stage may be deep NREM sleep. This suggests that the stability dimension

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may be integrated across several measurable sleep-state characteristics. Fragmented REM sleep takes on CAPlike features. Sleep-disrupting stimuli (e.g., sleep apnea, upper airway resistance, depression, pain) increase CAP sleep (Terzano et al., 1996; Farina et al., 2003; Rizzi et al., 2004; Guilleminault et al., 2007; Lopes et al., 2007) and low-frequency coupling, whereas sleep-enhancing conditions (e.g., sleep deprivation rebound, successful positive airway pressure titration, and sedative/ hypnotics) increase nonCAP (Parrino et al., 1993, 2000; Parrino and Terzano, 1996; Thomas, 2002; Lopes et al., 2007) and high-frequency coupling. This pattern of bimodal switching is also seen in rodents, suggesting that sleep (at least NREM sleep) is fundamentally bistable across mammalian species (Depootere et al., 1993). The developmental changes of sleep structure represent further risk factors. Both arousals and CAP rate correlate positively with aging (Boselli et al., 1998; Terzano et al., 2002), which is associated with increased levels of low-frequency unstable states during sleep. Increased total wake time is another sleep feature peculiar to aging. Accordingly, mean 24-hour interleukin-6 and cortisol levels are significantly higher in old than in young adults (Vgontzas et al., 2001b).

INSOMNIA OF INTEREST FOR NEUROLOGISTS Once it is established that insomnia is not only a subjective compliant but reflects an internal dysregulation of the sleep–wake mechanisms, a revision of disturbed sleep in different medical conditions can be carried out. In particular, difficulty initiating and maintaining sleep as well as nonrestorative sleep are common encounters in the neurological clinical practice (Table 44.3).

Hypnotic-dependent insomnia This type of insomnia occurs in association with tolerance to or withdrawal from sedative–hypnotic medications (Kales et al., 1974). Several patterns of hypnotic Table 44.3 Major neurological causes of insomnia Hypnotic-dependent or substance-dependent insomnia Synucleinopathies (Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy) Epilepsy Stroke Headache and migraine Neuromuscular disorders and painful syndromes Agrypnia excitata (fatal familial insomnia, Morvan’s chorea, delirium tremens)

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use have been associated with insomnia due to use of sleeping pills. In a first pattern, brief use of a hypnotic, for several consecutive nights, may lead to difficulty in sleeping when the drug is stopped (termed rebound insomnia), which may result in resuming use of the hypnotic. In the second pattern, sustained use of hypnotics frequently causes tolerance associated with a decrease in the drug’s hypnotic effects and return of symptoms. This often leads to an increase in the patient’s dosage. In the third pattern, partial withdrawal may occur in the presence of persistent drug tolerance. Despite dosage increases, partial withdrawal can cause a diminished hypnotic effect or the hypnotic effect to dissipate well before the end of the night. If the hypnotic therapy is stopped abruptly there may be central nervous system (CNS) withdrawal symptoms, which can include nausea, aches, irritability, and restlessness. The experience of withdrawal symptoms can predispose the patient toward resumption of chronic use, in search of more normal sleep and improved daytime functioning.

Synucleinopathies The synucleinopathies comprise a set of neurodegenerative disorders that share a common pathological lesion composed of aggregates of insoluble a-synuclein protein in selectively vulnerable populations of neurons and glial cells (Iwatsubo, 2007). These pathological aggregates appear to be closely linked to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders. The major synucleinopathies include Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy (Mahowald et al., 2007). Parkinson’s disease. Sleep abnormalities in PD are frequent and partially due to nocturnal recurrence of PD motor symptoms and side-effects of pharmacotherapy. Insomnia can be caused by a primary sleep disorder such as restless legs syndrome, periodic limb movements, sleep-disordered breathing, REM behavior disorder (Wetter et al., 2000; Ondo et al., 2002; Comella, 2003), psychophysiological and sleep hygiene factors, and from the parkinsonism itself, with the resulting inability to turn in bed (Lees et al., 1988). There is also increasing evidence that disease underlying the degenerative process accounts for impairment in the expression of wakefulness and REM sleep, which could be due to the primary degeneration of sleep-regulating centers such as the locus coeruleus and the involvement of nondopaminergic transmitters. It should be also noted that dopamine neurons show state-dependent fluctuations in their activity (Diederich et al., 2005).

Progressive supranuclear palsy (PSP). Patients with PSP show a number of sleep alterations (Petit et al., 2004), including decreased total sleep time, decreased sleep efficiency (approximately 50%), increased wakefulness and increased percentage of stage 1 sleep, decreased percentage and duration of REM sleep. A characteristic feature is the reduction in abundance and amplitude of sleep spindles.

Dementia Dementia is characterized by progressive cognitive decline, which can lead to sleep–wake disturbances. Nocturnal awakenings and uncontrolled wanderings are common features (Paniagua and Paniagua, 2008) and may reflect insomnia secondary to night/day reversal, medication effects, emotional distress, understimulation or overstimulation during the day, nocturia, pain, or restless legs syndrome. Patients with dementia also suffer from severe insomnia or hypersomnia (Boeve et al., 2002). They spend a significant portion of the night in bed awake and a significant portion of their daytime hours asleep (Okawa et al., 1991). However, each sleep or wake period may be as short as several minutes, with frequent transitions between sleep and wake over the course of the 24-hour day (Vitiello et al., 1991). The increase in diurnal sleep interferes with the homeostatic drive and does not compensate for the SWS and REM sleep decrease during the night (Vitiello et al., 1991).

Epilepsy The presence of nocturnal seizures affects the regular profile of the sleep architecture. In most cases, the immediate effect of an epileptic attack corresponds to an upward shift towards either awakening or more superficial sleep stage (Bazil, 2002). Enhanced sleep fragmentation and higher percentages of wakefulness and light sleep with a decrease in stages 3, 4, and REM are common PSG findings (Touchon et al., 1991). In addition, marked sleep instability is often observed in epileptic patients, even in the absence of nocturnal seizures (Terzano et al., 1992). Overall, sleep-related attacks mostly affect the conventional sleep parameters, whereas nocturnal interictal discharges basically have a destabilizing impact on CAP parameters. Patients with nocturnal frontal lobe epilepsy with sleep complaints and excessive daytime sleepiness present an enhanced degree of unstable sleep, as expressed by a high CAP rate (Nobili et al., 2006; Parrino et al., 2006).

Fatal familial insomnia, Morvan’s chorea, delirium tremens Some neurological conditions, characterized by movement disorders that start or persist during sleep, hinder

NEUROLOGICAL PERSPECTIVES IN INSOMNIA AND HYPERAROUSAL SYNDROMES sleep onset and/or sleep continuity, causing a poor sleep complaint. CNS lesions and/or dysfunction in three specific neurological conditions (fatal familial insomnia, Morvan’s chorea, and delirium tremens) impair the basic mechanisms of sleep generation inducing a syndrome in which the inability to sleep is consistently associated with motor and sympathergic overactivation. Agrypnia excitata is the term that aptly defines this generalized overactivation syndrome (Lugaresi and Provini, 2001).

Stroke About 20–40% of stroke patients have sleep–wake disorders, mostly in form of insomnia, excessive daytime sleepiness/fatigue, or increased sleep needs (Bassetti, 2005). Depression, anxiety, sleep-disordered breathing (SDB), stroke complications, and medications may contribute to sleep–wake disorders and should be addressed first therapeutically. Brain damage per se, often at thalamic or brainstem level, can be also a cause of persisting sleep–wake disorders. The latter are frequently reported in patients with cerebral hemorrhage. In a prospective study carried out on patients who survived an episode of subarachnoid hemorrhage, 34% had severe problems with sleep, frequently reporting problems initiating (25%) or maintaining (31%) sleep, difficulty returning to sleep (28%), tiredness (31%), and excessive sleepiness during the day (6%). In sleep-monitoring studies, severe sleep fragmentation, sleep apnea, restless legs syndrome/periodic limb movement disorder, or a combination of these disorders of sleep and wake were common findings (Schuiling et al., 2005). The risk of an ischemic stroke is increased in men whose sleep is frequently disturbed. In the Caerphilly cohort study (Elwood et al., 2006), up to one-third of the men reported at least one symptom suggestive of sleep disturbance, and one-third reported daytime sleepiness. Compared with men who reported no such symptoms, the adjusted relative odds of an ischemic stroke were significantly increased in men with any sleep disturbance, the strongest association being with sleep apnea (relative odds 1.97). More than 65% of stroke patients have SDB, mostly in the form of obstructive sleep apnea (Arzt et al., 2005; Bassetti et al., 2006). SDB represents both a risk factor and a consequence of stroke. The presence of SDB has been linked with poorer long-term outcome and increased long-term mortality from stroke (Yaggi et al., 2005).

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hemicrania (Kayed et al., 1978) and in cluster headache (Dexter and Riley, 1975; Manzoni et al., 1981). Hypnic headache is mostly related to REM sleep, with attacks occurring during REM sleep (usually the first REM period), and it has been considered a possible REM sleep disturbance even though the association of REM sleep and headache is generally nonspecific (Evers and Goadsby, 2003). However, the specific REM relationship of hypnic headache attacks was not confirmed in a study carried out on six polysomnographically recorded episodes: four arose from NREM and two from REM sleep (Manni et al., 2004). Headaches occurring during the night are often related to a sleep disturbance (Paiva et al., 1997), and episodic morning migraine can be associated with insomnia (Alstadhaug et al., 2007). PSG studies indicate that evaluation of patients with cluster headache should also include consideration that sleep-related breathing disorders may be present (Chervin et al., 2000).

Neuromuscular disorders Most of the sleep disturbances in neuromuscular disorders are secondary to sleep-related respiratory dysfunction. However, other factors such as pain, muscle cramps, muscle immobility, joint pains, contractures, kyphoscoliosis, obesity due to sedentary life, craniofacial abnormalities, anxiety, and depression may further contribute to sleep dysfunction.

FINAL CONSIDERATIONS There is a need for newer, more clinically useful classifications for insomnia. Existing classifications differ, and many terms remain inadequately defined, which leads to diagnostic confusion. Historically, insomnia has been classified according to symptom type, symptom duration, and underlying cause, but these classifications have not been based on evidence of their utility, and newer research suggests the need for change. The subtyping of insomnia in terms of whether there is an identifiable underlying cause such as a psychiatric or medical illness was based on an unproven assumption that in most instances other disorders caused insomnia. Recent studies suggest the need to revisit these classification strategies. (Krystal, 2005)

Headache and migraine

The underlying factors of insomnia

The relationship between sleep and migraine has long been recognized. REM sleep is a well-known precipitating factor in headache attacks in chronic paroxysmal

According to the dynamic model of insomnia of Spielman et al. (1996), a basic threshold for sleeplessness exists and if this threshold is exceeded insomnia

712 M.G. TERZANO AND L. PARRINO will occur. In particular, three dynamic factors contribnot necessarily stable. The orexin neurons in the lateral ute to insomnia. hypothalamus may help to stabilize this system by excitThe first is predisposition or basic sleep drive. ing arousal regions during wakefulness, preventing Some individuals may have a strong sleep drive and unwanted transitions between wakefulness and sleep are always far from the sleeplessness threshold. By (Saper et al., 2005). These mechanisms allow rapid contrast, some people have a weak sleep drive and arousal during times of emergency or behavioral are close to the sleeplessness threshold even under necessity, but activation of these circuits at inapproprithe best circumstances. Any small event can trigger ate times may be a mechanism for insomnia (Nofzintheir insomnia, and sometimes they will be sleepless ger, 2005). In a model of acute stress, male rats for no apparent reason. Usually, this is a lifelong experienced insomnia and presented simultaneous problem arising from a weak homeostatic drive or an activation of both wake and sleep circuitry in the brain overreactive autonomic nervous system. Among the resulting in faster flip-flop transitions (Lu et al., 2006). predisposing factors, the familial component seems to In human EEG sleep, the flip-flop switch could be play a significant role. In a study carried out by reflected by the periodic swings of CAP that rapidly Bastien and Morin (2000) on 285 subjects evaluated oscillate between states of activation (phase A) and for insomnia, 35% of patients had a positive family inhibition (phase B). history of sleep disturbance. Insomnia was the most common type of sleep disturbance identified (76%), Insomnia is not simply a mental problem and the mother was the family member most frequently In the last 15 years, quantification of arousals accordafflicted. A more recent investigation (Dauvilliers et al., ing to the American Academy of Sleep Medicine 2005) conducted on 256 consecutive chronic insom(AASM) rules has been carried out for a number of niacs, including both primary and psychiatric insomnia, sleep disorders as a translation of fragmented sleep, showed that 72.7% of patients with primary insomnia with increased amounts commonly described in sleepreported familial insomnia compared with 24.1% in the related breathing disorders. Surprisingly, the number no-insomnia control group. Among the psychiatric of EEG arousals may not appear to be increased in insomniacs, 43.3% reported familial insomnia. Even in insomniacs (Bonnet and Arand, 1996; Rosa and Bonnet, this case, the mother was the relative most frequently 2000), indicating that simple counting of these events affected. A tendency to a younger age at onset was may not reflect adequately the impaired processes of observed in familial and primary insomnia. disturbed sleep. The concept of arousals as stage marThe next factor is precipitation. Something happens – kers has been introduced in the recently published sleep perhaps stress, an illness, a grief reaction, or somescoring manual (AASM, 2007). thing else. Under normal circumstances, you would In the meantime, a number of experimental and clinexpect only transient or short-term insomnia, but the ical studies (Parrino et al., 1997; Terzano and Parrino, insomnia continues for a month, then another, and 1992; Terzano et al., 1990, 2003) have confirmed the another. The precipitating event has long gone, but topical role of unstable sleep in insomniacs and estabthe insomnia remains. If the insomnia persists long lished a significant correlation in these patients between after the precipitant has gone, there is something perCAP rate and subjective estimates of sleep quality. petuating the insomnia. This perpetuation factor can Regardless of any other change in the conventional be conditioned insomnia, a grief reaction turned to PSG measures, the higher the CAP rate the poorer the depression, dependence on alcohol to fall asleep, or quality of sleep. Accordingly, any sleep-improving counterproductive bedtime habits or routines. Because treatment reduces the amount of CAP and potentiates the brain acquires habits through frequent repetition, sleep stability through the increase of nonCAP (Terzano the sooner the perpetuating factor is eliminated, the and Parrino, 1993; Parrino and Terzano, 1996; Parrino faster the sleep system will bring the sleep–wake pattern et al., 2000; Thomas, 2002, 2007; Terzano et al., back to normal. 2003). PSG remains the “gold standard” for measuring Recent studies have shown that the control of wake sleep (American Sleep Disorders Association, 1995), and sleep emerges from the interaction of cell groups and especially insomnia (Chesson et al., 2000). Unlike that produce arousal with other nuclei that induce sleep, other sleep disorders, such as sleep-related breathing such as the ventrolateral preoptic nucleus (VLPO). The disorders and periodic leg movement, the nature and VLPO inhibits the ascending arousal regions and is in severity of which are quantified by specific respiratory turn inhibited by them, thus forming a mutually inhibiand motor indexes, no apparent organ dysfunction tory system resembling what electrical engineers call a underlies several cases of insomnia (in particular pri“flip-flop switch”. This switch may help produce sharp mary insomnia). Compared to subjectively defined transitions between discrete behavioral states, but it is

NEUROLOGICAL PERSPECTIVES IN INSOMNIA AND HYPERAROUSAL SYNDROMES good sleepers, PSG findings in insomniacs reveal impairment of sleep continuity parameters (i.e., longer sleep latencies, more time awake after sleep onset, lower sleep efficiency) and reduced total sleep time. In addition, insomniacs tend to spend more time in stage 1, less time in stages 3 and 4, and display more frequent stage shifts through the night. There is, however, a significant overlap in the distribution of sleep recordings of subjectively defined insomniacs and good sleepers, such that some individuals with insomnia complaints may show better conventional sleep measures than good sleepers (Carskadon et al., 1976). This overlap might account for some of the discrepancies between conventional PSG data and subjective evaluation of sleep quality. Investigation of the microstructure of sleep has begun to shed some light on these paradoxical findings. The extension of conventional sleep measures to CAP variables may improve our knowledge of the diagnosis and management of insomnia. These premises allow us to attribute a more objective identity to insomnia, which otherwise risks being considered an inscrutable, unexplainable, and immeasurable mental complaint.

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APPENDIX Technical and Methodological Requirements For Scoring A CAP Sequence The identification of CAP should be preceded by the definition of sleep stages according to the conventional criteria (AASM, 2007). Onset and termination of a CAP sequence A CAP sequence is composed of a succession of CAP cycles (see Figure 44.4). A CAP cycle is composed of phase A and the subsequent phase B. All CAP sequences begin with a phase A and end with a phase B. Each phase of CAP is 2–60 s in duration. This cutoff relies on the consideration that the great majority (about 90%) of A phases occurring during sleep are separated by an interval of less than 60 s (Terzano and Parrino, 1991).

sleep EEG pattern for >60 s), with the following three exceptions. There is no temporal limitation: (1) before the first CAP sequence arising in nonREM sleep; (2) after a wake to sleep transition; (3) after a REM to nonREM sleep transition (Terzano et al., 2001). Stage shifts Within nonREM sleep, a CAP sequence is not interrupted by a sleep stage shift if CAP scoring requirements are satisfied. Consequently, because CAP sequences can extend across adjacent sleep stages, a CAP sequence can contain a variety of different phase A and phase B activities (Terzano et al., 2001).

NonCAP

CAP in REM sleep

The absence of CAP for >60 s is scored as nonCAP. An isolated phase A (that is, preceded or followed by another phase A but separated by more than 60 s), is classified as nonCAP. The phase A that terminates a CAP sequence is counted as nonCAP (see Figure 44.5). This transitional phase A bridges the CAP sequence to nonCAP (Terzano et al., 2001).

CAP sequences commonly precede the transition from nonREM to REM sleep and end just before REM sleep onset. REM sleep is characterized by the lack of EEG synchronization; thus phase A features in REM sleep consist mainly of desynchronized patterns (fast low-amplitude rhythms), which are separated by a mean interval of 3–4 min (Schieber et al., 1971). Consequently, under normal circumstances, CAP does not occur in REM sleep. However, pathophysiologies characterized by repetitive phase As recurring at intervals <60 s (e.g., periodic REM-related sleep apnea events) can produce CAP sequences in REM sleep (Terzano et al., 1996).

Minimal criteria for the detection of a CAP sequence CAP sequences have no upper limits on overall duration and on the number of CAP cycles. In young adults, 3 min is the approximate mean duration of a CAP sequence, which contains an average of six CAP cycles (Smerieri et al., 2007). At least two consecutive CAP cycles are required to define a CAP sequence. Consequently, three or more consecutive phase As must be identified with each of the first two phase As followed by a phase B (interval <60 s) and the third phase A followed by a greater than 60 s nonCAP interval (Terzano and Parrino, 2005). General rule A phase A is scored within a CAP sequence only if it precedes and/or follows another phase A in the 2–60-s temporal range. CAP sequence onset must be preceded by nonCAP (a continuous nonREM

Movement artifacts Body movements can trigger or interrupt a CAP sequence. Body movements linked to one or more phase As in the temporal range of 2–60 s can be included within the CAP sequence if other scoring criteria are met (Terzano et al., 2001). Recording techniques and montages CAP is a global EEG phenomenon involving extensive cortical areas. Therefore, phase As should be visible on all EEG leads. Bipolar derivations such as Fp1–F3, F3–C3, C3–P3, P3–O1 or Fp2–F4, F4–C4, C4–P4, P4–O2 guarantee a favorable detection of the phenomenon. A calibration of 50 mV/7 mm with

NEUROLOGICAL PERSPECTIVES IN INSOMNIA AND HYPERAROUSAL SYNDROMES a time constant of 0.1 s and a high-frequency filter in the 30-Hz range is recommended for the EEG channels. Monopolar frontal, central, and occipital EEG derivations, eye-movement channels, and submentalis EMG, currently used for the conventional sleep staging and arousal scoring, are also essential for scoring CAP. Airflow and respiratory effort, cardiac rhythm, oxygen saturation, and leg movements should be included for clinical studies. Amplitude limits Changes in EEG amplitude are crucial for scoring CAP. Phasic activities initiating a phase A must be a third higher than the background voltage (calculated during the 2 s before onset and 2 s after offset of a phase A). However, in some cases, a phase A can present ambiguous limits owing to inconsistent voltage changes. Onset and termination of a phase A are established on the basis of an amplitude/frequency concordance in the majority of EEG leads. The monopolar derivation is mostly indicated when scoring is carried out on a single derivation. All EEG events that do not meet clearly the phase A characteristics cannot be scored as part of phase A (Terzano et al., 2001). Temporal limits The minimal duration of a phase A or a phase B is 2 s. If two consecutive phase As are separated by an interval <2 s, they are combined as a single phase A. If they are separated by a 2-s interval, they are scored as independent events (Terzano et al., 2001). The phase A subtypes of CAP In normal sleepers (Parrino et al., 1998), CAP rate (the percentage ratio of CAP time to NREM sleep time) varies according to a complex age-related curve. The lower values are found in young adults

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(32%), and the highest amounts appear in elderly subjects (55%). A physiological peak of CAP rate is reached also in the peripubertal age range, indicating a vigorous interaction between developmental factors and sleep microstructure (Bruni et al., 2002). Based on the amount and distribution of slow oscillation, the A phases of CAP can be classified in subtypes A1, A2, and A3 (Figure 44.10). In particular, subtypes A1 are composed almost entirely of <1-Hz rhythms, subtypes A2 contain approximately 50% slow oscillations and 50% low-voltage fast activities, whereas subtypes A3 include only a minimal proportion of slow oscillation with a predominance of rapid activities (Terzano et al., 2001). Accordingly, subtypes A1 dominate in the first part of the sleep cycle where they accompany the progressive transition from light sleep (stages 1 and 2) to deep sleep (stages 3 and 4), and therefore appear to be involved in the process of buildup and maintenance of EEG synchronization (Figure 4.11). By contrast, subtypes A2 and A3 prevail physiologically in the final part of the sleep cycle (Figure 44.11), where they disrupt EEG synchronization and prepare the appropriate desynchronized background for the onset of REM sleep (Terzano et al., 2005). With regard to motor and autonomic functions, subtypes A1 are associated with a mild activation, subtypes A2 with a moderate activation, and subtypes A3 with a powerful activation (Terzano and Parrino, 2000). Recent findings using topographic brain mapping show that different phase A subtypes involve separate regions of the cerebral cortex. Subtypes A1 are essentially the expression of transient activation restricted to the frontal lobe which seldom crosses the fronto-occipital midline; in contrast, subtypes A3 are projected into the parieto-occipital regions and subtypes A2, with mixed slow–rapid components, span from frontal to occipital lobes (Ferri et al., 2005).

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Fig. 44.10. Specimens of phase A subtypes framed in boxes. The thick black lines above the boxes indicate the portions of A phases characterized by rapid EEG rhythms (limited in subtype A1, approximately 50% in subtype A2, prevalent in subtype A3). Note the progressively stronger activation of muscle and vegetative functions from subtype A1 to subtype A3.

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0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 310 320 330 340 350 360 370 380 390 400 410 420 430 440 450 460 470 480 490 500

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W R S1 S2 S3 S4

Fig. 44.11. Distribution of CAP phase A subtypes in relation to the structural development of the sleep histogram in a healthy normal sleeper. Note the link between the buildup of slow-wave sleep and subtypes A1 (which also follow the exponential decline of sleep intensity) and the ultradian recurrence of subtypes A2 and A3 in close temporal connection with REM sleep.

Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 45

Insomnia: nature, diagnosis, and treatment CHARLES M. MORIN 1 * AND RUTH M. BENCA 2 1 Universit Laval, Quebec, Canada 2

University of Wisconsin, Madison, WI, USA

INTRODUCTION Insomnia is a prevalent complaint both in the general population and in clinical practice. Chronic insomnia can present as the primary problem or as a coexisting condition with another medical or psychiatric disorder. Insomnia diagnosis and therapeutic approaches have evolved over the past two decades (National Institutes of Health, 2005). Whereas it used to be conceptualized exclusively as a symptom of other psychiatric or medical disorders, current diagnostic classifications of sleep disorders make a distinction between the symptom and the syndrome of insomnia (American Psychiatric Association, 2000; American Academy of Sleep Medicine, 2005). In addition, there have been significant advances in the treatment of insomnia, from a predominantly symptomatic approach to more focused interventions on perpetuating factors with cognitive– behavioral therapy (CBT) and on more targeted brain receptors with pharmacotherapy (National Institutes of Health, 2005).

SIGNIFICANCE OF INSOMNIA Population-based estimates indicate that about 30% of adults report insomnia symptoms, 9–12% experience additional daytime symptoms, and 6–10% meet diagnostic criteria for an insomnia syndrome (Ohayon, 2002). In primary care medicine, approximately 20% of patients report significant sleep disturbances (Simon and VonKorff, 1997). Insomnia is more prevalent among women, middle-aged and older adults, shiftworkers, and patients with medical or psychiatric disorders. Difficulties initiating sleep are more common among young adults, and problems maintaining sleep are more frequent among middle-aged and elderly adults. The incidence of insomnia is higher among

first-degree family members (daughter, mother) than in the general population (Dauvilliers et al., 2005), although it is unclear whether this link is inherited through a genetic predisposition, learned by observations of parental models, or simply a byproduct of another psychopathology. Persistent insomnia can produce an important burden for the individual and for society, as evidenced by increased rates of absenteeism, reduced productivity, increased risks of depression, and higher rates of healthcare utilization (Ford and Kamerow, 1989; Breslau et al., 1996; Simon and VonKorff, 1997; Sivertsen et al., 2006b; Ozminkowski et al., 2007; Daley et al., 2009).

NATURE OF INSOMNIA Presenting complaints Insomnia is characterized by a spectrum of complaints reflecting dissatisfaction with the quality, duration, or continuity of sleep. These complaints may involve problems with falling asleep initially at bedtime, waking up in the middle of the night and having difficulty going back to sleep, waking up too early in the morning with an inability to return to sleep, nonrestorative or unrefreshing sleep (American Psychiatric Association, 2000; American Academy of Sleep Medicine, 2005). In addition, daytime fatigue, cognitive impairments, and mood disturbances (e.g., irritability, dysphoria) are extremely frequent and often the primary concerns prompting patients with insomnia to seek treatment. In addition to clinical diagnostic criteria (Table 45.1), several quantitative indicators are useful to evaluate the severity and significance of insomnia. These include the intensity, frequency, and duration of sleep difficulties and their associated daytime consequences. For example, sleep-onset and sleep-maintenance insomnia

*Correspondence to: Charles M. Morin, Ph.D., Universite´ Laval, 2325 Rue des Bibliothe`ques, E´cole de Psychologie, Pavillon F.A.S., Quebec City, Quebec, Canada G1V 0A6. Tel: (418) 656-3275, Fax: (418) 656-5152, E-mail: [email protected]

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Table 45.1 Diagnostic criteria for primary insomnia (adapted from DSM-IV-TR) ● ● ●

●

A subjective complaint of difficulty initiating or maintaining sleep, or of nonrestorative sleep Duration of insomnia longer than 1 month The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning The sleep disturbance does not occur exclusively in the context of another mental or sleep disorder, and is not the direct physiological effect of a substance or a general medical condition

are often defined by a latency to sleep onset and/or time awake after sleep onset greater than 30 or 45 minutes, with corresponding sleep time of less than 6.5 hours. Such criteria, while arbitrary, are useful to operationalize the definition of insomnia. Total sleep time alone is not a good index to define insomnia because there are individual differences in sleep needs. Some people may function well with as little as 5–6 hours of sleep and would not necessarily complain of insomnia, whereas others needing 9–10 hours may still complain of inadequate sleep. It is also important to distinguish the occasional insomnia that everyone experiences at one time or another in life from the more recurrent insomnia, usually defined by the presence of sleep difficulty for three or more nights per week. A distinction is also made between situational/acute insomnia, a condition lasting a few days and often associated with life events or jet lag, short-term insomnia (lasting between 1 and 4 weeks), and chronic insomnia, lasting more than a month. Finally, it is necessary to consider the impact of insomnia on a person’s psychosocial and occupational functioning to judge its clinical significance. As such, insomnia must be associated with marked distress or significant impairments of daytime functioning to make the diagnosis (American Psychiatric Association, 2000; Edinger et al., 2004; American Academy of Sleep Medicine, 2005).

Polysomnographic (PSG) findings PSG evaluation of self-defined insomniacs reveals more impairments of sleep continuity parameters (i.e., longer sleep latencies, more time awake after sleep onset, lower sleep efficiency) and reduced total sleep time compared with findings in self-defined good sleepers. Although sleep architecture is not always altered, a subset of individuals with chronic insomnia show increased amount of stage 1, reduced stages

3–4, and more frequent stage shifts through the night. Interestingly, sleep disturbances recorded in primary insomniacs are similar to those observed in patients with generalized anxiety disorder or some affective disorders such as dysthymia (Reynolds et al., 1984; Hauri and Fisher, 1986; Benca et al., 1992), perhaps suggesting a common underlying thread to these conditions. Investigations of the microstructure of sleep reveal increased beta activity in primary insomniacs relative to healthy controls, both around the sleep-onset period and during nonrapid eye movement (NREM) sleep (Lamarche and Ogilvie, 1997; Merica et al., 1998; Perlis et al., 2001b; Bastien et al., 2008). These data are consistent with the presumed role of attentional processes and information processing (Perlis et al., 2001a; Devoto et al., 2005; Jones et al., 2005), as well as with psychological findings of hypervigilance and a ruminative, worry-prone cognitive style among insomniacs. In general, there is a significant overlap in the sleep patterns of subjectively defined insomniacs and good sleepers, such that some insomniacs may show better objective sleep than good sleepers, and some good sleepers may show more sleep impairments than insomniacs.

Daytime complaints and findings Most patients with significant insomnia complaints also report impairments of daytime functioning, involving fatigue, mood disturbances, and difficulties with attention and concentration, memory, and completion of tasks (Buysse et al., 2007). Patients may initially report excessive daytime sleepiness, but a closer investigation usually reveals mental and physical fatigue rather than true physiological sleepiness, which is more likely among patients with insomnia comorbid with another medical (e.g., pain) or sleep disorders (e.g., sleep-related breathing disorders). Insomniacs have trouble sleeping at night, in part because of chronic state of hyperarousal, which may also interfere with the ability or propensity for sleep during the day. Despite significant subjective complaints, objective evaluation of daytime performance usually reveals fairly mild and selective deficits (e.g., attention) on various neurobehavioral measures (Riedel and Lichstein, 2000). In general, impairments on these measures are more strongly associated with subjective than with objective sleep disturbances. Individuals with insomnia tend to have lower expectations and to perceive their performance as more impaired relative to how they should perform, and as more impaired than that of normal controls. Discrepancies between subjective and objective performance are similar to those observed between subjective and objective

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT measures of sleep, which may reflect a generalized faulty appraisal of sleep and daytime functioning among individuals with insomnia (Vignola et al, 2000).

Subtypes of insomnia DSM-IV recognizes only one form of primary insomnia (American Psychiatric Association, 2000), whereas the International Classification of Sleep Disorders distinguishes different subtypes (Table 45.2), the most common being psychophysiological, paradoxical, and idiopathic insomnia (American Academy of Sleep Medicine, 2005). Psychophysiological insomnia is presumed to result from conditioned arousal, which is more likely to develop among individuals with an increased psychological (worry-prone) and biological predisposition (hyperarousability) to insomnia. The sleep of individuals with psychophysiological insomnia is more sensitive to daily stressors and is characterized by extensive night to night variability (Vallieres et al., 2005a). Table 45.2 Insomnia diagnostic subtypes Type of insomnia Primary insomnia Adjustment (< 3 months)

Psychophysiological (> 6 months) Paradoxical

Idiopathic insomnia

Inadequate sleep hygiene Behavioral insomnia of childhood Comorbid insomnia Associated with a mental disorder Associated with a drug or substance Associated with a medical condition Associated with another sleep disorder

Description

Temporally linked with a stressor and expected to resolve with disappearance of initial precipitating factor Conditioned arousal, heightened anxiety about sleep Marked discrepancy between subjective complaints and PSG findings Insidious onset during childhood, unrelated to psychological trauma or medical disorders; persistent throughout adulthood

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Paradoxical insomnia involves a genuine complaint of poor sleep that is not corroborated by objective findings. A patient may perceive very little sleep (e.g., 2–3 hours per night), whereas PSG recordings show normal or near-normal sleep duration and quality. This condition is not the result of an underlying psychiatric disorder or of malingering, but is likely to be mediated by psychological and cognitive (information processing) variables influencing the perception of sleep and wakefulness. To some degree, all insomniacs tend to overestimate the time it takes them to fall asleep and to underestimate the time they actually sleep. In paradoxical insomnia, however, the subjective complaint of poor sleep is disproportionate to objective findings. Thus, this condition may represent the far end of a continuum of individual differences in sleep perception. Idiopathic (childhood) insomnia presents an insidious onset during childhood, unrelated to psychological trauma or medical disorders, and is very persistent throughout the adult life. It does not present the variability observed with other forms of primary insomnia. A mild defect of the basic neurological sleep/wake mechanisms may be a predisposing factor, a hypothesis that comes from the observations that patients with this condition often have a history of learning disabilities, attention-deficit/hyperactivity disorder, or similar conditions associated with minimal brain dysfunction. Despite their heuristic value, these insomnia phenotypes and others remain to be validated empirically.

Course and prognosis The onset of Insomnia can occur at any time during life, but the first episode is more common in young adulthood. It is often precipitated by stressful life events, such as marital separation, occupational or family stress, and interpersonal conflicts (Bastien et al., 2004). In a small subset of cases (e.g., idiopathic insomnia), insomnia begins in childhood, in the absence of psychological or medical problems, and persists throughout adulthood (Hauri and Olmstead, 1980). Insomnia is a common problem among women during menopause and often persists even after other symptoms (e.g., hot flashes) have resolved with hormone replacement therapy. Insomnia may also have a latelife onset, which needs to be distinguished from normal (age-related) changes in sleep; such late-life onset is often associated with other health-related problems. Potential risk factors for insomnia include female sex, advancing age, a worry-prone cognitive style, hyperarousal, and a past history of insomnia (Klink et al., 1992; Morin and Espie, 2003). For most individuals, insomnia is transient in nature, lasting a few days, and resolving itself once the initial precipitating

726 C.M. MORIN AND R.M. BENCA event has subsided. For others, perhaps those more and increased cortisol and adrenocorticotropic horvulnerable to sleep disturbances, insomnia may persist mone levels during sleep and throughout the 24-hour long after the initial triggering event has disappeared; period (Vgontzas et al., 2001; Rodenbeck et al., other factors would then perpetuate sleep disturbances 2002). Reduced sleep efficiency was correlated with (Spielman and Glovinsky, 1991). The course of insomnia higher cortisol levels (Vgontzas et al., 2001; Rodenbeck may also be intermittent, with repeated brief episodes et al., 2002). A neuroimaging study revealed that, comof sleep difficulties following a close association with pared to healthy controls, insomniacs had increased the occurrence of stressful events (Vollrath et al., cerebral glucose metabolic rates during wakefulness 1989). Longitudinal studies have shown that chronicity and NREM sleep, and also exhibited smaller declines rates may range from 45% to 75% for follow-ups of in glucose metabolism from wakefulness to sleep in 1–7 years (Buysse et al., 2008; Morin et al., 2009). Even wake-promoting brain areas such as the ascending when insomnia has developed a chronic course, there is reticular activating system (Nofzinger et al., 2004). typically extensive night to night variability in sleep Positron emission tomography in patients with insompatterns, with an occasional restful night’s sleep internia demonstrated that increased wakefulness after twined with several nights of poor sleep (Vallieres sleep onset was correlated with increased activation in et al., 2005a). The subtype of insomnia (i.e., sleep onset the pontine region and in some thalamocortical netor maintenance insomnia) may also change over time. works during sleep (Nofzinger et al., 2006). Finally, a Although there is little information about its natural hisstudy of brain neurochemicals found that levels of tory, the prognosis for insomnia varies across indivigamma-aminobutyric acid (GABA) were nearly 30% duals and is probably mediated by a combination of lower in patients with primary insomnia than in conbiologically related predisposing factors and psychologtrols; GABA levels were negatively correlated with ical and behavioral perpetuating factors. It may also wake after sleep onset (Winkelman et al., 2008). be complicated by the presence of comorbid psychiatric or medical disorders. In fact, there is extensive comorPsychological basis. Psychological and behavioral bidity (40–50%) between insomnia and psychiatric factors also play an important role in the development disorders, most notably with major depression and and maintenance of insomnia, as evidenced by higher generalized anxiety disorder (Ford and Kamerow, levels of presleep cognitive arousal (e.g., intrusive 1989; Benca et al., 1992; Buysse et al., 1994; Breslau thoughts, worries) and general psychological reactivity et al., 1996; Ohayon and Roth, 2003). among individuals with insomnia relative to good sleepers. Although chronic exposure to stress may contribEtiology and pathophysiology ute to insomnia, it may be that sleep disturbance results from a reduced ability to cope with daily stresAlthough insomnia is likely multifactorial and the presors, combined with increased cognitive arousal at bedcise etiologies are not known, hyperarousal is considered time (Morin et al., 2003). to be a central feature of insomnia. A hyperarousal state Learning and conditioning are also involved in the can be conditioned to sleep-related stimuli or a more maintenance or exacerbation of sleep disturbances; enduring feature present throughout the 24-hour period. the discomfort associated with insomnia can lead to a It is likely that both biological and psychological factors negative association between temporal (bedtime) and contribute to increased arousal and interference with environmental (bed/bedroom) stimuli previously assonormal initiation and maintenance of sleep. ciated with sleep. Over time, the combination of Biological basis. In studies comparing patients with maladaptive sleep habits (e.g., napping, excessive insomnia to normal sleepers, a number of physiological amounts of time spent in bed) and sleep-related cognidifferences suggestive of increased arousal have been tions (e.g., unrealistic sleep expectations, worry about reported, including increases in body temperature, the consequences of insomnia, sleep-related monitorgalvanic skin response, heart rate, and metabolic rate, ing) may exacerbate or perpetuate what might otherboth near sleep onset and during sleep (Bonnet and wise have been a transient sleep problem (Espie, Arand, 1997). Patients with insomnia have also shown 2002; Morin and Espie, 2003; Morin et al., 2003). increased high-frequency (beta) EEG activity during Although it remains unclear whether hyperarousal is NREM sleep, and changes in patterns of event-related a direct cause, a byproduct, or even a consequence of potentials suggestive of increased arousal (Merica insomnia, it is a central feature in the pathophysiology et al., 1998; Perlis et al., 2001a, b; Devoto et al., 2005; of insomnia. Along with a reduced homeostatic sleep Bastien et al., 2008). Neuroendocrine studies have drive (Besset et al., 1998), it is likely to arise from the demonstrated increased levels of circulating catecholainteraction of biologically based predisposing factors mines and urinary free cortisol (Vgontzas et al., 1998), and psychologically based exacerbating factors.

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT

EVALUATION AND DIFFERENTIAL DIAGNOSIS Clinical and laboratory evaluations The diagnosis of insomnia is derived primarily from a detailed clinical evaluation of the patient’s subjective complaint (Table 45.3). The sleep history should cover the type of complaint (initial, middle, late insomnia), its duration (acute vs. chronic), and course (recurrent, persistent); typical sleep schedule; functional analysis of precipitating, perpetuating, and alleviating factors; perceived consequences and functional impairments, and the presence of medical, psychiatric, or environmental contributing factors. A complete history of alcohol and drug use, and of prescribed and over-the-counter medications is also essential (Morin and Espie, 2003; Buysse et al., 2006; Schutte-Rodin et al., 2008). The use of a sleep diary is essential in the evaluation of insomnia (Table 45.4). The patient should keep a daily diary to document the nature and initial severity of insomnia, identify behavioral and scheduling factors that may perpetuate insomnia, and monitor treatment compliance and progress. The Insomnia Severity Index (Bastien et al., 2001) is a brief questionnaire that can also be helpful to measure the patient’s perception of insomnia severity and its impact on daytime functioning (Table 45.5). Several additional measures of insomnia symptoms, fatigue,

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anxiety, and depressive symptomatology may also provide useful complementary information in the evaluation of insomnia (Buysse et al., 2006). A more comprehensive psychological evaluation may be necessary for patients with suspected psychiatric disorders. Although PSG is not indicated for the routine evaluation of insomnia, it is often necessary to rule out other sleep disorders that might contribute to the insomnia complaint (e.g., periodic movements during sleep, sleep apnea) (Littner et al., 2003). PSG can also be particularly useful in suspected case of paradoxical insomnia or when a patient is unresponsive to treatment. The role of actigraphy in insomnia evaluation and treatment monitoring is not well established. Although it may represent a useful adjunct, actigraphy is not clinically indicated for routine assessment, diagnosis, or management of insomnia (Ancoli-Israel et al., 2003; Buysse et al., 2006). In the research environment, actigraphy is useful for examining night to night variability and for identifying individuals with circadian rhythm disorders. It has also been used to document treatment adherence and outcome in clinical trials of behavioral therapy for insomnia (Morin et al., 2006). Although a potentially useful complement to selfreport and PSG measures, actigraphy devices and algorithms are not all equivalent and there may be significant variability in the reliability and validity of sleep–wake data derived from different devices.

Table 45.3 Evaluation of insomnia Nature of the complaint – difficulties falling or staying asleep, early morning awakening Daytime symptoms – fatigue, mood disturbances, attention/ concentration problems Clinical significance – frequency, severity, duration of sleep difficulties Onset and course of insomnia Typical sleep–wake schedule (weekdays, weekends) Sleeping environment (noise, light, temperature) Functional analysis – evening activities, pre-bedtime rituals, triggers of nocturnal and morning awakenings (pain, noise); behavioral responses to insomnia Perpetuating/exacerbating (worries about sleep loss, daytime napping, excessive amounts of time in bed) Beliefs about sleep requirement expectations and consequences of poor sleep Use of sleeping aids/substances (caffeine, alcohol, drugs) Other medical problems Recent life events contributing to insomnia Symptoms of other psychiatric disorders (anxiety, depression) Symptoms of other sleep disorders (restless legs syndrome, sleep apnea) Previous treatment for insomnia and outcome

Differential diagnosis The differential diagnosis of insomnia requires a distinction between primary insomnia and insomnia associated with a (comorbid) medical, psychiatric, or other sleep disorder. Although the essential clinical features of insomnia are similar for primary and comorbid insomnia, in primary insomnia the sleep disturbance does not occur exclusively during the course of another mental or sleep disorder and is not due to the direct physiological effects of a substance or general medical condition. Primary insomnia is a diagnosis essentially made by exclusion, after ruling out several other conditions such as psychiatric (depression and anxiety), medical (pain), circadian (phase-delay syndrome), or other sleep disorders (restless legs syndrome/periodic limb movements, sleep-breathing disorders) as the main contributing factor to sleep disturbances. A diagnosis of comorbid insomnia is made when the sleep disturbance is judged to be related temporally and causally to another psychiatric, medical, or sleep disorder (American Psychiatric Association, 2000; American Academy of Sleep Medicine, 2005). Such distinction is not always easily made, given the bidirectional relationship between insomnia and psychological symptoms

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Table 45.4 Sleep diary Week: __________ to ___________ Example 1.

Yesterday, I napped from ___ to ___ (Note the times of all naps)

2.

Yesterday, I took ___ mg of medication and/or ___ oz ___ of alcohol as sleep aid

3.

Last night, I went to bed and turned the lights off at ___ o’clock

11:15 pm

4.

After turning the lights off, I fell asleep in ___ minutes

40 min

5.

My sleep was interrupted ___ times (Specify number of nighttime awakenings)

2

6.

My sleep was interrupted for ___ minutes (Specify duration of each awakening)

10 min (45 min)

7.

This morning, I woke up at ___ o’clock (Note time of last awakening)

6:15 am

8.

This morning, I got out of bed at ___ o’clock (Specify the time)

6:40 am

9.

When I got up this morning I felt ___ (1 ¼ Exhausted, 2 ¼ Fair, 3 ¼ Refreshed)

2

10.

Overall, my sleep last night was ___ (1 ¼ Restless, 2 ¼ Fair, 3 ¼ Very Sound)

3

Mon

Tue

Wed

Thu

Fri

Sat

Sun

1:50 to 2:30 pm

Reproduced by permission of Guilford Press from Morin (1993).

and the difficulty in determining the relative onset and course of these different coexisting conditions. In clinical practice, the main differential diagnosis is usually between primary insomnia and insomnia comorbid with anxiety (generalized anxiety disorder; GAD) or depression (dysthymia or major depression). This distinction is not always clear as several symptoms (e.g., sleep disturbance, fatigue, mood and cognitive problems) overlap among those conditions. Excessive worrying is the predominant feature of GAD; this characteristic is also present in primary insomnia, but its main focus is limited to insomnia and its potential consequences, whereas in GAD worrying is about multiple sources (e.g., health, family, work). In depression, the predominant clinical feature is sadness and a significant loss of interest. In primary insomnia, the interest is present but there is a lack of energy or fatigue, presumably resulting from sleep disturbances, preventing the individual from

engaging in potentially pleasurable activities or social interactions. In addition to the nature of the symptoms, the history should also identify the relative onset and course of each condition in order to determine whether insomnia is primary or secondary in nature.

TREATMENT The first step in treating symptomatic insomnia is to identify and remove the contributing factors. General sleep hygiene recommendations are also useful as preventive strategies. Specific insomnia therapies include psychological and behavioral interventions, medications, and a variety of complementary and alternative therapies (e.g., acupuncture, yoga, herbal therapies). The rest of this chapter focuses on psychological/behavioral and pharmacological therapies; most of the alternative therapies have not been evaluated adequately with regard to their efficacy and safety in the management of insomnia.

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT

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Table 45.5 Insomnia Severity Index (ISI) For each question below, please circle the number corresponding most accurately to your sleep patterns in the LAST MONTH. For the first three questions, please rate the SEVERITY of your sleep difficulties. 1.

Difficulty falling asleep: None 0

2.

Moderate 2

Severe 3

Very Severe 4

Mild 1

Moderate 2

Severe 3

Very Severe 4

Satisfied 1

Neutral 2

Dissatisfied 3

Very Dissatisfied 4

A Little Interfering 1

Somewhat Interfering 2

Much Interfering 3

Very Much Interfering 4

How NOTICEABLE to others do you think your sleeping problem is in terms of impairing the quality of your life? Not at all Noticeable 0

7.

Mild 1

To what extent do you consider your sleep problem to INTERFERE with your daily functioning (e.g., daytime fatigue, ability to function at work/daily chores, concentration, memory, mood). Not at all Interfering 0

6.

Very Severe 4

How SATISFIED/dissatisfied are you with your current sleep pattern? Very Satisfied 0

5.

Severe 3

Problem waking up too early in the morning: None 0

4.

Moderate 2

Difficulty staying asleep: None 0

3.

Mild 1

A Little Noticeable 1

Somewhat Noticeable 2

Much Noticeable 3

Very Much Noticeable 4

How WORRIED/distressed are you about your current sleep problem? Not at all 0

A Little 1

Somewhat 2

Much 3

Very Much 4

Guidelines for Scoring/Interpretation: Add scores for all seven items ¼ _____ Total score ranges from 0–28 0–7 ¼ No clinically significant insomnia 8–14 ¼ Subthreshold insomnia 15–21 ¼ Clinical insomnia (moderate severity) 22–28 ¼ Clinical insomnia (severe) # Morin, C.M. (1993, 2006).

Psychological and behavioral therapies TREATMENT

RATIONALE AND INDICATIONS

Psychological and behavioral therapies for insomnia include sleep restriction, stimulus control therapy, relaxation-based interventions, cognitive strategies, sleep hygiene education, and combined cognitive and behavioral therapy. A summary of these interventions is provided below and in Table 45.6; more extensive descriptions are available in other sources (Morin and Espie, 2003). The main objectives of psychological and behavioral approaches are to alter the factors that

perpetuate or exacerbate sleep disturbances. Such features may include hyperarousal, sleep-scheduling factors, poor sleep habits, and misconceptions about sleep and the consequences of insomnia. Although numerous factors can precipitate insomnia, when it becomes a persistent problem, psychological and behavioral factors are almost always involved in perpetuating it over time, hence the need to target those factors directly in treatment (Spielman and Glovinsky, 1991). The primary indication for behavioral treatment is in the management of persistent insomnia, with evidence available for both primary and comorbid insomnia.

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Table 45.6 Psychological and behavioral treatments for primary insomnias Therapy

Description

Stimulus control therapy

A set of instructions designed to strengthen the association between the bed/bedroom with sleep and to re-establish a consistent sleep–wake schedule: (1) Go to bed only when sleepy; (2) get out of bed when unable to sleep; (3) use the bed/bedroom for sleep only (no reading, watching TV, etc.); (4) arise at the same time every morning; (5) no napping A method designed to restrict time spent in bed as close as possible to the actual sleep time, thereby producing mild sleep deprivation. Time in bed is then gradually increased over a period of few days/weeks until optimal sleep duration is achieved Clinical procedures aimed at reducing somatic tension (e.g., progressive muscle relaxation, autogenic training) or intrusive thoughts (e.g., imagery training, meditation) interfering with sleep. Most relaxation requires some professional guidance initially and daily practice over a period of a few weeks Psychotherapeutic method aimed at reducing worry and changing faulty beliefs and misconceptions about sleep, insomnia, and daytime consequences. Other cognitive strategies can also be used to control intrusive thoughts at bedtime and reduce excessive monitoring of the daytime consequences of insomnia General guidelines about health practices (e.g., diet, exercise, substance use) and environmental factors (e.g., light, noise, temperature) that may promote or interfere with sleep. This may also include some basic information about normal sleep and changes in sleep patterns with aging A combination of any of the above behavioral (e.g., stimulus control, sleep restriction, relaxation) and cognitive procedures

Sleep restriction therapy Relaxation training

Cognitive therapy

Sleep hygiene education Cognitive–behavioral therapy (CBT)

SLEEP

RESTRICTION

Poor sleepers often increase their time in bed in a misguided effort to provide more opportunity for sleep, a strategy that is more likely to result in fragmented and poor-quality sleep. Sleep restriction consists of curtailing the amount of time spent in bed to the actual amount of sleep (Spielman et al., 1987). For example, if a person reports sleeping an average of 6 hours per night out of 8 hours spent in bed, the initial sleep window (i.e., from initial bedtime to final arising time) would be set at 6 hours. Subsequent adjustments to this “sleep window” are based on sleep efficiency (SE) for a given period of time (usually the preceding week); time in bed is increased by about 20 minutes for a given week when SE exceeds 85%, decreased by the same amount of time when SE is lower than 80%, and kept stable when SE falls between 80% and 85%. Periodic (weekly) adjustments are made until optimal sleep duration is achieved. Changes to the prescribed sleep window can be made at the beginning of the night (i.e., postponing bedtime), at the end of the sleep period (i.e., advancing arising time), or at both ends. To prevent excessive daytime sleepiness, time in bed should not be reduced to fewer than 5 hours per night in bed. This procedure leads to improvements in sleep continuity through a mild sleep deprivation and reduction of sleep anticipatory anxiety. Caution is needed when using sleep restriction with patients operating heavy equipments or who are required to drive

long distances (e.g., truck drivers). Sleep restriction is contraindicated in patients with bipolar disorder, seizures, or with some parasomnias (sleep-walking, night terrors) (Smith and Perlis, 2006).

STIMULUS

CONTROL THERAPY

Individuals with insomnia may develop apprehension around bedtime and come to associate the bedroom with frustration and arousal rather than with sleep. Stimulus control therapy (Bootzin et al., 1991) consists of a set of instructions designed to strengthen the association between temporal (bedtime) and environmental (bed and bedroom) stimuli and rapid sleep onset, and to establish a regular circadian sleep–wake rhythm. These instructions are: ● ●

● ● ●

Go to bed only when sleepy. Get out of bed when unable to sleep (e.g., after 20 min), going to another room and returning to bed only when sleep is imminent. Curtail all sleep-incompatible activities (i.e., no TV watching, problem-solving in bed). Arise at a regular time every morning regardless of the amount of sleep the night before. Avoid daytime napping.

Despite the straightforward nature of these recommendations, the main challenge for most patients is to comply with all of them, which is essential to reverse

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT the conditioning processes perpetuating insomnia. Caution is advised in using some of these procedures (e.g., getting out of bed when unable to sleep) with the frail elderly, who may be at risk for falls.

RELAXATION-BASED

INTERVENTIONS

Relaxation is probably the most commonly used nondrug therapy for insomnia. Some relaxation methods (e.g., progressive muscle relaxation) focus primarily on reducing somatic arousal (e.g., muscle tension), whereas attention-focusing procedures (e.g., imagery training, meditation) target mental arousal in the forms of worries or intrusive thoughts. Most of these methods are equally effective for treating insomnia. The most critical issue is to practice diligently and daily the selected method for at least 2–4 weeks. Professional guidance is often necessary in the initial phase of training.

COGNITIVE

THERAPY

This psychotherapeutic method seeks to alter dysfunctional sleep cognitions (e.g., beliefs, expectations, attributions) and maladaptive cognitive processes (e.g., excessive self-monitoring) through Socratic questioning and behavioral experiments. The basic premise of this approach is that appraisal of a given situation (sleeplessness) and excessive monitoring of sleeprelated cues (e.g., fatigue, time left for sleep) can trigger an emotional response (fear, anxiety) that is incompatible with sleep. For example, when a person is unable to sleep at night and worries about the possible consequences of sleep loss on the next day’s performance, this can set off a spiral reaction and feed into the vicious cycle of insomnia, emotional distress, and more sleep disturbances. Cognitive therapy is designed to identify dysfunctional cognitions and reframe them into more adaptive substitutes in order to short-circuit the self-fulfilling nature of this vicious cycle. Treatment targets may include unrealistic expectations (“I must get my 8 hours of sleep every night”) and amplification of the consequences of insomnia (“Insomnia may have serious consequences on my health”) (Morin and Espie, 2003). Cognitive therapy is particularly useful to modify these maladaptive cognitions and to teach patients more adaptive skills to cope with insomnia (Harvey et al., 2007).

SLEEP

HYGIENE EDUCATION

Sleep hygiene education is intended to provide information about lifestyle (diet, exercise, substance use) and environmental factors (light, noise, temperature) that may either interfere with or promote better sleep. Sleep

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hygiene guidelines include: (a) avoiding stimulants (e.g., caffeine) for several hours before bedtime; (b) avoiding alcohol around bedtime as it fragments sleep; (c) exercising regularly (especially in late afternoon or early evening) as it may deepen sleep; (d) allowing at least a 1-hour period to unwind before bedtime; (e) keeping the bedroom environment quiet, dark, and comfortable. In addition to these guidelines, it is useful to provide basic information about normal sleep, individual differences in sleep needs, and changes in sleep physiology over the course of the lifespan. This information is particularly useful to help some patients distinguish clinical insomnia from short sleep or from normal (age-related) sleep disturbances. Although inadequate sleep hygiene is rarely the primary cause of insomnia, it may potentiate sleep difficulties caused by other factors or interfere with treatment progress. Addressing these factors should be an integral part of insomnia management, even though it is rarely sufficient for more severe insomnia, which often requires more directive and potent behavioral interventions.

MULTICOMPONENT

THERAPIES

Despite some unique features, the interventions described above can be combined together effectively. There is a general preference among investigators and clinicians for combining multiple interventions, with CBT becoming the standard approach in the field (Morin et al., 2006). The most common combination involves a behavioral (stimulus control, sleep restriction, and, sometimes, relaxation), a cognitive, and an educational (sleep hygiene) component, usually referred to as CBT. Such a combination is often preferred to address the different components presumed to perpetuate insomnia.

Evidence for efficacy, durability, and generalizability EVIDENCE

FOR EFFICACY

Several meta-analyses (Morin et al., 1994a; Murtagh and Greenwood, 1995; Smith et al., 2002) and systematic reviews commissioned by the American Academy of Sleep Medicine (Morin et al., 1999b, 2006) have summarized the findings from clinical trials evaluating the efficacy of psychological and behavioral therapies for persistent insomnia. Evidence from these sources shows that treatment produces reliable changes in several sleep parameters, including sleep-onset latency (effect sizes ranging from 0.41 to 1.05), number of awakenings (0.25–0.83), duration of awakenings (0.61–1.03), total sleep time (0.15–0.49), and sleep quality ratings (0.94–1.14). Based on Cohen’s criteria, the

732 C.M. MORIN AND R.M. BENCA magnitude of those therapeutic effects is large (i.e., over time, with data available up to 24 and even 36 d > 0.8) for sleep latency and sleep quality, and modmonths after treatment completion. Although intervenerate (i.e., d > 0.5) for other sleep parameters. When tions that restrict the amount of time spent in bed may transformed into a percentile rank, these data indicate yield only modest increases (and even a reduction) of that approximately 70–80% of patients with insomnia sleep time during the initial treatment period, this achieve a therapeutic response with psychological and parameter is usually improved at follow-up, with total behavioral therapies. sleep time often exceeding 6.5 hours. Long-term outIn terms of absolute changes, treatment reduces come must be interpreted cautiously, however, as few subjective sleep-onset latency and time awake after studies report long-term follow-up and, among those sleep onset from averages of 60–70 min at baseline that do, attrition rates increase over time. In addition, to about 35 min following treatment, and total sleep a substantial proportion of patients with chronic time is increased by 30 min, from 6 to 6.5 h after treatinsomnia who benefit from short-term therapy may ment. Thus, for the average patient with insomnia, remain vulnerable to recurrent episodes of insomnia treatment effects may be expected to reduce sleep in the long term. As such, there is a need to develop latency and time awake after sleep onset by about and evaluate the effects of long-term, maintenance, 50% and to bring the absolute values of those sleep therapies to prevent or minimize the occurrence of parameters below or near the 30-min cutoff criterion those episodes. initially used to define insomnia. Treatment effects are similar for sleep-onset and sleep-maintenance proTREATMENT OF COMORBID INSOMNIA blems, although fewer studies have targeted the later Insomnia is often a pervasive problem among patients type and, particularly, early-morning awakening prosuffering from other medical and psychiatric condiblems. Overall, findings from meta-analyses represent tions (Taylor et al., 2007b). Although sleep may fairly conservative estimates of treatment effects as improve with appropriate treatment of the comorbid they are based on averages computed across all noncondition, sleep disturbances are also likely to persist. pharmacological interventions and insomnia diagnoses Thus, the presence of a comorbid medical or psychiat(i.e., primary and comorbid). On the other hand, ric disorder should not preclude using a behavioral although the majority of patients benefit from treatintervention concomitantly, as behavioral factors are ment, only 20–30% achieve clinical remission (Morin often involved in perpetuating or even exacerbating et al., 1999b, 2006). the sleep problem. Evidence from clinical case series Treatment outcome has been documented primarily (Morin et al., 1994b; Dashevsky and Kramer, 1998; with prospective daily sleep diaries, although several Taylor et al., 2007a) suggests that patients with medistudies have also complemented those findings with cal and psychiatric conditions can also benefit from data from PSG (Morin et al., 1999a; Edinger et al., insomnia-specific treatment (Smith et al., 2005). 2001) and wrist actigraphy (Edinger et al., 2007; Espie Controlled studies have also shown that behavioral et al., 2007). In general, the magnitude of improvetreatment is effective for insomnia associated with ments is smaller on PSG measures, but those changes chronic pain (Currie et al., 2000), fibromyalgia (Edinger tend to parallel sleep improvements reported in daily et al., 2005), cancer (Savard et al., 2005; Espie et al., sleep diaries. PSG findings indicate that treatment 2008), and various medical conditions in older adults does not only alter sleep perception, as measured by (Lichstein et al., 2000; Rybarczyk et al., 2005). In patient reported outcomes, but also produces objective general, insomnia symptoms are more severe among changes on EEG sleep continuity measures. Except for patients with comorbid disorders, but the absolute a modest increase in stages 3–4 following sleep restricchanges in those outcomes during treatment are tion, there is little evidence of changes in sleep archicomparable to those obtained with primary insomnia. tecture with psychological and behavioral treatment. Insomnia in older adults is more likely to be comorIn addition to improving sleep continuity parameters, bid with another medical or another sleep disorder than there is also some evidence showing improvements on to be primary in nature. Recent studies have shown several secondary endpoints, including measures of that older adults respond to insomnia treatment, particdaytime fatigue, quality of life, and psychological ularly when they are screened for other sleep disorders symptoms (Morin et al., 2006; Espie et al., 2007). that increase in incidence in older age (e.g., restless legs syndrome, sleep apnea). A meta-analysis (Irwin LONG-TERM OUTCOMES et al., 2006) suggested that effect sizes were comparaA fairly robust finding across behavioral treatment ble (moderate to large) for middle-aged and older studies is that sleep improvements are well maintained adults on subjective measures of sleep latency, wake

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT 733 after sleep onset, and sleep quality. Older adults with treatment is effective with all forms of insomnia or either comorbid medical or psychological conditions acceptable to all patients. Even among treatment can benefit from sleep-specific treatment (Lichstein responders, few patients achieve complete remission et al., 2000; Rybarczyk et al., 2002, 2005; Pallesen and some residual sleep disturbances often persist et al., 2003). Three clinical trials have shown that a after treatment. Thus, combined approaches should supervised and time-limited withdrawal program, with theoretically optimize outcome by capitalizing on the or without behavioral treatment for insomnia, can more immediate and potent effects of hypnotics and facilitate discontinuation of hypnotic medications the more sustained effects of behavioral interventions. among older adults with insomnia who are prolonged Only a few studies have directly compared the users (Morgan et al., 2003; Morin et al., 2004; Soeffing effects of behavioral and pharmacological therapies et al., 2008). for insomnia. Three studies compared triazolam with relaxation (McClusky et al., 1991; Milby et al., 1993) or sleep hygiene (Hauri, 1997), and four other investiWHICH INSOMNIA THERAPIES WORK BEST? gations compared CBT with temazepam (Morin et al., Although there has been no complete dismantling of 1999a), zolpidem (Jacobs et al., 2004), or zopiclone cognitive–behavioral therapies to isolate the relative (Vallieres et al., 2005b; Sivertsen et al., 2006a). Collecefficacy of each component, direct comparisons of tively, findings from these studies indicate that both some of those components indicate that sleep restrictherapies are effective in the short term, with medication, alone or combined with stimulus control therapy, tion producing faster results in the acute phase (first is more effective than relaxation, which, in turn, is week) of treatment, whereas both treatments are more effective than sleep hygiene education alone equally effective in the short-term interval (4–8 weeks). (Morin et al., 2006). Sleep restriction tends to produce Combined interventions appear to have a slight advana better outcome than stimulus control for improving tage over single treatment modality during the initial sleep efficiency and sleep continuity, but it also course of treatment, but it is unclear whether this decreases total sleep time during the initial intervenadvantage persists over time. Long-term effects are tion. Although some basic education about sleep consistent for the single treatment modalities; patients hygiene is incorporated to most insomnia treatments, treated with CBT maintain their improvement, whereas sleep hygiene education produces little impact on sleep therapeutic effects are typically lost after discontinuawhen used as the only intervention. A recent study tion of medication. Long-term effects of combined showed that cognitive therapy alone can be effective interventions are more equivocal. Some studies indiin the management of insomnia (Harvey et al., 2007). cate that a combined intervention (triazolam plus There is no strong evidence that a multicomponent relaxation) produces more sustained benefits than approach is more effective than any of its single compomedication alone (McClusky et al., 1991; Milby et al., nents. However, the appeal for this multimodal approach 1993), whereas others report more variable long-term may come from the fact that it addresses different facets outcomes (Hauri, 1997; Morin et al., 1999a). Some presumed to perpetuate sleep disturbances. Although litpatients retain their initial sleep improvement, but tle information is available about the active treatment others return to baseline values. As behavioral and attimechanisms of CBT, some evidence suggest that stimutudinal changes are often essential to sustain sleep lus control and sleep restriction are particularly effective improvements, patients’ attributions of the initial benefor improving sleep continuity, whereas changes in sleepfits may be critical in determining long-term outcomes. related cognitions are associated with better maintenance Attribution of therapeutic benefits to the hypnotic of sleep changes over time (Morin et al., 2002). With alone, without integration of self-management skills, increasing evidence that hyperarousal is implicated in may place a patient at greater risk for recurrence primary insomnia, there is a need for greater attention of insomnia once medication is discontinued. Thus, to identify the biological, as well as the psychological, despite the intuitive appeal of combining behavioral mechanisms responsible for sleep changes. and medication therapies, it is not entirely clear when, how, and for whom it is indicated to combine these treatment modalities for insomnia. Additional research Combined behavioral and pharmacological is needed to evaluate the effects of combined treatapproaches ments and to examine optimal methods for integrating Behavioral and pharmacological therapies can play a these therapies. complementary role in the management of insomnia. Comparisons of effect sizes from meta-analyses There are some practical and clinical reasons for con(Morin et al., 1994a; Nowell et al., 1997; Smith et al., sidering combining therapies. For example, no single 2002) on different sleep variables indicate that

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Table 45.7 Drugs used to promote sleep

Drug

Dose range (mg) (dose range in the elderly)

Effects on sleep

Adverse effects

Increased total sleep time, stage 2%, REM latency Decreased sleep latency, WASO, stage 1%, SWS %, REM%

Dizziness, drowsiness, hypokinesia, dyskinesia, abnormal or impaired coordination, slurred speech, ataxia, amnesia, GI symptoms. Rebound/withdrawal effects more pronounced with shorter-acting agents

Flurazepam

15–30 (15)

1.5–5.5 6–16 10–24 Quazepam and 2-oxoquazepam: 25–41 N-desakyl-1oxoquazepam: 70–75 47–100

Nonbenzodiazepines Zaleplon Zolpidem Zolpidem CR Eszopiclone

10–20 (5–10) 10 (5) 6.25–12.5 (6.25) 2–3 (1–2)

1 1.4–4.5 2.8 5–5.8

Dizziness, drowsiness, amnesia, GI symptoms. Zaleplon also can cause myalgia and headache Eszopiclone has an unpleasant taste and can cause dry mouth

Melatonin receptor agonist Ramelteon

Decreased sleep latency Eszopiclone, Indiplon (10–15-mg doses) : decreased WASO Zolpidem CR: decreased WASO during first 6 h

8 (8)

2.6

Sleep latency #

Antidepressants Amitriptyline

Drowsiness, dizziness, fatigue. Do not use with fluvoxamine, ketoconazole, or fluconazole

50–100* (20 mg)

Doxepin

75–100* (25–50)

10–28, including metabolite nortriptyline 8–24

Mirtazapine

15–45* (7.5–15)

20–40

Drowsiness, dizziness, confusion, blurred vision, dry mouth, constipation, urinary retention, arrhythmias, orthostatic hypotension, weight gain. Exacerbation of restless legs, periodic limb movements or REM sleep behavior disorder Drowsiness, dizziness, increased appetite, constipation, weight gain, agranulocytosis (rare)

Trazodone

150–400* (150)

7

Total sleep time " Sleep latency # Stage 2% " REM% # REM latency: " Total sleep time: " Sleep latency: # WASO: # Sleep latency # WASO # SWS% "

Drowsiness, dizziness, headache, blurred vision, dry mouth, arrhythmias, orthostatic hypotension, priapism

C.M. MORIN AND R.M. BENCA

Benzodiazepine receptor agonists Benzodiazepines Triazolam 0.25–0.5 (0.125–0.25) Temazepam 7.5–30 (7.5) Estazolam 1–2 (0.5) Quazepam 7.5–15 (7.5)

Half-life (hours)

300–600* (300)

5–7

WASO $ to # SWS% "

Tiagabine

4–8* (4)

7–9

WASO # SWS% "

Pregabalin

50–100* (25–50)

6

Sleep latency # SWS% "

Antipsychotics Olanzapine

5–10* (5)

21–54

Sleep latency $ to # WASO # SWS% " REM% $ to #

Quetiapine

25–200* (25)

6

Insufficient data

Diphenhydramine chloride: 50* Diphenhydramine citrate: 76* (25 mg) 2.5 mg evaluated in the elderly, but no standard dosage determined empirically

2.4–9.3

Sleep latency # WASO $ to # SWS% $ to " REM% # Sleep latency #

Over-the-counter agents Diphenhydramine

Melatonin

0.5

*Recommended maximum amounts for a single dose. $, no change; ", increase; #, decrease. GI, gastrointestinal; REM, rapid eye movement; SWS, slow-wave sleep; WASO, wake after sleep onset.

Drowsiness, dizziness, emotional lability, ataxia, tremor, blurred vision, diplopia, nystagmus, myalgia, peripheral edema Drowsiness, dizziness, ataxia, tremor, new-onset seizures in patients without epilepsy, difficulty with concentration or attention, nervousness, asthenia, abdominal pain, diarrhea, nausea Drowsiness, dizziness, ataxia, confusion, peripheral edema Drowsiness, dizziness, tremor, agitation, asthenia, extrapyramidal symptoms, dry mouth, dyspepsia, constipation, orthostatic hypotension, weight gain, new-onset diabetes mellitus, tardive dyskinesia and neuroleptic malignant syndrome

Drowsiness, dizziness, dyskinesias, dry mouth, epigastric distress, constipation. Tachycardia, risk of delirium and falls in elderly Concentration difficulty, dizziness, fatigue, headache, irritability

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT

Anticonvulsants Gabapentin

735

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C.M. MORIN AND R.M. BENCA

behavioral therapy may have a slight advantage on measures of sleep-onset latency and sleep quality, and pharmacotherapy (benzodiazepine receptor agonists) a more favorable outcome on total sleep time. One recent study examined different sequences of CBT and medication therapies (Vallieres et al., 2005b). The best results were obtained when CBT was introduced first in the sequence, but medication was found helpful to improve total sleep time, which may be an important advantage given that one component of CBT (sleep restriction) reduces total sleep time during the initial course of therapy and could lead some patients to premature therapy discontinuation. Until more evidence-based treatment guidelines become available, several strategies can be considered for selecting the most appropriate treatment in the clinical management of insomnia. The use of hypnotic medication may be indicated particularly in the initial stage of therapy to break the vicious cycle of insomnia and to provide some rapid relief. On the other hand, CBT is essential to alter perpetuating factors and to teach coping skills. As such, it is an essential treatment component to maximize durability of sleep improvements. Ideally, hypnotic medications should be discontinued, under supervision, after an initial treatment course of a few weeks. However, given that insomnia may be a recurrent problem, even among those who benefit from treatment initially, it may be necessary to use medications intermittently after the initial acute treatment phase.

Pharmacotherapy A variety of medications are used for insomnia (Table 45.7), including both over-the-counter (OTC) and prescription agents; however, many of these are not approved by the US Food and Drug Administration (FDA) for the treatment of insomnia. Current FDA-approved insomnia medications include a group of benzodiazepine receptor agonists and one melatonin receptor agonist. Although not FDA-approved for treatment of insomnia, sedating antidepressants have been prescribed widely for insomnia; as recently as 2002, three of the top four most commonly prescribed medications for insomnia were sedating antidepressants (Walsh, 2004b). Other classes of prescription medication used for their potential sleep-inducing side-effects include atypical antipsychotics and anticonvulsants. According to population-based studies, almost twice as many individuals with insomnia self-medicate than take prescription medications (Johnson et al., 1998; Roehrs et al., 2002). Polls by the National Sleep Foundation have found that 16–28% of adults have used

alcohol and 22–29% have used OTC agents for sleep at some point during their life (National Sleep Foundation, 1991, 1995). In general, patients who self-medicate with alcohol or OTC agents tend to do so for shorter periods of time and have less severe insomnia than those who take prescription medications (Johnson et al., 1998).

BENZODIAZEPINE

RECEPTOR AGONISTS

(BZRAS)

The current FDA-approved BzRAs for insomnia include the older benzodiazepines (estazolam, flurazepam, quazepam, temazepam, triazolam) and the newer nonbenzodiazepines (eszopiclone, zaleplon, zolpidem) (see Table 45.7). These medications all bind to the GABA, type A, receptor complex. Benzodiazepines bind to all subtypes of GABAA receptor, whereas some of the newer nonbenzodiazepines, particularly zaleplon and zolpidem, bind preferentially to the type I GABAA receptor. The type I receptor is thought to mediate both the hypnotic and amnestic effects of BzRAs, but drugs acting selectively on this receptor may be less effective as muscle relaxants or anxiolytics. All BzRAs have the potential to produce amnesia. Benzodiazepines Benzodiazepine hypnotics, with the exception of triazolam, have relatively long half-lives. These agents (estazolam, flurazepam, quazepam, and temazepam) all reduce latency to sleep onset and tend to improve sleep maintenance, as indicated by decreased waking time after sleep onset, reduced number of awakenings, and/ or increased total sleep time (Aden and Thatcher, 1983; Hernandez Lara et al., 1983; Melo de Paula, 1984; Roehrs et al., 1986; Scharf et al., 1990; Cohn et al., 1991; Holbrook et al., 2000b). Triazolam also promotes sleep onset, but because of its short half-life does not appear to be as helpful for sleep maintenance (Ngen and Hassan, 1990; Kales et al., 1991). Benzodiazepines decrease time spent in stage 1 sleep and increase stage 2 sleep, but they also tend to suppress slow-wave sleep and, possibly, rapid eye movement (REM) sleep. Adverse effects of benzodiazepine hypnotics include daytime sedation, cognitive and psychomotor impairment, and memory impairment ( Ngen and Hassan, 1990; Holbrook et al., 2000b); such effects are more common with higher doses and longer-acting agents. Abrupt withdrawal may be associated with rebound insomnia (Kales et al., 1991; Mauri et al., 1993). As noted above, benzodiazepine hypnotics are indicated for the short-term treatment of insomnia. None has been studied in a randomized clinical trial for more than 12 weeks (Allen et al., 1987), so long-term efficacy data are not available.

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT 737 maintenance, and evidence of better next-day function, Nonbenzodiazepines as indicated by subjective reports of improved concenThe nonbenzodiazepine BzRAs include those with short tration and decreased morning sleepiness. half-lives (zaleplon and zolpidem) that are indicated priEszopiclone was the first hypnotic to be indicated for marily for promoting sleep onset, and those with either the treatment of insomnia without recommendations a longer half-life (eszopiclone) or controlled-release forfor restricted duration of use. It has a longer half-life mulations (zolpidem MR) that reduce sleep latency and than any of the other nonbenzodiazepines, which improve sleep maintenance. Zaleplon, with the shortest accounts for its effects on improving sleep maintehalf-life of currently available agents at about 1 hour, nance. In a 6-month placebo-controlled clinical trial, it may be dosed as long as the patient has at least 4 hours showed persistent efficacy in reducing latency to sleep remaining in bed; healthy volunteers did not demonstrate onset, decreasing wakefulness during sleep, and next-day impairment in driving ability, memory, or increasing total sleep time, as reported subjectively psychomotor function when tested 4–6 h after ingestion (Krystal et al., 2003). In another 6-month double-blind of 10–20 mg zaleplon (Verster et al., 2002). Although study, eszopiclone was shown not only to reduce insom5–10-mg doses of zaleplon primarily promote sleep nia, but also to enhance quality-of-life measures and onset, a dose of 20 mg increased subjective total reduce reported work limitations (Walsh et al., 2007). sleep time (Elie et al., 1999; Fry et al., 2000). It is also one of the first agents for which data suggest Zolpidem is currently the most commonly preimproved daytime function and/or decreased comorbidscribed sleep agent. It is effective in promoting sleep ity from other disorders. Elderly patients with insomnia onset, and also increases total sleep time at doses of taking 2 mg eszopiclone reported reduced daytime nap10 mg or above in both subjective and sleep laboratory ping (Scharf et al., 2005), and depressed patients given studies (Scharf et al., 1994). The increase in sleep effia combination of fluoxetine plus eszopiclone had ciency and/or total sleep is likely due to reduced sleep better sleep and higher rates of response and remission latency, as consistent effects on waking time after 8 weeks later in comparison with depressed patients sleep onset have not been observed. A 12-week, given fluoxetine plus placebo (Fava et al., 2006). placebo-controlled study demonstrated that intermittent use (three to five times per week) of zolpidem was associated with continued benefit on the night Efficacy of BzRAs the drug was taken and no obvious evidence of Several meta-analyses have assessed the efficacy of rebound insomnia on the nights it was not taken (Perlis BzRA hypnotics in comparison with placebo in the et al., 2004). Zolpidem has also been shown to be treatment of chronic insomnia. In a review of studies effective in subjects with depression treated with selecperformed on adults aged less than 65 years, benzodiative serotonin reuptake inhibitors (SSRIs), resulting in zepines and zolpidem were shown to produce signifisubjective increased total sleep, and improved sleep cant subjective improvement in sleep latency, total quality and daytime function (Asnis et al., 1999). Doses sleep, number of awakenings, and sleep quality, with of 10 mg zolpidem administered during the night did moderate effect sizes, ranging from 0.56 to 0.71 not lead to clinically significant effects on driving or (Nowell et al., 1997). A meta-analysis of studies performed psychomotor skills the next day, at least 4–6 h after on adults and elderly adults showed that benzodiazepines ingestion, in healthy subjects or insomnia patients produced significant improvements in both subjective (Verster et al., 2002; Staner et al., 2005), but higher and objective sleep parameters; sleep latency was reduced doses produced significant impairment (Verster et al., by 4.2 min objectively and 14.3 min subjectively, and 2002). The delayed-release zolpidem MR offers a lontotal sleep amount was increased by 61.8 min objectively ger duration of action with the same short half-life; and 48.4 min subjectively (Holbrook et al., 2000a, b). the dual-layer tablet consists of shell containing 7.5 mg Another analysis of drug effects in elderly insomnia immediate-release zolpidem and a core containing patients showed significant improvement in sleep qual5 mg delayed-release zolpidem for a total of 12.5 mg. ity (effect size 0.14), increased total sleep (25.2 min), A half-dose (6.25 mg) tablet contains 3.75 mg immediand decreased awakenings (effect size 0.63) with sedaate/2.5 mg delayed release. A recent double-blind, tive use compared with placebo (Glass et al., 2005). placebo-controlled, multicenter study showed clinical A comparison of benzodiazepine hypnotics with nonefficacy with zolpidem MR at a dose of 12.5 mg for benzodiazepines concluded that zolpidem may have up to 6 months when taken for 3–7 nights per week, benefits over temazepam in reducing sleep latency without significant rebound insomnia upon discontinuaand improving sleep quality, and over zaleplon in tion (Krystal et al., 2008). Subjects who took medication increasing sleep duration and improving sleep quality reported shorter sleep-onset latencies, improved sleep (Dundar et al., 2004). Zaleplon, however, may produce

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C.M. MORIN AND R.M. BENCA

less rebound insomnia than zolpidem. This analysis was limited, however, by the lack of directly comparative studies and short duration of the studies, which makes it difficult to assess longer-term effects. BzRA side-effects A number of adverse outcomes have been associated with drugs in this class. Sedation/daytime “hangover”, and impaired cognitive and psychomotor performance can be seen at peak blood levels, and may occur the following day with longer-acting agents (Verster et al., 2004). Anterograde amnesia, or loss of memory for events that occur after taking a hypnotic, is more common with higher doses and with drugs with rapidly increasing plasma levels, such as triazolam and the nonbenzodiazepines, or when combining BzRAs with alcohol. Confusional arousals or sleepwalking episodes may be a related phenomenon. BzRAs should therefore always be taken immediately prior to bedtime to minimize the risk of amnesia or parasomnias, and discontinued in patients who report these side-effects. All medications used for sleep, including BzRAs, but also antidepressants and anticonvulsants, can increase the risk of nighttime falls in elderly patients (Mendelson, 1992; Wang et al., 2001; Kelly et al., 2003). However, insomnia is an independent predictor of falls in the elderly (Brassington et al., 2000), and one study has suggested that insomnia, but not hypnotic use, was associated with a greater risk of falls (Avidan et al., 2005). Other side-effects associated with BzRAs include tolerance, rebound insomnia, abuse, and withdrawal. Rebound insomnia is generally seen for not more than 1–2 days, and not in all studies. Although concerns about tolerance may lead physicians and patients to limit use of these agents, the few longer-term studies that have been performed with eszopiclone, zolpidem, and zaleplon have, in fact, not shown evidence of obvious tolerance (Asnis et al., 1999; Walsh et al., 2000, 2007; Perlis et al., 2004). Abuse and dependence of BzRAs may occur in those with a history of substance abuse, and BzRAs should be avoided in those with a tendency to abuse substances. The risk is generally overestimated for those without such a history; patients with insomnia tend to show therapy-seeking, not drug-seeking, behavior (Mendelson et al., 2004). A recent attempt to assess risks and benefits for BzRAs in the treatment of insomnia concluded that, although these agents improved sleep, they also led to adverse effects in comparison to placebo (Holbrook et al., 2000a, b). These adverse effects, including increased daytime drowsiness (odds ratio 2.4) and dizziness or lightheadedness (odds ratio 2.6), did not, however, lead to increased rates of discontinuation of

hypnotics. A study of the use of BzRAs in elderly patients with insomnia, however, raised concerns that there were significant risks of both benzodiazepines and nonbenzodiazepines, including adverse cognitive events (4.78 times more common), adverse psychomotor events (2.61 times more common), and daytime fatigue (3.82 times more common) (Glass et al., 2005). The authors concluded that, in elderly patients, the risks of BzRAs might outweigh the benefits in some cases. Indications and limitations The benzodiazepines zolpidem and zaleplon are indicated for the “short-term treatment of insomnia”, whereas eszopiclone and zolpidem MR are indicated for the “treatment of insomnia”, without language-limiting duration of use. BzRAs should not be used during pregnancy (all are category C) or in those with a history of substance abuse. They should be used with caution in patients with pulmonary or liver disease, and in the elderly; dosage reductions at least are recommended in these populations. No hypnotics are approved for use in children under 18 years of age.

MELATONIN

AND MELATONIN RECEPTOR AGONIST

Melatonin, a hormone produced by the pineal gland, is available as an OTC preparation and has been used widely for insomnia and related sleep problems. Currently ramelteon is the only melatonin receptor agonist available for the treatment of insomnia and is available by prescription. These agents presumably act through their effects on melatonin receptors in the suprachiasmatic nucleus in the brain, although their exact mechanism has not been determined. Melatonin OTC melatonin preparations are absorbed rapidly and have a short half-life (up to 1 h). They are not regulated by the FDA. Melatonin’s hypnotic effects appear to be smaller than those of BzRAs; a recent meta-analysis showed an average decrease in sleep latency of 4 min (Brzezinski, 1997). Several studies have demonstrated that low doses of melatonin (300–500 mg) were effective in producing phase shifts in normal subjects and entraining circadian rhythms in blind individuals (Lewy et al., 1992, 2005; Sack et al., 2000). Melatonin does not appear to have obvious side-effects, other than sedation. Ramelteon Ramelteon, currently the only FDA-approved hypnotic that is not a BzRA, is an agonist of melatonin type 1 and 2 receptors and is structurally unrelated to melatonin; it does not show affinity for the GABA receptor

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT complex or for other receptors thought to be involved in sleep or wakefulness. It has a relatively short halflife (2.6 h) and its metabolite also acts as an melatonin receptor type 1 (MT1)/MT2 agonist. Ramelteon’s most robust sleep effects are the reduction of latency to sleep onset, and it is therefore indicated for the treatment of insomnia characterized by difficulty with sleep onset. It has also been reported to increase total sleep time in some studies (Erman et al., 2006), but it does not appear to decrease wakefulness after sleep onset. The main side-effects of ramelteon are somnolence, dizziness, and fatigue. Important distinctions from the BzRA class include no evidence of tolerance, withdrawal, rebound insomnia, cognitive or psychomotor impairment, or daytime sedation, and it is therefore not classified as a controlled substance by the FDA (Buysse et al., 2005). There are no data at present regarding its efficacy in treating circadian rhythm disorders. Ramelteon may not be as efficacious for insomnia as some of the BzRAs, but other factors make it an attractive alternative for many patients: its low toxicity and wide safety margin; few to no adverse effects; and its ability to be used in patients with a history of substance abuse and a variety of medical disorders, including mild to moderate pulmonary disease. It should not be used in combination with fluvoxamine or other potent inhibitors of cytochrome P450 1A2, because this leads to dramatically increased levels of ramelteon. It is not recommended for use in pregnant women.

NEW

WARNINGS FOR HYPNOTICS

In 2007, the FDA introduced a change in label for hypnotics, including benzodiazepines, BzRAs, and ramelteon, based on rare but potentially serious adverse events that had been reported following ingestion of hypnotics (US Food and Drug Administration, 2007). These included severe allergic reactions and complex sleep-related behaviors, such as sleep-driving, sleepeating, and sleep-sex, in which individuals engaged in these activities without awakening fully. Such reactions are more likely to occur when hypnotics are combined with other sedatives, including alcohol, or taken at higher than recommended doses.

SEDATING

ANTIDEPRESSANTS

Despite a relative lack of data and no FDA indication for insomnia, sedating antidepressants, such as the tricyclics, trazodone and mirtazapine, are some of the most commonly used agents for treating chronic insomnia. In general, there are relatively few efficacy data regarding the use of these agents in primary insomnia.

739

Tricyclic antidepressants (TCAs) Amitriptyline and doxepin are some of the more commonly used TCAs in the treatment of insomnia (Walsh, 2004a). Their therapeutic effects in depression are related to inhibition of serotonin and norepinephrine reuptake, whereas their effects on sleep are probably mediated by their antagonistic effects on histamine type 1 (H1), serotonin type 2 (5HT2) and a-adrenergic type 1 receptors. TCAs have long half-lives, which often leads to daytime sedation and other adverse effects. In general, when used to promote sleep they are prescribed at doses lower than those recommended for treating depression. The effects of TCAs on sleep have been studied more frequently in patients with major depressive disorder, where they have been shown to reduce latency to sleep onset and increase sleep efficiency (Roth et al., 1982; Shipley et al., 1985). PSG studies in adults and elderly adults with primary insomnia showed that low doses of doxepin (1, 3, or 6 mg) led to improvements in objective sleep and subjective sleep maintenance and duration in comparison with placebo, with no evidence of sideeffects such as anticholinergic effects, hangover, or memory impairment (Roth et al., 2007; Scharf et al., 2008). TCAs at higher doses have profound effects on sleep architecture, most notably suppression of REM sleep (Obermeyer and Benca, 1996; Mayers and Baldwin, 2005). REM sleep rebound and sleep disturbance may thus occur following abrupt discontinuation of TCAs, making them less attractive for intermittent dosing. TCAs can also have adverse effects on sleep, including the exacerbation of restless legs syndrome or periodic limb movements, or precipitation of REM behavior disorder (Wilson and Argyropoulos, 2005). They can also induce hypomania or mania in patients with underlying bipolar disorder, which is generally associated with severe insomnia. All tricyclics have significant anticholinergic effects, which leads to many of their side-effects, including dry mouth, constipation, urinary retention, and sweating, although amitriptyline has the strongest effects. Orthostatic hypotension can result from a1-receptor antagonism, increasing the risk of falls. The TCAs also have quinidine-like effects on cardiac conduction, which can result in prolongation of the QT interval; cardiotoxicity is a major concern and these drugs have a high risk of fatality in overdosage. Although there are relatively few studies documenting its effects on sleep, trazodone has been one of the most frequently prescribed drugs for insomnia, and is probably used almost exclusively for this purpose at present, usually in doses of up to 100 mg at bedtime. Its popularity is probably due to its low cost, low abuse potential, and lack of restrictions on long-term use.

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Its effects on sleep are probably due to its antihistaminergic effects at the H1 receptor, a1-receptor antagonism, and 5HT2 receptor antagonism. In several studies in depressed patients, trazodone administration resulted in reduced sleep latency, and increased sleep efficiency and total sleep (Mendelson, 2005). In the one double-blind, placebo-controlled study that has been performed in primary insomnia, trazodone 50 mg and zolpidem 10 mg were compared with placebo over a 2-week period (Walsh et al., 1998). During the first week, trazodone and zolpidem led to subjective reductions in sleep latency, increases in total sleep and sleep quality, and decreased wakefulness after sleep onset, but zolpidem produced a greater reduction in sleep latency than trazodone. During the second week, trazodone did not differ from placebo, whereas zolpidem still produced a significantly shorter sleep latency and more total sleep. There are insufficient data to conclude that trazodone does not lead to tolerance or rebound insomnia. Trazodone is associated with a number of frequent adverse effects, including daytime sedation/drowsiness, dizziness, dry mouth, gastrointestintal upset, blurred vision, and headache; these have led to fairly high discontinuation rates in clinical trials (Mendelson, 2005). Although less common, significant cardiovascular effects, such as orthostatic hypotension, prolonged QT interval, and cardiac arrhythmias may occur. Priapism, although quite rare, is a medical emergency and can occur even with low doses. One of the major metabolites of trazodone, meta-chlorophenylpeperazine (m-CPP), has serotonergic effects and may contribute to serotonin syndrome (confusion/delirium, hyperreflexia, autonomic instability) when trazodone is used in combination with other serotonergic agents. These potential side-effects raise concerns about using trazodone in elderly or medically ill populations. Mirtazapine tends to be used at low doses (7.5–15 mg) as a sleep-inducing agent and probably affects sleep through antagonism of H1 receptors, 5HT2 receptors, and a1-adrenergic receptors. It is generally believed that lower doses of mirtazapine are more sedating than higher doses, but there are few objective clinical data to support this or other efficacy claims for mirtazapine. Common side-effects of mirtazapine include drowsiness, daytime sedation, dry mouth, increased appetite, and weight gain. Its low toxicity is an advantage over some of the other sedating antidepressants.

ATYPICAL

ANTIPSYCHOTICS

Atypical antipsychotics, particularly quetiapine and olanzapine, are also used with increasing frequency for insomnia. Like the older antipsychotics, these

agents act through blockade of dopamine type 2 (D2) receptors, but they also act through antagonism of 5HT2A and 5HT2C receptors, antihistaminergic effects, and antagonism of a1-adrenergic receptors. Although they may have a role in treating comorbid insomnia in patients with primary indications for their use (e.g., psychotic disorders, bipolar disorder, treatmentrefractory depression), their use in primary insomnia should be avoided if possible, because of their adverse side-effects. One controlled study on the effects of quetiapine at 25 or 100 mg performed in healthy male volunteers (Cohrs et al., 2004) resulted in shorter sleep latency, increased total sleep and sleep efficiency, and improved subjective sleep quality. The 100-mg dose, however, caused a significant increase in periodic leg movements. One night of administration of olanzapine to healthy male volunteers produced similar effects to quetiapine in comparison with placebo (Sharpley et al., 2000). In an open-label study in depressed patients, olanzapine added to SSRI treatment led to increased sleep efficiency and slow-wave sleep (Sharpley et al., 2005). In addition to the lack of efficacy data for insomnia, potentially serious adverse events are associated with atypical antipsychotics. As with the older antipsychotics, extrapyramidal effects may occur. Other concerns are the risk of weight gain, glucose intolerance, dyslipidemia, daytime sedation, and cognitive impairment. These agents carry a “black box warning” for increased risk of sudden death in elderly patients with dementia.

ANTICONVULSANTS Several anticonvulsants acting on the GABA system to increase GABA effects in the brain have been used in the treatment of insomnia. There are currently few data regarding their use in insomnia, but they appear to have some sedating and/or sleep-promoting effects. Their advantages include low toxicity and that they are not controlled substances. Gabapentin is thought to increase synaptic levels of GABA, but its mechanism of action is not clearly understood (Czapinski et al., 2005). There are no systematic studies on the efficacy of gabapentin for insomnia, but it has been reported to increase slowwave sleep in patients with epilepsy (Legros and Bazil, 2003), improve insomnia ratings in an open-label study of alcoholics with insomnia (Karam-Hage and Brower, 2003), and increase slow-wave sleep in normal adults (Foldvary-Schaefer et al., 2002). Gabapentin is generally well tolerated and has low toxicity, but it can cause daytime sedation, dizziness, and leukopenia. Tiagabine inhibits GABA reuptake through inhibition of the GABA transporter. It is one of the few

INSOMNIA: NATURE, DIAGNOSIS, AND TREATMENT 741 anticonvulsants with data from placebo-controlled be useful for long-term treatment. Antihistamines can studies in insomnia. In a study of elderly subjects with cause adverse effects such as daytime sedation, cogniinsomnia, doses of 4–8 mg significantly increased tive impairment, increased risk of accidents, dizziness, slow-wave sleep, and doses of 6–8 mg led to decreased tinnitus, gastrointestinal symptoms, weight gain, and awakenings (Roth et al., 2006). At the 8-mg dose, howincreased intraocular pressure in narrow-angle glaucoma ever, subjects reported subjective decreases in total (Casale et al., 2003). sleep, less refreshing sleep, worse daytime functioning, and more adverse events. Similar effects were seen in Current status of pharmacotherapy a study of tiagabine in healthy elderly subjects (Walsh for insomnia et al., 2005). A study in nonelderly adults with primary The National Institutes of Health State of the Science insomnia using tiagabine doses of up to 16 mg also Conference on Manifestations and Management of showed that the drug produced increased slow-wave Chronic Insomnia in Adults was held in June 2005 sleep and decreased waking after sleep onset (at the (http://consensus.nih.gov/2005/2005InsomniaSOS026html. 16-mg dose), but no significant effect on latency to htm). This nonpartisan review of currently available persistent sleep (Walsh et al., 2006). Higher doses were treatments came to several conclusions regarding associated with more adverse effects. Thus, although pharmacotherapy for insomnia: potentially helpful for insomnia, the side-effects of tiagabine may limit its utility. BzRAs. BzRAs, including benzodiazepines and nonPregabalin, like gabapentin, was designed as a GABA benzodiazepines, are effective in the short-term treatanalog and its mechanism of action is unclear. A comparment of insomnia and most have not been studied ison of alprazolam with pregabalin in healthy subjects long term using randomized clinical trials; eszopliclone showed that both drugs reduced sleep latency and has shown sustained efficacy for 6 months in patients decreased the amount of REM sleep (Hindmarch et al., with primary insomnia. Adverse effects of BzRAs 2005); however, pregabalin led to significant increases include residual daytime sedation, motor coordination in slow-wave sleep, whereas alprazolam decreased it. and cognitive impairment, dependence, and rebound The most common side-effects of pregabalin are insomnia. Side-effects are greater in elderly patients. dizziness and somnolence. Side-effects related to the newer benzodiazepine receptor agonists are lower, probably related to their shorter ANTIHISTAMINES half-lives. Abuse liability of BzRAs does not appear to be a major problem, but data relating to long-term use Antihistamines are the active ingredient in most OTC for insomnia require further study. medications and act through antagonism of H recep1

tors. Diphenhydramine and doxylamine are found in virtually all OTC sleeping medications, but it is important to note that doxepin, described above, is a more potent antihistamine than any of the OTCs. H1 antagonists cause sedation in most individuals, but can lead to paradoxical excitation in some individuals, particularly with higher doses and/or in children and the elderly. Despite the widespread use of these agents, there are almost no data regarding their effects on sleep, and there are no rigorous, placebo-controlled studies in insomnia. An outpatient study found that patients with mild to moderate insomnia in a family practice setting reported more restful sleep and shorter sleep latency with 50 mg diphenhydramine in comparison to those taking placebo (Rickels et al., 1983). An assessment of motor activity and subjective sleep parameters in normal adults showed minimal or no effects on sleep parameters, and a tendency for increased motor activity (Borbely and Youmbi-Balderer, 1988). Finally, a study in normal men showed that diphenhydramine led to rapid tolerance of its sedative effects (Richardson et al., 2002), suggesting that these agents may not

Sedating antidepressants. Trazodone is the most commonly prescribed medication for insomnia in the USA. It is sedating and improves several sleep parameters, but there are no studies of long-term use for chronic insomnia. Doxepin has beneficial effects for insomnia for up to 4 weeks, but there are insufficient data for other antidepressants, such as amitriptyline and mirtazapine, in the treatment of insomnia; all antidepressants have significant adverse effects. Other agents. There are no data regarding the use of antipsychotics for the treatment of insomnia; these agents have significant risks, and they are not recommended for use in insomnia. Antihistamines are commonly used, but there are no data regarding their efficacy for insomnia and they have significant adverse effects. Melatonin is not regulated by the FDA and there is significant variability in preparations. It appears to be effective for circadian rhythm disorders, but there is little evidence for efficacy in the treatment of insomnia. There are no data regarding safety in long-term use (National Institutes of Health, 2005).

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SUMMARY AND CONCLUSIONS Insomnia is a prevalent health complaint that may present as a primary disorder or as a comorbid condition to a medical or psychiatric disorder. Persistent insomnia is associated with significant morbidity and healthcare costs. Progress has been made to standardize research diagnostic criteria, but there is still little information about the psychological and biological bases of insomnia, or about its natural history and long-term prognosis. Significant advances have also been made in developing and validating therapeutic approaches for the management of both acute and chronic insomnia. Despite these advances, insomnia remains underrecognized and undertreated in clinical practice. Additional research is needed to document further the etiology of insomnia and its natural history, and to optimize therapeutic outcomes, not only in terms of reducing insomnia symptoms but also in terms of impact on other indicators of morbidity and cost– effectiveness. A significant challenge for the future will be to disseminate validated therapies and practice guidelines more efficiently, and increase their use in practice.

ACKNOWLEDGEMENTS Preparation of this chapter was facilitated by research grants from the National Institute of Mental Health (MH60413) and the Canadian Institutes for Health Research (MT-42504).

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Roth T, Wright KP Jr., Walsh J (2006). Effect of tiagabine on sleep in elderly subjects with primary insomnia: a randomized, double-blind, placebo-controlled study. Sleep 29: 335–341. Roth T, Rogowski R, Hull S et al. (2007). Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep 30: 1555–1561. Rybarczyk B, Lopez M, Benson R et al. (2002). Efficacy of two behavioral treatment programs for comorbid geriatric insomnia. Psychol Aging 17: 288–298. Rybarczyk B, Stepanski E, Fogg L et al. (2005). A placebocontrolled test of cognitive-behavioral therapy for comorbid insomnia in older adults. J Consult Clin Psychol 73: 1164–1174. Sack RL, Brandes RW, Kendall AR et al. (2000). Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 343: 1070–1077. Savard J, Simard S, Ivers H et al. (2005). Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: Sleep and psychological effects. J Clin Oncol 23: 6083–6096. Scharf MB, Roth PB, Dominguez RA et al. (1990). Estazolam and flurazepam: a multicenter, placebo-controlled comparative study in outpatients with insomnia. J Clin Pharmacol 30: 461–467. Scharf MB, Roth T, Vogel GW et al. (1994). A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry 55: 192–199. Scharf MB, Erman M, Rosenberg R et al. (2005). A 2-week efficacy and safety study of eszopiclone in elderly patients with primary insomnia. Sleep 28: 720–727. Scharf M, Rogowski R, Hull S et al. (2008). Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, doubleblind, placebo-controlled crossover study. J Clin Psychiatry 69: 1557–1564. Schutte-Rodin S, Broch L, Buysse D et al. (2008). Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 4: 487–504. Sharpley AL, Vassallo CM, Cowen PJ (2000). Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT2C receptors in vivo. Biol Psychiatry 47: 468–470. Sharpley AL, Attenburrow ME, Hafizi S et al. (2005). Olanzapine increases slow wave sleep and sleep continuity in SSRI-resistant depressed patients. J Clin Psychiatry 66: 450–454. Shipley JE, Kupfer DJ, Griffin SJ et al. (1985). Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients. Psychopharmacology 85: 14–22. Simon GE, VonKorff M (1997). Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry 154: 1417–1423. Sivertsen B, Omvik S, Pallesen S et al. (2006a). Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 295: 2851–2858.

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Sivertsen B, Overland S, Neckelmann D et al. (2006b). The long-term effect of insomnia on work disability: the HUNT-2 historical cohort study. Am J Epidemiol 163: 1018–1024. Smith MT, Perlis ML (2006). Who is a candidate for cognitive-behavioral therapy for insomnia? Health Psychol 25: 15–19. Smith MT, Perlis ML, Park A et al. (2002). Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 159: 5–11. Smith MT, Huang MI, Manber R (2005). Cognitive behavior therapy for chronic insomnia occurring within the context of medical and psychiatric disorders. Clin Psychol Rev 25: 559–592. Soeffing JP, Lichstein KL, Nau SD et al. (2008). Psychological treatment of insomnia in hypnotic-dependant older adults. Sleep Med 9: 165–171. Spielman AJ, Glovinsky PB (1991). The varied nature of insomnia. In: P Hauri (Ed.), Case Studies in Insomnia. Plenum Press, New York, pp. 1–15. Spielman AJ, Saskin P, Thorpy MJ (1987). Treatment of chronic insomnia by restriction of time in bed. Sleep 10: 45–56. Staner L, Ertle S, Boeijinga P et al. (2005). Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring. Psychopharmacology 181: 790–798. Taylor DJ, Lichstein KL, Weinstock J et al. (2007a). A pilot study of cognitive-behavioral therapy of insomnia in people with mild depression. Behav Ther 38: 49–57. Taylor DJ, Mallory LJ, Lichstein KL et al. (2007b). Comorbidity of chronic insomnia with medical problems. Sleep 30: 213–218. US Food and Drug Administration (2007). FDA Requests Label Change for all Sleep Disorder Drug Products. Online. Available: http://www.fda.gov/bbs/topics/NEWS/ 2007/NEW01587.html. Vallieres A, Ivers H, Bastien CH et al. (2005a). Variability and predictability in sleep patterns of chronic insomniacs. J Sleep Res 14: 447–453. Vallieres A, Morin CM, Guay B (2005b). Sequential combinations of drug and cognitive behavioral therapy for chronic insomnia: an exploratory study. Behav Res Ther 43: 1611–1630. Verster JC, Volkerts ER, Schreuder AH et al. (2002). Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. J Clin Psychopharmacol 22: 576–583.

Verster JC, Veldhuijzen DS, Volkerts ER (2004). Residual effects of sleep medication on driving ability. Sleep Med Rev 8: 309–325. Vgontzas AN, Tsigos C, Bixler EO et al. (1998). Chronic insomnia and activity of the stress system: a preliminary study. J Psychosom Res 45 (Spec. No.): 21–31. Vgontzas AN, Bixler EO, Lin HM et al. (2001). Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab 86: 3787–3794. Vignola A, Lamoureux C, Bastien CH et al. (2000). Effects of chronic insomnia and use of benzodiazepines on daytime performance in older adults. J Gerontol B Psychol Sci Soc Sci 55: P54–P62. Vollrath M, Wicki W, Angst J (1989). The Zurich study. VIII. Insomnia: association with depression, anxiety, somatic syndromes, and course of insomnia. Eur Arch Psychiatry Neurol Sci 239: 113–124. Walsh JK (2004a). Clinical and socioeconomic correlates of insomnia. J Clin Psychiatry 65 (Suppl 8): 13–19. Walsh JK (2004b). Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep 27: 1441–1442. Walsh JK, Erman M, Erwin C (1998). Subjective hypnotic efficacy of trazodone and zolpidem in DSM-III-R primary insomnia. Hum Psychopharmacol 13: 191–198. Walsh JK, Vogel GW, Scharf M et al. (2000). A five week, polysomnographic assessment of zaleplon 10 mg for the treatment of primary insomnia. Sleep Med 1: 41–49. Walsh JK, Randazzo AC, Frankowski S et al. (2005). Dose– response effects of tiagabine on the sleep of older adults. Sleep 28: 673–676. Walsh JK, Zammit G, Schweitzer PK et al. (2006). Tiagabine enhances slow wave sleep and sleep maintenance in primary insomnia. Sleep Med 7: 155–161. Walsh JK, Krystal AD, Amato DA et al. (2007). Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life, and work limitations. Sleep 30: 959–968. Wang PS, Bohn RL, Glynn RJ et al. (2001). Zolpidem use and hip fractures in older people. J Am Geriatr Soc 49: 1685–1690. Wilson S, Argyropoulos S (2005). Antidepressants and sleep: a qualitative review of the literature. Drugs 65: 927–947. Winkelman JW, Buxton OM, Jensen JE et al. (2008). Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1H-MRS). Sleep 31: 1499–1506.

Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 46

Pharmacotherapy for insomnia STEPHEN FEREN 1, PAULA K. SCHWEITZER 1, AND JAMES K. WALSH 1, 2, 3 * Sleep Medicine and Research Center, St. John’s Mercy Medical Center and St. Luke’s Hospital, Chesterfield, MO, USA

1

2

Department of Psychology, St. Louis University, St. Louis, MO, USA

3

Department of Psychiatry, St. Louis University Health Sciences Center, St. Louis, MO, USA

INTRODUCTION Most insomnia researchers would likely agree that over the past 15 years our understanding of and ability to treat insomnia has improved significantly. This progress, however, like any small amount of light, casts into sharp focus the knowledge gaps that remain, and those same insomnia experts would also agree that we clearly do not know enough to provide evidenced-based treatment guidelines, especially for chronic insomnia. There are compelling efficacy data showing the benefit of a number of hypnotics for the sleep of insomniacs enrolled in carefully designed research trials, but there is an equal lack of effectiveness data showing a benefit for hypnotics in diverse clinical populations. A drug is effective if it is tolerable to the majority of patients in the clinical environment and the observed therapeutic effect is clinically relevant, i.e., affects the severity, duration, progression, or consequences of a disorder (in contrast to changing research measures, such as latency to sleep onset or total sleep time). An equally serious problem is the apparent disconnection between current scientific evidence of insomnia therapies and the translation of this knowledge into clinical practice. The statement summarizing the National Institutes of Health (NIH) State-of-the-Science Conference on Manifestations and Management of Chronic Insomnia in Adults concluded that evidence is available to support only the use of benzodiazepine receptor agonists (BzRAs) for the pharmacological treatment of insomnia (NIH, 2005). However, a variety of other drugs are increasingly used to treat insomnia despite the absence of efficacy and effectiveness data for this purpose, and the presence of known safety concerns

(Walsh and Schweitzer, 1999) It has been suggested that these medications are perhaps more safe or tolerable, but these perceptions have developed in the absence of well-designed safety studies, or in the presence of systematic evaluations that in fact show the opposite – that there is a significant burden of unwanted effects or risk of serious side-effects not shared by BzRAs. Regulatory issues have also been cited as influencing physician prescribing in this area (Walsh, 2004a). This chapter describes current knowledge about the medications used for promotion of sleep, beginning with the benzodiazepines and nonbenzodiazepine agents acting as agonists at the gamma-aminobutyric acid type A (GABAA) receptor complex. The focus then moves to other medications which have a sedating effect, including antidepressants, antihistamines, antipsychotics, and others. The side-effects of these medications and the precautions necessary for their use in special patient populations are discussed. A summary of the indications and contraindications for treatment of primary insomnia is followed by a discussion of the limited knowledge we have about the pharmacological treatment of comorbid insomnia.

Definition and symptoms of insomnia Insomnia, regardless of system of classification used, is commonly characterized by one or more of the following symptoms: difficulty initiating sleep, difficulty maintaining sleep, or nonrefreshing sleep. Inherent in the definition is the assumption that there is adequate time and opportunity for sleep. Finally, the inadequate quantity or poor quality of sleep is associated with clinically significant distress or impairment in daytime

*Correspondence to: James K. Walsh, Ph.D., Sleep Medicine and Research Center, 232 S. Woods Mill Road, Chesterfield, Missouri 63017, USA. Tel: 314-205-6030, Fax: 314-205-6025, E-mail: [email protected]

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functioning, an essential diagnostic feature of insomnia in both the International Classification of Sleep Disorders (American Academy of Sleep Medicine, 2005) and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (American Psychiatric Association, 2000) The daytime distress or impairment is most often a report of fatigue, irritability, impaired cognition, or poor performance at work. The efficacy of BzRAs in relieving various nocturnal symptoms of insomnia is well established, with some variability among drugs related largely to pharmacokinetic differences. On the other hand, little research has focused upon daytime symptoms, and a relatively modest amount of data exists to support improvement in daytime aspects of insomnia. A chronic symptom of insomnia can reflect a primary disorder or may be comorbid with a large number of medical, psychiatric, and circadian rhythm disorders. Transient insomnia, the duration of which is self-limiting by definition, commonly results from acute stress, illness, transmeridian travel (jet lag), or other lifestyle factors. Most investigations of BzRA efficacy and safety have been conducted with samples of primary insomniacs, or with models of transient insomnia. A small number of similar studies of comorbid chronic insomnia have also been published. A more detailed discussion of the etiology, clinical presentation, natural history, and differential diagnosis of insomnia can be found in Chapters 44 and 45. Of relevance to the major thrust of the present chapter, BzRAs provide symptomatic relief of insomnia. No compelling data exist to support the use of a specific medication for specific insomnia diagnoses. Thus, the patient’s symptom presentation, age, and other medical problems should direct the physician’s choice of drug.

Drugs used as hypnotic agents Barbiturates were frequently used as hypnotics after barbital was first developed in 1903 (Institute of Medicine, 1979). By the 1960s and 1970s, of the 50 or so barbiturates to be developed and used clinically, a number of short- and intermediate-acting agents became favored for sleep induction. These included secobarbital, amobarbital, and pentobarbital (Harvey, 1975). These barbiturates were, however, less than ideal. Their relatively long half-lives (15–20 hours) led to frequent residual sedation. Tolerance developed rapidly because of hepatic enzyme induction, leading to dose escalation. Respiratory depression, circulatory collapse, and coma could occur at dosages as low as 10 times the therapeutic hypnotic dose, and these fatal effects were easily potentiated by other sedating agents, particularly alcohol (Wilberg et al., 1969). Dependence was not uncommon.

Benzodiazepines were first introduced in 1961 with chlordiazepoxide (LibriumW), but barbiturates remained in common use through 1971 when half of all hypnotic prescriptions were still for barbiturates. In 1973, barbiturate hypnotics were classified as schedule II and by 1977 barbiturate use fell to only 17% of all hypnotic prescriptions (Balter andBauer, 1975). Through the 1970s and 1980s, benzodiazepines remained the mainstay of insomnia treatment, supplemented by a small handful of other sedative medications (chloral hydrate, glutethimide, methaqualone) and sedating tricyclic antidepressants (Institute of Medicine, 1979). Over the past 15–20 years, the use of agents with a Food and Drug Administration (FDA) indication for insomnia (until recently, all BzRAs) has progressively declined in favor of the use of medications for which much less known is known about their use for insomnia. For example, over the 9 years ending in 1996, the use of sedating antidepressants increased by 146%, while the use of medications with an FDA indication for the treatment of insomnia fell by 53.7% (Walsh and Schweitzer, 1999). Analysis of the pharmacological treatment for insomnia, based on the 2002 Verispan Physician Drug Audit, estimated that antidepressants were recorded 5.268 million times for the treatment of insomnia, compared with 3.442 million occurrences for medications with an FDA indication for insomnia (Walsh, 2004a). There was also significant use of anxiolytics, antipsychotics, and anticonvulsants (Figure 46.1). Of the 16

Medications used as Hypnotics Diphenhydramine Cyclobenzaprine Doxepin Burazepam Olanzapine

0.192 0.195 0.199 0.205 0.210

Lorazepam Alprazolam Hydroxyzine Clonazepam

0.277 0.287 0.293 0.394

Zaleplon Quetiapine Temazepam Mirtazapine

0.405 0.460 0.558 0.662

Amitriptyline Zolpidem Trazodone

0.774 2.074 2.73

0

0.5

1

1.5

2

3

2.5

Projected number of occurences (in millions) FDA indication Insomnia

Schizophrenia

Depression

Anxicty

Other

Fig. 46.1. The 16 drugs identified in the 2002 Verispan Physician Drug and Diagnosis Audit (Verispan, Yardley, PA) as having the highest projected number of drug occurrences associated with the desired actions of “hypnotic”, “promote sleep”, or “sedate night” (adapted from Walsh, 2004b).

PHARMACOTHERAPY FOR INSOMNIA Table 46.1 Medication classes for the drugs most commonly mentioned for the treatment of insomnia in 2002 (adapted from Walsh, 2004a) Class

Occurrence (in millions)

Hypnotics with an FDA indication NonFDA-approved sedatives Antidepressants Anxiolytics Antipsychotics Anticonvulsants Antihistamines

3.442 7.677 5.268 0.822 0.815 0.552 0.220

FDA, Food and Drug Administration.

most commonly identified drugs for the treatment of insomnia in 2002 (Table 46.1), three of the four drugs with the most insomnia-related occurrences were antidepressants, and only four of the top 16 had an FDA indication for insomnia. One interpretation of this pattern of medication use is that physicians believe that most insomnia is related to depression, as a sedating antidepressant would seem to be a reasonable choice for insomnia comorbid with depression. However, in 2002, 84% of trazodone occurrences for insomnia were at a dose of 100 mg or less, which is lower than the 150 mg recommended as the initial daily dose and even lower than the typical therapeutic dose range for depression, suggesting that trazodone is commonly used to treat insomnia symptomatically (Walsh, 2004a).

BENZODIAZEPINE RECEPTOR AGONISTS These agents are named based on their activity at one or more of the benzodiazepine binding sites located on the GABA complex. Although there are several classes of GABA receptor, the hypnotic effect of the BzRAs is mediated through members of the most common receptor class, GABAA. The GABAA receptor complex is, in brief, a chloride ion channel composed of five protein subunits. When the site is activated by GABA, the influx of negatively charged chloride ions into the neuron hyperpolarizes the cell resulting in a decrease in neuronal activity. BzRAs modulate the response of the receptor complex to GABA, enhancing entry of chloride and facilitating GABAergic inhibition (Wafford, 2005). BzRA activity requires the presence of GABA. The GABAA system is complex (Nutt, 2005). Various combinations of the five proteins result in multiple GABAA

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receptor complex subtypes. A variety of benzodiazepine receptors have been characterized, some even appearing to be insensitive to benzodiazepines. Zolpidem, zaleplon, and eszopiclone facilitate GABAergic activity by binding to benzodiazepine receptors, but they are not benzodiazepines. Moreover, not all GABAA complexes have benzodiazepine receptors. There are two types of BzRA (Table 46.2). The older group with a benzodiazepine chemical structure includes the hypnotics estazolam, flurazepam, quazepam, temazepam, and triazolam, as well as a number of anxiolytics and anticonvulsants. These agents are relatively similar in their receptor affinity, showing no strong selectivity for a particular subtype. Zaleplon, zolpidem, and eszopiclone are called nonbenzodiazepine BzRAs because they have different chemical structures but bind to identified benzodiazepine binding sites. Zolpidem was the first of this class to be used clinically in the USA, beginning in 1993. Because zolpidem and zaleplon have much higher affinities for the receptors on GABAA sites containing a1 subunits, and low affinity for other benzodiazepine receptors, they may have more specific activity. The GABAA receptors containing a1 subunits mediate sedative, amnestic, and some anticonvulsant properties, but neither anxiolysis nor myorelaxation (Mohler et al., 2002). Eszopiclone appears to be less selective for a specific receptor subtype.

Efficacy/effectiveness of the BzRAs All of the BzRA hypnotics are efficacious in the treatment of insomnia, although there are some differences among these drugs owing to variations in rapidity of onset and duration of hypnotic action. Their efficacy has been measured both by polysomnographic (PSG) studies and by patient observation on sleep diaries and questionnaires (NIH, 2005) The standard PSG measure of sleep induction is the latency to sleep onset, and the measures of sleep maintenance are wake time after sleep onset (WASO) or number of awakenings. Measures combining both sleep induction and maintenance include total sleep time (TST) and sleep efficiency, the ratio of TST to time in bed. Meta-analyses of the BzRAs have supported their hypnotic efficacy, based on both patient reports and PSG measures, at least over a short treatment period (Nowell et al., 1997; Holbrook et al., 2000). As an example, the median period of treatment for a typical individual trial was approximately 1 week. Because these meta-analyses combined studies of various agents at multiple doses, they are helpful in describing general effects of these medications but less helpful in guiding specific treatment decisions.

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Table 46.2 Characteristics of benzodiazepine receptor agonists with an FDA indication for treatment of insomnia Recommended dose (mg)* Drug

Chemical class

Adult

Elderly

t½ (h)

Receptor specificity

Metabolism

Indiplon Zaleplon Zolpidem Eszopiclone Triazolam Temazepam Estazolam Flurazepam Quazepam

Pyrazolopyrimidine Pyrazolopyrimidine Imidazopyridine Cyclopyrrolone Benzodiazepine Benzodiazepine Benzodiazepine Benzodiazepine Benzodiazepine

TBD 10 10 2–3 0.25 30 2 30 7.5–15

TBD 5 5 1–2 0.125 15 1 15 7.5–15

1–1.5 1 1.5–2.4 5–7 2–4 8–20 8–24 48–120 48–120

GABAA a1 GABAA a1 GABAA a1 GABAA GABAA GABAA GABAA GABAA GABAA

CYP450 oxidation Aldehyde oxidation CYP450 oxidation CYP450 oxidation CYP450 oxidation Glucuronidation CYP450 oxidation CYP450 oxidation CYP450 oxidation

Recommended dosages are for healthy adults; when administered to the elderly, hypnotics should be started at half of the specified adult dose. GABAA, gamma-aminobutyric acid type A receptor complex; CYP450, cytochrome P450; TBD, to be determined.

All of the BzRA hypnotics reduce sleep latency, attributable to rapid absorption and onset of hypnotic activity. Investigations assessing maintenance of sleep (number of awakenings or WASO) typically find that a drug is more likely to be efficacious in maintaining sleep as its duration of action lengthens. Within this class, elimination half-life and dose are the primary determinants of duration of hypnotic action. Most of the BzRAs also increase TST. The exception is zaleplon, which does not reliably increase TST. However, zaleplon’s short duration of action allows administration during the middle of the night with minimal risk of residual sleepiness after rise time, provided 5 hours of sleeping time remains at the time of administration (Walsh et al., 2000a). Longer duration of efficacy trials suggest continued hypnotic benefit of BzRAs. In the early 1980s, Oswald and colleagues (1982) reported on two benzodiazepines that retained their effect on some qualitative patient estimates of hypnotic efficacy over 5–6 months of use. More recent studies of zolpidem and zaleplon used PSG measures to show persistent efficacy over 5 weeks of nightly use (Scharf et al., 1994; Walsh et al., 2000b). A recent large study of more than 500 primary insomniacs taking eszopiclone 3 mg nightly over 6 months demonstrated persistent reductions in both subjective sleep latency and WASO when compared to placebo (Krystal et al., 2003). The amount of TST, number of awakenings, and quality of sleep were also better than placebo at each time point. In an open-label 6-month extension of this trial, subjects taking eszopiclone 3 mg continued to show significant improvements in latency to sleep onset, WASO, and an improved daytime sense of wellbeing and ability to function, when

compared to their original baseline prior to the doubleblind phase, as well as when compared to the time of entry into the open-label phase (Roth et al., 2005a). Alternative schedules of hypnotic administration, involving non-nightly use, have been studied, in part because of the assumption that tolerance and dependence would develop with long-term nightly use of BzRAs. It has also been suggested that intermittent administration more closely resembles the pattern of hypnotic use demonstrated by a large number of chronic insomniacs. There are few studies addressing this issue. Zolpidem 10 mg, taken as needed on a non-nightly schedule for up to 12 weeks, improved patient reports of sleep latency, number of awakenings, TST, and sleep quality, when compared to placebo (Walsh et al., 2000c; Perlis et al., 2004). No rebound insomnia was seen on nights that medication was not taken, and biweekly investigator global ratings of insomnia showed a reduction in severity even when treatment and nontreatment nights were considered as a whole. Similar improvements in subjective sleep latency, number of awakenings, TST, and quality of life were seen with zolpidem 10 mg when administered discontinuously (alternating with placebo) over 2 weeks on a fixed schedule (Hajak et al., 2002). Although it is reasonable to suspect that intermittent BzRA use reduces the risk of habituation or abuse, there is little evidence that these risks are significant even when these agents are taken chronically every night for periods of up to 3–9 months. Perhaps the most obvious benefits of intermittent use are the reduction in exposure to potential side-effects and the decrease in cost of treatment. Tolerance is often cited as a potential concern when hypnotic medications are administered nightly beyond

PHARMACOTHERAPY FOR INSOMNIA 751 a short period of time (Winkelman and Pies, 2005). tasks, and often report increased irritability and more However, tolerance to the hypnotic effects of BzRAs negative mood, primary insomniacs have not been has not developed in the vast majority of studies of hypfound to display consistent deficits in waking function. notic efficacy, most of which have been 4–12 weeks in Although patients with insomnia report a number of duration, with a few examining 3–6 months of nightly perceived impairments in how they feel and function, use. Tolerance refers to a reduction in the effect of a consistent experimental documentation is lacking. In drug when administered repeatedly at a constant dose, fact, there is evidence of reduced sleepiness during the or the need for higher doses to produce a constant level day, compared with that in control subjects (Stepanski of effect. Studies that are often cited as evidence for et al., 1988). These findings, along with diurnal and tolerance to the hypnotic effect demonstrate changes nocturnal evidence of heightened metabolic rate, faster in the control group over time (Mitler et al., 1984). Typiheart rates, and increased cerebral oxygen utilization. cally the improvement in sleep in the treatment group is have led to the hyperarousal hypothesis as a potenmaintained over time whereas the sleep of the placebo tial pathophysiological substrate of primary insomnia group gradually improves, resulting in loss of statistical (Bonnet and Arand, 1997). significance between groups by the end of the trial The absence of objective evidence of daytime period. The sleep of the treatment group does not impairment does not negate the significance of primary worsen with time. Explanations for the improvement insomnia. There are a number of associated conditions in the placebo group could include spontaneous remisand other correlates that not only deserve further sciension of insomnia or statistical regression to the mean tific inquiry, but are also relevant to the clinical situation (McCall et al., 2005). Improvements in sleep hygiene (Walsh, 2004b; Metlain et al., 2005). Quality of life (Katz are inherent in many study designs, and subjects’ behavand McHorney, 2002) is significantly reduced and healthior often improves under the watch of observers care utilization (Simon and VonKorff, 1997) increased in (Hawthorne effect). Finally, the placebo effect should primary insomnia. Insomnia is well known to be a risk not be underestimated. factor for both new onset and relapse of depression. Investigations into the effectiveness of BzRAs in Recovering alcoholics with insomnia are more likely to clinical populations have been limited to patient surveys relapse. Absenteeism (Walsh et al., 1996) and accidents or unblinded open-label protocols. In a large study of (Balter and Uhlenhuth, 1991; Brassington et al., 2000) 532 patients surveyed by Ohayon and colleagues appear to be more likely with chronic insomnia. (1999), 66.5% reported “a lot” of improvement in sleep If the daytime correlates of insomnia are related to quality, whereas only 14.4% reported little or no a dysfunction of sleep, it is reasonable to expect that improvement with the use of prescription hypnotics. In treatment of insomnia should translate into a measuranother survey relying on telephone interviews, there able improvement in daytime function. Only recently was a high rate of satisfaction with the effect that hyphave investigators begun to search for daytime notic medications had on sleep in individuals with a hisimprovements. For example, throughout a 6-month tory of either significant trouble with insomnia or use of period of efficacious eszopiclone treatment, primary a medication for sleep (Balter and Uhlenhuth, 1991). insomniacs reported improved daytime alertness, abilThis second survey study balanced the positive effects ity to function, and sense of wellbeing compared with of the hypnotics with their negative effects by asking placebo treatment (Krystal et al., 2003). Two studies the respondents: “Taking into account both the positive of individuals with insomnia comorbid with a medical effects on your sleep and daytime functioning and any condition such as rheumatoid arthritis (Walsh et al., negative effects you may have experienced, would you 1996) or periodic leg movements (Doghramji et al., take this medication again for the same purpose?” Of 1991) have shown reduced daytime sleepiness, as patients who responded, 84% of those taking triazolam reflected by mean sleep latency test scores, with hypand 74% of those taking temazepam indicated they notic therapy. Similar improvements in alertness were would continue to use these hypnotics. seen in a study of elderly individuals (Roehrs et al., 1985). These results must be contrasted, however, with studies of primary insomniacs in which improvements Daytime Function in daytime function, when assessed objectively, have In light of the established behavioral consequences not been found with treatment of insomnia. associated with sleep deprivation, measurement of An important distinction must be made between indidaytime performance in primary insomniacs has viduals with primary insomnia and those with comorbid largely yielded incongruous findings. Whereas normal insomnia. Conceptually, many individuals with comorsleepers deprived of sleep become sleepy, have diffibid insomnia have no primary dysfunction of their culty with attention, learning, and other cognitive sleep, or at least a less severe dysfunction. An

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exogenous or endogenous influence such as pain, noise, or an obstructed upper airway prevents or fragments sleep. In contrast, individuals with primary insomnia are inherently prone to shortened, fragmented, and/or unrestorative sleep. This inability to sleep is consistent with the observation that patients with primary insomnia, despite their poor-quality sleep, have increased wakefulness/alertness during the daytime compared with matched normal individuals (Stepanski et al., 1988). Their body temperature, metabolic rate, heart rate variability, and cortisol levels all demonstrate this increased level of arousal (Bonnet and Arand, 1995, 1998; Vgontzas et al., 2001). Studies that rely on measurement of daytime alertness or performance to document a response to a hypnotic are likely to be influenced by this “hyperaroused” state.

Safety The concerns expressed by most medical practitioners regarding the use of hypnotics for insomnia often include a risk for dependence, abuse, or injury as a consequence of ambulation while sedated. Available evidence, however, suggests that adverse events are much less frequent than commonly perceived, and that the side-effects that do occur are typically infrequent and mild. The most common are usually headache, sleepiness, and dizziness. Toxicity has also been cited but, when compared to other drug classes, the margin of safety or therapeutic index for the hypnotics is wide. The ratio of the effective dose to the fatal dose is, in fact, so large that toxicity is rare. When hypnotics were used in an inpatient setting at a large academic hospital, the median rate of adverse events was found to be about 1 in every 20 000 doses. Even when all benzodiazepine tranquilizers and hypnotics were considered, adverse events were seen in only 1 in every 10 000 doses, and typically were related to the sedative effect of the drug (Mendelson et al., 1996).

RESIDUAL

SEDATION

Residual sedation is the persistent drowsiness or sleepiness that occurs during the day as a consequence of hypnotic use during the previous night. Residual sedation occurs when the activity of the hypnotic persists beyond the period of desired sleep, and is determined primarily by the dose and drug’s rate of elimination (see Table 46.2 for the half-lives of typical hypnotic medications) (Roth and Roehrs, 1992). Short-acting hypnotics (e.g., zaleplon, zolpidem) are generally found to be free of residual effects at recommended doses. The sedative effects of slowly eliminated hypnotics (e.g., flurazepam) can last well into or throughout the next day.

One practical concern related to residual sedation is the possibility of driving impairment. The hypnotics, like all sedative medications, are well documented to slow reaction time and reduce performance on psychomotor tests, so it is likely they will have an impact on driving when blood concentrations are high. A limited number of studies, however, have looked at the effect of zolpidem, zaleplon, and temazepam on driving ability in the morning following nighttime administration. The majority of these studies evaluated the driving performance of normal volunteers after short-term hypnotic administration in a simulated test environment, so the generalizability of these data to insomniacs driving in the real world is not straightforward. In general, when zaleplon, zolpidem, and temazepam are administered in typical hypnotic doses (10, 10, and 20 mg respectively) there appears to be no impairment in driving the next morning. If administered 4–5 hours before driving, zaleplon remains identical with placebo, whereas zolpidem appears to impair driving (Patat et al., 2001; Verster et al., 2004). BzRAs with a similar duration of action would presumably show a similar profile. Very important variables not assessed by any of these studies include baseline driving ability, potential interactions with other sedating drugs (Maes et al., 1999), age, insomnia itself, and concurrent medical problems. All of these issues should be considered when discussing the potential impact of hypnotics on driving safety.

AMNESIA Memory impairment with BzRAs occurs in the form of anterograde amnesia or difficulty remembering information presented after drug was ingested. It is not specific to hypnotics or to BzRAs; all sedatives, including alcohol and barbiturates, have been associated with anterograde amnesia. The period of amnesia occurs in relationship to the rise and fall of the plasma concentration, with higher peak concentrations resulting in more memory impairment (Roth et al., 1990; Greenblatt et al., 1991). Sleepiness is probably a mediating factor, because memory impairment has been demonstrated to occur for material presented close to sleep onset.

DISCONTINUATION

EFFECTS

Rebound insomnia refers to a worsening of sleep, beyond pretreatment levels, when hypnotic treatment is stopped abruptly. If it occurs, it usually lasts for one night (American Psychiatric Association, 1990). It is seen following the discontinuation of short- and intermediate-acting hypnotics; the slow decline in plasma concentration that occurs with long-acting sedatives represents a gradual tapering of the drug

PHARMACOTHERAPY FOR INSOMNIA 753 effect and prevents rebound sleep disruption. Higher There are no studies of the risk for physical dependoses increase the likelihood for rebound to occur, dence during long-term use of hypnotics, although and it can occur following even short-term use of a there are reports of physical dependence at therapeutic hypnotic (Roehrs et al., 1990). The severity of rebound doses in long-term daytime use of benzodiazepines. insomnia does not seem to be related to the duration The potential or liability for physical dependence in of hypnotic use, at least when used over a period of these medications is low, based on studies of their reinseveral weeks. The risk of rebound can be minimized forcing effect during the day (Griffiths and Roache, by using the lowest effective dose during the treat1985), and similar studies in the setting of their use as ment period and by tapering short- or intermediatehypnotics have come to consistent conclusions (Roehrs acting drugs over several days when discontinuing et al., 1992, 1996). The newer and more selective BzRAs treatment. (zolpidem, zaleplon) have a lower affinity for GABAA receptors containing the a2 subunit that mediate myoreRebound insomnia is not a manifestation of a withlaxation and anxiolysis. The clinical difference this may drawal syndrome. It does not increase the likelihood have on dependence liability or abuse is unclear, at the of behavioral dependence (Greenblatt et al., 1991). Interpresent time. estingly, a similar sleep disturbance can be seen with discontinuation of placebo (Roehrs et al., 1992; Hajak et al., 1998). A withdrawal syndrome involves the develFALLS, COGNITIVE EFFECTS, AND OTHER opment of new symptoms that last for days to weeks, CONSIDERATIONS FOR THE ELDERLY not merely an exacerbation of the prior insomnia sympThe elderly constitute an important patient group mertoms for a night. In clinical practice it is very difficult to iting separate discussion. They are prone to a large and distinguish rebound from recrudescence of the insomvaried number of medical disorders that affect sleep, nia, which refers to a return of the original symptoms complicating the management of insomnia. Increased at their original severity. sensitivity to CNS-active medications, alterations in drug metabolism and excretion, and the greater likeliDEPENDENCE LIABILITY hood of drug–drug interactions emphasize the care The concern that physicians have for the development needed when hypnotics are considered. of dependence to a hypnotic, like their concern for In general, drugs that are metabolized by oxidation adverse effects, is not based on compelling data. Most are potentially less safe for the elderly because the oxipatients use hypnotics for 2 weeks or less (Mellinger dative pathways in the liver are most affected by aging et al., 1985; Roehrs et al., 2002a). The dependence liabil(Chutka et al., 1995). All BzRA hypnotics except temaity for short-term use of benzodiazepines appears low. zepam are metabolized by oxidation (Madhusoodanan When allowed to self-medicate with triazolam nightly and Bogunovic, 2004). Zaleplon metabolism does not over the period of a week, hypnotic use is stable and seem to be affected by age. Drugs that are metabolized determined primarily by degree of symptomatic relief by conjugation to glucuronide, such as temazepam, are (Roehrs et al., 1996). Patients with chronic insomnia potentially safer because this pathway is less dependent who use hypnotics for months or years rarely have dose on age. In practice, age-related metabolic and CNS senescalations (Balter and Uhlenhuth, 1991), nor do they sitivity changes are managed by reduction in the administer the hypnotics for purposes other than prorecommended starting dose. moting sleep. Daytime use of hypnotics is uncommon The risks for falling and injury are increased with (Roehrs et al., 2002b). When self-administered, the rate the use of sedative medications, such as the BzRAs, of hypnotic use depends more upon the severity of the but only in the elderly. In a large study by Kelly and individual’s insomnia, with the strongest determinant colleagues, reviewing the conditions associated with being the quality of sleep during the previous night falls and injury, seven categories of medication were (Roehrs et al., 2002c), emphasizing the therapy-seeking identified. When controlling for comorbid illness and nature of hypnotic use. hospitalization, the increased risk for falls in the nonLittle is known about the frequency with which hypelderly remained significant only with narcotics, antinotic medications are misused, although one study in depressants, and anticonvulsants (Kelly et al., 2003). the early 1980s indicated that the rate of misuse of all Ensrud et al. (2002, 2003) reported an increased risk benzodiazepines occurred at 2 per 10 000 prescriptions. of falls without an increased risk for fractures in older Because this study included patients for whom benzowomen taking benzodiazepines, consistent with the diazepines were prescribed regardless of indication, the gender effect noted by Kelly. There is no information results should be applied cautiously in patients for about differences in the fall risk for specific BzRAs, whom BzRAs are used as hypnotics (Ladewig, 1983). or even in subsets of BzRAs acting at different

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receptor subtypes or with different durations of action. Among the wide variety of CNS-active medications known to increase fall risk, antidepressants, narcotics, and anticonvulsants have the greatest liability; the risk from BzRAs is significant. More recently investigators have begun to focus on the risk of falls conveyed by insomnia itself. Based on telephone interviews of approximately 1500 California residents aged 64–99 years, Brassington and colleagues identified several risks for falling, including multiple chronic medical problems, sensory impairment, hypertension, and nighttime sleep problems; when all other identified variables were controlled, every nighttime sleep variable remained significant (Brassington et al., 2000). A smaller but otherwise similar study showed a similar increase in risk for falling regardless of sleep complaint (Campbell et al., 1989). It is reasonable to suspect that insomniacs are at greater risk for injury if they are more active at night in low-light circumstances or at a time in the 24-hour circadian period that predisposes to slowed reaction times. Sedative medication use was not addressed in these telephone survey studies, but a recent report on falls in nursing home residents, based on review of the incident database for 437 facilities, suggested that insomnia and not hypnotics was associated with an observed increase in fall risk when both factors were considered. The adjusted (other variables controlled) odds ratios for falls were statistically significant for insomnia without hypnotic use, and for insomnia with hypnotic use, but not significant for hypnotics without insomnia (Avidan et al., 2005). Cognitive changes in the elderly have been reported to occur as a consequence of long-term benzodiazepine use (Paterniti et al., 2002), but conflicting data exist as well (Allard et al., 2003). Interpretation of study results is complicated by extraneous factors such as normal aging processes and the confounding effects of other drugs and diseases. Changes attributed to hypnotics are often subtle (Curran et al., 2003) and of unclear clinical significance (Pat McAndrews et al., 2003). An unexplained increase in mortality has been identified with the use of sleeping pills in two large studies primarily designed to identify cancer-related behavioral risks (Kripke et al., 1979, 1998). Whether medications for sleep contribute in some causal manner has not been established, and an equally reasonable explanation is that medication for sleep is more likely to be taken by individuals with more severe medical comorbidities, despite statistical methods to reduce these influences. Importantly, the most commonly used medications for insomnia at the time of the earlier study were barbiturates, chloral hydrate, and diphenhydramine. For the second and later study, long-acting benzodiazepines,

tricyclic antidepressants, and barbiturates were the mainstays of treatment. The only study to verify the actual medication being taken for sleep problems found that the only reliable association between increased mortality and drugs taken for sleep occurred for drugs other than hypnotics, predominantly analgesics (Rumble and Morgan, 1992).

MELATONIN RECEPTOR AGONISTS In July 2005, the FDA approved ramelteon for the treatment of insomnia characterized by difficulty with sleep onset, making it the first FDA-approved hypnotic that is not a BzRA and is not a controlled substance. Ramelteon is a melatonin receptor agonist, selective for both the MT1 and MT2 melatonin receptor subtypes (Kato et al., 2005), which appear to be involved in the regulation of sleep and circadian rhythms. Ramelteon has no appreciable affinity for the GABA receptor complex. Ramelteon is rapidly absorbed (median tmax 0.5–1.5 h) and eliminated (t½ 1–2.6 h), but has an active metabolite, M-II, with a t½ of 2–5 h. The available details from early studies in primary insomniacs indicate that doses of 4–32 mg produce a modest but significant reduction in PSG sleep latency (Erman et al., 2003), which is maintained for up to 5 weeks at doses of 8–16 mg when administered nightly (Zammit et al., 2005). Similar improvements in subjective sleep latency have been reported in elderly primary insomniacs treated with ramelteon 4–8 mg over 5 weeks (Seiden et al., 2005). These studies have identified few, if any, differences in efficacy measures such as sleep latency over the 4–32-mg dose range. In one study of 16 and 64 mg ramelteon for transient insomnia, PSG sleep latency was reduced and TST was increased similarly for both doses. The majority of the increase in TST was accounted for by a shortening of sleep latency (Roth et al., 2005b). Reduction in patient-reported sleep latency has been inconsistent. It is possible that agonism of melatonin receptors promotes sleep onset without a detectable sedative effect, leading to an inconsistent perception of reduced time to sleep onset. This may particularly be true for patients with experience of traditional hypnotics. Ramelteon appears to have chronobiotic properties, producing a phase advance at doses as low as 4 mg (Richardson et al., 2005), potentially explaining the drug’s ability to promote sleep without appreciable sedation. Safety trials have detected no potential for abuse relative to placebo, and no withdrawal symptoms or rebound insomnia (Griffiths et al., 2005). Ramelteon has been found to increase prolactin levels in adult women and to reduce testosterone levels in adult men. The clinical significance of these findings has not been

PHARMACOTHERAPY FOR INSOMNIA 755 a1-adrenergic receptors (Brogden et al., 1981; Jenck established, nor have studies been conducted in adolescents. Ramelteon undergoes hepatic metabolism. et al., 1993). Amitriptyline inhibits the reuptake of 5HT Increases in serum concentration are seen even with mild and norepinephrine, and blocks both acetylcholine and liver disease, so caution is recommended for patients histamine binding (Preskorn, 1993; Richelson, 1994; with at least moderate liver disease. Fluvoxamine inhibits Frazer, 1997). Mirtazapine antagonizes 5HT2a, 5HT2c, and 5HT3 receptors. It also blocks a1-adrenergic recepcytochrome P450 1A2 (CYP1A2) dramatically, increasing tors and is a strong histamine1 antagonist (de Boer, the serum concentration of ramelteon, and coadministra1996; Radhakishun et al., 2000). The adrenergic, histation should be avoided. minergic, and cholinergic systems in the brainstem, At this point, ramelteon could be summarized as a midbrain, and basal forebrain are all strongly implicated hypnotic with a novel mechanism that shortens PSG in the promotion and maintenance of wakefulness, so sleep latency, but less consistently reduces patientantagonistic activity in relevant portions of these systems reported sleep latency. Because of its very low abuse could easily result in sedation. The serotonergic system potential, ramelteon is not a controlled substance plays a more controversial and less well established, or and safety concerns appear to be limited to administraperhaps more complicated, role in wakefulness. tion in patients with concomitant liver disease or who are taking potent CYP1A2 inhibitors. Effectiveness in broad clinical populations has not been studied Efficacy and effectiveness to date. The hypnotic efficacy of trazodone in nondepressed insomniacs has been investigated twice, to the authors’ SEDATING ANTIDEPRESSANTS knowledge. In the larger of the two studies, the effect Despite the absence of systematic research on antideof trazodone 50 mg on subjective sleep measures pressants in insomnia, there is a trend for greater reliwas compared with zolpidem 10 mg and placebo in ance on them for the treatment of insomnia. A number a 2-week, placebo-controlled, parallel-group design. of factors likely contribute to their utilization by physiTrazodone and zolpidem shortened latency to sleep cians (Walsh and Schweitzer, 1999) in spite of the onset and increased TST, with improvements with absence of an established efficacious dose. Sedating zolpidem being greater than those with trazodone antidepressants do not have a recommended limited (Walsh et al., 1998). In an earlier study, PSG and subduration of use on their package insert, in contrast to jective data were collected in nine individuals taking the BzRAs, leading to reduced scrutiny by government trazodone 150 mg a night for 3 weeks with comparison regulators and third-party payers when prescribed for made to measures taken before and after discontinuachronic treatment. The absence of this cautionary lantion of trazodone (Montgomery et al., 1983). There was guage in their inserts is also likely to contribute to no improvement in sleep latency or TST, but there was the misperception that sedating antidepressants are a reduction in stage 1 sleep and wakefulness, and both safer than BzRAs and carry a lower risk of increased stage 3–4 sleep. Subjectively, there was an dependence. Finally, insomnia is frequently interpreted improvement in sleep quality. These findings suggest solely as a manifestation of depression. that trazodone may have some short-term hypnotic Among the sedating antidepressants prescribed benefits in primary insomnia, but when compared for the treatment of insomnia, trazodone, amitriptydirectly with zolpidem the BzRA showed a greater line, and mirtazapine are most commonly used (see effect. Amitriptyline and mirtazapine are often used Figure 46.1). Although sedating antidepressants are as hypnotics for nondepressed insomniacs, in the often used for insomnia coexistent with a mood disorabsence of published studies as to their efficacy in this der, their use is likely not limited to that situation. group of patients. Trazodone is generally prescribed at doses far below Among the less commonly used sedating antidepresthe range typically needed for the treatment of depressants data are also limited. Improved TST was found in sion and is often prescribed in the absence of other a trial of 15 primary insomniacs taking trimipramine antidepressant medications, both of which suggest (mean 166  48 mg), but there was no parallel placebo use to treat insomnia in nondepressed patients. control and PSG measures were made before an adeThe neural mechanism mediating the sedating activquate period of washout from prior medications had ity of these antidepressants has not been identified, occurred (Riemann et al., 2002). Subjective sleep quality but the likelihood that one mechanism is common to was improved by trimipramine 100 mg when compared all of these agents is very low. Trazodone inhibits with placebo (taken nightly for 1 month) in a study by 5-hydroxytriptamine (5HT) reuptake and antagonizes Hohagen and colleagues (1994), but there were insignif5HT2a and 5HT2c receptors. Trazodone also blocks icant increases in TST. Doxepin 25–50 mg produced

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increased TST and improved subjective sleep quality (Hajak et al., 2001). A number of studies have been carried out to investigate the efficacy of sedating antidepressants in depressed insomniacs. However, small sample sizes and experimental design weaknesses limit the value of these studies. There was no consistent improvement in the continuity of sleep in subjects taking amitriptyline, in two small studies that lacked placebo controls (Hartmann and Cravens, 1973; Gillin et al., 1978). Subjective improvements in the latency to sleep onset and TST were reported by six patients with major depression when treated with mirtazapine for 2 weeks (15 mg increasing to 30 mg in the second week), again without a placebo control (Winokur et al., 2000). When a fixed dose of mirtazapine was compared with an escalating dose, similar subjective improvements in sleep latency and TST were reported (Radhakishun et al., 2000).

Safety As a class, the antidepressants have more frequent and troublesome side-effects than BzRAs. The tricyclic antidepressants in particular are known for their less than ideal side-effect profile, which has led in part to the reliance now placed on the selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression. The majority of safety data for the sedating antidepressants have been acquired from individuals using them for mood or anxiety disorders in doses higher than those used for insomnia, making generalizability problematic. However, in trials of tricyclics used to treat primary insomnia there have been reports of leucopenia, thrombocytopenia, increased liver enzymes with doxepin (Hajak et al., 2001), dizziness, dry mouth, and nausea with trimipramine (Riemann et al., 2002), and daytime somnolence and weight gain with mirtazapine (Mir and Taylor, 1997). Given the pharmacokinetics of these drugs (mean half-life 9–30 h for most drugs), residual sedation following bedtime administration is likely, although this has not been assessed directly. Although trazodone has been viewed as having a more favorable side-effect profile than the tricyclics, supportive data are lacking; moreover, the margin between fatal and safe doses is much smaller than for the BzRAs. Troublesome side-effects with trazodone include orthostatic hypotension, cardiac conduction abnormalities, and priapism (Mendelson, 2005). In summary, the use of sedating antidepressants for primary insomnia cannot be recommended based on available information regarding either their overall safety or efficacy, because there is, respectively, either discouraging or inadequate data (Mendelson, 2005). The use of such agents may have more to do with

regulatory issues and perceived risks about the BzRAs, which do not seem warranted based on available studies. Individuals with insomnia and coexistent depression may be one group for whom the sedating antidepressants would be a reasonable choice, with the understanding that the side-effect profile of the BzRAs still seems more favorable than the profiles of trazodone or the SSRIs. Substance abusers are another patient group for which sedating antidepressants may have a more favorable risk to benefit ratio, given the greater reinforcing effect of the BzRAs.

OTHER DRUGS USED AS HYPNOTICS Many other drugs have been used for the treatment of insomnia, including antipsychotics (quetiapine, olanzapine), antihistamines (hydroxyzine, diphenhydramine), and muscle relaxants (cyclobenzaprine). Little is known regarding their hypnotic efficacy. Diphenhydramine at doses of 25–50 mg has been evaluated in several brief and small trials lacking parallel placebo control, showing global improvement in general condition with treatment (Kudo and Kurihara, 1990) and improvement in subjective sleep latency and sleep quality (Rickels et al., 1983). Tolerance to the sedative effect of diphenhydramine has, however, been shown clearly to develop within 3–4 days of regular treatment with diphenhydramine 25–50 mg when the drug is administered in the daytime following a two or three times daily schedule (Schweitzer et al., 1994; Richardson et al., 2002). The atypical antipsychotics quetiapine and olanzapine are active across a broad range of neurotransmitter systems, including H1 receptors (antagonist), 5HT2C (antagonist), and adrenergic, muscarinic, and dopaminergic circuits. Efficacy data are practically nonexistent. Quetiapine and olanzapine at various dosages improved subjective measures of sleep in two small open-label studies of patients with comorbid insomnia (Estivill et al., 2004; Juri et al., 2005). Although the sedative property of these medications (possibly mediated in part through histaminergic antagonism) makes them potentially useful, their broad activity across the CNS resulting in a number of undesirable side-effects makes them less tolerated, to say nothing of their troubling drug–drug and drug–enzyme interactions. Both of these antipsychotics reach peak plasma levels relatively slowly and have half-lives that make residual sedation likely. In the case of olanzapine, the duration of action is very long (elimination half-life 20–50 h). In any event, their sleep-promoting effects have not been adequately assessed for any form of insomnia. Finally, patients with chronic insomnia often resort to over-the-counter remedies of questionable benefit.

PHARMACOTHERAPY FOR INSOMNIA Although most of these agents produce sedation through an antihistaminergic mechanism, alcohol is not infrequently chosen. The rapid development of tolerance, the exacerbation of other sleep disorders (restless leg syndrome and obstructive sleep apnea), and the fragmentation of sleep that occurs later in the night following at least the acute administration of alcohol make these common remedies relatively poor choices for the treatment of chronic insomnia.

INDICATIONS FOR PHARMACOTHERAPY OF INSOMNIA For the treatment of transient and short-term insomnia (lasting 4 weeks or less), the consensus has been that BzRAs are preferred, to be administered at the lowest effective doses for the shortest possible period of time (NIH, 2005). Short- or intermediate-acting drugs are preferred. When the National Institute of Mental Health issued its consensus statement in 1984 regarding treatment of insomnia, the majority of chronic insomnia was thought to be a symptom of a primary condition that was often psychiatric or medical but not infrequently behavioral. The opinion then was that the disorder underlying the insomnia should be treated and that, if separate treatment of the insomnia was necessary, adjunctive BzRA use should be limited to a short trial of less than a month. Advances in knowledge about insomnia have led sleep researchers in recent years to reassess past treatment opinion (McCall, 2002; Roehrs and Roth, 2003; Mendelson et al., 2004). A large number of chronic insomniacs do not have an underlying medical, psychiatric, or behavioral disorder (Buysse et al., 1994; Ohayon, 1997). In situations where an underlying disorder does exist, treatment of the psychiatric or medical condition, although essential, may have no significant effect on the insomnia (Stark and Hardison, 1985). In addition, there are suggestions that insomnia should be treated independently. Chronic insomnia is a risk factor for the subsequent development of a mood disorder (Breslau et al., 1996; Chang et al., 1997). When insomnia coexists with a mood disorder, treatment of the insomnia seems to foster a quicker response to antidepressants (Perlis et al., 1997) and results in a greater reduction in risk of suicide (Agargun et al., 1997; Hall and Platt, 1999). These challenges to the conceptualization of insomnia as a symptom and the growing recognition of insomnia as a risk factor for psychiatric disease in part led the NIH in 2005 to conduct a conference to explore the state of scientific knowledge of insomnia and its treatment (NIH, 2005). In brief, the expert panel concluded that insomnia is a significant public health

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problem and recognized the chronic nature of the problem. Additionally they recommended the term “comorbid insomnia” rather than “secondary insomnia”, reflecting the lack of clarity regarding the association of various illnesses and insomnia. Finally, they concluded that BzRAs are safe and efficacious (although additional long-term studies are needed), whereas evidence is lacking to support the use of sedating antidepressants, antihistamines, alcohol, and a variety of other substances to treat insomnia. A consensus regarding long-term pharmacological treatment for chronic insomnia has yet to be established, but there are few reasons to withhold or discontinue long-term use of BzRAs (Winkelman and Pies, 2005) when such treatment is effective, and no evidence of dependence or abuse.

CONTRAINDICATIONS TO PHARMACOTHERAPY Hypnotics should be used cautiously, if at all, in individuals with certain medical conditions. Patients with a history of alcoholism or drug abuse should be supervised closely during treatment with BzRA hypnotics. The concomitant use of moderate amounts of alcohol by social drinkers will potentiate the hypnotic effect and narrow the therapeutic safety margin. Because the sleep-promoting effects of all sedatives impair arousal, BzRAs have the potential to exacerbate obstructive sleep apnea. Hypnotics should be used in lower doses if they are used at all in patients with significant liver disease, because the majority of hypnotics undergo hepatic metabolism (Chouinard et al., 1999). The safety of the BzRAs and ramelteon in pregnancy has not been established, so they should not be used in pregnant women and used with caution in sexually active women. BzRA hypnotics, like all sedating medications, have the potential to reduce motor and cognitive function as a consequence of their sedative effect. The potential for this impairment should be discussed with individuals who might have duties or obligations in the middle of their sleep period, typically parents with small children, medical or public safety professionals with on-call obligations, or even individuals with nocturia who need to ambulate safely to the bathroom.

CONSIDERATIONS FOR PHARMACOLOGICAL TREATMENT OF INSOMNIA Treatment should be considered for insomnia if the patient is distressed by the sleep disruption or when there is reason to believe the patient’s health or safety

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is at risk. Pharmacotherapy provides significant relief to most individuals experiencing transient insomnia, and to many with chronic insomnia. In the case of transient insomnia, the periods of disturbed sleep are often predictable and easily managed with hypnotics. Management of chronic insomnia can be a therapeutic challenge; however, several general guidelines are useful to consider. In the absence of a history of substance abuse, the BzRAs are the hypnotics of choice. Although shortand intermediate-acting hypnotics are preferable to avoid or minimize residual sedation, agents with longer half-lives may be appropriate in patients for whom daytime sedation is not a significant concern. Shortacting hypnotics are appropriate for patients having predominantly sleep-onset problems. Hypnotics with an intermediate duration of action are generally helpful for patients having sleep maintenance difficulties, with or without sleep initiation problems. Age and concurrent illnesses should be closely considered in choosing a hypnotic, and the dose and schedule should be clearly established by the physician. It is useful for the patient to agree explicitly to a treatment regimen, particularly if there is concern about substance abuse or other forms of addictive behavior. Ramelteon is a potentially useful alternative when there are concerns regarding substance abuse, with the caveat that ramelteon seems to be effective only for insomnia at the beginning of the night. The effect of ramelteon on cognitive function has not been well characterized and no direct comparison has been made to BzRAs, although cognitive impairment due to ramelteon appears to be less than for BzRAs (Stubbs and Karim, 2003). Adjustments in dosage and schedule should be carried out only under the guidance of the physician, particularly early in the treatment course, and they should be based not only on global assessments of sleep but also on change in the specific nighttime and daytime symptoms that led to treatment. Close monitoring is desirable for certain populations at higher risk, including patients who are elderly, have impaired cognition, use other sedating medications, might misuse a BzRA, or have liver disease or another general medical condition likely to alter response to a hypnotic. The schedule of use is generally nightly, but studies examining non-nightly use have not identified any significant problems with rebound phenomenon on nonmedication nights. Among the BzRAs, zaleplon is unique in that it is very short acting and can be taken after the usual bedtime, as long as 5 hours or more remain before rise time. This allows an “as needed” treatment schedule, as patients can wait to determine whether they are having difficulty with sleep onset on any given night.

There is little guidance beyond expert opinion to direct clinicians in the appropriate manner for combining hypnotics with psychological methods for the treatment of insomnia. Although hypnotics are effective, these medications do not address the maladaptive beliefs or behaviors that develop in some chronic insomniacs and may contribute to their sleep problems. Cognitive–behavioral therapy (CBT) can deal effectively with these thoughts and behaviors, and is often suggested as an alternative to hypnotics for the treatment of insomnia. A small number of studies have investigated the efficacy of hypnotics in combination with CBT for the treatment of primary insomnia. In the most informative trial by Morin and colleagues (1999), chronic insomniacs received either CBT, temazepam at typical therapeutic dosages, or a combination of the two. Over the 8 weeks of treatment, there was no statistical difference between the three approaches when considering measures such as sleep efficiency, TST, and reduced waking after sleep onset. There was a nonsignificant trend for increases in these measures when temazepam was combined with CBT. In the absence of clear direction, the decision to use CBT, hypnotics, or a combination of the two is influenced more by the individual’s motivation and ability to change, sense of control over their disorder, level of daytime stress, age, concurrent medical problems, and attitude towards hypnotic medications – to say nothing of the degree to which the physician is comfortable with CBT or hypnotics. Long-term nightly hypnotic use appears to be an option for some chronic insomniacs, although exactly whom and for how long is unclear at present. Available safety data on BzRAs used nightly for weeks to several months indicates that several months of nightly use or longer is an acceptable treatment approach, at least for primary insomniacs. Future studies will need to focus upon the pros and cons of various treatment durations in both primary and comorbid chronic insomnia, and to determine whether drugs other than BzRAs have a place in long-term management.

CONCLUDING STATEMENT Currently available efficacy data support the use of BzRAs, and to a lesser extent ramelteon, for the pharmacological treatment of insomnia. Clinicians have turned away from these data and are instead using a wide variety of sedating antidepressants, antihistamines, antipsychotics, and other sedative drugs, despite both the absence of supportive data and the presence of known safety concerns. A number of sedating medications, including melatonin, gabapentin, tiagabine,

PHARMACOTHERAPY FOR INSOMNIA gaboxadol, and valerian, are being investigated as potential hypnotics, but compelling support for their use is lacking and further work is needed to establish the role they might play in the management of insomnia. Studies designed to demonstrate a hypnotic effect in a diverse population using clinically relevant endpoints such as daytime function or quality of life have yet to be conducted for any sedative or hypnotic. The choice of specific BzRA and dose should be based on patient age, specific insomnia symptoms, predilection for substance abuse, and the presence of other medical conditions such as liver disease.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 47

Hypothalamus, hypocretins/orexin, and vigilance control SEIJI NISHINO * Sleep and Circadian Neurobiology Laboratory and Center For Narcolepsy, Stanford University, and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA

INTRODUCTION The hypothalamus has re-emerged as a key regulator of sleep and wakefulness, shifting the focus away from the brainstem and thalamocortical systems (i.e., ascending reticular activating systems). This role for the hypothalamus was recognized from the early days of the encephalitis lethargica epidemic (1918–1926), when affected individuals were found to exhibit major sleep abnormalities. Based on detailed pathological examinations, von Economo (1931) suggested that posterior hypothalamic and midbrain junction lesions resulted in sleepiness, whereas anterior hypothalamic inflammation resulted in insomnia. Although Nauta and Ranson (Ranson, 1939; Nauta, 1946) followed up the findings by von Economo via lesion studies in animals, these earlier findings were often overshadowed in subsequent animal studies where profound physiological abnormalities occurred after hypothalamic lesions, thus easily masking sleep phenotypes. The identification of the ascending reticular activating system and the brainstem rapid eye movement (REM) sleep-generating system also fostered a shift away from the hypothalamus. Several new sleep control systems in the hypothalamus and their interaction with the circadian pacemaker in the suprachiasmatic nucleus (SCN) have been identified recently. More recently, using the tools of molecular biology (by searching for mRNAs specifically expressed in the hypothalamus using subtractive polymerase chain reaction), de Lecea et al. (1998) discovered new hypothalamic neuropeptides, named hypocretins (1 and 2). Almost simultaneously, Sakurai et al. (1998) discovered the same peptides by searching the endogenous ligands for orphan G protein-coupled

receptors. Orphan receptors are receptors whose sequence/structure is known, but their endogenous ligands are unknown. The latter group named these new peptides orexins (A and B) after the Greek word for appetite, because they found that central administration of orexins potently increased food intake in rats (Sakurai et al., 1998). Only a year after the discoveries of the hypocretin/orexin system (using positional cloning in a canine model of narcolepsy and mouse gene knockouts), hypocretin-related genes were found to be narcolepsy genes; hypocretin/orexin ligand and hypocretin/orexin receptor genes are key to the pathogenesis of narcolepsy in these animals (Chemelli et al., 1999; Lin et al., 1999). Human narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, and other REM sleep abnormalities (hypnagogic hallucinations and sleep paralysis) (Nishino and Mignot, 1997). These phenotypes of narcolepsy are often explained by an inability to maintain wakefulness combined with the intrusion of REM sleep-associated phenomena into wakefulness (see Chapter 48 for a further discussion of narcolepsy). In contrast to narcolepsy in animals, mutations in hypocretin-related genes are rare in humans, although hypocretin ligand deficiency is found in most patients with narcolepsy or cataplexy (Nishino et al., 2001b; Mignot et al., 2002). The results from a series of experiments suggest that the hypocretin system is involved in the maintenance of wakefulness and stabilizes the vigilance states (for a review see Sakurai, 2005). The hypocretin system also plays a role in the link between sleep and other fundamental hypothalamic functions, such as the regulation of food intake, metabolism, hormone release, and temperature (for a

*Correspondence to: Seiji Nishino MD, PhD, Stanford University, Sleep and Circadian Neurobiology Laboratory and Center for Narcolepsy, 1201 Welch Road RM213, Palo Alto, CA 94304-5489, USA. Tel: (650) 723-3724, Fax: (650) 723-5873, E-mail: [email protected]

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review see Willie et al., 2001; Sakurai, 2005). Sleep deprivation is known to alter hormone release, increase body temperature, stimulate appetite, and activate the sympathetic nervous system. Sleep control systems within the hypothalamus may therefore be closely integrated with homeostatic systems needed for survival. In this chapter, the role of the hypothalamus in vigilance control, emphasizing especially the hypocretin/orexin system, is discussed.

OVERVIEW OF VIGILANCE STATE
REGULATORY MECHANISMS AND SYSTEMS To understand the role of the hypothalamus in behavioral state control, it is helpful briefly to review current understandings of brain anatomical sites and neurotransmitter systems that control sleep and wakefulness (Figure 47.1).

Ascending reticular and forebrain activating systems The cholinergic system is a major component of the ascending reticular activating system underlying electroencephalograph (EEG) desynchronization. Notably, brainstem cholinergic neurons near the pons–midbrain junction (laterodorsal tegmentum (LDT) and pedunculopontine (PPT) nuclei) have high discharge rates in wakefulness and REM sleep, and low discharge rates in nonREM sleep (see Steriade and McCarley, 1990). These neurons project heavily to the thalamic nuclei, important

in EEG desynchronization and synchronization. Target neurons in the thalamus respond to cholinergic agonists in a way that is consistent with EEG activation. An additional input from the basal forebrain cholinergic nucleus basalis to the cortex also contributes to the generation of EEG desynchronization during wakefulness. Cholinergic systems, however, are not the exclusive substrate of EEG desynchronization. Excitatory amino acid (projections from brainstem reticular formation to the thalamus) and monoaminergic projections to various other brain areas are also likely to contribute.

Thalamocortical sleep oscillations The fact that some species (such as dolphins) can experience unilateral nonREM sleep suggests that EEG synchronization is expressed in the anterior brain. Intracellular and extracellular recording studies in freely moving cats (and in cat brain slices) have shown that neocortical and thalamic neurons function in an intrinsic oscillatory mode that is synchronized across the neocortex during nonREM sleep (Steriade et al., 1993a, b). In this mode, the cortex is, in a sense, deafferented from external stimuli. This is thought to be the natural state for these neurons when they are not activated by inputs from the ascending reticular arousal system and the basal forebrain. Two frequencies of electrical oscillation have received the most attention: the spindle frequency (7–14 Hz) and the delta frequency (1–4 Hz). The spindle oscillations are characteristic of lighter stages of sleep (stage 2 in humans), and are believed to be generated by the interaction of Thalamus Cortical Activation Sleep Spindle EEG synchronization

Cortex

Reticular Formation SCN Circadian Clock

Brainstem Ascending Cortical Activation REM/SWS Switch

Fig. 47.1. General overview of vigilance state-regulatory systems showing the distinct roles of the thalamus, brainstem, hypothalamus, cortex, and four critical brain structures for vigilance control. REM, rapid eye movement; SCN, suprachiasmatic nucleus; SWS, slow-wave sleep.

HYPOTHALAMUS, HYPOCRETINS/OREXIN, AND VIGILANCE CONTROL 767 pacemaker gamma-aminobutyric acid (GABA)ergic above the junction of the pons and midbrain produces thalamic reticular neurons that oscillate at the spindle a state in which the periodic occurrence of REM sleep frequency and thalamocortical neurons. Spindle oscilcan still be observed through recordings of the isolated latory waves are blocked primarily by brainstem cholinbrainstem. In contrast, recordings of the isolated foreergic projections to the thalamus, which hyperpolarize brain show no sign of REM sleep. EEG depth recordthalamic reticular neurons. The basal forebrain nucleus ings in animals show another important component basalis also provides cholinergic and GABAergic input of REM sleep: the pontogeniculo-occipital (PGO) to thalamic reticular neurons with similar effects. waves, recorded from the pons, the lateral geniculate Delta frequency oscillations are characteristic of nucleus, and the occipital cortex. The PGO waves arise “deeper” nonREM sleep (stages 3 and 4 in humans). in the pons and are transmitted to the thalamic lateral These oscillations reflect pacemaker activity from both geniculate and to the visual occipital cortex during the neocortex and thalamus. This activity occurs when REM sleep. these neurons are hyperpolarized, allowing delta-wave Most physiological events occurring during REM propagation. During waking, input from the cholinergic sleep have effector mechanisms in the brainstem reticforebrain nucleus basalis suppresses slow-wave activity. ular formation, especially in the pontine reticular Brainstem noradrenergic and serotonergic projections formation (PRF) (see Steriade and McCarley, 1990; (from the locus ceruleus (LC) and dorsal raphe (DR), Siegel, 2005). PRF neurons that are important for the respectively) may also disrupt delta activity during generation of REM and PGO waves have been identiwakefulness. These neurons are wake-active neurons, fied, and a subgroup of dorsolateral PRF neurons also and decrease activity during nonREM sleep and cease controls muscle atonia during REM sleep. These during REM sleep (see Jones, 2005). During REM sleep, neurons become active just before the onset of muscle cholinergic input from the brainstem plays a major role atonia. in membrane depolarization with reticular formation The importance of cholinergic transmission for the input, probably via excitatory amino acid neurotransmisregulation of REM sleep has been established by pharsion, which also plays a role. Delta waves during sleep macological and neurophysiological studies. A group may represent thalamocortical oscillations occurring in of cholinergic neurons in the LDT and PPT discharges the absence of any activating input. The relative intensity selectively in REM sleep, with activity onset beginning of cortical desynchronization correlates best with the just prior to REM sleep. This LDT/PPT discharge patintensity of cholinergic input to the thalamus. tern and the presence of excitatory projections to the Although a series of pharmacological studies sugPRF suggest that these cholinergic neurons may be gested that amfetamine-like stimulants (the most important in producing the depolarization of reticular potent wake-promoting agents), decrease nonREM formation neurons that become active during REM sleep and increase wakefulness by blocking dopamine sleep. In fact, injection of cholinergic agonists in the reuptake and/or by stimulating dopamine release (see PRF induces REM sleep-like states. These PRF neurons Nishino and Mignot, 2005), little attention has been are often referred to as REM-on neurons. In contrast, paid to the role of dopamine in sleep control. This is wake-active monoaminergic neurons (adrenergic LC mainly due to dopaminergic neurons not greatly changneurons and serotonergic DR neurons) are silent during their activity across the sleep cycle (Jones, 2005). ing REM sleep (REM-off neurons) (see Jones, 2005). However, there is accumulating evidence, some based The opposition of cholinergic and adrenergic/serotoon observations of sleep disturbances in dopaminergic nergic activity during REM sleep led to the hypothesis disorders (e.g., Parkinson’s disease), that dopaminergic of reciprocal interactions between these cell groups to mechanisms are important. There may be a greater explain the periodicity of REM sleep (Hobson et al., than generally known functional heterogeneity of 1975). This hypothesis agrees with earlier pharmacologdopaminergic neuronal groups, and some of these ical experiments using cholinergic and monoaminergic dopaminergic neurons are specifically involved in more drugs (Karczmar et al., 1970). In this model (revised specialized wakefulness (such as motivated wakefulby McCarley and Massaquoi, 1986), the timing and ness) or sleep-related motor control (such as periodic proportion of REM sleep over the night and its variamovements during sleep). tion with the circadian temperature rhythm are predicted by monoaminergic–cholinergic interactions. Although histamine neurons located in the posterior Brainstem REM sleep-generating system hypothalamus are also known to be REM-off, these Lesion studies by Jouvet and coworkers established cells are generally excluded from this model based on the importance of the pons in generating REM sleep transection studies. Similarly, hypothalamic hypocretin (Jouvet, 1962; see also Siegel, 2005). Transection just neurons have recently been shown to be wake-active

768 S. NISHINO and REM-off neurons (Lee et al., 2005; Mileykovskiy just above the optic chiasm in the anterior hypothalaet al., 2005), and they are also likely to have significant mus (see Dijk et al., 1995). The SCN acts as a master impacts on both brainstem monoaminergic and cholinclock, keeping time with an accuracy of a few minutes ergic neuronal activities, and REM sleep control. each day (Czeisler et al., 1999) and adjusting body rhythms to seasonal variations in day length. The importance of this nucleus is apparent in people and Circadian/homeostatic regulation of sleep animals with lesions of the SCN, who may sleep and The regulation of sleep has classically been viewed as wake at any time of day. the dual interaction of circadian (SCN clock-based) The identification of genetic mutations in Drosophand homeostatic processes. It is often assumed that ila and mice have resulted in the description of a the pressure to sleep (sleep propensity) is lowest detailed intracellular translation–transcription feedshortly after awakening, increasing during the day, back loop (regulated by several transcription genes: peaking at bedtime, and declining during sleep. Yet, Per1-3, Cry1,2, Clock, BMAL1, casein kinase 1 epsilon if one stays awake all night, sleepiness, and therefore (CSNK1E)) that occurs in single SCN cells and genersleep propensity, increases until a specific circadian ates highly accurate 24-hour rhythms to the rest of timepoint (usually the individual’s customary morning the organism (see Takahashi, 1995). awakening time) at which time he or she will feel less A stimulating area of current research is to detersleepy again for a while. This second signal, of circamine how the signal leaves the circadian clock to regudian origin, interacts with the sleep debt to maintain late sleep. Neurons in the SCN shell project to the alertness evenly across the day. Several models have preoptic area, but not significantly to the posterior tried to integrate these two factors. The most estabhypothalamus. Similarly, the SCN sends only minor, lished model is Borbe´ly’s two-process model (Borbely direct projections to the brainstem nuclei implicated and Wirz-Justice, 1982) where one process, process S, in state control (Abrahamson et al., 2001; Chou et al., measures the homeostatic sleep pressure. Process S is 2002). Thus, the existence of indirect pathways is sugthought to be dependent on the amount of prior wakegested (see also Humoral factors below). The fact that fulness and is reflected by the amount of EEG slowthe SCN is day-active in both nocturnal and diurnal aniwave activity (0.5–4.5 Hz). Process S increases during mals also suggests the existence of multisynaptic conextended wakefulness, thereby increasing “sleepiness” nections in at least some cases. Lesion studies with sleep deprivation, and sleep propensity can be indicate that a major projection from the SCN to the relieved only by sleep. The second process, process C, subparaventricular zone (SPZ) (a region that also varies as a sinusoidal function across the day, with its receives direct retinal input) is essential to entrain locointensity being unrelated to the amount of prior wakemotor activity rhythms (Watts and Swanson, 1987; fulness. Process C is postulated to promote wakefulWatts et al., 1987). The SPZ projects to the dorsomedial ness during the individual’s customary period of nucleus of the hypothalamus (DMH), a region impliactivity (daytime in humans) and promotes sleep cated in autonomic stress responses, feeding, and the during the customary period of sleep. The circadian circadian release of corticosteroids (Bernardis and activity of process C is also reflected by circadian flucBellinger, 1998), and the DMH neurons project to other tuations in physiological parameters such as core body hypothalamic and brainstem areas important for the temperature, and plasma melatonin and cortisol levels. vigilance control. In one of the variations of this model, the opponent Beside the circadian regulatory system, regulatory process of sleep regulation was proposed in animal mechanisms for rapid sleep cycle changes, such as an species that have a consolidated wake period (such as alternation of nonREM sleep and REM sleep and their monkeys and humans); a wake-promoting signal is cyclicity (i.e., ultradian rhythm) exist. REM sleep generated by a circadian clock in the latter part of occurs within 90–110-minute intervals in human, and the active period (evening in humans). This clock30-minute intervals in cats and dogs (Zepelin, 1994). generated wake-promoting signal opposes the sleep Earlier brain transection studies suggested that the debt that increases from sleep onset, ensuring an even generation of REM sleep cyclicity originated in the degree of alertness throughout the day, and produces pons (see the section Brainstem REM sleep-generating consolidated wakefulness (Edgar et al., 1993; Dijk and system above). However, neuronal afferent systems to Czeisler, 1994). this structure, as well as many other factors (such as Whereas the neurobiological substrates mediating temperature and/or humoral factors), are also likely process S are still unknown, lesion studies have indito affect the cyclicity of REM sleep and other REM cated that process C is generated primarily by the cirsleep characteristics, such as REM sleep amount and cadian clock in the SCN, a small cluster of neurons stability of REM sleep (Jouvet, 1994).

HYPOTHALAMUS, HYPOCRETINS/OREXIN, AND VIGILANCE CONTROL 769 hypothalamus and, in some cases, a secondary etiolHumoral factors modulating sleep ogy. Neuropathological studies on the encephalitis and wakefulness lethargica pandemic (1916–1923) revealed involvements A number of humoral factors (endogenous sleep subof the midbrain periaqueductal gray matter and postestances) have been shown to alter sleep (see Borbely rior hypothalamus in the hypersomnolent variant, with and Tobler, 1989; Krueger et al., 2001), presumably frequent extensions to the oculomotor nuclei, whereas by modulating the brain circuitry described above. anterior hypothalamic inflammation resulted in insomSleep-promoting substances include muramyl dipeptide nia and chorea (with striatal involvement). This led von (a chemical found in bacterial cell walls), interleukin-1, Economo to speculate that the anterior hypothalamus tumor necrosis factor-a (and other cytokines), adenocontained a sleep-promoting area, whereas an area sine, delta sleep-inducing peptide (a substance isolated spanning from the posterior wall of the third ventricle from the blood of sleeping rabbits), prostaglandin D2, to the third nerve was involved in actively promoting and the long-chain fatty acid primary amide, cis-9, wakefulness (von Economo, 1931). Following up on 10-octadecenamide (see also section on Hypothalamic von Economo’s reports of intense sleepiness in patients sleep-promoting systems below). with encephalitis of the posterior hypothalamus, Nauta The pineal hormone, melatonin, also deserves menand others demonstrated that mechanical and electrotion. Melatonin secretion is strongly regulated by the lytic lesions of the posterior hypothalamus produced circadian clock and peaks at nighttime in both diurnal marked and persistent somnolence in rats (Ranson, and nocturnal animals (Lavie, 1997). Melatonin has 1939; Nauta, 1946). Additionally, Nauta (1946) observed powerful hypnotic effects in birds, and stimulates that destruction of the anterior hypothalamus, in the wakefulness when administered to rats in the daytime region of the preoptic area, produced unrelenting (inactive period). Human studies have not shown a insomnia. Based on these observations, Nauta agreed consistent hypnotic effect, although recent studies with von Economo that the posterior hypothalamus have indicated that it can facilitate sleep onset in older likely contained a “waking center” and the anterior people who may be melatonin deficient (Lavie, 1997). hypothalamus contained a “sleep center”. Humoral factors secreted from the SCN also influThe involvement of the hypothalamus in the occurence the timing of sleep. SCN-lesioned animals lack rence of narcoleptic symptoms was recently refined circadian rhythms, but rhythms can be restored with by Aldrich and Naylor (1989), who noted that tumors SCN transplants. This restoration of rhythm does not or other lesions located close to the third ventricle were require synaptic connections because the daily rhythm associated with symptomatic narcolepsy, and hypotheof locomotor activity can be partially restored with sized that the posterior hypothalamic region may be SCN transplants encased in a polymer that blocks the the culprit. The symptoms of narcolepsy (EDS and outgrowth of neuritis, yet allows passage of small REM sleep abnormalities) can also occur during the molecules (Silver et al., 1996). Two potentially imporcourse of other neurological conditions; these conditant molecules, transforming growth factor (TGF)-a tions are defined as symptomatic narcolepsy. Inherited and prokineticin 2 (PK2), have recently been identified disorders, tumors, and head trauma are the three most from the SCN (Kramer et al., 2001; Cheng et al., 2002). frequent causes for symptomatic narcolepsy (FigIn nocturnal rodents, TGF-a (transforming protein) ure 47.2). A recent meta-analysis of 33 symptomatic and PK2 (secreted protein) expression is high during cases of narcolepsy associated with brain tumor furthe day, and infusion of these peptides suppresses ther illustrated that the hypothalamus structures (the locomotor activity. TGF-a and PK2 receptors are pituitary, suprasellar, or optic chasm) are most often expressed in targets of the SCN, including the SPZ (70%) involved (Nishino and Kanbayashi, 2005) and DMH. Chronic infusions of TGF-a block the circa(Figure 47.2). In contrast, the brainstem lesions were dian variation in sleep/wake behavior in a pattern very much less frequent, found in only 10% of these cases. similar to that seen with lesions of the SPZ. Thus, the These results further confirm that an existence of a release of TGF-a and PK2 from the SCN may act upon “wake center” in the hypothalamus, and this center nearby hypothalamic regions to drive the circadian (or adjacent structures) is also likely to involve REM rhythms of locomotor activity and wakefulness. sleep regulation. Along with these clinical observations, recent HYPOTHALAMIC WAKE-PROMOTING electrophysiological studies in animals demonstrated SYSTEM AND ITS IMPAIRMENT that the lateral and posterior hypothalamus contains Von Economo (1931) was probably the first person to wake-active, wake-promoting neurons. Many neurons suggest that narcolepsy (hypersomnia with REM sleep in these regions fire more rapidly during waking abnormalities) may have its origins in the posterior than during nonREM sleep (Steininger et al., 1999;

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S. NISHINO Other 1% Inherited disorders 34%

CA

Tumor 29%

SOREMP

Multiple 9% Posterior foss 6%

CA

SOREMP

Frontal Lob 3% CA

CA SOREMP Head trauma 16%

Temporal Lob 3%

Vascular 5%

CA

Brainstem 9%

Encephalopathy 3% Degeneration 3% Demyelinating 9% CA

CA

A Category of neurogic diseases associated with symptomatic narcolepsy.

Hypothalamus 70%

B The brain lesions involved symptomatic cases with narcolepsy associated with brain tumor.

Fig. 47.2. (A) Category of neurological diseases associated with symptomatic narcolepsy and (B) the brain lesions involved in symptomatic cases with narcolepsy associated with brain tumor. Thirty-three symptomatic cases of narcolepsy were included. The percentage of each neurological category (with cataplexy (CA)/with sleep-onset REM periods (SOREMPs)) was displayed. (A) Tumors, inherited disorders, and head trauma are the three most frequent causes. (B) Analysis of symptomatic narcolepsy with tumor cases clearly showed that the lesions most often involved the hypothalamus and adjacent structures (the pituitary, suprasellar, or optic chasm).

Alam et al., 2002; Koyama et al., 2003). In anesthetized animals, electrical or chemical stimulation of the posterior hypothalamus increases EEG activation (Sakai et al., 1990). Furthermore, chemical lesions of these regions decrease waking (Gerashchenko et al., 2001) and inhibition of this region with the GABA agonist, muscimol, increases nonREM sleep (Lin et al., 1989). Combined, these observations indicate that wake-promoting neurons in the posterior hypothalamus are critical for the production of wakefulness. One of these hypothalamic wake-promoting systems comprises the histamine-producing neurons of the tuberomammillary nucleus (TMN) (see Lin et al., 1990). These posterior hypothalamic neurons are the only neuronal source of histamine (though neuronal mast cells also release histamine), and they project extensively throughout the cortex, basal forebrain, hypothalamus, and brainstem (Inagaki et al., 1988). As with other aminergic neurons, TMN neuronal activity is highest during waking, lower during nonREM sleep, and lowest during REM sleep (Steininger et al., 1999). Drugs that enhance histamine signaling increase waking, and extracellular levels of histamine are high during spontaneous waking (Lin et al., 1990; Mochizuki et al., 1992). Much of this arousing influence may be mediated by histamine H1 receptors, as drugs that block H1 receptors increase nonREM and REM sleep in both

animal studies and clinical practice (Roehrs et al., 1984; Lin et al., 1990). On the other hand, H3 antagonists promote wakefulness and reduce REM sleep, whereas H3 agonists produce sleep, most likely by acting on autoinhibitory H3 receptors on histamine and other aminergic neurons (Monti et al., 1996). Histidine decarboxylase (a limiting enzyme for histamine synthesis) knockout (KO) mice have wake fragmentation, increased REM sleep, slower EEG activity during wake, and, most strikingly, an inability to maintain wakefulness in novel, alerting environments (Parmentier et al., 2002). Overall, 24-hour sleep and wake amounts were normal under undisturbed conditions, and similar results have been reported using locomotor measurements in H1 receptor knockouts (Yanai et al., 1998).

HYPOCRETIN AND THE CONTROL OF BEHAVIORAL STATE Although hypocretins were originally thought to promote feeding (Sakurai et al., 1998; Edwards et al., 1999), extensive evidence, together with their involvement in the sleep disorder “narcolepsy”, now suggests that hypocretins significantly modulate arousal and arousal-related processes with the interaction of other wake-promoting systems, and are the best candidates for the hypothalamic wake center.

HYPOTHALAMUS, HYPOCRETINS/OREXIN, AND VIGILANCE CONTROL

Hypocretin neurons and hypocretin receptors

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shares similar sequence homology, especially at the C-terminal side, but has no disulfide bonds (a linear peptide) (Sakurai et al., 1998) (Figure 47.4A,B). This structural difference likely contributes to the difference in the stability of the two peptides (hypocretin-1 is much more stable in biological fluids) (Yoshida et al., 2003). There are two G protein-coupled hypocretin receptors, hypocretin receptor 1 and 2 (Hcrtr1 and Hcrtr2), also called orexin receptor 1 and 2 (OX1R and OX2R), and a distinct distribution of these receptors in the brain is known (Marcus et al., 2001). Hcrtr1 is abundant in the LC (Lin et al., 1999; Marcus et al., 2001), whereas Hcrtr2 is found in the TMN and basal forebrain (including the diagonal band where wake-promoting basal forebrain cholinergic neurons are located). Both receptor types are found in the midbrain dopaminergic nuclei, raphe nuclei, and mesopontine reticular formation (Marcus et al., 2001) (Figure 47.4C). Genetic canine narcolepsy is caused by mutations in Hcrtr2, suggesting a primary role for this receptor subtype in sleep disturbances (Lin et al., 1999; see also Ripley et al., 2001a). Hypocretin neurons are medium in size and multipolar to fusiform in shape, and they number 1000 to 3000 in rats (Peyron et al., 1998; Harrison et al., 1999), 20 000 in dogs (Ripley et al., 2001a), and 70 000 in humans (Thannickal et al., 2000). The neurons are observed in a restricted area of the tuberal

The discovery of hypocretin neuropeptides (also called orexins) and their involvement in narcolepsy has been reviewed by several authors (see Chapter 48; see also Willie et al., 2001; Sakurai, 2005). Most human narcolepsy cases are caused by deficient hypocretin neurotransmission in the lateral hypothalamus, and this manifests clinically as undetectable or low cerebrospinal fluid (CSF) hypocretin levels (less than 30% of mean normal values) (Mignot et al., 2002) (Figure 47.3). Preprohypocretin KO mice (Chemelli et al., 1999) and hypocretin/orexin cell ablated mice with ataxin-3 (Hara et al., 2001) have abnormal wake to REM transitions, behavior arrests reminiscent of cataplexy, and increased sleep during the active period. Orexin/ ataxin-3 transgenic mice are produced by transferring the human ataxin-3 cDNA with human prepro-orexin promoter gene as a cell-specific enhancer, and result in postnatal cell death of hypocretin neurons (Hara et al., 2001). Hypocretins (hypocretin-1 and hypocretin-2), also called orexins (A and B), are hypothalamic neuropeptides that are cleaved from a precursor preprohypocretin (prepro-orexin) peptide (De Lecea et al., 1998; Sakurai et al., 1998). Hypocretin-1, with 33 residues, contains four cysteine residues forming two disulfide bonds. Hypocretin-2 consists of 28 amino acids and

CSF Hypocretin-1 Levels (pg/ml)

800

Narcoleptic

Control

600 Familial case

400 DQB1+0602 (−)

f

f 200

DQB1+0602

(−)

1 cm

1 cm

B

C

0

A

Narcolepsy Neurological Healthy (n=38) Control Control (n=19) (n=15)

Fig. 47.3. (A) CSF hypocretin-1 levels in narcoleptic and control subjects. Preprohypocretin mRNA in situ hybridization in the hypothalamus of control and narcoleptic subjects. CSF hypocretin-1 levels are undetectably low in most narcoleptic subjects (84.2%). Note that two HLA DqB1*0602-negative and one familial case have normal or high CSF hypocretin levels. Preprohypocretin transcripts are detected in the hypothalamus of control (C) but not narcoleptic (B) subjects. f, Fornix. Bar denotes 1 cm. Melanin-concentrating hormone transcripts are detected in the same region in control and narcoleptic sections (data not shown).

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Prepro-hypocretin (Prepro-orexin)

Hypocretin-1 (Orexin A)

Hypocretin-2 (Orexin B)

Hcrtr1 (OX1R)

Hcrtr2 (OX2R)

Gq

Gq

B

Gi/Go

Cerebral Cortex

Cortex

Thalamus

LC (1)

LHA 1 < 2

DR (1 = 2)

VLPO

LDT/PPT (1>2)

VTA (1 = 2) TMN (2)

Pons

C Fig. 47.4. (A) Structures of mature hypocretin-1 (orexin A) and hypocretin-2 (orexin B) peptides, showing the topology of the two intrachain disulfide bonds in hypocretin-1. Amino acid identities are indicated by shaded areas. Asterisks indicate that human and mouse sequences were deduced from the respective cDNA sequences and not from purified peptides. (B) Schematic representation of the hypocretin (orexin) system. Hypocretin-1 (orexin A) and hypocretin-2 (orexin B) are derived from a common precursor peptide, preprohypocretin (prepro-orexin). The actions of hypocretins are mediated via two G protein-coupled receptors named hypocretin receptor 1 (Hcrtr1) and hypocretin receptor 2 (Hcrtr2), also known as orexin-1 (OX1R) and orexin2 (OX2R) receptors, respectively. Hcrtr1 is selective for hypocretin-1, whereas Hcrtr2 is nonselective for both hypocretin-1 and hypocretin-2. Hcrtr1 is coupled exclusively to the Gq subclass of heterotrimeric G proteins, whereas in vitro experiments suggest that Hcrtr2 couples with Gi/o and/or Gq (adapted from Sakurai, 2005). (C) Projections of hypocretin neurons in the rat brain and relative abundances of hypocretin receptors 1 and 2. Hypocretin-containing neurons project to monoaminergic, cholinergic, and cholinoceptive regions where hypocretin receptors are enriched. These structures have previously been shown to be involved in sleep/wake regulation. Impairments of hypocretin input may thus result in cholinergic and monoaminergic imbalance and generation of narcoleptic symptoms. DR, dorsal raphe; LC, locus coeruleus; LDT/PPT, laterodorsal tegmental nucleus/pedunculopontine tegmental nucleus; LHA, lateral hypothalamic area; TMN; tuberomammillary nucleus; VLPO, ventrolateral preoptic nucleus; VTA, ventral tegmental area. (Adapted from Zeizter et al., 2006.)

HYPOTHALAMUS, HYPOCRETINS/OREXIN, AND VIGILANCE CONTROL region of the hypothalamus, more precisely in the perifornical nucleus, the dorsomedial hypothalamic nucleus, and the dorsal and lateral hypothalamic areas (a few cells were seen in the posterior hypothalamic area and the subincertal nucleus at the junction of the thalamus and the hypothalamus). The hypocretin neurons project to the olfactory bulb, cerebral cortex, thalamus, hypothalamus, and brainstem, particularly the LC, raphe nuclei, and to the cholinergic nuclei and cholinoceptive sites (such as the pontine reticular formation) thought to be important for sleep regulation (Peyron et al., 1998) (Figure 47.4C).

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ventricles, LC, or within select basal forebrain regions, increases waking and suppresses nonREM and REM sleep (Hagan et al., 1999; Bourgin et al., 2000; Piper et al., 2000). These wake-promoting actions in animals are accompanied by marked increases in locomotor activity as well as other behaviors, such as grooming and burrowing activities (Ida et al., 1999; Espana et al., 2002). As demonstrated originally, an increase in wakefulness is also associated with increased food intake, but hypocretin-1-stimulated food intake was weaker than with neuropeptide Y (Edwards et al., 1999). There is a clear diurnal fluctuation of hypocretin levels in extracellular microdialysis perfusates or in CSF hypocretin levels in rats, which increase gradually toward the end of the active period and become low during the resting period (Taheri et al., 2000; Fujiki et al., 2001b; Yoshida et al., 2001; Zeitzer et al., 2003; Zhang et al., 2004). Several acute manipulations, such as exercise, low glucose utilization in the brain, as well as forced wakefulness, increase hypocretin levels (Yoshida et al., 2001). These changes were, however, hardly detected by the changes in mRNA levels (Terao et al., 2000), suggesting the slow feedback and synthetic processes of hypocretin peptides. Hypocretin neurons synthesize Fos protein during wakefulness, and the number of Fos-positive, hypocretin-containing neurons correlates closely with the amount of

Functional roles of hypocretin system in vigilance control A series of studies have now shown that the hypocretin system is a major excitatory system that affects the activity of monoaminergic (dopamine, norepinephrine, serotonin, and histamine) and cholinergic systems with major effects on vigilance states (Brown et al., 2001; Eriksson et al., 2001; Korotkova et al., 2003; Sakurai, 2005). The efferent and afferent systems of hypocretin neurons suggest interactions between these cells and arousal/sleep–wakefulness centers in the brainstem as well as important feeding centers in the hypothalamus (Figure 47.5). Hypocretin-1, when injected into the

Hypocretin/Orexin Cortex

A11 VLPO

LC TMN A10

BF (Extracellular Adenosine)

LDT/PPT DR PRF Ach GABA/Gal His DA NE 5HT Ach-receptive

Fig. 47.5. Hypothalamic and brainstem sleep/wake regulation system. The role of the hypothalamus has been re-recognized by the recent discoveries of the wake-promoting hypocretin/orexin system in the lateral hypothalamic area, the sleep-promoting GABA/galanin (Gal), and the ventrolateral preoptic nucleus (VLPO). Destruction of these systems induce narcolepsy and insomnia respectively, mirroring the pioneering von Economo’s clinical findings on encephalitis lethargica. Although no direct interactions of both systems are reported, both hypocretin and the VLPO systems innervate the main component of the ascending arousal system, such as the adrenergic locus ceruleus (LC), serotonergic dorsal raphe (DR), and histaminergic tuberomammillary nucleus (TMN). The hypocretin system activates, and the VLPO system inhibits, these systems. Thus, the hypothalamus may serve as a center for the “sleep switch” under the influence of the circadian clock. Beside these ascending arousal systems, pharmacological research has suggested the involvement of the dopamine (DA), system, especially for the ventral tegmental area (A10) in the control of alertness. ACh, acetylcholine; BF, basal forebrain cholinergic nuclei; CR, caudal raphe; 5HT, 5-hydroxytriptamine (serotonin); LDT/PPT, laterodorsal tegmental/pedunculopontine tegmental; NE, norepinephrine; PRF, pontine reticular formation.

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wakefulness, whether it is naturally occurring, produced by sleep deprivation, or caused by stimulants such as amfetamine or modafinil (Scammell et al., 2000; Estabrooke et al., 2001). Recent in vivo electrophysiological studies (single unit recordings) in rats also demonstrated that hypocretin neurons are active during wakefulness and reduce the activity during slow-wave and REM sleep, but an increase in the neuronal activity is also associated with body movements or phasic REM activity (Lee et al., 2005; Mileykovskiy et al., 2005). In vitro electrophysiological studies have shown that hypocretin neurons are regulated by monoamines and acetylcholine, as well as metabolic cues, including leptin, glucose, and ghrelin (Yamanaka et al., 2003a, b). Thus, hypocretin neurons have the requisite functional interactions with hypothalamic feeding pathways and monoaminergic/cholinergic centers, and provide a critical link between peripheral energy balance and the central mechanisms that coordinate sleep/wakefulness and motivated behavior such as food seeking (Willie et al., 2001; Sakurai, 2005). Compelling evidence indicates that hypocretin neurons in the lateral hypothalamus receive inputs from diverse sensory and limbic systems, and drive hyperarousal through modulation of stress responses (Winsky-Sommerer et al., 2004). In addition, they may be involved in reward processes. Along this line, Harris et al. (2005) recently showed that c-Fos activation of the lateral hypothalamus hypocretin neurons in rats is correlated with preference for an environment repeatedly paired with food and cocaine rewards, and that activation of lateral hypothalamus hypocretin neurons reinstates an extinguished drug-seeking behavior. This reinstatement effect was blocked by prior administration of a hypocretin-1 antagonist. Similarly, Boutrel et al. (2005) showed that intracerebroventricular infusions of hypocretin-1 lead to a dose-related reinstatement of cocaine seeking without altering cocaine intake in rats (hypocretin-1 also dramatically increased intracranial self-stimulation thresholds). Hypocretin-induced reinstatement of cocaine seeking was prevented by a blockade of noradrenergic and corticotropin-releasing factor systems, suggesting that hypocretin-1 reinstated drug seeking through the induction of a stress-like state. Clinically, subjects with EDS are treated with amfetamine-like stimulants, but they rarely develop amfetamine abuse. Preliminary results using narcoleptic mice suggest that amfetamine-induced locomotor sensitization is greatly attenuated in mice that do not produce hypocretin ligands (Fujiki et al., 2001a); these results also suggest that the availability of hypocretin signaling may affect the susceptibility to stimulant abuse. As a result, further studies are warranted.

Hypocretin status in symptomatic cases of narcolepsy and EDS Although undetectably low CSF hypocretin levels are very specific for “idiopathic” cases of narcolepsy– cataplexy (hypocretin-1 in most neurology patients, including those with Alzheimer’s or Parkinson’s disease, was within the control range), intermediate CSF hypocretin levels are also seen in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma, central nervous system (CNS) infections, and Guillain–Barre´ syndrome (Ripley et al., 2001b). As symptomatic narcolepsy/EDS is often associated with some of these neurological conditions (see Figure 47.2), CSF hypocretin-1 measurements were also carried out in patients with symptomatic narcolepsy/EDS (see Nishino and Kanbayashi, 2005). Reduced CSF hypocretin-1 levels were seen in most patients with symptomatic narcolepsy and EDS with various etiologies, including tumors, head trauma, and demyelinating disorders. Furthermore, EDS in these patients, especially in acute/subacute demyelinating disorders (acute disseminated encephalomyelitis and multiple sclerosis), are sometimes reversible with an improvement of the causative neurological disorder combined with an improvement of the hypocretin status (Yoshikawa et al., 2004). Particular symptomatic EDS cases (with Parkinson’s disease and thalamic infarction) without hypocretin ligand deficiency have been, however, reported (Ripley et al., 2001b; Overeem et al., 2002; Tohyama et al., 2004), suggesting a heterogeneous pathophysiology of symptomatic EDS. In contrast to idiopathic narcolepsy, occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in these symptomatic cases (see Nishino and Kanbayashi, 2005). These results suggest that impairments of hypocretin system are likely to be involved in symptomatic narcolepsy/EDS, at least in some patients. However, it is still not conclusive whether a large majority of patients with low CSF hypocretin-1 levels with CNS lesions exhibit EDS/cataplexy, as CSF hypocretin measures are still experimental. Patients with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measurements and further studies are necessary.

Hypocretin–histamine interactions in physiological and pathophysiological conditions A series of studies has suggested the importance of hypocretin–histamine interactions in the vigilance control and in the pathophysiology of hypersomnia. Fibers containing hypocretin densely innervate the soma and proximal dendrites of TMN cells. TMN exclusively

HYPOTHALAMUS, HYPOCRETINS/OREXIN, AND VIGILANCE CONTROL expresses Hcrtr2 (Marcus et al., 2001), the hypocretin receptor subtype important for sleep. Recent electrophysiological studies have demonstrated consistently that hypocretin potently excites TMN histaminergic neurons through Hcrtr2 (Bayer et al., 2001; Eriksson et al., 2001; Yamanaka et al., 2002). This was further confirmed by experiments using the brain slices of Hcrtr2 KO mice; Ca2þ influx of TMN neurons by hypocretin-1 stimulation is abolished in these mice (Willie et al., 2003). Furthermore, it has recently been demonstrated that wake-promoting effects of hypocretins were totally abolished in histamine H1 receptor KO mice, suggesting that the wake-promoting effects of hypocretin are dependent on histaminergic neurotransmission (Huang et al., 2001). Interestingly, impaired histamine neurotransmission may also be involved in hypocretin-deficient narcolepsy, as well as in other hypersomnias. A study using Hcrtr2-mutated narcoleptic dogs found that histamine content in the cortex and thalamus was significantly lower in narcoleptic Dobermans than in controls (Nishino et al., 2001a). Furthermore, two independent human studies also demonstrated that CSF histamine content is significantly lower in hypocretin-deficient narcolepsy (Nishino et al., 2002; Kanbayashi et al., 2004). Interestingly, low CSF hypocretin levels were also observed in other primary hypersomnias, such as narcolepsy without cataplexy and idiopathic hypersomnia (hypocretin-nondeficient hypersomnias), but histamine levels in patients with sleep apnea were in the normal range (Kanbayashi et al., 2004). Although the functional roles of CSF histamine is not well understood, this finding is interesting because altered central histamine transmission may be involved in broader categories of hypersomnia (not limited to hypocretindeficient narcolepsy). CSF histamine levels may thus be a new biological marker for the central hypersomnias, although the functional significance of the findings should be studied further. Indeed, although several studies have suggested that the histamine system may be an important executive system for mediating the wake-promoting effect of hypocretins, a recent study has shed some doubt. Yoshida et al. (2005) measured hypocretin and histamine release simultaneously in rats before and after administration of a-fluoromethylhistidine (a-FMH), a histamine synthetic enzyme inhibitor. Administration of 100 mg/kg a-FMH significantly reduced the histamine release (by more than 70%) and abolished the diurnal fluctuation pattern, but had no influence on hypocretin release, or any effect on sleep parameters. Although the lack of influence of histaminergic tonus on hypocretin activity is consistent with recent in vitro data showing that histamine does not modify

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the activity of hypocretin neurons (Yamanaka et al., 2003a), the results are difficult to reconcile if the histamine system is physiologically important for mediating the wake-promoting effect of hypocretins. The histamine system may play more specific roles for some aspects of physiology associated with wakefulness; wakefulness may be coordinated with activity of these two systems with partial specialization. For example, hypocretin neurons may be more sensitive to peripheral metabolic cues (see section Links between vigilance control and other hypothalamic functions below), whereas the histaminergic system may be involved in attention or cognition during wakefulness, as this has been postulated in other neurological conditions (Higuchi et al., 2000).

HYPOTHALAMIC SLEEP-PROMOTING SYSTEMS AND THEIR INTERACTIONS WITH HYPOTHALAMIC AND OTHER WAKE-PROMOTING SYSTEMS The importance of the preoptic hypothalamus in the generation of nonREM sleep has also been refined by many recent studies. Electrophysiological recordings have identified nonREM sleep-active neurons in the preoptic hypothalamus (Kaitin, 1984; Szymusiak and McGinty, 1986a; Koyama and Hayaishi, 1994). Subsequent studies determined that injury to the preoptic area (the most rostral part of the anterior hypothalamus) produced marked reductions in sleep (McGinty and Sterman, 1968; Szymusiak and McGinty, 1986b), whereas electrical or chemical stimulation of this region increased nonREM sleep (Sterman and Clemonte, 1962a, b). Interest in the preoptic area has been renewed by recent observations that activation of a subgroup of GABAergic cells in the ventrolateral preoptic area (VLPO) correlated with the amount of nonREM sleep (Sherin et al., 1996). Electrophysiological recordings in freely moving animals demonstrated that VLPO neurons fire rapidly during nonREM and REM sleep, and are virtually inactive during waking (Szymusiak et al., 1998). These cells also contain galanin (an inhibitory peptide) (Gaus et al., 2002), project to all wake-active monoaminergic systems (especially the TMN) (Sherin et al., 1998), and are supposed to inhibit activity of these monoaminergic neurons during nonREM sleep. Projections from the VLPO may also be an important substrate for the hypnotic action of GABAergic compounds. An extended VLPO area has also been identified as REM active, and these neurons are more specifically involved in REM sleep regulation (Lu et al., 2002). These neurons are also project to brainstem serotonergic and adrenergic nuclei. A second cluster of slow-wave sleep active neurons has

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also been identified in the median preoptic nucleus (MnPN), and the MnPN has been shown previously to be involved in water balance and blood pressure regulation and to be responsive to hyperthermia, and interactions between sleep control and these physiological variables must be considered (McGinty et al., 2004). The activity of these sleep-producing preoptic neurons may be regulated by endogenous somnogens such as adenosine and prostaglandin D2 (a somnogenic autacoid; see section on Humoral factors) (see Hayaishi and Urade, 2002). Adenosine has been proposed as a mediator of sleep homeostasis and a link between metabolism and sleep control (see Benington and Heller, 1995; Porkka-Heiskanen et al., 2003). The nonselective adenosine receptor antagonist, caffeine, is widely used to induce wakefulness, although its efficacy is low compared with amfetamine-like stimulants. Prolonged waking increases the concentration of adenosine in the basal forebrain, and adenosine levels fall rapidly during the subsequent recovery sleep (Porkka-Heiskanen et al., 1997). Raised levels of extracellular basal forebrain adenosine may also have long-tem intracellular effects, such as actions on transcription factors in cholinergic neurons (Basheer et al., 2001), and central administration of adenosine agonists or prostaglandin D2 increases sleep (Ueno et al., 1985; Portas et al., 1997). These somnogens also increase Fos within VLPO neurons, suggesting that they may produce sleep by activating the VLPO directly or indirectly (Scammell et al., 1998; Scammell et al., 2001). Prostaglandin D2 increases adenosine release (see Satoh et al., 1996), and adenosine may promote sleep by disinhibiting the VLPO sleep active neurons through adenosine A2a receptors (Chamberlin et al., 2003; Gallopin et al., 2005). Reciprocal interactions between the VLPO and monoaminergic systems have been suggested. The VLPO is innervated by TMN histaminergic neurons and by noradrenergic terminals from the LC, and receives serotonergic inputs from the midbrain raphe nuclei (Sherin et al., 1998). Recordings from individual VLPO neurons in hypothalamic slices show that they are inhibited by norepinephrine (noradrenaline) and 5-hydroxytryptamine (5HT). Saper et al. (2001) proposed the existence of mutual inhibition between the VLPO and the major arousal systems. When VLPO neurons fire rapidly during sleep, they inhibit the monoaminergic cell groups, thus disinhibiting and reinforcing their own firing. Similarly, when monoamine neurons fire at a high rate during wakefulness, they inhibit the VLPO, thereby disinhibiting their own firing. This reciprocal relationship is similar to a type of circuit that electrical engineers call flip-flop. The two halves of a flip-flop circuit, each strongly inhibiting the other, create a feedback loop that is bistable, with

two possible stable patterns of firing and a tendency to avoid intermediate states. Such properties would be very useful in sleep–wake regulation, as an animal that walked about while half asleep would be in considerable danger. The flip-flop switch changes behavioral states infrequently, but rapidly, in contrast to the homeostatic and circadian inputs, which change slowly and continuously. According to this theory, a loss of wake- or sleepregulating neurons should destabilize this switch, resulting in poor control of the behavioral state. It is reported that rats with lesions of the VLPO display half the normal amount of nonREM sleep with very brief sleep episodes, but they enter sleep much more frequently than normal (Lu et al., 2000). These authors also propose the importance of hypocretin signaling in stabilizing the flip-flop circuit, as sleep and wakefulness of narcoleptic humans and animals are highly fragmented, and exhibit abnormal transition to REM sleep and abnormal manifestation of REM sleep atonia. Although hypocretin increases the firing rate of neurons in the LC, DRN, TMN, and the (dopaminergic) ventral tegmental area through direct excitatory inputs (Hagan et al., 1999; Brown et al., 2001; Eriksson et al., 2001), VLPO neurons lack hypocretin receptors (Marcus et al., 2001) and have no direct physiological response to hypocretin (Eggermann et al., 2001). If hypocretin is an important stabilizer for this sleep switch, it may act presynaptically in the VLPO region, enhancing the release of amines and resulting in inhibition of the VLPO neuron.

LINKS BETWEEN VIGILANCE CONTROL AND OTHER HYPOTHALAMIC FUNCTIONS THROUGH THE HYPOCRETIN SYSTEM Obesity in patients with narcolepsy was described decades ago, but this phenotype has not received much attention as it could be secondary to behavioral changes (inactivity) (see Nishino et al., 2001b). However, a study of hypocretin neuron-ablated mice demonstrated that these animals exhibit hypophagia and late-onset obesity, possibly associated with reduced energy expenditure or low metabolic rate (Hara et al., 2001). Decreased calorie intake was also reported in some human subjects (Lammers et al., 1996). These findings are consistent with the original idea that hypocretin plays a role in the regulation of feeding and energy homeostasis (Sakurai et al., 1998). This function is also likely to contribute a physiological link between energy balance and vigilance control. Proper maintenance of arousal during food search and intake of an animal is essential for its survival.

HYPOTHALAMUS, HYPOCRETINS/OREXIN, AND VIGILANCE CONTROL For example, a mouse seeking food must be alert, hungry, and physically active with a relatively high sympathetic tone (blood pressure, heart rate, metabolic rate, etc). The hypocretin neurons respond directly to neuromodulators implicated in feeding, such as ghrelin and leptin (Lopez et al., 2000; Lawrence et al., 2002), and send projections to appetite-regulating regions including the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus (Peyron et al., 1998). The hypocretin neurons innervate cells in autonomic regulatory regions such as the lateral hypothalamus, ventrolateral medulla, nucleus of the solitary tract, and intermediolateral cell column (Peyron et al., 1998), and ventricular injection of hypocretin increases sympathetic activity and modulates body temperature (Balasko et al., 1999). Through their projections to the arcuate nucleus and median eminence, the hypocretin neurons also influence neuroendocrine responses (Taylor and Samson, 2003). The integrating role of the hypocretin neurons is apparent in the behavioral response to food deprivation. In normal mice, food deprivation increases waking and locomotor activity, possibly to facilitate food-seeking behavior. However, these responses are absent in mice lacking the hypocretin neurons (Yamanaka et al., 2003b). Food restriction markedly increases locomotor activity (Morse et al., 1995), promoting and consolidating wakefulness (Welsh et al., 1988). This locomotor response may depend on hypocretin, as exogenous hypocretin increases locomotion and wheel running, and the hypocretin neurons are most active during periods of high locomotor activity (Espana et al., 2003). We also observed a higher hypocretin release during long-term food deprivation in the hypothalamus in rats, together with an increase in wake and suppression of REM sleep during resting period (unpublished data). The response to food deprivation may also be mediated by appetite-regulating signals, as food deprivation increases ghrelin, and ghrelin excites the hypocretin neurons (Yamanaka et al., 2003b). Conversely, fasting decreases leptin levels, and leptin inhibits the hypocretin neurons (Yamanaka et al., 2003b). Thus, a combination of increased locomotor activity, increased ghrelin, and decreased leptin levels may contribute to increased hypocretin signaling and wakefulness during food deprivation. Coordination of these signals confers an essential behavioral advantage, allowing the hypocretin neurons to promote alertness in order for a hungry animal to remain awake for longer periods and seek food more effectively. Another important interaction with the hypocretin system for vigilance control may occur with other peptidergic systems within the vicinity of the lateral

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hypothalamus. Peptidergic neurons containing melanin-concentrating hormone (MCH) and the hypocretins are intermingled in the zona incerta, perifornical nucleus, and lateral hypothalamic area. MCH has been implicated in the integrated regulation of energy homeostasis and body weight. Studies of MCH and hypocretin gene expression in impaired leptin signaling/obese mice (ob/ob and db/db mice) suggest that hypocretin is regulated in a manner opposite to that of MCH; MCH expression is upregulated in ob/ob and db/db mice (Qu et al., 1996), whereas hypocretin expression is decreased in these mice (Yamamoto et al., 1999). It has been reported recently that MCH, but not hypocretin, neurons are strongly active in REM sleep during the rebound following REM sleep deprivation, as observed by c-Fos expression (Modirrousta et al., 2005). Furthermore, intracerebroventricular administration of MCH induces a dosedependent increase in REM sleep (up to 200%) and slow-wave sleep (up to 70%) (Verret et al., 2003). Bayer et al. (2005) recently reported that norepinephrine (NE) and carbachol (a cholinergic agonist) hyperpolarize MCH neurons in rat hypothalamic slices by direct postsynaptic actions, and both agonists depolarized and excited hypocretin neurons. From these results, the authors hypothesized that hypocretin neurons may stimulate arousal in tandem with other arousal systems, whereas MCH neurons may function in opposition with other arousal systems and thus potentially dampen arousal to promote sleep.

CONCLUSIONS Clinical observations have consistently demonstrated that lesions of the posterior hypothalamus induce hypersomnia (and REM sleep-related abnormalities), suggesting the existence of a “wake center” in the hypothalamus. The hypocretin system plays a central role in the hypothalamic control of sleep and wakefulness. Recent experiments revealed that hypocretin neurons are wake-active and hypocretin release is high during the active phase when animals spend most of their time awake, and low during the resting/sleeping phases. Several in vivo manipulations that enhance hypocretin release have been identified, and forced wakefulness by behavioral manipulation and some wake-promoting compounds increased hypocretin levels. Stress reactions, locomotor activation, and high brain temperatures are often associated with forced wakefulness, and these may also activate the hypocretin system. Most uniquely, hypocretin systems are also activated by fasting or by decreased glucose utilization in the brain. The hypocretin neurons may thus play an essential role in integrating hypothalamic signals

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related to stress and appetite into appropriate sleep/ wake behavior. Anatomical and functional findings suggest that this integration is likely to be mediated through the activation of other wake-active monoaminergic systems, such as histaminergic, noradrenergic, and cholinergic neurons, and the inhibition of the hypothalamic sleep-promoting systems. Recent electrophysiological studies have started to reveal the in vitro cellular mechanisms modulating hypocretin tonus. Complex feedback loops with the monoaminergic and cholinergic system, and peripheral metabolic clues (ghrelin and leptin), are likely to be involved in this regulation. The phenotype of hypocretin-deficient narcolepsy is characterized as a fragmentation of sleep and wake (instability of vigilance state), and dissociated manifestations of REM sleep. Narcoleptic subjects do not maintain wakefulness and do not respond to the alerting stimuli as normal people do. Taken together with the cumulated functional correlates of the hypocretin system, the wake-promoting hypothalamic center is likely to be involved in (1) stabilizing the vigilance state, (2) mediating various alerting stimulus (including by peripheral humoral factors related to energy metabolism) to wakefulness, and (3) REM sleep inhibition/modulation. The hypocretin system is one of the systems critical for regulating vigilance, and for linking fundamental hypothalamic functions required for survival.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 49

Recurrent hypersomnias MICHEL BILLIARD * Department of Neurology, Gui de Chauliac Hospital, Montpellier, France

RECURRENT HYPERSOMNIAS Recurrent hypersomnias refer to a group of relatively rare sleep disorders characterized by recurrent episodes of more or less continuous sleep, with an average duration of 1 week. These episodes recur at highly variable intervals of between one and several months. The most classical picture is that of the Kleine–Levin syndrome in which abnormal sleep episodes are diversely associated with abnormal behaviors including binge eating, hypersexuality and other compulsions, cognitive abnormalities, and depressed mood. In comparison with clinical features, the pathophysiology of these disorders is still largely unknown and the therapeutic options are limited.

HISTORICAL VIEW The first description of the Kleine–Levin syndrome is to be found in a book by Brierre de Boismont (1862). Sixty years later, Kleine (1925), a German psychiatrist, published five cases of periodic somnolence, Periodische Schlafsucht, two of which were accompanied by increased appetite during the episodes of hypersomnia (cases 3 and 4). The patients’ behavior suggested epidemic encephalitis, and frequent sexual disturbances were observed. One year later, Lewis (1926) reported on a 12-year-old boy who had suffered from episodes of somnolence, weakness, callousness, and increased appetite since he reached the age of 10. Each episode lasted from 2 to 12 weeks. All these episodes were accompanied by behavioral disturbances. Levin, from Philadelphia, later described five cases of narcolepsy and three of morbid somnolence, including a 16-yearold boy who experienced recurrent episodes of somnolence, irritability, restlessness, and megaphagia lasting from 1 to 6 weeks, beginning 3 days after the termination of a 4-day illness characterized by sore throat,

feverishness, and occipital headaches (Levin, 1929). Seven years later, Levin collated several case reports, publishing them as examples of “a new syndrome of periodic somnolence and morbid hunger”, occurring solely in men, starting after puberty and characterized by attacks of somnolence lasting for several days or weeks, associated with excessive appetite, unstable motor control, incoherent remarks, and occasionally hallucinations (Levin, 1936). In 1942, the eponymous term Kleine–Levin syndrome was coined by Critchley and Hoffman (1942). Clear diagnostic criteria were not established until 1962, when Critchley published a comprehensive review paper, including 15 instances collected from the literature and 11 cases of his own. The criteria listed by Critchley included “recurring episodes of undue sleepiness lasting some days associated with an inordinate intake of food, and often with abnormal behaviour”. He also established four hallmarks of the disease: males being predominantly if not wholly affected; adolescent onset; spontaneous eventual disappearance of the symptoms; and megaphagia defined as a compulsive eating disorder rather than bulimia. Furthermore, he noted that certain events frequently preceded the onset of the syndrome: feverish malaise, viral infection, physical stress, fright, alcohol intoxication, and physical injury. For years, the description of the condition has remained more or less identical, laboratory tests have been developed without providing consistent keys in the diagnosis and in understanding the pathophysiology, and the treatment has not made significant progress. More recently, a systematic review of 186 cases in the literature (Arnulf et al., 2005) and a controlled study based on a semistandardized medical telephone interview focusing on medical history, symptoms, and evolution of the Kleine–Levin syndrome conducted in

*Correspondence to: Michel Billiard MD, Honorary Professor of Neurology, Department of Neurology, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, 34295, Montpellier cedex 5, France. Tel: þ33 6 75 028 364, Fax: þ33 4 67 661 862, E-mail: [email protected]

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the families of 108 new cases (Arnulf et al., 2008) have extended our knowledge of the syndrome.

DEMOGRAPHICS Recurrent hypersomnia is rare. No epidemiological study is yet available. Approximately 200 patients with Kleine– Levin syndrome have been reported in the literature. The male to female ratio for Kleine–Levin syndrome is between 3 and 2:1 (Arnulf et al., 2005, 2008), with a more balanced male to female ratio where recurrent hypersomnia is the only symptom. Early adolescence is the usual age of onset. A wider distribution of age of onset has been reported in females (Billiard and Cadilhac, 1988). It is noteworthy that the prevalence is six times higher in Jewish patients, all Ashkenazi, than expected (Arnulf et al., 2008). The Kleine–Levin syndrome is predominantly a sporadic condition. However a few multiplex families have been identified (Bonkalo, 1968; Janicki et al., 2001; Dauvilliers et al., 2002; Katz and Ropper 2002; Arnulf et al., 2008), supporting a role for a major genetic susceptibility factor.

PAST MEDICAL HISTORY A recent finding has been the significantly higher percentage of patients with Kleine–Levin syndrome who have problems at birth (long labor, hypoxia, premature or postmature birth) in comparison with control subjects (25% versus 7.4%), and in development (delayed speech, walking, or reading) (Arnulf et al., 2008).

CLINICAL FEATURES Episodes of recurrent hypersomnia are often preceded by prodromes such as fatigue or headache lasting a few hours. The onset of episodes may occur in a couple of hours or gradually over several days. During the episode the subject may sleep as long as 16–18 hours per day, waking or getting up only to eat and void. Sleep may be calm or agitated. Parasomnia may occur. Intense dreaming is sometimes reported. In the Kleine–Levin syndrome, hypersomnia is typically accompanied by behavioral and cognitive abnormalities, and depression. Behavioral abnormalities include binge eating, hypersexuality, irritability, and odd behaviors. Binge eating refers to the consumption of a large amount of food, especially sweet foods such as candies, chocolates, and cakes, in a compulsory manner, to the point that some patients may steal food in shops or from the plates of other patients in the hospital. This behavior does not necessarily occur during all episodes, and some patients may experience decreased appetite during some episodes. Hypersexuality can take the form of sexual advances, shamelessly expressed

sexual fantasies, or masturbation in public. It is more frequent in boys than in girls. Irritability is present in almost all patients and can develop into outright aggressiveness, hence the frequent difficulty in performing polysomnography and multiple sleep latency test in a satisfactory way. Odd behaviors are diverse and surprising. They include talking in a childish manner, singing loudly, talking on the telephone without dialing, doing a headstand, writing on walls, etc. Cognitive abnormalities include an unbearable altered perception (people and objects seem distorted, unreal, dream-like), confusion, fragmentary delusions, visual or auditory hallucinations. Depression is present in almost half of the patients, and some may report suicidal thoughts. However, it is to be noted that the simultaneous occurrence of many of these symptoms is the exception rather than the rule, and any symptom may be present in only one or two of several episodes. A reddish face and severe perspiration may be noted during physical examination. Weight gain of a few kilograms may be observed in relation to binge eating. A higher body mass index in patients versus control subjects has been found (Arnulf et al., 2008). The episode of hypersomnia may end abruptly or insidiously. It is not uncommon for the episode to be followed by amnesia, manic behavior with insomnia lasting 1 or 2 days, as if the subject were trying to make up for lost time, or depression, occasionally with suicidal thoughts. The defining element is the recurrence of episodes after a lapse of one to several months. Between episodes, the alertness and behavior of subjects is normal, although neurotic traits or slight mental deficiency may be seen in some cases.

DIAGNOSTIC CRITERIA According to the second edition of the International Classification of Sleep Disorders (ICSD-2) (American Academy of Sleep Medicine, 2005), diagnostic criteria for recurrent hypersomnia (including Kleine–Levin syndrome and menstrual-related hypersomnia) are: ● ● ● ●

The patient experiences recurrent episodes of excessive sleepiness lasting from 2 days to 4 weeks. Episodes recur at least once a year. The patient has normal alertness, cognitive functioning, and behavior between attacks. The hypersomnia is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder.

The specific diagnosis of Kleine–Levin syndrome should be reserved for patients in whom recurrent

RECURRENT HYPERSOMNIAS episodes of hypersomnia are clearly associated with behavioral abnormalities, especially binge eating, at least during some episodes, and cognitive alterations.

LABORATORY TESTS The diagnosis of recurrent hypersomnia is purely clinical. Laboratory investigations serve merely to exclude the possibility of secondary recurrent hypersomnia, with a recognizable organic cause. Except in rare cases, reports of laboratory tests concern subjects with the Kleine–Levin syndrome.

Electroencephalography The typical pattern shows a general slowing of the background activity, often with bursts of bisynchronous, generalized, moderate to high voltage: 5–7-Hz waves 0.5–2 s in duration (Thacore et al., 1969; Smirne et al., 1970).

Polysomnography Nocturnal polysomnography alone, diurnal polysomnography alone, nocturnal polysomnography plus a multiple sleep latency test (MSLT), or 24-hour polysomnography have been used. An important reduction in stages 3 and 4 during the first half of the symptomatic period, with progressive return to normal during the second half, has been reported, as well as a decrease of rapid eye movement (REM) sleep during the second half of the symptomatic period (Huang et al., 2008). Sleep efficiency is poor during the symptomatic period, but not significantly different during the asymptomatic period (Gadoth et al., 2001; Huang et al., 2008). Sleeponset REM periods have been reported during diurnal recordings (Messimy et al., 1967; Wilkus and Chiles, 1975) and during MSLT performed during a symptomatic period (Reynolds et al., 1984; Rosenow et al., 2000; Huang et al., 2008). However, the results of the MSLT are highly dependent on the subject’s willingness to comply with the procedure. In practice, it is easier and more instructive to carry out a continuous polysomnographic recording for 24 hours, providing an indication of the total sleep time over 24 hours, which is generally increased, and of possible sleep-onset rapid eye movement (SOREM) episodes (Barontini and Zappoli, 1967; Popoviciu and Corfariu, 1972; De Villard et al., 1980).

Biological tests With few exceptions in literature, blood count, plasma electrolytes, urea, creatinine, calcium, and phosphorus levels, and hepatic function tests are normal. Increased leptin and C-reactive protein levels have been reported

817

during hypersomniac episodes (Arnulf et al., 2008). Plasma bacterial and viral serological tests are negative. Cerebrospinal fluid (CSF) cytology and protein are normal.

Hormonal levels Baseline levels of the main anterior pituitary hormones, growth hormone (GH), prolactin, thyroid-stimulating hormone (TSH), luteinizing hormone, follicle-stimulating hormone, testosterone, and cortisol are normal. The same applies to levels obtained after stimulation tests, with a few exceptions: a paradoxical GH response to thyroid-releasing hormone (TRH, thyrotropin) (Gadoth et al., 1987), an attenuated or no cortisol response to insulin-induced hypoglycemia (Koerber et al., 1984; Fernandez et al., 1990), and an absent TSH response to TRH (Fernandez et al., 1990). Contradictory hormonal secretory patterns during sleep or over 24 hours have been reported (Gilligan, 1973; Kaneda et al., 1977; Hishikawa et al., 1981; Thomson et al., 1985; Gadoth et al., 1987; Chesson et al., 1991; Mayer et al., 1998) (Table 49.1).

Human leukocyte antigen (HLA) class II association An increased HLA-DQB1*0201 allele frequency has been reported (Dauvilliers et al., 2002), but not confirmed by later authors (Arnulf et al., 2008; Huang et al., 2008).

Hypocretin levels A few reports of CSF hypocretin-1 measurements are available. Two subjects with Kleine–Levin syndrome have been investigated during episodes of hypersomnia alone, one with intermediate levels (Mignot et al., 2002) and the other one with normal levels (Katz and Ropper, 2002). Of more interest is the report of three subjects investigated during asymptomatic intervals and of one subject investigated during both an asymptomatic interval and an episode of hypersomnia (Dauvilliers et al., 2003). The four cases investigated during asymptomatic intervals had CSF hypocretin-1 levels in the normal range (221–897 pg/ml), whereas the subject investigated during both an asymptomatic interval and an episode of hypersomnia had a twofold decrease (from 221 to 111 pg/ml) during the latter. Finally, a twofold decrease in hypocretin-1 concentration was observed during the period of hypersomnia in comparison with the asymptomatic interval in a 14-year-old girl severely affected with Kleine–Levin syndrome (Podesta et al., 2006). These data suggest a possible intermittent alteration of the hypocretin system during episodes of hypersomnia.

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Table 49.1 Night sleep or 24-hour hormonal secretory patterns during hypersomniac episodes of recurrent hypersomnia or Kleine–Levin syndrome with regard to baseline

Reference

Hormones

Gilligan (1973)

hGH

Kaneda et al. (1977)

hGH

Hishikawa et al. (1981)

hGH Cortisol Cortisol Prolactin Melatonin hGH Prolactin TSH FSH hGH Cortisol Prolactin TSH hGH Melatonin TSH Cortisol

Thomson et al. (1985)

Gadoth et al. (1987)

Chesson et al. (1991)

Mayer et al. (1998)

Sleep disorder (no. of subjects)

Period of sampling

Periodicity of sampling

Variation in night or 24-h plasma level compared with baseline

Kleine–Levin syndrome (1) Recurrent hypersomnia (2) Recurrent hypersomnia (4) Kleine–Levin syndrome (1)

24 h

4h

No change

Night

30 min

Increased

Night

30 min

24 h

1h

Kleine–Levin syndrome (1)

Night

20 min

Kleine–Levin syndrome (1)

24 h

20 min

Kleine–Levin syndrome (5)

24 h

2h

Abnormal No change No change No change No change Increased Increased No change No change Decreased Increased Increased Increased Decreased (in 2) Increased (in 5) No change No change

Note the inconsistent results among authors. FSH, follicle-stimulating hormone; hGH, human growth hormone; TSH, thyroid-stimulating hormone

Neuroimaging Computed tomography and magnetic resonance imaging of the brain show no abnormality. In a few cases, single-photon emission computed tomography (SPECT) has demonstrated hypoperfusion of the left or right temporal and/or frontal lobes (Yassa and Nair, 1978; Argentino and Sideri, 1980; Lu et al., 2000; Arias et al., 2002; Portilla et al., 2002; Landtblom et al., 2002, 2003; Peraita-Adrados, 2003). More recently, two studies have shown hypoperfusion of both thalami during the symptomatic period, completely disappearing during the asymptomatic period. In a first study performed in 7 patients with Kleine–Levin syndrome during asymptomatic periods and in 5 during symptomatic periods (Huang et al., 2005), the thalami showed hypoperfusion during the symptomatic period in 5 of 5 cases, the basal ganglia in 4 of 5 cases, and the cortices in 3 of 5 cases, and in a second study performed in a single patient (Hong et al., 2006) the substracted SPECT showed significant hypoperfusion in both

thalami, left hypothalamus, basal ganglia, and cortices during the symptomatic period. These cerebral hypoperfusion areas support the diencephalic hypothesis for the Kleine–Levin syndrome.

Psychological investigation Psychological interview and testing should always be carried out both during the episode of hypersomnia – not an easy task – and when the subject is no longer experiencing an episode, to ensure that there is no background personality disorder or that the subject is not expecting some benefit from the “symptomatic” episodes.

Brain neuropathological examination Four post-mortem neuropathological case reports have been published, with inconsistent findings. One subject showed a significant degree of lymphocytic cuffing of the small vessels in the hypothalamus, amygdala, and gray matter of the temporal lobes suggesting mild

RECURRENT HYPERSOMNIAS localized encephalitis (Takrani and Cronin, 1976). The second and third cases showed similar lesions in two different locations, the thalamus in one case (Carpenter et al., 1982) and the diencephalon and midbrain in the other (Fenzi et al., 1993). In the fourth case, the only finding was a small locus coeruleus and decreased pigmentation in the substantia nigra (Koerber et al., 1984).

COURSE The course of recurrent hypersomnia is characterized by episodes of hypersomnia lasting for a few days to several weeks, appearing 1 to 10 times a year with normal functioning between episodes. Case report review suggests a usually benign course with episodes lessening in duration, severity, and frequency over one or several years. However, in a number of cases, followup is lacking after the last episode and, in rare cases, episodes have been shown to recur over a period of 10–20 years (Critchley, 1962; Gran and Begemann, 1973; Bu¨cking and Palmer, 1978; Lavie et al., 1981). In the systematic study of 108 patients with the Kleine– Levin syndrome by Arnulf et al. (2008), the median disease duration was 13.64.3 years. Complications are mainly social and occupational. One particular form of evolution is that of a psychotic nature (Robinson and McQuillan, 1951; Wyss, 1968). In exceptional cases, subjects have been reported to choke while eating voraciously during the episode and to suffer cardiopulmonary arrest (Carpenter et al., 1982; Koerber et al., 1984).

CLINICAL VARIANTS Menstrual-related periodic hypersomnia occurs within the first months after menarche. Episodes generally last for 1 week, with rapid resolution at the time of menses. Behavioral and cognitive abnormalities are variably associated, as in the Kleine–Levin syndrome (Kaplinsky and Schulmann, 1935; Lhermitte and Dubois, 1941; Lhermitte et al., 1943; Gilligan, 1973; Gran and Begemann, 1973; Billiard et al., 1975; Roth and Nevsimalova, 1981; Papy et al., 1982; Sachs et al., 1982). Hormonal imbalance is a likely explanation for the condition, as oral contraceptives usually lead to prolonged remission. Monosymptomatic recurrent hypersomnia is characterized by recurrent episodes of hypersomnia, usually associated with irritability as in the Kleine–Levin syndrome, but without behavioral symptoms and limited cognitive symptoms. Considering the number of published cases in the world literature (45 cases of monosymptomatic recurrent hypersomnia versus 200 cases of Kleine–Levin syndrome), the condition is probably less frequent than the Kleine–Levin syndrome.

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DIFFERENTIAL DIAGNOSIS Recurrent episodes of sleepiness may be secondary to organic insult to the central nervous system. Tumors proliferating within the third ventricle, such as colloid cyst (Guillain et al., 1925; Lindon, 1938; Grossiord, 1941), astrocytoma (Haugh and Markesbery, 1983), or craniopharyngioma, may produce intermittent obstruction of ventricular flow, leading to headache, vague sensorial disturbance, and a paroxysmal impairment of alertness. Tumors in other locations (e.g., pinealoma; Gabriel, 1935), encephalitis (Gordon, 1939; Merriam, 1986; Salters and White, 1993), head trauma (Will et al., 1988), or stroke (Takahashi, 1965; Semionowa-Tian-Shanskaya, 1966; Pohl and Hairs, 1968) may less frequently mimic symptoms of recurring hypersomnia. Recurrent episodes of hypersomnia have also been described in the context of psychiatric disorders, such as bipolar disorder (Jeffries and Lefebvre, 1973) or somatoform disorder (Godenne, 1966; Billiard and Cadilhac, 1988).

PREDISPOSING AND PRECIPITATING FACTORS As already mentioned, an increased association with HLA-DQB1*0201 has been found recently in subjects with Kleine–Levin syndrome, but not confirmed by later authors. However, the Jewish predisposition and the identification of a few multiplex families may point to a genetic background. Precipitating factors are frequently reported immediately before the onset of the first episode of hypersomnia (Table 49.2). Of these factors, the most frequent Table 49.2 Precipitating factors identified in 162 subjects (128 males and 34 females) with Kleine–Levin syndrome

Precipitating factor Influenza-like or ENT infection Drunkenness Blow to the face Emotional shock General anesthesia Seasickness Exhausting effort First menstrual period Other factor No identified factor ENT, ear, nose, and throat.

Males (n ¼ 128)

Females (n ¼ 34)

50 (39.1%)

9 (26.4%)

4 (3.1%) 3 (2.3%) 3 (2.3%) 2 (1.6%) 2 (1.6%) 2 (1.6%) – 3 (2.3%) 59 (46.1%)

– – – – – – 3 (8.8%) 2 (5.9%) 20 (58.8%)

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is infection or fever, and less frequently reported triggering events include drunkenness, a blow to the face, anesthesia, seasickness, etc. (Billiard and Cadilhac, 1988; Arnulf et al., 2008). Given the already mentioned pathological abnormalities found in a few cases, it is important to emphasize that pathogens may attack specific brain regions (Salters and White, 1993).

PATHOPHYSIOLOGY The symptoms typically observed in Kleine–Levin syndrome may reflect an intermittent dysfunction of the hypothalamus, given the critical role of this structure in the regulation of sleep, appetite, and sexual behavior. However, no consistent hypothalamic abnormalities have been identified and SPECT studies indicate a thalamic involvement. A hypocretin neurotransmission abnormality has been hypothesized on the basis of the role of hypocretin neuropeptides in both sleep–wake regulation and feeding behavior, and of a decreased CSF hypocretin-1 level during the symptomatic period of the Kleine– Levin syndrome found in a few recent cases, as reviewed above. Whatever the pathophysiological mechanism, its origin could lie in environmental factors, infectious or other, acting on a vulnerable genetic background. Given the recurrence of episodes, the young age at onset and the frequent infectious precipitating factors, an autoimmune process has recently been suggested (Dauvilliers et al., 2002). Regarding the recurrence of episodes, it is noteworthy that precipitating events often play a major role in the onset of the first episode of hypersomnia, but not in subsequent episodes, which seem to be more autonomous with precipitating events contributing little or nothing to the process. Interestingly the same remark applies to both bipolar disorder and unipolar depression, and it has been hypothesized that stressors may not only precipitate the first episode but also increase a pre-existing vulnerability, sensitizing the individual and thereby leaving him or her more vulnerable to further episodes (kindling effect) (Post et al., 1984). The occasional presence of mood disorders in family members of subjects with Kleine–Levin syndrome is to be underlined (Sagripanti, 1952; Critchley, 1962; Bonkalo, 1968; Cawthron, 1990).

TREATMENT Given the rarity of recurrent hypersomnia or Kleine– Levin syndrome, no randomized placebo-controlled clinical study has been published on the treatment of these conditions. Therefore, all available information comes from case reports or personal experience.

It is logical to use a stimulant such as methylphenidate or an awakening drug such as modafinil during the episode of hypersomnia, and positive results have been claimed. However, results must be treated with caution, because these treatments are usually started several days after the onset of the episode and thus not long before spontaneous remission. Moreover, the methods of evaluation are purely subjective. According to the most recent study (Arnulf et al., 2008), amantadine, a drug with dopamine reuptake inhibitory stimulant and antiviral properties, has the most significant effect. Of greater interest is the prophylactic use of mood stabilizers. Positive results with the relief or disappearance of symptoms throughout the period of administration of these agents, and the recurrence of symptoms when treatment is stopped, have been reported in certain cases with the use of carbamazepine (Savet et al., 1986; Wurthmann et al., 1989; Mukaddes et al., 1999), lithium carbonate (Ogura et al., 1976; Abe, 1977; Roth et al., 1980; Goldberg, 1983; Hart, 1985; Muratori et al., 2002; Poppe et al., 2003; Mapari et al., 2005), and valproate (Crumley, 1997; Mapari et al., 2005). In other cases, in contrast, these drugs failed to prevent the recurrence of episodes. Altogether, mood stabilizers, valproic acid, and amantadine produce a benefit in only 6–12% of cases (Arnulf et al., 2008). These drugs should not be resorted to systematically, but only in the case of socioprofessional repercussions. For menstrual-related periodic hypersomnia, estrogen and progestogen, which inhibit ovulation, seem consistently to be effective (Billiard et al., 1975; Sachs et al., 1982).

CONCLUSION Recurring hypersomnia in general, and the Kleine–Levin syndrome in particular, remain intriguing conditions. The symptomatology of the Kleine–Levin syndrome is rich and well described, although odd behaviors are often not mentioned. Laboratory tests such as EEG, polysomnography, neuroimaging, and hormonal assays have provided inconsistent results. On the other hand, more recent procedures such as hypocretin-1 measurement or functional neuroimaging seem promising. Familial cases are extremely rare but of potential interest in view of a possible genetic basis in some cases. Pathophysiology is poorly understood. Based on SPECT studies, a recurrent bilateral thalamic dysfunction seems to be the best current candidate. The autoimmune hypothesis is of interest. Further research should concentrate on hypocretin measurement in both asymptomatic intervals and symptomatic episodes, functional neuroimaging including SPECT and positron emission tomography, and

RECURRENT HYPERSOMNIAS autoimmune markers. Genetic studies should be pursued in rare familial cases or in twins, either discordant or concordant. Regarding treatment, the conducting of randomized placebo-controlled clinical trials is nor realistic. However, multicenter prophylactic programs should be developed to assess the potential value of current or future pharmacological compounds.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 48

Narcolepsy and cataplexy 1

SEIJI NISHINO 1, 2 * AND EMMANUEL MIGNOT 1 Stanford University School of Medicine and Center for Narcolepsy, Stanford Sleep Research Center, Palo Alto, CA, USA 2

Circadian Neurobiology Laboratory, Palo Alto, CA, USA

INTRODUCTION Narcolepsy is a syndrome characterized by “excessive daytime sleepiness (EDS) that is typically associated with cataplexy and other REM sleep phenomena such as sleep paralysis and hypnagogic hallucinations” (American Academy of Sleep Medicine, 2005). Cataplexy, the sudden occurrence of muscle weakness in association with emotions such as laughing, joking, or anger, has long been considered a pathognomonic symptom of the syndrome (Guilleminault, 1994; Aldrich, 1996; Nishino and Mignot, 1997; Anic-Labat et al., 1999; Overeem et al., 2001a; Dauvilliers et al., 2003a). A broader definition of narcolepsy includes patients with sleepiness and abnormal rapid eye movement (REM) sleep, such as sleep-onset REM periods (SOREMPs) during the Multiple Sleep Latency Test (MSLT), sleep paralysis, or hypnagogic hallucinations (American Academy of Sleep Medicine, 2005). Disturbed nocturnal sleep is also central to the syndrome (Guilleminault, 1994; Aldrich, 1996; Nishino and Mignot, 1997; Anic-Labat et al., 1999; Overeem et al., 2001a; Dauvilliers et al., 2003a). The definition of narcolepsy was revised recently, owing to recent scientific advances. In most patients with cataplexy, a deficiency in the neuropeptide system hypocretin is involved in the pathophysiology of human narcolepsy (Nishino et al., 2000b, 2001b; Peyron et al., 2000; Thannickal et al., 2000; Kanbayashi et al., 2002; Krahn et al., 2002; Mignot et al., 2002). A tight association with the human leukocyte antigen (HLA) DQB1*0602 is also usually found in patients with cataplexy (Mignot et al., 1997a, 2001). In contrast, most patients with narcolepsy without cataplexy are

HLA-DQB1*0602 negative and do not have hypocretin deficiency, as measured in the cerebrospinal fluid (CSF) (Kanbayashi et al., 2002; Mignot et al., 2002; Dauvilliers et al., 2003b). Hypocretin deficiency is likely to be due to postnatal hypocretin cell loss, possibly through autoimmune mechanisms, but the etiology involved in this process has not been elucidated. Based on the pathophysiological differences, narcolepsy with and without cataplexy has been separated in the most recent revision of the International Classification of Sleep Disorders, second edition (ICSD-2) (see Table 48.1) (American Academy of Sleep Medicine, 2005). Since hypocretin deficiency can be clinically assessed by measuring hypocretin-1 in the CSF, CSF hypocretin-1 evaluations are now included as one of the possible diagnostic criteria for narcolepsy–cataplexy in the ICSD-2 (American Academy of Sleep Medicine, 2005). Narcolepsy is currently treated with amfetaminelike central nervous system (CNS) stimulants (for EDS) and antidepressants (for cataplexy). Some other classes of compounds, such as modafinil (a nonamfetamine wake-promoting compound for EDS) and g-hydroxybutyrate (GHB, a short-acting sedative for EDS/fragmented nighttime sleep and cataplexy, given at night), are also employed. Hypocretin replacement is also likely to be a new therapeutic option for patients with hypocretin-deficient narcolepsy, but this is still not available for use in humans. The development of small-molecule synthetic hypocretin agonists is likely required for this option to become viable. In this chapter, the clinical, pathophysiological, and pharmacological aspects of narcolepsy are discussed.

*Correspondence to: Seiji Nishino MD, PhD, Stanford University, Sleep and Circadian Neurobiology Laboratory and Center for Narcolepsy, 1201 Welch Road RM213, Palo Alto, CA 94304-5489, USA. Tel: (650) 723-3724, Fax: (650) 723-5873, E-mail: [email protected]

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EPIDEMIOLOGY The prevalence of narcolepsy The prevalence of narcolepsy has been investigated in multiple ethnic groups and countries. One of the most sophisticated prevalence studies was performed using a Finnish cohort consisting of 11,354 twin individuals (Hublin et al., 1994b). All subjects who responded to a questionnaire with answers suggestive of narcolepsy were contacted by telephone. Clinical interviews were performed and polysomnographic (PSG) recordings conducted in five subjects considered likely to have narcolepsy–cataplexy. Sleep monitoring finally identified three narcoleptic subjects with cataplexy, thus leading to a prevalence of 0.026% (Hublin et al., 1994b). All three subjects were dizygotic twins: cotwins were not affected. Other prevalence studies have led to similar prevalence values (0.02–0.067%) in Great Britain (Ohayon et al., 1996), France (Ondze´ et al., 1999), the Czech Republic (Roth, 1980), five European countries (Ohayon et al., 2002), and the USA (Dement et al., 1973; Silber et al., 2002). A study performed in 1945 in African American navy recruits also showed a prevalence of 0.02% in this ethnic group for narcolepsy–cataplexy (Solomon, 1945). Narcolepsy–cataplexy may be more frequent in Japan and less frequent in Israel. Two populationbased prevalence studies led to 0.16% and 0.18% prevalence figures in Japan (Honda, 1979; Tashiro et al., 1994). However, these studies used only questionnaires and interviews, but not polysomnography, to confirm the diagnosis. In Israel, only a few narcoleptic patients have been identified from the large population of subjects recruited into sleep clinics (Lavie and Peled, 1987). This has led to the suggestion that the prevalence of narcolepsy could be as low as 0.002% in this country/ ethnic group. It is notable to notice that the carrier frequency of DQB1*0602 is lowest in Israel (6%), followed by Japan and Korea (12%), North American and northern European Caucasians (25%), and African Americans (32%). Onset is variable in terms of age and may appear as either progressive or sudden. Age of onset distribution covers the entire age range from early childhood to 50 years of age (Okun et al., 2002). Two peaks, a larger one occurring at around 15 years of age and a smaller peak at approximately 36 years, have been reported (Dauvilliers et al., 2001b). Similar results were found in two different populations, although the reasons for this bimodal distribution remain obscure. The incidence of the disease was reported to be 1.37/100 000 per year (1.72 for men and 1.05 for women) in Olmsted County in Minnesota, and the incidence rate was highest in the second decade, followed in descending order by the third, fourth, and first decade (Silber et al., 2002).

Genetic versus environmental factors A familial tendency for narcolepsy has been recognized since its description in the late 19th century (Westphal, 1877). Starting in the 1940s, several studies were published that investigated the familial history of small cohorts of narcoleptic probands (Krabbe and Magnussen, 1942; Yoss and Daly, 1960; NevsimalovaBruhova and Roth, 1972; Baraitser and Parkes, 1978; Kessler et al., 1979; Honda et al., 1983). Using standard diagnostic criteria, more recent studies have shown rates of familial cases as 4.3% in Japan (Honda, 1988), 6% in the USA (Guilleminault et al., 1989), 7.6% in France (Dauvilliers et al., 2001b), and 9.9% in Canada (Dauvilliers et al., 2001b). In addition to subjects who fulfill all diagnostic criteria for narcolepsy– cataplexy, other relatives may report isolated recurrent sleep episodes and unexplained EDS; these subjects may suffer from an incomplete and milder form of the disorder (Billiard et al., 1994). Studies also revealed that the risk of a first-degree relative developing narcolepsy–cataplexy is 1–2.0%, 10 to 40 times higher than the risk in the general population (Billiard et al., 1994; Hublin et al., 1994a; Mignot, 1998). A limited number of twin cases studies have been published. Of 16 monozygotic (MZ) twin pairs with at least one affected twin, only four (or five depending on the criteria used for concordance) were concordant (Mignot, 1998). Although genetic predisposition is likely to be involved in the development of narcolepsy, the relatively low rate of concordance in narcoleptic MZ twins indicates that environmental factors also play a role in the development of the disorder. The nature of the possible environmental factors involved is not known. Frequently cited factors are head trauma (Lankford et al., 1994), sudden change in sleep/wake habits (Orellana et al., 1994), and various infections (Roth, 1980). Although these factors may be involved, there are no documented studies demonstrating increased frequency when compared to multiple control groups. Methodological issues such as bias recall or, in the case of changes in sleep–wake habits, the possibility of an early narcolepsy symptom have not been excluded.

SYMPTOMS OF NARCOLEPSY Sleepiness or excessive daytime sleepiness (EDS) EDS and cataplexy are considered the two primary symptoms of narcolepsy. EDS most typically mimics the feeling that people experience when they are severely sleep deprived. It may, however, also manifest as a chronic tiredness or fatigue. Narcoleptic subjects

NARCOLEPSY AND CATAPLEXY generally experience a permanent background of baseline sleepiness that easily leads to actual sleep episodes in monotonous sedentary situations. This feeling is most often relieved by short naps (15–30 minutes), but in most cases the refreshed sensation lasts for only a short time after awaking (Table 48.1). The refreshing value of short naps is of diagnostic value. Sleepiness also occurs in irresistible waves in these patients, a phenomenon best described as “sleep attacks”. Sleep attacks may occur in very unusual circumstances, such as in the middle of a meal or conversation, or while riding a bicycle. These attacks are often accompanied by microsleep episodes (Guilleminault, 1987) where the patient “blanks out”. The patient may then continue his or her activity in a semiconscious manner (writing incoherent phrases in a letter, speaking incoherently on the phone, etc.), a phenomenon called automatic behavior (Broughton and Ghanem, 1976; Dement, 1976; Guilleminault, 1987). Learning problems and impaired concentration are frequently associated (Broughton and Ghanem, 1976; Dement, 1976; Guilleminault, 1987; Cohen and Smith, 1989; Rogers and Rosenberg, 1990), but psychophysiological testing is generally normal. Sleepiness is usually the first symptom to appear, followed by cataplexy, sleep paralysis, and hypnagogic hallucinations (Yoss and Daly, 1957; Parkes et al., 1975; Roth, 1980; Billiard et al., 1983; Honda, 1988). Cataplexy onset occurs within 5 years after the occurrence of daytime somnolence in approximately two-thirds of cases (Roth, 1980; Honda, 1988). Less frequently, cataplexy appears many years after the onset of sleepiness. The mean age of onset of sleep paralysis and hypnagogic hallucinations is 2–7 years later than that of sleepiness (Kales et al., 1982; Billiard et al., 1983). In most cases, EDS and irresistible sleep episodes persist throughout the lifetime, although they often improve after retirement (possibly due to better management of activities, daytime napping, and adjustment of nighttime sleep).

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emotions (such as laughter, having a good hand at a card game, the pull of the fishing rod with a biting fish, the perfect hit at a baseball game) and less frequently by negative emotions (most typically anger or frustration). All antigravity muscles can be affected, leading to a progressive collapse of the subject. Respiration is not affected, although a feeling of oppression may be reported. The patient is typically awake at the onset of the attack but may experience blurred vision or ptosis. The attack is almost always bilateral and usually lasts for a few seconds to a minute. Neurological examination performed at the time of an attack shows a suppression of the patellar reflex and sometimes Babinski’s sign. Cataplexy is an extremely variable clinical symptom (Gelb et al., 1994). Most often, it is mild and occurs as a simple buckling of the knees, head dropping, facial muscle flickering, sagging of the jaw, or weakness in the arms. Slurred speech or mutism is also frequently associated. It is often imperceptible to the observer and may even be only a subjective feeling, such as a feeling of warmth or that somehow time is suspended (Wilson, 1927; Gelb et al., 1994). In other cases, it escalates to actual episodes of muscle paralysis that may last for up to several minutes. Falls and injury are rare, and most often the patient will have time to find support or to sit down while the attack is occurring. Long episodes occasionally blend into sleep and may rarely be associated with hypnagogic hallucinations. Patients may also experience “status cataplecticus”. This rare manifestation of narcolepsy is characterized by cataplexy that lasts several hours per day and confines the subject to bed. It can occur spontaneously or more often upon withdrawal from anticataplectic drugs (Passouant et al., 1970; Parkes et al., 1975; Hishikawa and Shimizu, 1995). Cataplexy often improves with advancing age. In rare cases, it disappears completely but in most patients it is better controlled (probably after the patient has learned to control his or her emotions) (Billiard et al., 1983; Rosenthal et al., 1990).

Cataplexy Cataplexy is distinct from EDS and pathognomonic of the disease (Guilleminault et al., 1974). The importance of cataplexy for the diagnosis of narcolepsy has been recognized since its description (Lo¨wenfeld, 1902; Henneberg, 1916) and in subsequent reviews on narcolepsy (Wilson, 1927; Daniels, 1934). Most authors now recognize patients with recurring sleepiness and cataplectic attacks as representing a homogeneous clinical entity; this has not been substantiated by the tight association with DQB1*0602 and hypocretin deficiency (see section on Pathophysiology). Cataplexy is defined as a sudden episode of muscle weakness triggered by emotional factors, most often in the context of positive

Sleep paralysis Sleep paralysis is present in 20–50% of all narcoleptic subjects (Yoss and Daly, 1960; Parkes et al., 1974; Hishikawa, 1976; Roth, 1980). It is often associated with hypnagogic hallucinations. Sleep paralysis is best described as a brief inability to perform voluntary movements at the onset of sleep, upon awakening during the night, or in the morning. Contrary to simple fatigue or locomotion inhibition, the patient is unable to perform even a small movement, such as lifting a finger. Sleep paralysis may last a few minutes and is often finally interrupted by noise or other external stimuli. The symptom is occasionally bothersome in

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Table 48.1 Clinical characteristics of narcolepsy–cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia Daytime sleepiness

Duration

Without long sleep time

Short (<30 min) Short (<30 min) Variable

(þ) (þ) ()

Long (>30 min)

()

Variable

()

SOREMPs

HLA-DQB1*0602 positivity

8 min*

2

>90%

8 min*

2

40–50%

8 min*

2

Not studied systematically

8 min*

1

No consistent results

Normal

8 min*

1

No consistent results

Normal

Other symptoms Cataplexy REM sleep-related symptoms Cataplexy () REM sleep-related symptoms With and without cataplexy REM sleep-related symptoms

Cataplexy () Prolonged nighttime sleep (10 h) Autonomic nervous system dysfunction Cataplexy () No prolonged nighttime sleep (<10 h) Autonomic nervous system dysfunction

Low CSF hypocretin-1 level (<110 pg/ml)

Sleep latency

85–90% >90% in HLA positive 10–20% (all HLA positive) Most cases studied{

*As per International Classification of Sleep Disorders, second edition (ICSD-2); previous ICSD classifications suggested 5 min. {CSF hypocretin-1 measurements have been studied in a limited number of cases of secondary narcolepsy. CSF, lumbar sac cerebrospinal fluid; HLA, human leukocyte antigen; MSLT, Multiple Sleep Latency Test; SOREMPs, sleep-onset rapid eye movement sleep periods.

S. NISHINO AND E. MIGNOT

Narcolepsy– cataplexy Narcolepsy without cataplexy Secondary narcolepsy (due to the medical condition) Idiopathic hypersomnia With long sleep time

Awaken refreshed

MSLT

NARCOLEPSY AND CATAPLEXY narcoleptic subjects, especially when associated with frightening hallucinations (Rosenthal, 1939). Whereas EDS and cataplexy are cardinal symptoms of narcolepsy, sleep paralysis occurs frequently as an isolated phenomenon, affecting 5–40% of the general population (Goode, 1962; Fukuda et al., 1987; Dahlitz and Parkes, 1993). Occasional episodes of sleep paralysis are often seen in adolescence and after sleep deprivation, and the prevalence is therefore high for single-episode occurrences.

Hypnagogic and hypnopompic hallucinations Abnormal visual (most often) or auditory perceptions that occur while falling asleep (hypnagogic) or upon waking up (hypnopompic) are frequently observed in narcoleptic subjects (Ribstein, 1976). These hallucinations are often unpleasant and typically associated with a feeling of fear or threat (Rosenthal, 1939; Hishikawa, 1976). Polygraphic studies indicate that these hallucinations occur most often during REM sleep (Hishikawa, 1976; Chetrit et al., 1994). These episodes are often difficult to distinguish from nightmares or unpleasant dreams, which also occur frequently in narcolepsy. Hypnagogic hallucinations are most often associated with sleep attacks. Importantly, unlike in schizophrenia, the hallucinatory content is well recognized by the patient. The hallucinations are most often complex, vivid, dream-like experiences (“half sleep” hallucinations) and may follow episodes of cataplexy or sleep paralysis, a feature that is not uncommon in severely affected patients. These hallucinations are usually easy to distinguish from hallucinations observed in schizophrenia, but the two conditions can coexist.

Other important associated symptoms One of the most frequently associated symptoms is insomnia, best characterized as a difficulty in maintaining nighttime sleep. Typically, narcoleptic patients fall asleep easily, only to wake up after a short time unable to fall asleep again for an hour or so. Narcoleptic patients do not usually sleep more than normal individuals over the 24-hour cycle (Hishikawa et al., 1976; Montplaisir et al., 1978; Broughton et al., 1988b) but frequently have a very disrupted nighttime sleep (Hishikawa et al., 1976; Montplaisir et al., 1978; Broughton et al., 1988b). This symptom often develops later in life and can be very disabling. Other frequently associated sleep problems include periodic leg movements (Mosko et al., 1984; Godbout and Montplaisir, 1985), REM behavior disorder, other parasomnias (Schenck and Mahowald, 1992; Mayer et al., 1993),

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and obstructive sleep apnea (Guilleminault et al., 1976; Mosko et al., 1984; Chokroverty, 1986). Narcolepsy is also associated with changes in energy homeostasis regulation. Narcoleptic patients are frequently obese (Honda et al., 1986; Schuld et al., 2000), have insulin-resistant diabetes mellitus more frequently (Honda et al., 1986), exhibit reduced food intake (Lammers et al., 1996), and have lower blood pressure and temperature (Sachs and Kaisjer, 1980; Mayer et al., 1997). These findings have not received much attention, as they have long been believed to be secondary to sleepiness or inactivity. More recently, however, it was shown that these metabolic changes are specific to hypocretin-deficient patients (Hara et al., 2001; Nishino et al., 2001b), suggesting a more direct pathophysiological link. Additional research in this area is warranted to clarify this association. Plazzi et al. (2006) recently reported on two children (aged 7 years) with narcolepsy–cataplexy associated with obesity and precocious puberty. These subjects were HLA-DQB1*0602 positive and had low CSF levels of hypocretin-1. Although it is not known whether these symptoms are due to impaired hypocretin neurotransmission or broader hypothalamic abnormalities (e.g., in the context of an inflammatory process toward hypocretin cells), these cases are informative for understanding the pathophysiology of hypocretin cell death. The association with precocious puberty may be more common, because this symptom is noted only in early-onset cases. Narcolepsy is a very incapacitating disease. It interferes with every aspect of life. The negative social impact of narcolepsy has been studied extensively. Patients experience impairments in driving and a high prevalence of either car or machine-related accidents. Narcolepsy also interferes with professional performance, leading to unemployment, frequent changes of employment, working disability, or early retirement (Broughton et al., 1981; Aldrich, 1989; Alaila, 1992). Several subjects also develop symptoms of depression, although these symptoms are often masked by anticataplectic medications (Roth and Nevsimalova, 1975; Broughton and Ghanem, 1976; Broughton et al., 1981).

ANIMAL MODELS OF NARCOLEPSY Canine narcolepsy models In the past 20 years, narcolepsy research has been facilitated by the existence of a unique animal model, canine narcolepsy. Canine narcolepsy was first reported in the early 1970s in two small breeds by Knecht et al. (1973) and Mitler et al. (1974). Early attempts to establish genetic transmission were unsuccessful, suggesting a

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S. NISHINO AND E. MIGNOT

nongenetic etiology in most cases of canine narcolepsy. In 1975, two narcoleptic Dobermans were reported in a single litter (Baker et al., 1982). The breeding of these animals led the demonstration that narcolepsy was transmitted as a single autosomal recessive gene with full penetrance in this breed. A narcoleptic colony of Doberman Pinschers was then established and maintained at Stanford University for more than 20 years. Familial canine narcolepsy was also reported in Labrador Retrievers and Dachshunds (Baker et al., 1982; Hungs et al., 2001). Interestingly, experiments indicate that animals heterozygous for the canine narcolepsy gene have subclinical abnormalities such as increased daytime sleepiness. In heterozygous animals, the administration of drugs that increase cholinergic and reduce monoaminergic transmissions (manipulations known to promote REM sleep) has been shown to induce cataplexy at specific developmental times (Mignot et al., 1993b). The parallel between human and canine narcolepsy is striking. In MSLT-like procedures, narcoleptic canines have short sleep and short REM latencies (Nishino et al., 2000c). Twenty-four-hour recording studies show sleep fragmentation and more daytime sleep than in control animals (Kaitin et al., 1986). Finally, as in human narcolepsy, sudden episodes of muscle weakness akin to cataplexy can be observed in association with strong positive emotions, most typically during the presentation of appetizing food or while at play. These episodes usually last a few seconds and preferentially affect hind legs, neck, or face. Cataplexy may also escalate into complete muscle paralysis with abolition of tendon reflexes. During these episodes, the animal is conscious and able visually to track nearby movement (for a video, see: http://www. med.stanford.edu/school/Psychiatry/narcolepsy/). Polygraphic recording indicates a desynchronized, wakelike EEG pattern at the onset of cataplexy, followed by increased theta activity and genuine REM sleep in long-lasting episodes (Kushida et al., 1985). Sequential pictures of cataplectic attacks in a narcoleptic Doberman are presented in Figure 48.1. The cause of autosomal recessive canine narcolepsy was identified through positional cloning (Lin et al., 1999; Hungs et al., 2001). Three mutations causing a complete dysfunction of a receptor for the newly identified neuropeptide system hypocretin (the hypocretin receptor 2 or Hcrtr2) were identified in Doberman, Labrador, and Dachshund pedigrees (Lin et al., 1999; Hungs et al., 2001) (Figure 48.2, Table 48.2). Sporadic cases of canine narcolepsy were later shown to be associated with low CSF and brain hypocretin levels (Ripley et al., 2001a), as found in human narcolepsy (Nishino et al., 2000b; Peyron et al., 2000; Thannickal

et al., 2000; Mignot et al., 2002) (see Table 48.2) (see section on Hypocretin deficiency in human narcolepsy and Figure 47.3 in Chapter 47).

Rodent narcolepsy models Several rodent models of narcolepsy are now also available (see Table 48.2). In one model, Chemelli et al. (1999) knocked out the preprohypocretin gene. The resulting model has fragmented sleep, transitions from wakefulness into REM sleep, and episodes of behavioral arrests akin to cataplexy or sleep-onset paralysis (Chemelli et al., 1999). In another model, a toxic transgene derived from an ataxin-3 human gene mutation (from a patient with Machado–Joseph disease), was driven by the preprohypocretin promoter, resulting in narcoleptic mice lacking hypocretin-containing cells (Hara et al., 2001). Rodents lacking either of the two hypocretin receptors, Hcrtr1 or Hcrtr2, are also available (Kisanuki et al., 2000; Willie et al., 2003). In these models, only Hcrtr2 receptor knockout animals experience behavioral arrest episodes similar to cataplexy. Interestingly, however, Hcrtr1 knockout animals have fragmented sleep but no behavioral arrest episodes (Kisanuki et al., 2000; Willie et al., 2003). It is also suggested that Hcrtr2 receptor knockout animals are less affected than hypocretin peptide knockout animals, suggesting a role for Hcrtr1 in increasing the severity of the phenotype (Willie et al., 2003). The rodent models are revolutionizing research in the area. Importantly, however, it is difficult to differentiate cataplexy from REM sleep onset or sleep paralysis in these models. The link between behavioral arrest and positive emotions is unclear and a systematic pharmacological characterization has not been performed (see the pharmacology section below).

NARCOLEPSY EVALUATION Diagnostic criteria for narcolepsy with and without cataplexy The clinical diagnosis of narcolepsy with cataplexy is based on the presence of EDS and/or sudden onsets of sleep occurring almost daily during a period of at least 3 months and on the presence of a clear clinical history of cataplexy (American Academy of Sleep Medicine, 2005). The EDS is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication, or substance use disorder (American Academy of Sleep Medicine, 2005). In the ISCD-2, it is described that the diagnosis of narcolepsy with cataplexy should, whenever possible, be confirmed by nocturnal polysomnography followed by a MSLT; in narcolepsy, MSLT mean sleep

NARCOLEPSY AND CATAPLEXY

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Fig. 48.1. Cataplectic attacks in Doberman pinschers. Emotional excitations, appetizing food, or playing readily elicit multiple cataplectic attacks in these animals, mostly bilateral (97.9%). Atonia initiated partially in the hind legs (79.8%), front legs (7.8%), neck/face (6.2%), or whole body/complete attacks (6.2%). Progression of attacks was also seen (49% of all attacks) (Fujiki et al., 2002).

latency is 8 minutes or less and more than two SOREMPs are observed despite sufficient nocturnal sleep prior to the test (American Academy of Sleep Medicine, 2005) (see Table 48.1). The MSLT is, however, not mandatory, and a clear history of typical and frequent cataplexy is most relevant to the diagnosis of narcolepsy with cataplexy (American Academy of Sleep Medicine, 2005). In contrast, the diagnosis of narcolepsy without cataplexy is mostly made by polygraphic findings and EDS (almost daily for a period of at least 3 months). REM sleep-related abnormalities (SOREMPs) should be confirmed by nocturnal

polysomnography followed by a MSLT (American Academy of Sleep Medicine, 2005). The regular MSLT consists of five naps, scheduled at 2-hour intervals starting between 9 and 10 a.m. (Richardson et al., 1978; Carskadon et al., 1986; Chervin et al., 1995). The test is terminated after a sleep period of 15 minutes, or after 20 minutes if the patient did not fall asleep. SOREMPs are defined as the occurrence of REM sleep within 15 minutes after sleep onset. Alternatively to the MSLT findings, CSF hypocretin measures can be applied; hypocretin-1 levels in the CSF are 110 pg/ml or less, or one-third of mean normal control

790

S. NISHINO AND E. MIGNOT

Fig. 48.2. Genomic organization of the canine Hcrtr2 locus. The Hcrtr2 gene is encoded by seven exons. Sequence of the exon–intron boundary at the site for deletion of the transcript revealed that the canine short interspersed nucleotide element (SINE) was inserted 35 base pairs (bp) upstream of the 50 splice donor site of the fourth encoded exon in narcoleptic Doberman Pinschers. This insertion falls within the 50 flanking intronic region needed for pre-mRNA Lariat formation and proper splicing, causing exon 3 to be spliced directly to exon 5, and exon 4 to be omitted. This mRNA potentially encodes a nonfunctional protein with 38 amino acids deleted within the fifth transmembrane domain, followed by a frameshift and a premature stop codon at position 932 in the encoded RNA. In narcoleptic Labradors, the insertion was found 5 bp downstream of the 30 splice site of the fifth exon, and exon 5 is spliced directly to exon 7, omitting exon 6.

values. Low CSF hypocretin-1 levels are found in over 90% of patients with narcolepsy with cataplexy, and almost never in controls or rarely in other pathologies (see section on CSF hypocretin-1 levels). A nocturnal polysomnogram is useful for eliminating other possible causes of EDS such as periodic leg movements and obstructive sleep apnea prior to the MSLT. The diagnosis of upper airway resistance syndrome must also be considered very carefully. Sleep efficiency during nocturnal polysomnography may be normal or low. The diagnostic value of the MSLT for narcolepsy has been questioned by some authors (Lammers and Van Dijk, 1992; Moscovitch et al., 1993) on the basis of its specificity and sensitivity. First, approximately 15% of narcoleptic subjects with clearcut cataplexy do not have a short sleep latency and/or more than two SOREMPs during a single MSLT (Moscovitch et al., 1993; Mignot et al., 2002). Conversely, a small number

of patients with abnormal breathing may display typical narcolepsy-like MSLT results. As the prevalence of upper airway resistance syndrome and sleep apnea is 100 times greater than narcolepsy–cataplexy, false positives may be frequent if the test is interpreted without carefully excluding all other causes of EDS (Aldrich, 1993). A recent study in the general population also found that 3.6% of 556 adults had a MSLT finding consistent with narcolepsy (mean sleep latency 8 minutes or less, two or more SOREMPs) (Mignot et al., 2006), many without a clear complaint of EDS. In a number of countries, the MSLT is not commonly performed, especially if clearcut cataplexy is present. Some investigators rely on the presence of SOREMPs during a single night recording, an abnormality present in approximately half of narcoleptic patients with cataplexy. A single daytime nap study is also used by some to analyze for the presence of a

Table 48.2 Characterization of narcolepsy in human, dog, and mouse

Human Sporadic

DQB1*0602 (þ) (90–95%)

Hypocretin ligand deficiency (90%)

?

DQB1*0602 (þ) (75–80%)

Hypocretin ligand deficiency (75%)

De novo mutant (?), dominant

DQB1*0602 ()

Mutation in preprohypocretin gene Hypocretin ligand deficiency

?

()

Hypocretin ligand deficiency

Autosomal recessive, 100% of penetrance

()

Mutation in Hcrtr2 gene

Adolescence

EDS, cataplexy, SP, HH, SOREMPs, sleep fragmentation, obesity (þ) EDS, cataplexy, SP, HH, SOREMPs, sleep fragmentation, obesity (þ) EDS, severe cataplexy

Hypocretin mutant (only one case identified)

Extremely early onset (6 months)

Dog Sporadic (17 breeds)

7 weeks to 7 years

Familial (Dobermans, Labradors, Dachshunds) Mouse Hypocretin KO

Earlier than 6 months

Hypocretin cell death, hypocretin/ataxin-3 transgenic Hcrtr1 KO

6 weeks

4 weeks

Cataplexy, short sleep latency, SOREMPs Cataplexy, short sleep latency, SOREMPs Cataplexy, SOREMPs, short sleep latency, obesity (?) Cataplexy, SOREMPs, short sleep latency, obesity (þþ) Fragmented sleep, obesity (?) Cataplexy, SOREMPs, short sleep latency, obesity (?) Same sleep phenotype as preprohypocretin KO mice, obesity (?)

Autosomal recessive, 100% of penetrance

Hypocretin ligand deficiency

Autosomal dominant, 100% of penetrance

Hypocretin/dynorphin deficiency

NARCOLEPSY AND CATAPLEXY

?

Transmission

Earlier onset than sporadic cases

Double receptor KO

Abnormality in hypocretin system

Symptoms/phenotype

Familial

Hcrtr2 KO

Association with HLA/DLA

Onset

Absence of Hcrtr1 Autosomal recessive, 100% of penetrance

Absence of Hcrtr2

Recessive for each receptor gene

Absence of Hcrtr1 and 2

791

DLA, dog leukocyte antigen; EDS, excessive daytime sleepiness; HH, hypnagogic hallucinations; HLA, human leukocyte antigen; KO, knockout; SOREMPs, sleep-onset rapid eye movement sleep periods; SP, sleep paralysis.

792 S. NISHINO AND E. MIGNOT SOREMP or short sleep latency (Raynal, 1976; Roth of the third ventricle, suggestive of hypothalamic et al., 1986; Broughton et al., 1988a). Other groups have atrophy. Interestingly, some of these symptomatic advocated the use of continuous 24- or 36-hour PSG cases of narcolepsy are reported to be associated with recordings (Billiard et al., 1986) or ambulatory EEG a moderate decline in CSF hypocretin levels (Arii polygraphic recordings (Genton et al., 1995). Most inveset al., 2001; Melberg et al., 2001; Overeem et al., tigators have, however, found that the MSLT is more 2001b; Scammell et al., 2001) (see also pathophysiolpredictive than all of the above tests for diagnosing ogy section). narcolepsy, and is now the de facto “gold standard”. In the ICSD-2, narcolepsy with or without cataplexy Other polygraphic methods have been developed to associated with these conditions is classified under measure EDS in narcolepsy, most notably the mainte“narcolepsy due to a medical condition”, and a signifinance of wakefulness test (MWT) (Mitler et al., 1982). cant underlying medical or neurological disorder must The major difference between the MWT and the MSLT account for the EDS and/or cataplexy (American is the instruction given to the subject. In a MWT, the Academy of Sleep Medicine, 2005). The other diagnossubject is told to attempt to remain awake during the tic criteria (symptoms, polysomnographic and laborascheduled naps. MWTs are not used for diagnosis but tory findings) are the same as those for narcolepsy rather in the context of clinical trials to assess the effect with and without cataplexy. of treatment with psychostimulants (Mitler et al., 1998) or other drugs (e.g., modafinil and sodium oxybate, Differential diagnosis/Idiopathic also called GHB (g-hydroxybutyrate)) (US Modafinil in hypersomnia and other primary EDS Narcolepsy Multicenter Study Group, 2000; Mamelak Narcolepsy is often misdiagnosed as a psychiatric condiet al., 2004). In addition to these clinical and PSG tion (typically depression) or as epilepsy (especially in criteria, HLA typing showing the association with children). It may also be confounded with other forms HLA-DQB1*0602 is supportive of the diagnosis, but of hypersomnia, such as sleep apnea syndrome (SAS), the specificity of DQB1*0602 positivity is low (Mignot, idiopathic hypersomnia, or hypersomnia associated with 1998) (see pathophysiology section). depression. The presence of cataplexy is the key factor distinguishing narcolepsy from the other forms of Symptomatic narcolepsy hypersomnia. However, when cataplexy is predominant, Several cases of narcolepsy in association with brain narcolepsy can also be confused with syncope, drop tumors (most often localized in the posterior hypoattacks, atonic attacks, or attacks of histrionic nature. thalamus and the superior part of the brainstem) have Furthermore, some well informed individuals may been reported. Narcolepsy has also been reported in mimic the symptoms of narcolepsy in order to benefit patients with multiple sclerosis, encephalitis, cerebral from disability leave from work or to obtain a prescripischemia, cranial trauma, brain tumor, and cerebral tion of psychostimulants. degeneration (Aldrich and Naylor, 1989; Arii et al., Narcolepsy without cataplexy may overlap with 2001; Melberg et al., 2001; Scammell et al., 2001). idiopathic hypersomnia, a less common and heteroHypothalamic sarcoidosis has caused narcolepsy in geneous disorder with chronic sleepiness (Bassetti at least two patients, although neither had cataplexy and Aldrich, 1997; Black et al., 2004). By definition, (Aldrich and Naylor, 1989; Malik et al., 2001). Symppatients with idiopathic hypersomnia lack cataplexy tomatic narcolepsies are also present in children and have fewer than two SOREMPs on the MSLT. affected with Niemann–Pick type C disease (Challamel Some of these individuals have deep, excessively et al., 1994). The diagnosis of symptomatic narcolepsy long, periods of sleep, difficulty waking from sleep, requires that narcolepsy be developed in close temand long unrefreshing naps, but many have symptoms poral relationship with the neurological disorders, similar to those of narcolepsy (Aldrich, 1996; Bassetti because the association may be incidental rather and Aldrich, 1997) (see Table 48.1). than causal. A recent report described patients with Recurrent hypersomnia is another primary disorder paraneoplastic anti-Ma antibodies who had hypoof EDS. In these disorders, sleepiness occurs in epithalamic inflammation, sleepiness, and cataplexy, but sodes and not on a continuous basis. Kleine–Levin PSG findings were not reported (Overeem et al., syndrome, a pervasive functional disorder of the 2001b; Rosenfeld et al., 2001). Melberg et al. (2001) hypothalamus characterized by cognitive abnormaldescribed a Swedish family with autosomal dominant ities, hypersexuality, binge eating, and irritability cerebellar ataxia, deafness, and narcolepsy. Affected associated with periods of EDS and sleep periods as members gradually develop chronic sleepiness and long as 18–20 hours (Smolik and Roth, 1988; Billiard, cataplexy in young adulthood along with enlargement 1989) is the most typical variant.

NARCOLEPSY AND CATAPLEXY

PATHOPHYSIOLOGY OF NARCOLEPSY Pathophysiological consideration of narcolepsy–cataplexy In humans, the first REM sleep episode typically occurs approximately 90 minutes after sleep onset. Further REM sleep episodes reoccur every 90 minutes (every 30 minutes in dogs and cats) (Zepelin and Siegel, 2005). Four or five REM sleep episodes may occur during the night. Shortly after the discovery of REM sleep, it was found in narcolepsy that REM sleep often occurs at sleep onset (sleep-onset REM periods), even during short daytime naps (Jimbo et al., 1963; Rechtschaffen et al., 1963). Ever since, cataplexy, sleep paralysis, and hypnagogic hallucinations have been considered as disassociated manifestations of REM sleep. In this model, the occurrence of these symptoms is explained by an abnormal rapid transition to fullblown or partial REM sleep during active wake or sleep onset, and narcolepsy is regarded as a “disease of REM sleep” (Dement et al., 1966). This hypothesis may, however, be too simplistic. It does not explain the presence of sleepiness during the day and the short latency to both nonREM and REM sleep during nocturnal and nap recordings. Another complementary hypothesis is that narcolepsy results from vigilance and state boundary problems (Broughton et al., 1986). According to this hypothesis, a cataplectic attack represents an intrusion of REM sleep atonia during wakefulness, and the hypnagogic hallucinations appear as dream-like imagery taking place in the waking state, especially at sleep onset in patients who frequently have SOREMPs. During REM sleep, complete and “tonic” inhibition of muscle tone, together with “phasic” bursts of REM and swift muscle twitching, occurs physiologically. Electromyographic (typically monitored in neck or chin muscles combined with sleep EEG recordings) activity is at its lowest. Importantly, however, pyramidal tract motor cortex neuronal activity, which mediates limb movements, is as high during REM sleep as it is during active wake (Evarts, 1964, 1965). It is suggested that a tonic inhibitory signal originating in the dorsal pons overcomes the pyramidal motor activation system during REM sleep, resulting in complete muscle atonia during this sleep state (Siegel, 2005). This notion is supported by brain lesion studies in animals: when lesions are made in the dorsal pons, a phenomenon called “REM sleep without atonia” is observed, and the animals move their limbs during REM sleep (Hendricks et al., 1982). Similar phenomena (i.e., REM sleep behavior disorder) have been reported in humans associated with various neurological conditions (including stroke in the pons) (Kimura et al., 2000).

793

A number of experiments suggest that common pathways are shared in the mediation of cataplexy and REM sleep atonia. In narcoleptic Dobermans, a population of cell groups in the brainstem that is responsible for the loss of muscle tone during REM sleep is also active during cataplexy (Siegel et al., 1991). It has also recently been demonstrated that REM-off cells in the adrenergic locus coeruleus (LC) in the pons cease to discharge during cataplexy (Wu et al., 1999). Further, H-reflex activity (an electrically stimulated muscle response with monosynaptic latency due to excitation of Ia afferents in the spinal cord) profoundly diminishes or disappears during both REM sleep and cataplexy in humans (Guilleminault et al., 1974). Finally, the major mechanism of action of anticataplectics is thought to be the suppression of REM sleep by activating the central adrenergic system (Mignot et al., 1993a; Nishino et al., 1993). Therefore, the motor inhibitory components of REM sleep at the level of the lower brainstem and the spinal cord are also operative during cataplexy. In contrast, mechanisms of the induction of cataplexy are not well understood. Other experiments, however, point to differential mechanisms for the regulation of cataplexy and REM sleep. First, cataplexy in narcoleptic dogs can be elicited at any time by emotional excitation, whereas the occurrence of REM sleep in these animals is regulated by a normal 30-minute cyclicity (Nishino et al., 2000c). Second, injection of the cholinergic agonist carbachol in the basal forebrain (anterior hypothalamus) induces long-lasting cataplexy-like atonia in narcoleptic dogs, but this manipulation does not affect the 30-minute cyclicity of the occurrence of the phasic REM sleep phenomena (i.e., REMs) (Nishino et al., 1995, 2000c). Finally, dopamine D2/3 receptor agonists potently aggravate, and D2/3 receptor antagonists potently inhibit, cataplexy in narcoleptic dogs (see pharmacology section below) (Nishino et al., 1991), but these classes of compound have little effect on the occurrence of REM sleep (Okura et al., 2000). These experiments suggest that cataplexy and REM sleep atonia may share common executive systems, but are not identical. Cataplexy may be viewed as somewhat distinct from other REM-related symptoms such as sleep paralysis and hypnagogic hallucinations that can occur in normal individuals, and sleep paralysis and hypnago- gic hallucinations are not as predictive of hypocretin deficiency. The fact that patients with other sleep disorders, such as sleep apnea, and even healthy controls can manifest SOREMPs, hypnagogic hallucinations, and sleep paralysis when their sleep/wake patterns are sufficiently disturbed, yet these subjects never develop cataplexy, provides further support for the proposal that cataplexy may be distinct from other REM-associated symptoms (Fukuda et al., 1987;

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Bishop et al., 1996; Ohayon et al., 1996; Aldrich et al., 1997). The mechanisms explaining emotional triggering of cataplexy are also not well understood.

Deficiency in hypocretin (orexin) transmission in human narcolepsy MUTATION

SCREENING AND

CSF

HYPOCRETIN-1

MEASUREMENTS

Following on the cloning of the canine narcolepsy gene mutation, hypocretin-related genes were screened for mutations in human narcolepsy cases (Peyron et al., 2000). As expected from the observation that most cases of human narcolepsy are sporadic and not genetically transmitted (in contrast to the canine model), an extensive screening study did not identify preprohypocretin, Hcrtr1, or Hcrtr2 mutations in most human narcolepsy cases (Peyron et al., 2000; Hungs et al., 2001; Olafsdottir et al., 2001). Polymorphisms were observed but were not found to be associated with narcolepsy. Surprisingly, even familial cases of narcolepsy (some of which were HLA-DQB1*0602 negative) did not have any hypocretin mutations, suggesting heterogeneity in genetic cases (Peyron et al., 2000). Rather, only a single patient with a signal peptide mutation of the preprohypocretin gene was identified. This patient had an extremely early onset (6 months), severe narcolepsy–cataplexy, DQB1*0602 negativity, and undetectable CSF levels of hypocretin-1 (Peyron et al., 2000). This important observation indicates that hypocretin system gene mutations can cause narcolepsy in humans, as in animal models. Importantly, however, hypocretin gene polymorphisms or mutations do not contribute significantly to overall narcolepsy predisposition in the population. The hypocretin system is nonetheless functionally involved in the pathophysiology of narcolepsy, but not through genetic mutations in the hypocretin system. Most sporadic, HLA-DQB1*0602-positive narcoleptic patients with cataplexy have undetectable hypocretin-1 levels in the CSF (Nishino et al., 2000b, 2001b; Peyron et al., 2000; Kanbayashi et al., 2002; Mignot et al., 2002) (Figure 47.3 in Chapter 47). Follow-up neuropathological studies in 10 narcoleptic patients indicated dramatic loss of hypocretin-1, hypocretin-2, and preprohypocretin mRNA in the brain and hypothalamus of narcoleptic patients (Peyron et al., 2000; Thannickal et al., 2000) (see Figure 47.3 in Chapter 47). As mentioned above, these subjects have no hypocretin gene mutations (Peyron et al., 2000) and have a peripubertal or postpubertal disease onset as opposed to a 6-month onset in subjects with a preprohypocretin mutation (Peyron et al., 2000). Together with the tight HLA association (Mignot et al., 1997a, 2001), a likely pathophysiological mechanism in most

narcolepsy cases could thus involve an autoimmune alteration of hypocretin-containing cells in the CNS (see the autoimmune section). Furthermore, Dauvilliers et al. (2004b) recently reported a HLA-DQB1*0602-positive MZ twin pair discordant for narcolepsy and CSF hypocretin-1 (only the affected subject had a low hypocretin-1 level), suggesting that altered CSF hypocretin levels are state, and not trait, dependent and likely to be an acquired deficit. In other words, the genetic background is likely not sufficient to develop an abnormality in the hypocretin system. This finding is also complementary to the autoimmune hypothesis. The observation that CSF hypocretin-1 levels are decreased in patients with narcolepsy provides a new test to diagnose this disorder. Using a large sample of patients and controls, we determined that 110 pg/ml (30% of mean control values) was the most specific and sensitive cutoff value for diagnosing narcolepsy (Mignot et al., 2002) (Figure 48.3). Most samples had undetectable levels (< 40 pg/ml), and a few had detectable but very diminished levels. None of the patients with idiopathic hypersomnia, sleep apnea, restless legs syndrome, or insomnia had abnormal hypocretin levels.

DIAGNOSTIC

VALUE OF

CSF

HYPOCRETIN-1

MEASUREMENTS

Using the 110-pg/ml cutoff, CSF hypocretin-1 measurements are especially predictive in patients with definite cataplexy (99% specificity, 87% sensitivity). In these cases, sensitivity and specificity are higher than for the MSLT. In contrast, CSF hypocretin-1 measurements have a more limited predictive power in patients with atypical or absent cataplexy. Specificity is still extremely high (99%) but sensitivity is low (16%) (see Mignot et al., 2002, and Figure 48.3), with most patients having normal levels (Kanbayashi et al., 2002; Krahn et al., 2002; Mignot et al., 2002). This is clearly a dilemma for the clinician as there is more often a need for a definitive diagnosis in these atypical cases. The diagnostic value of the CSF hypocretin-1 test needs to be weighed against the trauma associated with obtaining CSF. Lumbar punctures (LPs) are well known to be safe, but post-LP headaches are often observed. The trauma associated with the LP must be balanced against the risk of mislabeling a patient with narcolepsy and possibly introducing lifelong treatment. In general, the MSLT is a more useful first step as it is more determinant to the diagnosis and treatment strategies. If a LP is still required, HLA typing could be useful as a first step, as almost all cases of narcolepsy with low CSF hypocretin-1 levels are also positive for the HLA-DQB1*0602 subtype (Dalal et al., 2001; Kanbayashi et al., 2002; Krahn et al., 2002; Mignot et al., 2002); only

NARCOLEPSY AND CATAPLEXY

795

800 Controls

Narcolepsy/Hypersomnia

Other Sleep Disorders

700

600

CSF Hypocretin-1 (pg/mL)

(17%)

500

(18%)

400 47

17

37 10 (56%) (31%)

194

32 38 (43%) (46%)

22 (22%)

9 (100%)

12 (20%)

12

16

12

300

200 30

100 13 (92%)

(100%) 129

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Fig. 48.3. Cerebrospinal fluid (CSF) hypocretin-1 concentrations in various control and sleep disorders. Each point represents the crude concentration of hypocretin-1 in a single person. The cutoffs for normal (>200 pg/ml) and low (110 pg/ml) hypocretin-1 concentrations are shown. Also noted is the total number of subjects in each range, and the percentage human leukocyte antigen (HLA)-DQB1*0602 positivity for a given group in a given range is noted parenthetically for certain disorders. Note that control carrier frequencies for DQB1*0602 are 17% to 22% in healthy control subjects and secondary narcolepsy, consistent with control values reported in Caucasians. In other patient groups, values are higher, with almost all hypocretin-deficient narcolepsy being HLA DQB1*0602 positive. The median value in each group is shown as a horizontal bar. (Updated from previously published data in Mignot et al., 2002.)

three exceptions have been reported (in several hundred patients with low hypocretin-1), including one case where cataplexy was very mild and atypical (Peyron et al., 2000; Dalal et al., 2001; Mignot et al., 2002). We estimate that the probability of observing low levels in HLA-negative cases without cataplexy to be far less than 1%. A rational argument can be made that neither the MSLT nor a CSF hypocretin-1 measurement will affect treatment plans in patients with cataplexy, and therefore such testing may be extraneous in such cases. In fact, in the ICSD-2, the MSLT is not required for the diagnosis of narcolepsy if clear, definite cataplexy is present. However, in many patients presenting with cataplexy, objective data are still recommended. In patients with cataplexy, CSF hypocretin-1 testing may be most helpful when the MSLT is difficult to conduct or interpret. In patients without cataplexy, most (but not all) cases with low CSF hypocretin-1 levels have been observed in

children who develop cataplexy later in the course of the disease (Mignot et al., 2002; Hecht et al., 2003; Kubota et al., 2003; Arii et al., 2004). Therefore, we generally advise that young children with EDS but without cataplexy undergo CSF hypocretin-1 testing, as well as patients in whom there is a suspicion that cataplexy is present but not clearly reported. Although the diagnostic value of low CSF hypocretin-1 (< 110 pg/ml) has been established, it is interesting to note that all healthy control values have been shown to be above 200 pg/ml (Mignot et al., 2002) (see Figure 48.3). In rare cases of narcolepsy and hypersomnia, we have found hypocretin-1 levels between these two values, raising the possibility of partial hypocretin deficiency in these patients (Mignot et al., 2002). Such values should, however, be interpreted cautiously, as in a large series of individuals with various neurological disorders we found that up to 15% had CSF

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S. NISHINO AND E. MIGNOT

hypocretin-1 values within this intermediate range (see Figure 48.3); most of these cases represented severe brain pathology, most notably head trauma, encephalitis, and subarachnoid hemorrhage (Ripley et al., 2001b; Dohi et al., 2005). Decreased hypocretin-1 levels in these cases may reflect damage to hypocretin transmission, or may be related to changes in CSF flow. Other authors have shown that CSF hypocretin-1 increases with locomotor activity and decreases with treatment with serotonin reuptake inhibitors (but never to near undetectable, narcolepsy-like levels) (Salomon et al., 2003). Therefore, the finding of hypocretin-1 levels in this intermediate range should alert the clinician to the possibility of underlying brain pathology, which may require additional clinical evaluation, laboratory testing, or imaging. Whether genuine hypocretin deficiency explains abnormal sleep in patients with these neurological disorders is in need of further investigation (see also next section). Although the etiology of hypocretin deficiency in humans still needs to be determined, the fact that a large majority of human narcolepsy–cataplexy subjects are hypocretin ligand deficient suggests that hypocretin agonists may be promising in the treatment of narcolepsy (see pharmacology section below).

HLA and narcolepsy NARCOLEPSY–CATAPLEXY Juji et al. (1984) were the first to report a tight association of HLA in narcolepsy. In this study, 100% of Japanese narcoleptics were found to be positive for HLA-DR2, in contrast to 25% of controls. The association was subsequently confirmed in Europe (Langdon et al., 1984; Billiard and Seignalet, 1985) and North America (Poirier et al., 1986). HLA is the general name for a group of genes located in the human major histocompatibility complex (MHC) region of human chromosome 6 (mouse chromosome 17). HLA genes encode cell-surface antigen-presenting proteins. The HLA region is divided into three subregions (Figure 48.4), HLA classes I, II, and III. HLA plays a key role in the recognition and processing of foreign antigens by the immune system. HLA-DR2 is implicated in several autoimmune diseases such as insulin-dependent diabetes mellitus and multiple sclerosis (see section on narcolepsy and the immune system). More specific antisera were used to characterize HLA-DR2 better, and it was shown that the serological haplotype, DR15-DQ6 (DR2-DQw1 subtype) was associated with narcolepsy (Honda and Matsuki, 1990). Furthermore, the amplification of the polymorphic exon (second exon) of the HLADQA and DQB genes by polymerase chain reaction has shown that all Caucasian narcoleptic subjects have the

same alleles, DRB1*1501, DQA1*0102, and DQB1*0602 (Kuwata et al., 1991). However, in African American narcoleptics the susceptibility to narcolepsy is more tightly associated with the DQ6 subtype than with the DR15. In fact, only 70% of African American narcoleptics are DR15 positive, whereas they are almost all positive for the DQ6 (Matsuki et al., 1992; Mignot et al., 1994b, 1997a, 1997b). The most specific marker of narcolepsy in a number of different ethnic groups studied to date is DQB1*0602, a HLA subtype found in 12% of Japanese, 25% of Caucasians, and 38% of African Americans (Mignot, 1998). HLA-DQB1*0602 is always associated with DQA1*0102, another HLA allele encoded by the nearby DQA1 gene, located less than 20 kilobases telomeric to DQB1 (see Figure 48.4). Interestingly, a significant reduction in REM sleep latency in normal subjects was also noted when they were DQB1*0602 positive (Mignot et al., 1998). Similarly, a recent study has found a weak DQB1*0602 association with MSLT SOREMPs in males drawn from the general population in the same sample (Mignot et al., 2006). Almost all patients with typical cataplexy carry HLA-DQB1*0602, and the DQB1 association is especially tight in subjects with hypocretin deficiency, as only four non-HLA-DQA1*0102-DQB1*0602-negative narcolepsy subjects with low or undetectable CSF hypocretin-1 levels have been identified to date (of several hundred subjects with CSF testing). The HLA association in narcolepsy is primary and not due to linkage disequilibrium with other loci (Mignot et al., 2001). Association studies across ethnic groups and the study of additional genetic markers in the region all indicate a primary DQ effect (Table 48.3). It is mostly due to DQA1*0102-DQB1*0602, but is not simply a dominant effect. Indeed, DQB1*0602 homozygotes have a 2–4fold higher risk than DQB1*0602/X heterozygotes (Pelin et al., 1998), and specific DQB1*0602 heterozygotes are at either increased (e.g., DQB1*0602/DQB1*0301) or decreased (e.g., DQB1*0602/DQB1*0601 or DQB1* 0602/DQB1*0501) risk (Mignot et al., 2001). Additional smaller effects have also been suggested for specific DRB1 alleles, another HLA locus located in the same region (see Figure 48.4 & Table 48.3). The complexity of the HLA allele association in narcolepsy (Mignot et al., 2001) mirrors that reported in various autoimmune diseases, such as type I diabetes.

HLA

AND OTHER GENETIC FACTORS IN

FAMILIAL NARCOLEPSY

Interestingly, the HLA association may be less tight in familial versus sporadic narcolepsy cases. Several of the concordant twin pairs that have been reported were HLA negative (Mignot, 1998). Approximately 25% of

NARCOLEPSY AND CATAPLEXY

797 Chromosome 6

Class II

Class III

C4 21A Bf C2 DP

DQ

Structure of Genes around HLA

TNF α,β BC

E

DQA1

A

DRA

Gemomic map of the DQ and DR resion

160 kb

DQ1-9

DR1-18 DR2

Serological typing

DQ1

DQB1*0601

GF

DRB1 85 kb

12 kb

DQ6

4000 kb

HSP40

DR

DQB1

Class I 3000

2000

1000

0

DQ5

DNA low resolution typing

DR15

DR16

DNA high resolution typing DQB1*0501

DQB1*0602 and DQA1*0102

DRB1*1502

DRB1*1501 (Caucasians and Asians) DRB1*1503 (African Americans)

Fig. 48.4. Major human leukocyte antigen (HLA) subtypes involved in narcolepsy susceptibility. The HLA genes are located on chromosome “6p21” and distributed over more than 4000 kilobases (kb). Antigen-presenting cells (macrophages and dendritic cells) have HLA class I (A, B, and C) and II (DQ, DR, and DP) protein, and the locations of genes enclosing these protein are shown. The HLA gene family is divided into two classes and located in major histocompatibility complex (MHC) class I (A, B, and C) and class II (DQ, DR, and DP) regions. Close to the HLA genes in the MHC class III region there are genes encoding complement 2 and 4, tumor necrosis factor (TNF), and heat shock protein (HSP40). The HLA DR and DQ genes are located very close to each other. HLA class II DR and DQ genes are heterodimers encoded by two genes each, one generating an a-chain, the other a b-chain. All of these genes are located within a small genetic distance, leading to extremely high linkage disequilibrium. Subtypes in bold increase susceptibility and underlined subtypes reduce predisposition to narcolepsy. DRA is nonpolymorphic and does not contribute significantly to HLA diversity, in contrast with DQA1, DQB1, and DRB1, which have several hundred possible alleles. The most important genetic factor in narcolepsy is HLA DQB1*0602, a subtype of DQ1 (DQ6). In Caucasians and Asians, the associated DR2 subtype DRB1*1501 is typically observed with DQB1*0602 (and DQA1*0102) in narcoleptic patients. In African Americans, either DRB1*1503, a DNA-based subtype of DR2, or DRB1*1101, a DNA-based subtype of DR5, is observed most frequently, together with DQB1*0602. DQB1*0602, a molecular subtype of the serologically defined DQ1 antigen is the most specific marker for narcolepsy across all ethnic groups.

the familial narcoleptic cases (including narcoleptic subjects and subjects presenting with only recurrent, isolated sleep episodes) are negative for DQB1*0602 (Mignot et al., 1996), supporting the existence of one or more genes with high penetrance not associated with

HLA. These genes could be located using systematic genome screening methods in extended families. Significant linkage was found at 4q13-q21 (logarithm of odds score 3.09) in eight small, multigenerational, HLA-positive families of narcoleptics, favoring the

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S. NISHINO AND E. MIGNOT

Table 48.3 Genotype distribution of DQB1 alleles in narcolepsy versus controls in three ethnic groups Caucasian

DQB1 allele 0602/0602 0602/0301 0602/other DQB1 0602/0501 0602/0601 Non-0602/ non-0602

African American

Japanese

Narcolepsy (n ¼ 238)

Control (n ¼ 146)

Odds ratio

Narcolepsy (n ¼ 77)

Control (n ¼ 243)

Odds ratio

Narcolepsy (n ¼ 105)

Control (n ¼ 698)

Odds ratio

18.1%{ 20.6%{ 45.8%{

2.10% 2.70% 17.10%

10.30 9.35 4.10

23.4%{ 15.6%{ 48.1%{

3.70% 3.30% 23.00%

7.95 5.42 3.10

15.2%{ 19.0%{ 56.0%{

0.70% 0.90% 7.70%

25.76 26.17 15.47

5.00% 0% 10.5%{

1.40% 0% 76.70%

3.71 – 0.00

6.5%* 0% 6.5%{

1.20% 0% 68.70%

5.72 – 0.03

1.90% 7.6%{ 0%*

0.70% 2.10% 87.80%

2.78 3.89 0.00

Allele groupings are ranked from the most predisposing to most protective combinations The highest risk is carried by subjects homozygous for DQB1*0602, followed by DQB1*0602/0301 heterozygotes. DQB1*0501, a subtype common in many ethnic groups, reduces susceptibility in Caucasian and Japanese subjects, even in the presence of DQB1*0602. DQB1*0601, a predominantly Asian subtype, is also relatively protective in the presence of DQB1*0602. Non-DQB1*0602 combinations confer a very high protective effect for narcolepsy–cataplexy. *P<0.05, {P<0.005 versus respective controls.

involvement of other genes such as the CLOCK gene and the g-aminobutyric acid (GABAA) receptor, subunit b1 (Gabrb1) gene in these families (Nakayama et al., 2000). In a large HLA-positive pedigree including 4 patients with and 10 without cataplexy, linkage to 21q was also reported (Dauvilliers et al., 2004c). The candidate gene strategy has also been used. Along this line, it has been reported that the tumor necrosis factor (TNF)-a gene with a thymine residue at position 857 in its promoter region (TNF-a(857T)) is associated with human HLA-DRB1*1501-positive (Hohjoh et al., 2001) and -negative narcolepsy (Wieczorek et al., 2003). In addition, a different distribution of the catechol-Omethyltransferase genotype, a key enzyme in dopaminergic and noradrenergic degradation, was found as well as a correlation between this phenotype and the severity of narcolepsy in female narcoleptic subjects (Dauvilliers et al., 2001a). Novel studies using genomewide associations are ongoing and likely to yield additional candidates.

HLA

IN NARCOLEPSY WITHOUT CATAPLEXY

Studies of HLA association were also conducted in narcoleptic subjects without cataplexy. An association with DQB1*0602 was found in only 40.9% of cases. This result clearly shows the close association between DQB1*0602 and the presence of cataplexy (Mignot et al., 1997a). This is also matched by a much lower percentage of patients without cataplexy who have low CSF hypocretin-1 levels (5–30% of patients, depending on the specific case series) (Mignot et al.,

2002). Some of these patients (approximately onethird) are children with recent onset (4 years or less) who are likely to develop cataplexy within a few years.

Narcolepsy and the immune system The strong association between HLA type and narcolepsy with cataplexy raises the possibility that narcolepsy is an autoimmune disease (Mignot et al., 1992). This hypothesis is also consistent with the peripubertal onset of the disease, but not the even sex ratio found in the disorder. The recent discovery of hypocretin-producing cells as a potential target has given further credence to the autoimmune hypothesis. Some earlier studies testing a variety of serological tests in narcoleptics yielded higher levels of antistreptolysine 0 and anti-DNase antibodies in narcoleptics than in controls (Billiard et al., 1989; Montplaisir et al., 1989). There is, however, not strong evidence for inflammatory processes or immune abnormalities associated with narcolepsy (Mignot et al., 1992), and studies have found no classical autoantibodies and no increase in oligoclonal CSF bands in narcoleptics (Frederickson et al., 1990). Typical autoimmune pathologies (erythrocyte sedimentation rate, serum immunoglobulin levels, C-reactive protein levels, complement levels, and lymphocyte subset ratios) are apparently normal in narcoleptic patients (Matsuki et al., 1988). Recent studies by Black et al. (2002) examined the presence of many neuron-specific and organ-specific autoantibodies, but no antibody association was found in patients with narcolepsy (HLA-DQB1*0602 positive and negative).

NARCOLEPSY AND CATAPLEXY 799 How HLA molecules in general, and HLA-DQ in of the same disease continuum, with similar pathophysparticular, predispose to autoimmune disorders is not iological effects on hypocretin transmission. Narcolepsy well understood. HLA-DQ is expressed on the surface with cataplexy is generally a more severe form of of B-cells, macrophages (including microglia), and the disease, most commonly associated with an almost activated T-cells. It is a heterodimer composed of an complete destruction of the hypocretin system. HLAa and a b chain, encoded by the polymorphic DQA1 DQB1*0602 may be a severity factor more likely to preand DQB1 genes, two genes in tight linkage disequilibdispose to complete hypocretin destruction. Only in rare rium (see Figure 48.4). HLA-DQ binds peptide fragcases of cataplexy would hypocretin cell loss be partial ments and can present the resulting complex to other but sufficient to produce normal levels of hypocretin cells of the immune system, as recognized by the T-cell and a narcolepsy phenotype. In these cases, compensareceptor complex. Autoimmune processes associated tion by the remaining hypocretin cells likely maintains with HLA probably involve the ability of some HLA CSF hypocretin-1 at normal levels. Projections with more alleles to bind and consequently present specific autoeffects on CSF hypocretin-1 but of less functional imporantigens to the rest of the immune system. In other tance for the phenotype (e.g., hypocretin afferents to HLA-associated diseases, however, antibodies directed the spinal cord) may also be more spared in patients with toward the potential target (e.g., islet cell antibodies in cataplexy and normal CSF levels. The observation that type I diabetes) or T-cell clones with primary responrare HLA-DQB1*0602-negative patients with cataplexy, siveness to target antigens (e.g., against myelin basic who have generally normal CSF hypocretin-1 levels, protein in multiple sclerosis) can be detected. In narcomay share a HLA genetic susceptibility with HLAlepsy, however, all attempts at demonstrating T-cell DQB1*0602-positive patients beyond DQB1*0602 – for reactivity against hypocretin peptides, or at detecting example, both groups have an increased frequency of autoantibodies directed at hypocretin-producing cells, DQB1*0301 – also supports this hypothesis (Mignot have failed (Black et al., 2005b). A recent report in et al., 2001) (see Table 48.3). mice suggested a possible functional antibody with In narcolepsy without cataplexy, cell loss would be indirect effects on cholinergic systems after passive less pronounced. The severity of the disease would be transfer, but this finding requires replication (Smith generally lower and the cell loss insufficient to result et al., 2004). Similarly, a possible reaction of CSF in low CSF hypocretin-1 levels. The HLA-DQB1*0602 immunoglobulin with hypothalamic extracts has been association with narcolepsy without cataplexy is weaker. reported recently (Black et al., 2005a). Only in rare cases might neuroanatomical destruction be These generally negative results do not necessarily pronounced, resulting in a low CSF hypocretin-1 concenexclude the possibility of an autoimmune mechanism, tration, but still sparing a select hypocretin cell subpopbut do raise the possibility of other, more complex, ulation projecting to cataplexy-triggering pathways. In neuroimmune mechanisms. Another possibility is an favor of this model is the study of Thanickal et al. infectious agent with particular tropism toward hypo(2000) reporting 14% remaining hypocretin cells in a cretin-producing cells, although HLA associations in patient without cataplexy, versus 4.4–9.4% remaining infectious diseases are usually not very tight or primarcells in five other subjects with cataplexy. However, ily to a single allele. Interest in the autoimmune arena lesion studies in rats also indicated a 50% decrease in has been recently rekindled by case reports that intraCSF hypocretin-1 with a 77% destruction of hypocretin venous immunoglobulin may reduce the development cells, suggesting that a substantial reduction in CSF of narcolepsy severity if administered within a year hypocretin-1 levels must be present in this patient withof onset (Dauvilliers et al., 2004a). Most of these studout cataplexy. ies are still preliminary or non-conclusive, but deserve The fact that HLA-DQB1*0602 is slightly increased to be developed further in order to strive towards prein frequency in patients without cataplexy but with norvention of the disease (Scammell, 2006). mal CSF hypocretin-1 concentration is also consistent with this hypothesis. This finding, however, remains to be confirmed in a population-based sample, as HLA Pathophysiological considerations for positivity may have been increased in clinical samples narcolepsy without cataplexy due to a bias in inclusion (some clinicians use HLA typAs up to 40% of narcoleptic subjects do not display ing to confirm the diagnosis of narcolepsy without catacataplexy, the pathophysiology of “narcolepsy without plexy). The model also predicts that a large number of cataplexy” holds clinical importance. Two possible, narcolepsy without cataplexy cases may exist in the gennonexclusive, pathophysiological models for narcoeral population but have a milder phenotype, consistent lepsy without cataplexy can be proposed. In the first with the observation of slightly decreased REM latency model, narcolepsy with and without cataplexy is part in normal population subjects with HLA-DQB1*0602

800 S. NISHINO AND E. MIGNOT (Mignot et al., 1998) and the finding of increased and the superior part of the brainstem) have been pubDQB1*0602 in subjects with multiple SOREMPs during lished. Narcolepsy has also been reported in patients MSLTs in the same sample (Mignot et al., 2006). Simiwith multiple sclerosis, encephalitis, cerebral ischemia, lar milder forms of the disease or long latent periods cranial trauma, brain tumor, and cerebral degeneration have been suggested for other autoimmune diseases (Aldrich and Naylor, 1989; Arii et al., 2001; Melberg such as DQ2-associated celiac disease, B27-associated et al., 2001; Scammell et al., 2001). Hypothalamic sarspondylarthropathies, and DR3/DR4-associated type I coidosis has caused narcolepsy in at least two patients, diabetes. In type I diabetes, for example, a larger numalthough neither had cataplexy (Aldrich and Naylor, ber of individuals, especially relatives of affected pro1989; Malik et al., 2001). Symptomatic narcolepsy is also bands, may be positive for islet cell antibodies without present in children affected with Niemann–Pick disease ever developing the disease. (Challamel et al., 1994). The diagnosis of symptomatic In the second model, the cause of cases without low narcolepsy requires that narcolepsy be developed in CSF hypocretin does not involve partial hypocretin cell close temporal relationship with the neurological disloss. Other systems downstream of hypocretin itself orders, as the association may be incidental rather may be involved, for example hypocretin receptors, than causal. histamine, or neuroanatomical systems unconnected In a recent meta-analysis, we collated 116 patients with hypocretin neurobiology. This pathophysiology with symptomatic secondary narcolepsy reported in may mirror that of those with hypocretin-nondeficient the literature; all met the ICSD criteria for secondary narcolepsy–cataplexy, which represent about 10% of narcolepsy (Nishino and Knbayashi, 2005). As several all narcolepsy–cataplexy subjects (see Figure 48.3). As authors have reported previously, inherited disorders the occurrence of cataplexy is tightly associated with (n ¼ 38), tumors (n ¼ 33), and head trauma (n ¼ 19) impairments of hypocretin neurotransmissions in were the three most frequent causes of symptomatic humans, canines, mice, and rats, it is likely that impairnarcolepsy. Of the 116 patients, 10 had multiple sclerosis ments of downstream hypocretin pathway are likely and one had acute disseminated encephalomyelitis. involved in these cases, although this cannot be tested Relatively rare cases were reported with vascular disordirectly at present. Minor degrees of impairment or a ders (n ¼ 6), encephalitis (n ¼ 4), neurodegeneration subset of pathways may also cause isolated EDS (i.e., (n ¼ 1), and heterodegenerative disorder (three cases narcolepsy without cataplexy). in one family). EDS without cataplexy or any REM Although two models are proposed, they may not be sleep abnormalities is also often associated with these entirely exclusive. A partial hypocretin cell loss may, for neurological conditions, and defined as symptomatic example, not be sufficient in itself to produce sympcases of EDS. toms but could lead to narcolepsy when associated with Although it is difficult to rule out comorbidity of additional defects downstream. A similar model, albeit idiopathic narcolepsy in some cases, review of the literspeculative, has been proposed in some obese-type ature reveals numerous unquestionable cases of sympdiabetic children where both type I and type II may tomatic narcolepsy (Nishino and Kanbayashi, 2005). coexist. In these cases, subjects with partially reduced These include patients with HLA negativity and/or late islet cell numbers may be asymptomatic when lean but onset, and patients in whom the occurrence of the nardevelop insulin resistance if obesity develops and the coleptic symptoms paralleled the rise and fall of the remaining islet population is unable to produce enough causative disease. Interestingly, a review of these insulin to keep up with increased tissue demand. patients (especially those with brain tumors) clearly To distinguish between these models, neuropathoindicated that the hypothalamus was involved most logical studies of patients with narcolepsy without catoften (Nishino and Kanbayashi, 2005). aplexy (as well as patients with hypocretin-nondeficient CSF hypocretin-1 levels were measured in a limited narcolepsy–cataplexy) are needed urgently. It is also number of symptomatic patients with narcolepsy and imperative to study narcolepsy without cataplexy not EDS of various etiologies; most had reduced levels. only in clinical samples but also in the general populaEDS in these patients is sometimes reversible, with an tion, as clinical cases may represent a more severe and improvement in the causative neurological disorder selected subpopulation. and in the hypocretin status. It has also been noted that in some symptomatic patients with EDS (with Parkinson’s disease and thalamic infarction), hypocretin staSymptomatic narcolepsy and EDS, and tus was in the normal range. In contrast to idiopathic the hypocretin system narcolepsy cases, the occurrence of cataplexy was not Several cases of narcoleptic patients with brain tumors as tightly associated with hypocretin ligand deficiency (most often localized in the posterior hypothalamus in symptomatic cases.

NARCOLEPSY AND CATAPLEXY 801 cataplexy)) are needed to reduce the symptoms of narcoHypocretin/orexin system and lepsy (Nishino and Mignot, 1997). sleep regulation Histamine is another monoamine implicated in the Hypocretins/orexins were discovered only in 1998, control of vigilance, and the histaminergic system is also 1 year before the cloning of the canine narcolepsy likely to mediate indirectly the wake-promoting effects gene. Two independent research groups made this disof hypocretin (Eriksson et al., 2001; Huang et al., covery. One group called the peptides “hypocretin”, 2001; Yamanaka et al., 2002). Interestingly, brain histabecause of their primary hypothalamic localization mine content is reduced dramatically in both Hcrtr2 and similarities with the hormone secretin (De Lecea gene-mutated and ligand-deficient narcoleptic dogs et al., 1998). The other group called the molecules (Nishino et al., 2002). The role of the histaminergic sys“orexin” after observing that central administration tem in the pathophysiology of narcolepsy, with possible of these peptides increased appetite in rats (Sakurai therapeutic applications, is a novel area worthy of inveset al., 1998). The precursor, preprohypocretin, is tigation (Shiba et al., 2004; Fujiki et al., 2006). cleaved to generate two active and related peptides, Many measurable behavioral activities and biochemhypocretin-1 (orexin A) and hypocretin-2 (orexin B). ical indices manifest rhythmic fluctuations over the Hypocretin-1 is a 33-residue peptide. It contains four 24-hour period. Whether hypocretin tone changes with cysteine forming two disulfide bonds. Hypocretin-2 conZeitgeber time was assessed by measuring extracellular sists of 28 amino acids and shares significant sequence hypocretin-1 levels in the rat brain CSF over 24 hours homology with hypocretin-1, especially at the C-terminal using in vivo dialysis (Fujiki et al., 2001; Yoshida end, but has no disulfide bonds (a linear peptide) et al., 2001; Zeitzer et al., 2003). The results demon(Sakurai et al., 1998) (Figure 47.4 in Chapter 47) (see strated the involvement of a slow diurnal pattern of also review in Sakurai, 2005). There are two G proteinhypocretin neurotransmission regulation (as in the coupled hypocretin receptors, Hcrtr1 and Hcrtr2), also homeostatic and/or circadian regulation of sleep). called orexin receptor 1 and 2 (OX1R and OX2R), with Hypocretin levels increase during the active periods a distinct distribution within the CNS (Sakurai et al., and are highest at the end of the active period, and 1998) (Figure 47.4 in Chapter 47). the levels decline with the onset of sleep. Furthermore, Hypocretin-1 and -2 are produced exclusively by a sleep deprivation increases hypocretin levels (Fujiki well-defined group of neurons localized in the lateral et al., 2001; Yoshida et al., 2001; Zeitzer et al., 2003). hypothalamus (Figure 47.4 in Chapter 47). The hypocreRecent electrophysiological studies have shown that tin neurons project to the olfactory bulb, cerebral cortex, hypocretin neurons are most active during wakefulthalamus, hypothalamus, and brainstem, particularly the ness, and reduce their activity during slow-wave and locus coeruleus and raphe nucleus, and to cholinergic REM sleep. Increased neuronal activity is associated nuclei and cholinoceptive sites (such as pontine reticular with body movements or phasic REM activity (Lee formation) thought to be important for sleep regulation et al., 2005; Mileykovskiy et al., 2005). In addition to (Peyron et al., 1998). this short-term change, our results of microdialysis A series of recent studies has shown that the hypoexperiments also suggest that basic hypocretin neurocretin system is a major excitatory system affecting transmission fluctuates over 24 hours and slowly the activity of monoaminergic (dopamine (DA), norepibuilds up during the active period. Adrenergic locus nephrine (NE), serotonin (5HT), and histamine) and chocoeruleus neurons are typical wake-active neurons linergic systems with major effects on vigilance states involved in vigilance control, and it has been demon(Willie et al., 2001; Taheri et al., 2002) (Figure 47.4 in strated recently that basic firing activity of wakeChapter 47). It is thus likely that a deficiency in hypoactive locus coeruleus neurons also significantly cretin neurotransmission induces an imbalance between fluctuates across various circadian intervals (Astonthese classical neurotransmitter systems, with primary Jones et al., 2001). effects on sleep-state organization and vigilance. Indeed, Several acute manipulations, such as exercise, low DA and/or NE contents have been reported to be high glucose utilization in the brain, and forced wakefulin several brain structures in narcoleptic Dobermans, ness, increase hypocretin levels (Willie et al., 2001; and in human narcolepsy brains examined post mortem Yoshida et al., 2001; Wu et al., 2002). It is therefore (Nishino and Mignot, 1997; Nishino et al., 2001a). These hypothesized that a buildup or acute increase of hypochanges are possibly due to compensatory mechanisms, cretin levels may counteract the homeostatic sleep because drugs that enhance dopaminergic neurotranspropensity that typically increases during the daytime mission (such as amfetamine-like stimulants and modaand during forced wakefulness (Yoshida et al., 2001). finil (for EDS)) and NE neurotransmission (such as Owing to the lack of increase in hypocretin tone, narnorepinephrine (noradrenaline) uptake blockers (for coleptic subjects may not be able to stay awake for

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prolonged periods and do not respond to various alerting stimuli. Conversely, reduction of the hypocretin tone at sleep onset may contribute to the profound deep sleep that normally inhibits REM sleep at sleep onset, and the lack of this system in narcolepsy may allow the occurrence of REM sleep at sleep onset.

TREATMENTS FOR NARCOLEPSY AND PHARMACOLOGICAL MECHANISMS Current treatments for human narcolepsy Nonpharmacological treatments (i.e., by behavioral modification) are often reported to be useful additions to the clinical management of patients with narcolepsy (Rogers, 1984; Roehrs et al., 1986; Thorpy and Goswami, 1990; Mullington and Broughton, 1993). Regular napping usually relieves sleepiness for 1–2 hours (Roehrs et al., 1986) and is the treatment of choice for some patients, but this often has negative social and professional consequences. Exercising to avoid obesity, keeping a regular sleep–wake schedule, and having a supportive social environment (e.g., patient group organizations and support groups) are also helpful. In almost all cases, however, pharmacological treatment

is needed: 94% of patients reported using medications in a recent survey by a patient group organization (American Narcolepsy Association, 1992). For EDS, amfetamine-like CNS stimulants or modafinil (nonamfetamine stimulant for which mechanisms of action are debated) are most often used (Table 48.4). These compounds possess wake-promoting effects in narcoleptic subjects as well as in control populations, but very high doses are required to normalize abnormal sleep tendency during daytime for narcolepsy (Mitler, 1994). For consolidating nighttime sleep, benzodiazepine hypnotics or GHB (also called sodium oxybate) are used occasionally, and nighttime administration of GHB reduces EDS and cataplexy during daytime (Scrima et al., 1989; Lammers et al., 1993). Occasional abuse in the context of rave parties has been reported, and prescription of the compound is highly supervised. Because slow-wave sleep is associated with growth hormone (GH) release, GHB also induces GH release and has been abused by athletes. GHB was classified as a schedule I controlled substance in 2000, but has recently been approved for the treatment of narcolepsy (schedule IV controlled substance). GHB, when administered at night, consolidates sleep and improves

Table 48.4 Current pharmacological treatments for excessive daytime sleepiness in human narcolepsy and related disorders Mode of action

Usual daily dose

Half-life (h)

Side-effects/notes

Irritability, mood changes, headaches, palpitations, tremors, excessive sweating, insomnia Same as amfetamines, less reduction of appetite or increase in blood pressure Less sympathomimetic effect, milder stimulant, slower onset of action, occasionally produces liver toxicity

Wake-promoting compounds for EDS Sympathomimetic stimulants D-Amfetamine sulfate Dopamine enhancer (dopamine release/ dopamine uptake inhibition) Methylphenidate HCl Dopamine enhancer

5–60 mg

16–30

10–60 mg

3

Pemoline*

20–115 mg

11–13

Nonamfetamine wake-promoting compounds Modafinil Unknown, inhibits dopamine uptake

100–400 mg

11–14

No peripheral sympathomimetic action, headaches, nausea

Short-acting hypnotics g-Hydroxybutyrate (GHB)

6–9 g (divided nightly)

2

Sedation, nausea

Dopamine enhancer

Unknown, may act on GABAB or specific GHB receptors, reduces dopamine release

*Potentially hepatotoxic – frequent liver function monitoring required.

NARCOLEPSY AND CATAPLEXY daytime functioning. Because of its short half-life, it must be administered twice a night. As amfetamine-like stimulants and modafinil have little effect on cataplexy, tricyclic antidepressants, such as imipramine or clomipramine, are used in addition to control cataplexy (Nishino and Mignot, 1997; Mignot, 2000; Nishino et al., 2000a) (Table 48.5). However, these compounds can cause a number of side-effects, such as dry mouth, constipation, or impotence. GHB is also used for the treatment of cataplexy. The antidepressants and GHB are also effective for the other REM sleep phenomena. Most of these compounds are known to act on the monoaminergic systems (Table 48.4). Most of the

803

compounds effective for EDS target the presynaptic enhancement of dopaminergic neurotransmission (DA release and DA uptake inhibition) (Nishino et al., 1998; Wisor et al., 2001), whereas anticataplectics are mediated mostly by enhancement of noradrenergic neurotransmission (Nishino et al., 1998). Animal data suggest that these compounds are effective for EDS and cataplexy, regardless of hypocretin receptor dysfunction and ligand deficiency (Babcock et al., 1976; Nishino and Mignot, 1997), and are likely to act on downstream pathways of hypocretin neurotransmission. A series of anatomical and functional findings suggested that these monoaminergic systems are likely to mediate effects of hypocretin on vigilance and

Table 48.5 Antidepressants currently used as anticataplectic agents Usual daily dose (mg)

Half-life (h)

Notes/side-effects

Tricyclics Imipramine Desipramine

10–100 25–200

5–30 10–30

Protriptyline

5–60

55–200

Clomipramine

10–150

15–60

SSRIs Fluoxetine

Dry mouth, anorexia, sweating, constipation, drowsiness (NE >> 5HT > DA) A desmethyl metabolite of imipramine; effects and side-effects similar to those of imipramine (NE > 5HT > DA) Reported to improve vigilance measures; anticholinergic effects (5HT > NE >> DA) Digestive problems, dry mouth, sweating, tiredness, impotence. Anticholinergic effects. Desmethylclomipramine (NE >> 5HT > DA) is an active metabolite

20–60

24–72

Fluvoxamine

50–300

15

NSRIs Venlafaxine

150–375

4

Milnacipran

30–50

8

NRI Atomoxetine

40–60*

5.2

No anticholinergic or antihistaminergic effects; good anticataplectic effect but less potent than clomipramine. Active metabolite norfluoxetine has more adrenergic effects No active metabolite; pharmacological profile similar to that of fluoxetine; less active than clomipramine; gastrointestinal side-effects New serotonergic and adrenergic uptake blocker; no anticholinergic effects; effective in cataplexy and sleepiness; nausea New serotonergic and adrenergic uptake blocker; no anticholinergic or antihistaminergic effects; effective in cataplexy Normally indicated for attention-deficit/hyperactivity disorder (ADHD)

SSRI, selective serotonin reuptake inhibitor; NSRI, norepinephrine/serotonin reuptake inhibitor; NRI, norepinephrine reuptake inhibitor. Reboxetine is another NRI, but is not available in the USA. *Dosage for ADHD treatment. It is suggested to start with smaller doses for anticataplectic treatment. g-Hydroxybutyric acid (GHB, sodium oxybate) is also reported to be effective in cataplexy and may act via GABAB or via specific GHB receptors. Reduces dopamine release. NE, norepinephrine; 5HT, 5-hydroxytriptamine; DA, dopamine. Selectivity of the compounds on these monoaminergic systems is indicated by >> (much greater) and > (greater), respectively.

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muscle tonus control (Peyron et al., 1998; Hagan et al., 1999; Horvath et al., 1999; Nambu et al., 1999; Yamanaka et al., 2002). In addition, the loss of hypocretin input would possibly induce monoaminergic dysfunction (Nishino et al., 2001a). Current pharmacological treatments are rather symptomatic, and are not satisfactory for many patients as they bring undesirable side-effects and drug tolerance. Furthermore, most patients need to take two different classes of compound to manage both EDS and cataplexy, creating a variety of complications (Nishino and Mignot, 1997; Mignot, 2000; Nishino et al., 2000a). For these reasons, people have awaited an ideal treatment that is more directly pathophysiologically oriented. Hypocretin/orexin peptides or its mimetics are, theoretically, the most promising agents. Unfortunately, however, large molecular peptides do not penetrate to the brain efficiently (Fujiki et al., 2003) and oral administration is not applicable for neuropeptides; nonpeptide agonists thus need to be developed. As hypocretin receptors are G protein-coupled, seven-transmembrane receptors (Figure 47.4 in Chapter 47), like most neuropeptide receptors, this deployment may be possible in the near future.

Pharmacological control of symptoms of narcolepsy ADRENERGIC

UPTAKE INHIBITION MEDIATES

THE ANTICATAPLECTIC EFFECTS OF CURRENTLY PRESCRIBED ANTIDEPRESSANT MEDICATIONS

In the past, the most commonly prescribed anticataplectic agents were tricyclic antidepressants. More recently, more selective monoaminergic reuptake inhibitors have become available. Antidepressants have a complex pharmacological profile that includes monoamine (serotonin, norepinephrine, epinephrine, and dopamine) uptake inhibition, and for older tricyclic antidepressants, cholinergic, histaminergic and a-adrenergic blocking properties (Mignot et al., 1993a; Nishino et al., 1993; Nishino and Mignot, 1997). In narcoleptic canines, inhibition of adrenergic, but not dopaminergic or serotonergic, uptake or other properties mediates the therapeutic efficacy of antidepressant compounds (Mignot et al., 1993a; Nishino et al., 1993). This observation fits well with available human pharmacological data (see Nishino and Mignot, 1997, and Table 48.5). Protriptyline, desipramine, viloxazine, and atomoxetine, four adrenergicspecific uptake blockers with no effect on serotonin transmission, are effective and potent anticataplectic agents (see Table 48.5). In contrast, fluoxetine and other serotonin-specific uptake inhibitors are active in cataplexy only at relatively high doses, an effect possibly mediated by the weak adrenergic uptake effects of these

compounds and their metabolites (Mignot et al., 1993a; Nishino et al., 1993). The observation that adrenergic uptake blockers are excellent anticataplectic agents correlates well with their potent inhibitory effects on REM sleep. Adrenergic transmission is reduced during REM sleep (for a review see Siegel, 2005). Firing rate in the locus coeruleus decreases during cataplexy in narcoleptic canines (Wu et al., 1999). Adrenergic uptake blockers might thus increase activity in projection sites involved in REM sleep regulation. The fact that serotonergic uptake blockers, also known to have inhibitory effects on REM sleep, have little or no effect on cataplexy is more surprising. Like adrenergic cells of the locus coeruleus, serotonergic cells of the raphe nuclei dramatically decrease their activity during REM sleep (Siegel, 2005). This discrepancy could be explained by a preferential effect of serotonergic projections on REM sleep features other than atonia, for example in the control of eye movements. In this model, adrenergic projections may be more important than serotonergic transmission in the regulation of REM sleep atonia and thus cataplexy (Mignot et al., 1993a). In favor of this hypothesis, a recent experiment has shown that serotonergic activity does not decrease during cataplexy in narcoleptic canines (Wu et al., 2004), in contrast with locus coeruleus activity (Wu et al., 1999).

INCREASED

DOPAMINERGIC TRANSMISSION MEDIATES

THE WAKE-PROMOTING EFFECTS OF CURRENTLY PRESCRIBED STIMULANT COMPOUNDS

The most commonly prescribed stimulants are amfetamine-like drugs, such as dextroamfetamine, methamfetamine, methylphenidate, pemoline, and the wake-promoting compound modafinil (see Table 48.4). Like tricyclic antidepressant compounds, amfetaminelike drugs are very nonspecific pharmacologically. Their main effect is to increase monoaminergic transmission globally, by stimulating monoamine release and blocking monoamine reuptake. Abuse and dose escalation can occur with amfetamine, especially in patients without cataplexy. Less abuse is reported with methylphenidate, and modafinil is believed not to be addictive. Recent studies have demonstrated that the wakepromoting effect of these compounds is secondary to dopamine release stimulation and dopamine reuptake inhibition (Nishino et al., 1998; Wisor et al., 2001). The mode of action of modafinil is debated, but this compound also selectively inhibits dopamine uptake (Mignot et al., 1994a). All of these compounds are ineffective in dopamine transporter knockout mice, suggesting a primary mediation of wake promotion via dopaminergic systems (Wisor et al., 2001). Interestingly,

NARCOLEPSY AND CATAPLEXY compounds selective for dopaminergic transmission have no effect on cataplexy, whereas amfetamine-like compounds with combined dopaminergic and adrenergic effects have some anticataplectic properties at high dosages (Mignot et al., 1993a; Kanbayashi et al., 2000). Adrenergic effects of amfetamine-like stimulants also correlate with the respective effects of these compounds on normal REM sleep (Nishino and Mignot, 1997; Kanbayashi et al., 2000). Dopaminergic specific uptake blockers have little effect on REM sleep when compared to adrenergic or serotonergic compounds (Nishino and Mignot, 1997). The most important effects of dopaminergic uptake blockers are to reduce total sleep time and slow-wave sleep (Nishino et al., 1998). This preferential effect of dopaminergic uptake blockers on nonREM sleep correlates with electrophysiological data. As opposed to adrenergic or serotonergic neurons, the firing rate of dopaminergic neurons is known to remain relatively constant during REM sleep (Miller et al., 1983; Steinfels et al., 1983). Interestingly, studies in both humans and narcoleptic canines have shown that large doses of stimulants are needed to “normalize” narcoleptic subjects polygraphically. In our narcoleptic Doberman population, amfetamine doses equivalent to 60 mg/day were needed to reduce daytime sleep to control levels (Shelton et al., 1995). In both control and narcoleptic animals, however, the dose–response curves for modafinil and amfetamine were parallel. This finding suggests that there is no difference in sensitivity to stimulants in narcoleptic animals; rather higher doses are needed in narcoleptic animals because of their extreme baseline sleepiness (Shelton et al., 1995).

OTHER

KNOWN MODULATORS OF NARCOLEPSY

SYMPTOMS

The effects of more than 200 compounds with various modes of action have been examined in human patients and narcoleptic canines (for a review see Nishino and Mignot, 1997). Almost all the compounds studied are monoaminergic and cholinergic modulators. These systems have been studied more intensively than others because selective pharmacological probes for these systems are more generally available. With cataplexy being easier to study than sleep in canines, most studies have also focused on cataplexy rather than sleepiness. For cataplexy, the findings were consistent with pharmacological studies of REM sleep. As is the case for REM sleep, the regulation of cataplexy is modulated positively by cholinergic systems and negatively by monoaminergic tone (Nishino and Mignot, 1997). Muscarinic M2 or M3 receptors mediate the cholinergic effects, whereas monoaminergic effects are modulated

805

mostly by postsynaptic a1-adrenergic receptors and presynaptic D2/D3 dopaminergic autoreceptors (Nishino and Mignot, 1997). A number of studies have shown abnormal cholinergic and monoaminergic receptor density and neurotransmitter levels in human or canine narcolepsy brain and CSF samples (Faull et al., 1983; Mefford et al., 1983; Baker and Dement, 1985; Kilduff et al., 1986; Bowersox et al., 1987; Miller et al., 1990; Kish et al., 1992; Aldrich et al., 1994; Khan et al., 1994; Rinne et al., 1995; MacFarlane et al., 1997; Nishino and Mignot, 1997; Nishino et al., 2001a). Local injection studies in selected brain areas of narcoleptic canines have also shown functional relevance for some of these abnormalities (Reid et al., 1994, 1996; Nishino et al., 1995, 1997). Cholinergic hypersensitivity, dopaminergic abnormalities, and decreased histaminergic tone are likely to be critical downstream mediators of the expression of the hypocretin deficiency/narcolepsy symptomatology (Reid et al., 1994, 1996; Nishino et al., 1995, 1997, 2001a). The cholinergic/monoaminergic imbalances observed in narcolepsy are best illustrated by the finding that in asymptomatic animals heterozygotes for the hypocretin receptor-2 mutation, a combination of cholinergic agonists with an a1 blocker or a D2/D3 agonist can trigger cataplexy (Mignot et al., 1993b).

MODES

OF ACTION OF

GHB

The mode of action of GHB on sleep and narcolepsy is unclear. GHB has a major effect on dopamine transmission, reducing firing rate and raising brain content of dopamine (Maitre, 1997; Nishino and Mignot, 1997; Castelli et al., 2003). Other effects on opioid, glutamatergic, and acetylcholine transmission have been reported (Castelli et al., 2003). Specific GHB binding sites have been identified, but the compound is also a GABAB agonist (Castelli et al., 2003). Most studies to date suggest that the sedative hypnotic effect is mediated via GABAB agonist activity (Castelli et al., 2003; Queva et al., 2003). Whether this effect also mediates the anticataplectic effects after long-term administration is unknown. Human or animal studies using other GABAB agonists, for example high-dose baclofen, would be needed to answer these questions.

Future therapies Eventually, the treatment of narcolepsy is likely to involve hypocretin cell transplant or gene therapy technology (Table 48.6) (see Mignot and Nishino, 2005; Fujiki and Nishino, 2006). These therapies are, however, many years away, and the efficacy of exogenously administered hypocretin analogs (i.e., nonpeptide agonists) should be established first in humans. Meanwhile, more specific

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Table 48.6 Potential future narcolepsy therapies Type of compound

Description

Nonhypocretin-based therapy Novel monoamine reuptake inhibitors Novel SWS enhancers

Histaminergic H3 antagonists/inverse agonists Hypocretin-based therapy Hypocretin-1

Nonpeptide agonists Hypocretin cell transplant

Gene therapy Immune-based therapy Steroids IVIg Plasmapheresis

Anatomically targeted DA (stimulant) and NE (anticataplexy) reuptake inhibitors to reduce side-effects and abuse potential Novel GABAB agonists, such as a longer-acting GHB analogs; GABAA subtype-specific compounds (e.g., gaboxadol) or GABA reuptake inhibitors (e.g., tiagabine) may be effective Blockade of histamine autoreceptor is effective in sleepiness and cataplexy in animals models; effects in humans are still uncertain, but multiple compounds are in early human trials Disappointing effects after intravenous, intracisternal, and intranasal administration to date, but extremely high doses could still be effective; would likely be effective if could be delivered intracerebroventricularly High potential on a medium-term basis; peptide receptor agonists are, however, often difficult if not impossible to make May eventually provide a cure; results to date in other diseases are disappointing because of graft rejection, low survival rate of implant, and lack of supply for graft availability. All of these problems may be alleviated by improved stem cell technology. Likely to be more than 10 years away Promising in the future; potentially dangerous side-effects; could be combined with cell-based therapies Ineffective thus far; unlikely to be useful due to late clinical presentation of cell loss Equivocal results thus far; generally safe but occasional life-threatening side-effects Similar to IVIg but even fewer available data; more invasive than IVIg

DA, dopamine; GHB, g-hydroxybutyrate; H3, histamine receptor 3; IVIg, intravenous immunoglobulin; NE, norepinephrine; SWS, slowwave sleep.

targeting of the systems that interact closely with the hypocretin system or downstream effector mechanisms with increasingly refined pharmacological agents may be the best short-term solution for the symptomatic treatment of narcolepsy (Mignot and Nishino, 2005).

CONCLUSION Narcolepsy–cataplexy is most commonly caused by a loss of hypocretin-producing cells in the hypothalamus. Low CSF hypocretin-1 levels can be used to diagnose the condition. The disorder is tightly associated with HLA-DQB1*0602, suggesting that the cause in most patients may be autoimmune destruction of these cells. The hypocretin system sends strong excitatory projections on to monoaminergic cells. Studies in canine narcolepsy demonstrated that the loss of hypocretin neurotransmission creates a cholinergic–monoaminergic imbalance in narcolepsy. Abnormally sensitive cholinergic transmission, together with depressed dopaminergic

and histaminergic transmission, are believed to underlie abnormal REM sleep and daytime sleepiness in narcolepsy. Current treatments are symptomatically based and act downstream of the hypocretin abnormality. Presynaptic stimulation of dopaminergic transmission and adrenergic uptake inhibition mediate the wakepromoting and anticataplectic effects of stimulants and antidepressants respectively. GHB, a sedative compound, may act via GABAB receptors or specific GHB receptors. Whereas most cases of narcolepsy–cataplexy are caused by a hypocretin cell loss, some cases with cataplexy and most of those without cataplexy have normal CSF hypocretin-1 levels. This may reflect either disease heterogeneity or a partial loss of hypocretin neurons without significant CSF hypocretin-1 decrements. A critical area in need of further inquiry is the role of CSF hypocretin-1 testing in predicting therapeutic response to medications already in use to treat narcolepsy (Mignot et al., 2003). Developing an assay that could

NARCOLEPSY AND CATAPLEXY measure hypocretin-1 in plasma reliably may be possible and would also be useful when low levels were observed in narcolepsy (Nishino, 2006). The findings in animal models suggest that hypocretin replacement therapy is a promising new therapeutic option, and may improve both EDS and cataplexy (Mieda et al., 2004). However, the development of small molecular synthetic hypocretin receptor agonists is likely the next step for this therapeutic option in humans, because hypocretin peptides themselves do not penetrate to the brain effectively (Fujiki et al., 2003). If ligand replacement therapy is demonstrated to be effective in hypocretin-deficient narcolepsy, hypocretin cell transplant or gene therapy technology may also be applicable in the near future. These therapies are, however, many years away, and the efficacy of exogenously administered hypocretin analogs (nonpeptide agonists) in humans should be established first. Whether or not narcolepsy is an autoimmune disorder is still unclear, but highly suspected. Other possible explanations could involve an infectious agent, with participation of the immune system. Explaining the link between the HLA association and hypocretin deficiency must be a high priority. It may be possible to use CSF hypocretin-1 testing to evaluate the extent of hypocretin cell loss in early stages of the disease (e.g., in children), thus facilitating the development of treatments that may be able to arrest, or at least delay, disease progression. Similar strategies using immunosuppression have been used in other autoimmune diseases, such as type I diabetes mellitus. In one case, 2 months after an abrupt onset, high-dose prednisone was administered but no significant effects on symptoms and CSF hypocretin-1 levels were observed (Hecht et al., 2003); however, in this patients, levels of hypocretin-1 were already very low, suggesting the possibility that irreversible damage to cells had already occurred. In other cases with recent onset, intravenous immunoglobulin administration was reported to have positive effects (Lecendreux et al., 2003), suggesting the need for further studies. We anticipate that, in time, patients with narcolepsy will benefit from studies currently under way in sleep medicine as well as in other areas of medicine.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 50

Excessive daytime sleepiness 1

MUJAHID MAHMOOD 1 AND CLETE A. KUSHIDA 2 * Kaiser Permanente South San Francisco Medical Center, San Francisco, CA, USA

2

Stanford University Center of Excellence for Sleep Disorders, Stanford, CA, USA

INTRODUCTION Sleepiness is welcome when sleep is desired, but when it results in a tendency to fall asleep in inappropriate situations, it becomes unwanted and pathological. It is this unwanted sleepiness that is termed excessive daytime sleepiness (EDS). EDS can take numerous forms, from mild drowsiness to falling asleep continually throughout the day. Many people confuse fatigue or tiredness with EDS, but EDS is characterized by the inability to stay awake, alert, and optimally functional throughout the day. Conversely, patients with fatigue or tiredness are typically unable to take daytime naps, because the same mechanisms that prevent them from falling asleep at night prevent them from falling asleep during the day. Sleepiness, like wakefulness, is a complex state. Multiple factors, such as the quantity and quality of preceding sleep, environmental stimuli, circadian rhythms, drugs, attention, and various sleep disorders and medical conditions all affect the degree of wakefulness and sleepiness.

NEUROLOGICAL BASIS OF SLEEPINESS Numerous regions of the brain are known to participate in promoting wakefulness or sleep (reticular activating system, locus coeruleus, dorsal raphe, basal forebrain, thalamus, hypothalamic nuclei, cortex, and other brainstem nuclei), but there is no consensus among sleep specialists as to which are critical. Likewise, numerous neurotransmitters and neuromodulators are known to be involved in these regions (e.g., histamine, glutamate, adenosine, norepinephrine, serotonin, g-aminobutyric acid, acetylcholine, interleukin-1, substance P, neuropeptide Y, prostaglandins, hypocretins). The interactions and relative contributions of these numerous

participants remain elusive. Additionally, it is not known whether the mechanisms that govern normal versus pathological sleepiness simply represent an imbalance in a shared system or whether the two are mediated by altogether different neurophysiological systems.

SYNDROMES OF SLEEPINESS The various etiologies of EDS may be divided into two broad categories. (1) Insufficient sleep is often a byproduct of sleep restriction, circadian rhythm disorders, and sleep disorders that produce sleep fragmentation (e.g., obstructive sleep apnea, periodic limb movement disorder, restless legs syndrome [RLS]). (2) Hypersomnias are characterized by primary hypersomnias such as narcolepsy and idiopathic hypersomnia, recurrent hypersomnias (e.g., Kleine–Levin and menstrualrelated hypersomnias), and hypersomnias associated with nervous system disorders. These etiologies and syndromes are discussed in the following section. EDS is also a symptom of numerous medical (e.g., hypothyroidism, chronic pain syndromes) and psychiatric (e.g., depression) conditions and disorders that are beyond the scope of this chapter.

Insufficient sleep Insufficient sleep in healthy, nonsleep-disordered individuals represents the most common cause of EDS. Sleep restriction may be self-imposed or socially dictated. Circadian rhythm sleep disorders, insomnia, and inadequate sleep hygiene (behaviors impacting sleep) may be a contributing factor. The underlying pathology is usually one of chronic partial sleep deprivation that overwhelms compensatory mechanisms for maintaining wakefulness.

*Correspondence to: Clete A. Kushida MD, PhD, Stanford Sleep Medicine Center, 450 Broadway Street, MC 5704, Pavilion C, 2nd Floor, Redwood City, CA 94063-5704, Tel: 650-723-6601, Fax: 650-721-3465, E-mail: [email protected]

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Circadian disorders Wakefulness and sleepiness are a delicate balance of multiple factors. The two-process model (Borbely, 1982) posits a balance between two opposing factors and is one way to conceptualize the dynamics of wakefulness and sleep regulation: the homeostatic factor (process S) is determined by the amount of time since the last sleep period (it rises during waking and declines during sleep), and the circadian factor (process C), which is independent of sleep and waking, varies with a 24-hour periodicity. The circadian clock is controlled by the suprachiasmatic nucleus and this nucleus, in turn, governs process C. A free-running circadian clock has a cycle greater than 24 hours but is environmentally entrained to the more socially acceptable 24-hour cycle. A disturbance in the balance between these two processes can result in sleepiness intruding upon activities where wakefulness is desired, and vice versa. A commonly seen form of circadian disorders is the delayed sleep-phase disorder. This is a condition in which the major sleep episode is delayed in relation to the desired sleep time. This typically results in symptoms of sleep-onset insomnia and/or difficulty awakening at the desired time, which manifests as EDS. Treatment for circadian sleep disorders relies mainly on phototherapy and the short-term use of hypnotics, such as zolpidem, zaleplon, and eszopiclone. Phototherapy, or light therapy, is the use of light exposure (e.g., sunlight, light boxes) at specific times to shift the circadian rhythms. In the case of delayed sleep-phase disorder, morning bright light exposure would induce an advance of the sleep phase, enabling the affected individual to become sleepier earlier at night. The use of exogenous melatonin is controversial in its ability to reset the circadian pacemaker and also raises questions of long-term safety.

INSOMNIA There are many different types of insomnia. For instance, insomnia can be the result of learned sleeppreventing associations (psychophysiological) or a presumed central nervous system (CNS)-mediated process by an as yet unidentified mechanism (idiopathic). Psychophysiological insomnia is a disorder where heightened arousal and conditioned sleep difficulty result in an inability to initiate and/or maintain sleep and decreased functioning during wakefulness. Idiopathic insomnia is a lifelong inability to obtain adequate sleep that may be due to an as yet undefined abnormality of the neurological control of the sleep– wake system. These two entities frequently overlap and some degree of abnormal circadian phase disturbance frequently accompanies insomnia as well.

The treatment of insomnia may involve such behavioral techniques (Chesson et al., 1999; Morin et al., 1999) as phototherapy, sleep restriction (limiting the amount of time in bed so that the time spent asleep is optimized), stimulus control therapy (eliminating sleep-hampering cues associated with wakefulness so that the bedroom environment is reassociated as a place to sleep), progressive muscle relaxation (systematically tensing and relaxing various muscle groups), cognitive–behavioral therapy (multipart treatment approach involving cognitive therapy that is used to correct a patient’s inaccurate attitudes or beliefs about sleep as well as sleep restriction, stimulus control, or progressive muscle relaxation), and the short-term use of hypnotic medications.

Hypersomnias due to sleep disorders OBSTRUCTIVE

SLEEP APNEA

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of complete or partial upper airway obstruction during sleep. The common presenting symptoms of OSA are excessive daytime sleepiness, snoring, and witnessed breathing pauses. In many cases of OSA, loud disruptive snoring has typically been present for many years, often since childhood, and may increase dramatically before the patient’s presentation. The snoring is usually loud enough at this point to disrupt the sleep of a bed partner. However, patients and their bed partners are typically unaware of the patient’s breathing pauses, frequent arousals, and countless brief awakenings that occur throughout the night. Patients may complain of disruption of sleep by choking or gasping sensations. Gastroesophageal reflux, nocturia, and reports of a dry mouth after sleep are common. Upon awaking, patients usually feel unrefreshed, and may complain of morning headaches as well as concentration and memory difficulties. EDS is most evident in relaxing situations (e.g., meetings, watching television), and naps can be more than an hour in duration yet still be unrefreshing because the abnormal breathing events may occur during naps as well. The consequences of excessive daytime sleepiness can be devastating, with the resultant loss of a job, relationship problems, and motor vehicle and work-related accidents. A misdiagnosis as depression, attention-deficit/ hyperactivity disorder (ADHD), or other medical or psychiatric disorders may also occur. Not surprisingly, patients with OSA often have worsening symptoms with increasing weight. Morbid obesity, however, is not the norm. In the absence of obesity, craniofacial abnormalities such as micrognathia, retrognathia, maxillomandibular malformation or adenotonsillar enlargement may be present.

EXCESSIVE DAYTIME SLEEPINESS 827 There is a continuum of sleep-related breathing disstereotyped, repetitive movements occur once asleep. turbances in the general population. Polysomnography These periodic limb movements (PLMs) usually occur reveals abnormal breathing events: apneas (complete in the legs and consist of extension of the big toe with or near-complete pauses in oronasal airflow), hypoppartial flexion of the ankle, knee, and hip. These may neas (decreased oronasal airflow), and/or respiratory be associated with partial arousals with subsequent effort-related arousals despite respiratory muscle sleep fragmentation. There can be marked nightly effort. Oxygen desaturation related to the breathing variability in the number of movements. abnormality typically occurs. Sleep-disordered breathPatients are frequently unaware of the movements ing, usually measured in terms of the respiratory disand often present with EDS, sleep-onset insomnia, turbance index or apnea–hypopnea index, is the or frequent nocturnal awakenings. It is vital to correcalculated number of abnormal breathing events per late the clinical history and objective (polysomhour of sleep. These abnormal breathing events are nographic) findings, as this can be an incidental often associated with fragmented sleep due to the frefinding without significant impact on the patient’s quent arousals or brief awakenings that typically folsleep. Periodic limb movements during sleep (PLMS) low these events. Sleep-related disturbances are thus have been reported to occur in 1–15% of patients extremely frequent, most typically in those complainwith insomnia, and the prevalence increases with age ing of sleepiness in addition to respiratory symptoms with observations of up to 34% of individuals over of sleep-disordered breathing. These polysomnographic the age of 60 years (American Academy of Sleep findings, combined with symptoms such as snoring, Medicine, 2005). breathing pauses, and EDS, are diagnostic for OSA. Polysomnography typically shows brief repetitive The prevalence of OSA in the general population is jerks in either or both of the lower limbs, lasting from approximately 2% for women and 4% for men (Young 0.5 to 10 seconds and repeating about every 5–90 secet al., 1993). It is most common in overweight, middleonds. PLMS are currently counted when four or more aged men and women, and a familial tendency for consecutive movements are present. The movements OSA has been postulated. OSA is characterized by are often reported as the periodic limb movement upper airway narrowing at one or more sites (Rama index (PLMI), or number of movements per hour of et al., 2002). The occurrence of increased effort of total sleep time. A PLMI of 15 or more in adults, combreathing and EDS with the frank absence of apneas bined with a clinical sleep disturbance or a complaint and hypopneas is seen in the upper airway resistance of daytime fatigue, is diagnostic for PLMD (American syndrome (Guilleminault et al., 1993). Academy of Sleep Medicine, 2005). Sleep-disordered breathing must be considered as an PLMD may be associated with or aggravated by a important cause or contributor to EDS. The detection of number of medical conditions, such as uremia and OSA is important not only to initiate proper treatment other metabolic disorders. Tricyclic antidepressants, but also because sleep-disordered breathing is an selective serotonin reuptake inhibitors, and monoamine increasingly recognized risk factor for hypertension oxidase inhibitors can also induce or aggravate PLMD, and cardiovascular events. Interestingly, OSA has also as well as alcohol, caffeine, and stimulant medication. been reported to increase after numerous CNS insults, Withdrawal from a variety of medications such as for example head trauma, stroke, and Alzheimer’s disanticonvulsants, benzodiazepines, barbiturates, and ease, and may be present in pathologies with impaired other hypnotic agents may also induce or aggravate neuromuscular function (e.g., myotonic dystrophy). the condition. PLMD should be differentiated from Treatment of OSA consists of nasal positive airway nocturnal seizures as well as myoclonic epilepsy and pressure (PAP) therapy (Gay et al., 2006; Kushida other neurological conditions, such as waking myocloet al., 2006a), upper airway surgery (to correct or minnus associated with dementia. PLMD must also be imize anatomical defects) (Sher et al., 1996; Thorpy differentiated from simple PLMs. Indeed, PLMs as a et al., 1996), or oral appliances (that advance either polysomographic finding are frequently observed in the tongue or the mandible, thereby widening the the general population but not thought to have clinical airway) (Ferguson et al., 2006; Kushida et al., 2006b). consequences, unless they are associated with dayAdjunctive therapy for OSA may include weight loss time symptoms and meet the criteria for PLMD. and behavioral modification (e.g., sleeping in a nonInterestingly, however, isolated PLMs may have daysupine position). time consequences in children, and PLMS may be particularly common in children with ADHD (Hening PERIODIC LIMB MOVEMENT DISORDER et al., 2004). Originally called “nocturnal myoclonus”, periodic limb Treatment modalities for both PLMD and RLS are movement disorder (PLMD) is a condition in which similar, and are discussed in the next section.

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M. MAHMOOD AND C.A. KUSHIDA risk compared with the general population prevalence RESTLESS LEGS SYNDROME (American Academy of Sleep Medicine, 2005). NarcoRLS is characterized by an often indescribable urge to lepsy most commonly begins in the second decade, move with an unpleasant feeling in the legs, typically with EDS the first symptom to appear, followed by occurring at rest, temporarily improving with movecataplexy. ments, and worsening later in the evening or night. The EDS observed in narcolepsy can be characterThe dysesthesia may be described as “pins and neeized by a background of chronic sleepiness throughout dles”, “an itch”, “creeping or crawling”, or may simply the day punctuated by irresistible episodes of sleep, be an indescribable sensation that causes the sufferer colloquially referred to as “sleep attacks”. The typical to move the legs. Partial or complete relief of the narcoleptic will usually fall asleep in inactive settings sensations are obtained with vigorous muscle activity, (e.g., in a lecture, at a movie), sleep for a short duratypically movement, flexing, stretching, and crossing tion (typically 10–20 minutes). and awaken feeling the legs. Sensations usually occur bilaterally and rarely refreshed. However, after a few hours, the individual affect the arms. Symptoms are typically present at rest begins to feel sleepy once again and the pattern repeats especially just prior to the patient’s sleep period, but itself. The sleep attacks may occur in situations where may present at any time with prolonged inactivity one would normally not fall asleep, such as interactive (e.g., driving, sitting in a theater). The decreased alertconversation, while eating, and even during interness and emotional distress of RLS appear to be seccourse. Many narcoleptics also experience disrupted ondary to the sleep disturbance associated with RLS nighttime sleep with frequent awakenings as well, (Kushida et al., 2004). further contributing to EDS. RLS can be associated with anemia, uremia, pregCataplexy is a feature unique to narcolepsy. It is nancy, and rheumatoid arthritis. Many patients with characterized by a sudden loss of bilateral postural RLS show PLMD as well. The prevalence is 5–15% in muscle tone provoked by strong emotion, typically posthe general population. Similar to PLMD, it typically itive (e.g., laughter, elation), although negative emoappears in middle age. There appears to be a familial tions less commonly provoke cataplexy as well. pattern, with an apparent autosomal dominant pattern Consciousness remains intact, memory of the event is seen in some families. The pathophysiology of RLS complete, and respiration undisturbed. Duration is typis still unknown but is thought to involve a brain ically a few seconds to a few minutes, and complete, dopamine–iron connection. Severity ranges from an immediate recovery is the norm. The degree of muscle occasional event to daily, excruciating symptoms. tone lost is variable, ranging from a mild sensation of Symptomatic treatment using dopaminergic agoweakness, head droop, facial sagging, jaw drop, and nists (e.g., ropinirole, pramipexole) is effective in slurred speech, to buckling of the knees and collapse 70% or more cases. Levodopa or other dopaminergic to the ground. Patients often learn to avoid conditions agents (Hening et al., 2004; Littner et al., 2004), benzothat provoke cataplexy. diazepines, opiates, and certain antiepileptic medicaHypnagogic hallucinations are vivid sensations occurtions (e.g., gabapentin) have all been used with ring at sleep onset. They may be visual, auditory, tactile, variable degrees of benefit. Monitoring of the blood or kinetic phenomena. Hallucinations may involve a ferritin level should be considered, and, even if modersensation of someone or something in the room, and freately low, iron supplementation may be beneficial for quently are frightening. Sleep paralysis typically precases of RLS associated with iron deficiency. sents during the transition from sleep to wakefulness as a transient, generalized inability to move or speak. Hypersomnias of central origin This can last from seconds to several minutes, and often occurs with hypnagogic hallucinations, exacerbating the NARCOLEPSY psychological distress of the experience. The narcolepsy tetrad consists of excessive sleepiness, The Multiple Sleep Latency Test (MSLT) (Arand cataplexy, sleep paralysis, and hypnagogic hallucinaet al., 2005; Littner et al., 2005) provides an objective tions. Disturbed nocturnal sleep is also typically presmeasure of EDS and documents the presence of sleepent. Narcolepsy is considered to be a disorder where onset rapid eye movement periods (SOREMPs), which normal sleep and wakefulness boundaries are impaired are the hallmark of narcolepsy. For the MSLT results so that features of sleep intrude into wakefulness, and to be valid, an overnight polysomnogram the night prior vice versa. to the test is recommended to rule out EDS resulting Narcolepsy with cataplexy is estimated to occur in from or associated with sleep apnea, dramatically 0.02–0.18% of US and western European populations, reduced nocturnal sleep (sleep restriction or deprivaand first-degree relatives are at 10 to 40 times greater tion), or any other sleep disorder that could account

EXCESSIVE DAYTIME SLEEPINESS for the degree of EDS observed. Medications that influence sleep, such as stimulants and antidepressants, can also be confounding factors and should be eliminated or washed out prior to the MSLT (Littner et al., 2005). During overnight polysomnography, narcoleptics commonly show a short sleep latency (usually less than 10 minutes) and a SOREMP, in which rapid eye movement (REM) occurs within 15 minutes of sleep onset. There may also be frequent awakenings. The MSLT of a narcoleptic typically shows a mean sleep latency of 8 minutes or less, and two or more SOREMPs (American Academy of Sleep Medicine, 2005). Human leukocyte antigen (HLA) analysis provided one of the first clues to the genetic nature of narcolepsy, with the biomarker HLA DQB1*0602 associated with narcolepsy across all ethnic groups. Almost all patients with cataplexy are positive for this marker; the absence of this HLA marker should prompt one to question the diagnosis of narcolepsy with cataplexy. Recent studies have uncovered the cause of narcolepsy with cataplexy, demonstrating the absence or profoundly decreased production of hypocretin/orexin as measured in the cerebrospinal fluid (CSF) of patients with narcolepsy with cataplexy. Hypocretin/orexin is a wake-promoting, excitatory neuropeptide produced by hypothalamic neurons. These neurons are destroyed in the brains of patients with narcolepsy–cataplexy, possibly as a result of an autoimmune process. Measurement of CSF hypocretin-1 is highly specific and sensitive for narcolepsy with cataplexy, although issues of standardization still remain. Importantly, most subjects with narcolepsy without cataplexy have normal CSF hypocretin-1 levels, suggesting that the pathophysiology of narcolepsy without cataplexy may be different from that of narcolepsy with cataplexy. The HLA association is also weaker in those without cataplexy, suggesting disease heterogeneity. Treatment typically consists of stimulant therapy, such as modafinil, armodafinil, methylphenidate, or dextroamfetamine, and anticataplectic medication, such as tricyclic antidepressants. Those with narcolepsy typically live on a metaphorical double-edged sword, because too much stimulation may induce cataplexy, whereas not enough may provoke EDS or sleep attacks. However, newer medications, such as sodium oxybate, may offer better treatment options for those afflicted with this debilitating condition.

IDIOPATHIC

HYPERSOMNIA

In cases where sleepiness is very pronounced but not explained by narcolepsy (no cataplexy and no SOREMPs during the MSLT), idiopathic hypersomnia should be considered. Two types of idiopathic

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hypersomnia are typically distinguished, depending on the amount of sleep time. In the first, idiopathic hypersomnia with prolonged sleep time, sleepiness is extreme and the patient typically sleeps for more than 10 hours but still feels sleepy. It is a true hypersomnia in the sense that 24-hour sleep amounts are genuinely increased. This condition is rare and must be distinguished from causes of recurrent hypersomnia such as Kleine–Levin syndrome, which is discussed in the next section. In the second and more common type of hypersomnia, sleep amounts are normal (e.g., 8–9 hours per night) but the patient still complains of sleepiness. The daytime sleepiness is documented by an abnormal mean sleep latency during the MSLT, but the patient does not meet criteria for narcolepsy with or without cataplexy as two or more SOREMPs are not observed. One of the most difficult aspects in the diagnosis of these entities is the frequent presence of concomitant pathologies. For example, narcolepsy may occur in a patient with OSA. A refractory insomnia may also be present, making PAP therapy difficult to tolerate. Similarly, the diagnosis of idiopathic hypersomnia without long sleep time or of narcolepsy without cataplexy can be made in a patient with obstructive sleep apnea, but only once the sleep apnea has been adequately controlled, most typically with PAP. Similarly, associated psychiatric conditions can be involved; without a sleep evaluation, it is often difficult to differentiate hypersomnia with prolonged sleep time from cases of depression. Similarly, narcolepsy can also be confused or associated with depression or schizophrenia (if hypnagogic hallucinations are prominent). Some of these complex cases present formidable therapeutic and diagnostic challenges. Indeed, the clinician is often slowly drawn into using drugs with abuse potential, such as methylphenidate or dextroamphetamine, with variable results. Establishing an accurate diagnosis is therefore paramount.

KLEINE–LEVIN

SYNDROME

This rare disorder is a form of recurrent hypersomnia that occurs primarily in adolescents, with a male predominance. It is characterized by the occurrence of episodes of EDS, usually accompanied by hyperphagia, aggressiveness, and hypersexuality. These episodes last days to weeks and are separated by asymptomatic periods of weeks to months. During symptomatic periods, individuals sleep up to 18 hours per day and are usually still drowsy (often stuporous), and frequently confused and irritable the remainder of the time. Polysomnography during symptomatic periods show a long total sleep time with a high sleep efficiency (increased time

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spent asleep while in bed) and decreased deep slowwave sleep. The MSLT typically shows a short mean sleep latency and occasionally SOREMPs. The etiology of this condition is still unknown. Most cases are idiopathic, although associated structural brain lesions have been reported, and SPECT studies have shown hypoperfusion in both thalami in patients during the symptomatic period (Huang et al., 2005). Treatment with stimulant medication is usually only partially effective. Treatment with lithium, valproate, or carbamazepine have been variable, but generally unsatisfactory. Fortunately, in most cases, episodes become less frequent over time and eventually subside.

Menstrual-related hypersomnia This represents another form of recurrent hypersomnia in which EDS occurs during the several days prior to menstruation. The prevalence of this syndrome is unknown. The etiology, similarly, is unknown, but presumably the symptoms are related to hormonal changes, as the condition occurs within the first months after menarche and in association with the menstrual cycle. This condition typically shows a good response to the blocking of ovulation with estrogen and progestogen.

Hypersomnias associated with nervous system disorders EDS is often associated with disorders of the nervous system, central or peripheral. It is seen in many toxic or metabolic encephalopathies as well as structural brain lesions (e.g., strokes, tumors, vascular malformations, hydrocephalus, and multiple sclerosis). These disorders often present with other signs and symptoms, but EDS may dominate the clinical picture, especially in chronic disease states. EDS may result from direct involvement of discrete brain regions involved in normal sleep generation and regulation, or because of effects on sleep continuity (e.g., nocturnal seizures). Encephalitis or head trauma frequently results in EDS, historically described by Von Economo as suffering from “encephalitis lethargica” and found to have lesions of the midbrain, subthalamus, or hypothalamus. Posttraumatic narcolepsy with cataplexy has also been described. Infectious agents have also been implicated in producing EDS by affecting the CNS. The best known is the “sleeping sickness” caused by trypanosomiasis owing to the prominent hypersomnia. Sleepiness may occur with acute infectious illness, even without direct invasion of the nervous system. Such effects are likely mediated by cytokines, including interferon, interleukins, and tumor necrosis factor. EDS may also persist chronically after certain viral infections.

Neurodegenerative disorders commonly result in sleep disruption and EDS. This is seen in Parkinson’s disease, multiple system atrophy, Alzheimer’s disease, and other dementias. Patients with neuromuscular disorders or peripheral neuropathies commonly complain of EDS, likely due to associated sleep-related breathing disorders (SRBDs), pain or PLMD. Patients with myotonic dystrophy often suffer from EDS, even in the absence of SRBDs.

CONCLUSIONS EDS is a prevalent, if not growing, problem in modern society and is reflected in its growing predominance in patients seen in clinical practice. The costs to society as well as to the individual can be great, reflected in lost productivity, memory, and concentration as well as growing evidence of health effects, both accident related as well as an increased risk for chronic, lifethreatening illnesses. Several syndromes of EDS have been identified, and the diagnosis of these syndromes may sometimes be difficult without evaluation by a sleep specialist. Treatment options are available for the majority of patients. The causes of EDS are numerous and a thorough evaluation is necessary to determine the etiology in an individual case. The recent phenomenal progress in the pathophysiology of narcolepsy is promising, but provides just a glimpse into the work that needs to be done to understand the other primary causes of EDS.

REFERENCES American Academy of Sleep Medicine (2005). ICSD-2 – International Classification of Sleep Disorders. 2nd edn. Diagnostic and Coding Manual. American Academy of Sleep Medicine, Westchester, IL. Arand D, Bonnet M, Hurwitz T et al. (2005). The clinical use of the MSLT and MWT. Sleep 28: 123–144. Borbely AA (1982). A two process model of sleep regulation. Hum Neurobiol 1: 195–204. Chesson AL Jr., Anderson WM, Littner M et al. (1999). Practice parameters for the nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep 22: 1128–1133. Ferguson KA, Cartwright R, Rogers R et al. (2006). Oral appliances for snoring and obstructive sleep apnea: a review. Sleep 29: 244–262. Gay P, Weaver T, Loube D et al. (2006). Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults. Sleep 29: 381–401. Guilleminault C, Stoohs R, Clerk A et al. (1993). A cause of excessive daytime sleepiness. The upper airway resistance syndrome. Chest 104: 781–787.

EXCESSIVE DAYTIME SLEEPINESS Hening WA, Allen RP, Earley CJ et al. (2004). An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 27: 560–583. Huang YS, Guilleminault C, Kao PF et al. (2005). SPECT findings in the Kleine–Levin syndrome. Sleep 28: 955–960. Kushida CA, Allen RP, Atkinson MJ (2004). Modeling the causal relationships between symptoms associated with restless legs syndrome and the patient-reported impact of RLS. Sleep Med 5: 485–488. Kushida CA, Littner MR, Hirshkowitz M et al. (2006a). Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders. Sleep 29: 375–380. Kushida CA, Morgenthaler TI, Littner MR et al. (2006b). Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances: an update for 2005. Sleep 29: 240–243. Littner MR, Kushida C, Anderson WM et al. (2004). Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 27: 557–559.

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Littner MR, Kushida C, Wise M et al. (2005). Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 28: 113–121. Morin CM, Hauri PJ, Espie CA et al. (1999). Nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine review. Sleep 22: 1134–1156. Rama AN, Tekwani SH, Kushida CA (2002). Sites of obstruction in obstructive sleep apnea. Chest 122: 1139–1147. Sher AE, Schechtman KB, Piccirillo JF (1996). The efficacy of surgical modifications of the upper airway in adults with obstructive sleep apnea syndrome. Sleep 19: 156–177. Thorpy M, Chesson A, Derderian S et al. (1996). Practice parameters for the treatment of obstructive sleep apnea in adults: the efficacy of surgical modifications of the upper airway. Report of the American Sleep Disorders Association. Sleep 19: 152–155. Young T, Palta M, Dempsey J et al. (1993). The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 328: 1230–1235.

Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 51

Motor control in sleep ADRIAN R. MORRISON * Laboratory for Study of the Brain in Sleep, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

INTRODUCTION Two important findings in the 1950s inspired researchers to investigate the neural systems that might be responsible for the overt inactivity of the sleeping individual: the recognition of rapid eye movement (REM) sleep by Aserinsky and Keitman (1953) and then the demonstration by Jouvet and Michel (1959) that during REM or sleep the skeletal muscles are atonic. These two discoveries initiated the intense interest in sleep research that continues to this day. Cessation of movement, reduction of muscle tone, and, periodically, striated muscle atonia interrupted by irregularly occurring twitches are cardinal signs of sleep in all land mammals, including human beings. This progression parallels the changes in the electroencephalogram (EEG) as an individual becomes drowsy and then progresses through the various stages of nonrapid eye movement (NREM) sleep and, finally, the “paralytic” state of REM sleep with its periodic myoclonic twitches. We will see that the motoric changes at sleep onset are relatively “gentle” and that those occurring at REM onset are quite dramatic. The latter involve multiple systems, and the net results are a combination of disfacilitation, active inhibition, and excitatory barrages emanating from the lower brainstem, which operates on the final common pathway – the spinal motor neuron (Sherrington, 1906). Chase and Morales (1990, p. 560) characterize the nervous system during REM sleep quite poetically, saying that the “underlying motor control landscape is actually ravished by storms of inhibition and brief whirlwinds of excitation directed toward ‘the final common pathway,’ the somatic motor neuron”.

A brief chapter on the fascinating and complex subject of motor control during sleep, particularly REM sleep, cannot do justice to the subject. Fortunately, there are more thorough reviews. For the years from the ancients up to 1966, one can find all included in the two compendia written by Gottesmann (2001, 2005). The later years including those reasonably close to the present have been covered by Steriade and McCarley (2005), Chase (2005), and Siegel (2005).

THE ACTIVE ONSET OF MOTOR SUPPRESSION IN SLEEP Prior to the discovery of REM sleep, the relatively few who studied sleep saw its onset as a passive process, the result of a withdrawal of the excitation of the brain from without and within the body. Indeed, Kleitman is famous for saying that wakefulness, not sleep, had to be explained (Moruzzi, 1964). The cerveau isol preparation of Bremer (1935), which resulted in a forebrain with an unchanging slow-wave pattern in the EEG reminiscent of sleep, reinforced such thinking beginning with the ancients (Moruzzi, 1964). The discovery of the activating role played by the reticular formation (Moruzzi and Magoun, 1949) merely shifted that emphasis from passive removal of sensory inputs via specific sensory pathways to the reticular formation as the major player in a still basically passive process. Only the discovery of REM sleep would alter this view. However, even from the beginning of interest in sleep processes, there was behavioral evidence that entering sleep could not be passive. Normal individuals do not simply collapse in place, suddenly withdrawing

*Correspondence to: Adrian R. Morrison, D.V.M., Ph.D., Professor Emeritus of Behavioral Neuroscience, Laboratory for Study of the Brain in Sleep, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6045, USA. Tel: 215-898-8891, Fax: 215-573-2004, E-mail: [email protected]

836 A.R. MORRISON from the conscious world. All land mammals, includsleep in normal individuals (Jouvet, 1962; Villablanca, ing people, seek a place to sleep: a den, a fork in a tree, 1966). Eye movements could occur because the sixth or a bed, to name three. They then lie down and nerve nucleus remains intact caudal to the transection. close their eyes – most that is. Horses usually enter According to one of those who studied this preparaNREM sleep while standing, thanks to structural feation, the decerebrate cat in REM sleep could not be tures in their limbs that permit them to stand with distinguished from a normal cat by a naive observer almost no muscular effort: only during relatively infre(Villablanca, 1968). After such an episode, a refractory quent periods of repose do they experience the atonia period ensued regarding elements of REM sleep other of REM sleep (Ruckebusch et al., 1970; Morrison, than atonia. However, a transection caudal to the pons 2003). Note, then, that all the acts I have described eliminated these episodes of flaccidity (Jouvet, 1962). are active motoric processes. They represent the appeThese observations demonstrated two important things: titive phase of an instinctual behavior, sleep being the the peripheral expressions of REM sleep are organized consummatory phase, as both Parmeggiani (1962, in the lower brainstem, and structures in the pons are 1968) and Moruzzi (1969) have discussed in so many necessary for its expression. words. Pompeiano’s laboratory in Pisa, Italy, again using Neither the Nobel Laureate Hess (Parmeggiani, cats as experimental subjects, then made major con1962), who had shown that electrical stimulation in tributions to early understanding of motor control the thalamus could elicit a variety of behaviors, includ(Pompeiano, 1970). He and his coworkers first asked ing sleep, nor his student, Parmeggiani, believed that whether suppression of motor neuronal activity during sleep was a merely passive process (P. L. Parmeggiani, REM sleep was active or passive. A logical structure to personal communication). For example, Parmeggiani investigate was the lateral vestibular (Deiter’s) nucleus, (1962) demonstrated that electrical stimulation of the because it innervates the axial and extensor motor hippocampus and caudate nucleus elicited preparative neurons. Depression in firing rate during different motor acts in the awake cat, such as yawning, groomsleep states would have indicated that disfacilitation ing, and curling up, which were not directly assoof the motor neurons was a contributing factor. In ciated with signs of drowsiness (hippocampus), and fact, these neurons decreased their firing rates somemotor inhibition (caudate nucleus) that could termiwhat only on passing from quiet wakefulness (QW) nate in the consummation of NREM sleep. Sterman to NREM sleep and then did not change when the aniand Clemente (1962) later demonstrated that stimulamal entered REM sleep (Bizzi et al., 1964). This study tion more rostrally in the basal forebrain with both ruled out that simple disfacilitation, at least that low and high frequencies induced EEG slow waves related to firing of Deiter’s nucleus neurons, was not and almost immediate full behavioral manifestathe cause of muscle atonia. The same study revealed tions of NREM sleep. Thus, active brain mechanisms that neurons in the medial and descending nuclei are associated with the organized arrest of motor increased their rate of discharge during bursts of activity and sleep, although it must be granted that a REMs, which was the first indication that these nuclei certain amount of reticular formation deactivation is might be critical for their generation. Indeed, a later required to set the stage for the onset of sleep itself study revealed that bilateral lesions of the medial and (Moruzzi, 1969). descending vestibular nuclei abolished the REMs of REM sleep (Pompeiano and Morrison, 1965). In a later investigation by Morrison and Pompeiano EARLY STUDIES OF REM SLEEP (1965a), direct electrical stimulation of the lumbar motor MOTOR CONTROL neuronal pool with a constant intensity revealed little Following the major discoveries by Aserinsky and change in the amplitudes of the efferent nerve impulses Kleitman, and Jouvet and Michel, a flurry of reports recorded from hind-limb nerves during NREM sleep, of investigations into the neural substrates underlying but then a profound diminution appeared during the the remarkable atonia of REM sleep appeared in the ensuing REM sleep period. Using a different extracellu1960s. (In reading the experimental literature one will lar approach, Kubota and Kidokoro (1965) reached simalso see the terms “paradoxical sleep”, “desynchroilar conclusions; however, these workers could suggest nized sleep” and “active sleep”.) First came the imporonly that an active inhibitory mechanism might be at tant discovery that transections between the midbrain work. Proof of active inhibition awaited the developand pons of cats led to periods in which the extensor ment of a technique for chronic intracellular recording, rigidity of the decerebrate waned to flaccidity, coupled which revealed that the motor neuronal membrane was with the appearance of the twitches of the digits, REMs, hyperpolarized during REM sleep (Figure 51.1) (Glenn and the pontine waves that are observed during REM et al., 1978; Morales and Chase, 1978).

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Fig. 51.1. Intracellular recording from a trigeminal jaw-closer motor neuron: correlation of membrane potential and state changes. The membrane potential hyperpolarized rather abruptly at 3.5 min in conjunction with the decrease in neck muscle tone and transition from quiet to active sleep. At 12.5 min, the membrane depolarized and the animal awakened. After the animal passed into quiet sleep again, a brief, aborted episode of active sleep occurred at 25.5 min that was accompanied by a phasic period of hyperpolarization. A minute later, the animal once again entered active sleep, and the membrane potential hyperpolarized. EEG trace, marginal cortex, membrane potential band pass on polygraphic record, direct current to 0.1 Hz. EEG, electroencephalogram; EMG, electromyogram; EOG, electro-oculogram; PGO, pontogeniculo-occipital potential. Figure and legend reprinted with permission from Chase et al. (1980). #American Physiological Society.

THE MOTOR NEURON IN SLEEP A decrease in spinal motor neuronal activity is necessary, of course, for the hypotonia and atonia of sleep. One can see from Figure 51.1 that the motor neuronal membrane changes only slightly in NREM sleep but rapidly hyperpolarizes at the transition from NREM to REM sleep (Chase et al., 1980). Spontaneous inhibitory postsynaptic potentials (IPSPs) occur occasionally in QW and NREM sleep, but they are far more numerous during REM sleep. In addition, much larger IPSPs with a longer time course appear only in REM sleep (Chase and Morales, 1983; Morales et al., 1987a). The intervals between IPSPs in REM sleep are significantly shorter than those in both QW and NREM sleep. Thus, the large, REM sleep-specific IPSPs are undoubtedly the source of the atonia of REM sleep. Brief excitatory neural volleys during REM sleep occur seemingly randomly and without “purpose”, inducing a brief hyperpolarization followed by a

depolarization and the generation of an action potential. These excitatory events differ from those occurring in active wakefulness (AW), when there is a gradual depolarization of the membrane leading to the action potential (Chase and Morales, 1983). The muscle twitches, or myoclonic jerks, are the result of these volleys, and they occur paradoxically in association with the phasic hyperpolarizations. Gassel et al. (1964) made various partial sections of the spinal cord, which revealed that fibers descending in the dorsolateral funiculus were responsible for the phasic discharges and that the sources were not the pyramidal or rubrospinal tracts because destruction of either does not affect the twitches (Pompeiano, 1970). Rather, facilitatory reticulospinal fibers were a possibility, although hemisection of the cord abolished the twitches almost completely; however, the reticulospinal pathway is bilateral, leaving the probable brainstem origin of the excitatory volleys as an uncertainty. Dorsal root sections ruled out the possibility that the myoclonic jerks depend

838 A.R. MORRISON on g-motor neurons: the excitatory volleys act directly THE CAUDAL BRAINSTEM: ORGANIZER on a-motor neurons. OF MOTOR CONTROL IN REM SLEEP Regarding the inhibitory transmitter responsible for As the decerebration experiments revealed, the brainstem the motor neuronal membrane hyperpolarization, glysystems generating profound inhibition of spinal motor cine rather than g-aminobutyric acid (GABA) had been neurons originate in the pons; they are multiple, and established in studies of acute preparations to be the they relay in nuclei in the medulla, nucleus paramedianus major inhibitory substance acting on the motor neurons (NPM), and NMC. These two nuclei contain neurons with (Chase and Morales, 1990). Glycine was, therefore, the receptors for acetylcholine and glutamate, respectively obvious candidate operating in the sleeping cat. Using (Figure 51.2). (For detailed reviews see Siegel and Lai microiontophoresis juxtaposed to the neuronal mem(1994) and Lai and Siegel (1999).) Magoun and Rhines brane, Chase et al. (1989) found that strychnine, which (1946) first demonstrated that unilateral electrical stimuantagonizes glycine, blocked the IPSPs, whereas picrolation of the medial medulla induced bilateral supprestoxin, an antagonist of GABA, did not. Whether the sion of spinal reflexes in a nonreciprocal fashion, which glycinergic inhibition stems from local glycinergic was unusual. It was a finding that awaited the discovery interneurons and/or from the glycinergic neurons proof REM sleep with complete collapse of muscle tone to jecting from nucleus magnocellularis (NMC) to the spiplace it in a normal biological context. nal interneurons (Holstege and Kuypers, 1987) remains Years later this region remains the most important an open question. However, trigeminal motor neurons immediate source for the brainstem suppression of spiare definitely inhibited by glycinergic neurons located nal motor neurons, as several workers have recorded in NMC and the adjoining gigantocelluar reticular REM-ON neurons in the medulla (Siegel and Lai, nucleus (Morales et al., 1999). 1994). Of particular interest, Siegel et al. (1979) discovSpinal reflexes are essentially abolished during ered that, unlike the vast majority of the medullary and REM sleep but only depressed during NREM sleep. pontine neurons active in REM sleep and silent in AW, Hodes and Dement (1964) and Hishikawa et al. (1965) many in the medulla increased their discharge in QW in established this for humans by studying the electrically association with reduced muscle tone. Siegel and Lai elicited H-reflex in the leg and hyoid muscles respec(1994, p. 62) argue that “these cells may therefore tively. Pompeiano and colleagues performed a series mediate reductions in tone in waking and slow wave of studies in cats demonstrating that both monosynapsleep, in addition to the abolition of tone in REM sleep”. tic and polysynaptic reflexes followed a similar patThis proposal is quite reasonable, for the mechanisms tern: lower amplitudes in NREM sleep compared with regulating motor activity must be organized in a way QW and abolition of the reflexes during REM sleep that is not all-or-none during W (wakefulness). (Pompeiano, 1970). During bursts of REMs, though, a Cholinergic neurons lie dorsally at the pontine– further diminution in the reflex amplitudes was mesencephalic border, largely in the laterodorsalis observed. and pedunculopontine nuclei (Lydic and Baghdoyan, The early work based on direct electrical stimulation 2005). Their axons terminate in the pontine inhibitory of lumbar motor neuron pools (Kubota and Kidokoro, area (PIA) where they encounter cholinoceptive neu1965; Morrison and Pompeiano, 1965a) indicated that rons there (Mitani et al., 1988) as well as in NPM (see phasic inhibition of motor neurons did not occur durFigure 51.2). Lai and Siegel (1999) define the PIA as ing bursts of REMs when the reflexes were further the nucleus pontis oralis (NPO) and the rostral portion depressed. Further experiments suggested that the phaof the nucleus pontis caudalis. Electrical stimulation in sic suppressions of reflexes were the consequence of PIA has induced bilateral reflex suppression (Sprague presynaptic inhibition of primary afferents, which et al., 1948) and muscle tone suppression in the neck would reduce the excitatory level of the motor neuro(Lai and Siegel, 1999) and hind limbs (Iwakiri et al., nal membrane (Morrison and Pompeiano, 1965b, 1994) of decerebrate cats. Many workers (Chase, 1965c; Baldissera et al., 1996). This view had to be 2005; Lydic and Baghdoyan, 2005) have induced modified, though, after the refinement of intracellular REM sleep or one of its components, including atonia, recording from motor neurons during natural sleep. by injections of the cholinergic agonist, carbachol, in Morales and Chase (1981) revealed that in addition to some part of the PIA. Morales et al. (1987b) further the tonic hyperpolarization during REM sleep the brief demonstrated that the various features of carbacholadditional hyperpolarizations contributed to the reflex induced atonia recorded at the motor neuronal level suppressions. Thus, their study demonstrated the operin intact cats were also present in decerebrate cats. This ation of postsynaptic as well as presynaptic mechanfinding obviously opened the way for more convenient isms that only chronic intracellular recording could and less stressful studies of atonia. reveal.

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Fig. 51.2. Model of the circuit producing atonia in rapid eye movement (REM) sleep and cataplexy. Sagittal view of the brainstem of the cat, with pontomedullary areas, transmitters, and pathways implicated in atonia. The model depicts two possible sources of glycine for motoneuronal hyperpolarization: a direct glycinergic medullospinal projection and a glycinergic spinal interneuron. AMG, amygdala; CRF, corticotropin releasing factor; IO, inferior olive; LC, locus coeruleus; NMC, nucleus magnocellularis; NPM, nucleus paramedianus; PPN, pedunculopontine nucleus; RRN, retrorubral nucleus; TH, thalamus. Figure and modified legend reprinted with permission from Siegel and Lai (1994).

A number of workers have found glutamatergic neurons in association with the cholinergic neurons and in the retrorubral nucleus (RRN) (cf. Rye, 1997). As demonstrated in Figure 51.2, these neurons contribute to the inhibition of the motor neurons via their connection with neurons with glutamate receptors in NMC. Corticotropin releasing factor (CRF) is also effective in inducing atonia comparable to that induced by acetylcholine and glutamate (Siegel and Lai, 1994). Rye (1997) adds: “Given that many nocturnal movements, including those in REM sleep, are responsive to dopamine, it is tempting to hypothesize that a subpopulation of dopamine responsive neurons in the PPN [pedunculopontine nucleus] region innervate a ventral medullary region widely recognized to modulate atonia, particularly atonia that accompanies REM sleep”. At the motor neuronal level a glutamatergic substance acts sporadically to depolarize motor neurons, thereby causing the muscle twitches that briefly override REM sleep atonia (Soja et al., 1988). Another group of neurons that play a role in motor control, again primarily in REM sleep, are the noradrenergic neurons of the locus coeruleus (LC), which is found in the dorsolateral pons (see Figure 51.2). These cells, together with their monoaminergic cousins, the

serotonergic neurons in the raphe nuclei (not illustrated), which extend from the caudal midbrain to the caudal medulla, were early candidates for a significant role in sleep regulation. Because they are silent in REM sleep, they had early been assigned a “permissive” role in allowing REM sleep onset. Further work has demonstrated that there is a more specific function associated with motor control. LC neurons disperse their axons widely in the brain, including the spinal motor neuronal pools (Proudfit and Clark, 1991). They have the interesting property of gradually decreasing their discharge from W through NREM to REM sleep when they fall essentially silent (Steriade and McCarley, 2005), and the silent LC neurons then begin firing just prior to return of muscle tone as the animal emerges from REM sleep (Sakai, 1980). During cataplexy in narcoleptic dogs, those neurons in LC that are REM-OFF are also silent during cataplectic attacks (Wu et al., 1999). Noradrenergic neurons contribute to atonia, then, by withdrawal of input rather than active inhibition. Serotonergic raphe neurons gradually decrease their firing rates in passing from W to NREM to REM sleep (McGinty et al., 1973; Trulson and Jacobs, 1979). Jacobs and colleagues (2002) have amassed evidence that the primary role of serotonergic neurons of the caudal

840 A.R. MORRISON brainstem raphe nuclei is motor control. The REM The model encompasses data that demonstrate that sleep without atonia phenomenon (see below), during during active sleep the medullary neurons are selecwhich organized behavior replaces the usual atonia of tively activated via a neuronal projection from the REM sleep, provided the first clue. In cats with pontine NPO (Sakai et al., 1979; Chase et al., 1981, 1984). As lesions, normally silent neurons of the dorsal raphe the activity of NPO neurons increases during active nucleus (DRN) resumed activity during REM sleep sleep, a subsequent increase in the activity of medullary without atonia (Trulson et al., 1981). Additional experineurons leads to the monosynaptic glycinergic postsynments revealed that the increase was related to degree aptic inhibition of spinal cord motor neurons (M. H. of tone and movement, not level of arousal, because Chase, personal communication, 2005). DRN neurons were silent in cats made cataplectic by pontine carbachol injection (Steinfels et al., 1983). FOREBRAIN MODULATION These cats were determined to be awake, however, Of course, neurons situated more rostrally to the pons because they were responsive to visual threat. A cenmust play a role in modulating the caudal brainstem trally active muscle relaxant also silenced the DRN inhibitory areas. Workers tended to ignore this obvious neurons, but neuromuscular blockade did not. The fact in the 1960s and 1970s, though, when they focused same held true for pallidus and obscurus neurons. This their attention on the pons as the site of REM sleep suggests that it is not movement or proprioceptive generation. This focus was natural, however, given feedback that drives the raphe but a message received the results of the decerebration studies, and the intenfrom the central motor command system. sity of the exploration of the caudal brainstem led to Those nuclei projecting to the spinal cord, the nuclei major advances. Nevertheless, Morrison and Reiner raphe obscurus and pallidus, fire during waking motor (1985) reasoned that, because the decerebrate cat is activity, such as when a cat is locomoting on a moving not a normal animal, forebrain structures had to be a treadmill (Veasey et al., 1995), whereas a subset of DRN part of the normal REM sleep-generating process. cells fires in association with repetitive movements such After all, REM sleep always follows NREM sleep in as grooming (Fornal et al., 1996). With much additional intact individuals, and a very striking and important supporting evidence, Jacobs et al. (2002, p. 51) conevent must occur at the NREM–REM transition: a supcluded: “The primary function of this increased 5-HT pression of the normal hypothalamic control of homeoneuronal activity in association with tonic and repetitive stasis (Parmeggiani, 1980). motor output is to coordinate autonomic and neuroenFor example, cats are essentially poikilothermic durdocrine function in association with the existing motor ing REM sleep. Warming the hypothalamus to a level demand, and to suppress activity in most sensory inforthat induces panting in QW and NREM sleep is inefmation processing channels”. Like noradrenergic LC fective in REM sleep (Parmeggiani, 1980). In turn, neurons, the serotonergic neurons contribute to suppresdecerebration removes the caudal brainstem from sion of motor activity in REM sleep, in particular by the hypothalamic control. Furthermore, such nonsleepmechanism of disfacilitation. promoting stimuli as the passing of a stomach tube Variations in the control of the somatic reflexes by or a rectal thermometer readily (and abnormally) the reticular formation are state dependent, which Chase induces the REM sleep-like state in these animals and Babb (1973) termed reticular response-reversal. (Jouvet, 1964). In other words, the decerebrate animal When they stimulated the NPO in W and NREM sleep, is in an unstable condition – much like the narcoleptic, they facilitated the monosynaptic masseteric reflex, but one might add (Guilleminault, 1976; Saper et al., 2005). stimulation during REM sleep suppressed the reflex. Later, the view of Morrison and Reiner found support Chase has reasoned that neurons in NPO are responsible in the experiments of Baghdoyan et al. (1993). They for motor excitation during W, but during REM sleep revealed that cholinergic stimulation of the basal forethe effect is diametrically opposite: inhibition. During brain would prevent the usual onset of REM sleep W, stimulation of NPO powerfully induces a postsyninduced by the cholinomimetic drug, carbachol, placed aptic drive of the motor neurons; during REM sleep, in the pontine tegmentum. Much attention is now the reverse happens (Chandler et al., 1980a; Fung directed toward forebrain mechanisms regulating et al., 1982; Chase et al., 1986). Chase hypothesizes that REM sleep, including motor control. reticular response-reversal is achieved by the blockade The pontomesencephalic junction is a complex of of a neuronal pathway from the NPO to medullary nuclei with a multiplicity of transmitters being used by neurons during W (and NREM sleep); during REM their neurons, as illustrated informatively in Figure 51.3. sleep, this pathway (or gate) opens, resulting in the This figure is taken from Rye’s (1997) excellent review functional coupling of these two nuclei (Chase, 1976; of this region and its involvement in a number of Chandler et al., 1980b; Chase and Morales, 1983).

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Fig. 51.3. Schematic diagram summarizing connectional/neurochemical features of basal ganglia output to the mesopontine tegmentum, including the retrorubral field (RRF), midbrain extrapyramidal area (MEA), and pedunculopontine region. g-Aminobutyric acid (GABA)ergic hyperpolarizing outputs from dopamine-responsive basal ganglia circuits and the adjacent “extended amygdala” are segregated to specific sites within the pedunculopontine tegmental nucleus (PPN) region. Projections from these regions in turn innervate the thalamus and/or pontine and medullary reticular fields, and thereby influence thalamocortical processing and the excitability of premotor and motor neurons, respectively. Ascending cholinergic and glutamatergic pathways innervate “specific” and “nonspecific” thalamic nuclei and promote cortical arousal, whereas descending pathways modulate rapid eye movement (REM) atonia and other REM sleep-related phenomena. ACh, acetylcholine; EA, extended amygdala; Glu, glutamine; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; IC, inferior colliculus; IV, trochlear nucleus; MEA, midbrain extrapyramidal area; Put, putamen; RRF, retrorubral field; VP, ventral pallidum; VS, ventral striatum. Figure and abbreviated legend reprinted with permission from Rye (1997). #Associated Professional Sleep Societies.

neurological disorders associated with sleep. The cholinergic and glutamatergic neurons that project to the medulla, directly or indirectly via the PIA, thereby inhibiting spinal motor neurons via the medullary neurons (see Figure 51.2), normally receive a modulatory influence from forebrain structures illustrated in Figure 51.3 as well as the hypothalamus and amygdala (Swanson et al., 1984; Mogenson, 1987; Siegel, 2000, 2004; Saper et al., 2005). Interruption of these modulatory inputs

would appear to contribute to the greatly lowered threshold for entrance into REM sleep in narcoleptics, as well as cataplectic attacks and the induction of cataplexy seen in decerebrate cats (Jouvet, 1964). Perhaps the most exciting recent development from the turn to interest in the forebrain is the discovery of neurons containing two related peptides, hypocretin-1 (Hcrt1) and hypocretin-2 (Hcrt2), located with minor exceptions only in the hypothalamus. They are excitatory

842 A.R. MORRISON to the brainstem neurons (Siegel, 2004), discussed in cats with lesions in the pons that would not ordinarily the section above on the caudal brainstem. The Hcrt1 release aggressive behavior during REM sleep removed neurons are lost to a great extent in narcoleptic brains an inhibitory check on midbrain originators of such (Siegel, 2004). When Hcrt1 was administered systemibehavior. Removal of atonia does not depend upon cally, narcoleptic dogs studied for many years at destruction of the cholinergic neurons of the dorsolatStanford and the University of California, Los Angeles, eral pons but probably requires interruption of neurons had an extraordinary relief from symptoms: an increase from the retrorubral field and other noncholinergic in activity level, longer waking periods, decrease in afferents to the PIA (Shouse and Siegel, 1992). REM sleep without effects on NREM sleep, reduced This state is usually referred to as REM sleep (or sleep fragmentation, and a dose-dependent reduction paradoxical sleep) without atonia. Episodes of REM in cataplexy. Repeated daily doses will eliminate catasleep without atonia completely supplant normal epiplexy for at least 3 days (John et al., 2000). These and sodes of REM sleep: episodes of REM sleep with norother results, such as the fact that Hcrt neurons are parmal atonia never appear intermixed with the abnormal ticularly active during exploration of the environment episodes, and the animals are as easily awakened from (Saper et al., 2005) and that Hcrt levels collected via REM sleep without atonia as they are from an episode microdialysis are significantly higher in active waking of normal REM sleep (Henley and Morrison, 1974). than in quiet waking (Kiyashchenko et al., 2002), led (Interestingly, their self-generated movements – and Siegel (2004) to propose that the role of Hcrt is to facilthose of patients with REM sleep behavior disorder itate the motor activity that underlies any motivated (RBD) – do not awaken them unless they bump into behavior. However, injection of both Hcrt1 and Hcrt2 a barrier.) Furthermore, the episodes occur within the into the NPO of cats induces a state resembling normal same circadian pattern as normal REM sleep (Sanford REM sleep with accompanying atonia (Xi et al., 2002), et al., 1994). Although some cats lose the full phenomand juxtacellular presentation of Hcrt in the NPO enon (including the ability to raise their heads) over a excites the cells (Xi et al., 2003), suggesting that comfew to many weeks, the REM sleep episodes in these plex mechanisms are intervening between the hypothaanimals are still characterized by abnormal, vigorous lamic home of the hypocretin cell bodies and the movements, of the trunk in particular. terminus of their axons in the NPO. As Hcrt is a transThe term, REM sleep without atonia, is misleading mitter that facilitates motivated behaviors by promotthough. Simply eliminating the inhibition of the spinal ing movement, one can see that it could instigate motor neurons is obviously not enough to release the the activated state of REM sleep, a state so like AW elaborate behaviors observed: lesion site predicts the (Morrison, 1983a), with other systems holding an indibehavior that a particular animal will exhibit (Hendricks vidual in check so that he or she is unable to move or et al., 1982). And some recovery of the systems then to act on the subject matter of dreams. The following driving behavior must be necessary because the behavior two sections elaborate on these mechanisms. becomes more elaborate over a few days. Furthermore, acute temporary inactivation with tetrodotoxin (Sanford et al., 2005) of the same region in rats does not induce REM SLEEP WITHOUT ATONIA the phenomenon that when damaged electrolytically Limited bilateral electrolytic lesions of the pons in cats leads to REM sleep without atonia (Mirmiran, 1982; made during the 1960s eliminated the atonia induced Sanford et al., 2001). It would have obviously been by the brainstem mechanisms just discussed – and in better had we referred to the phenomenon as “REM dramatic fashion. Cats with such lesions may appear sleep with overt behavior” in order to acknowledge this completely normal while awake. They curl up and enter complexity. Nevertheless, thanks to REM sleep without NREM sleep, which appears normal except for some atonia discovered in animals, Schenck, Mahowald, and body jerks if the cerebellum suffered damage. As coworkers recognized RBD for what it is: a release of REM sleep begins, the animal lifts its head and appears muscle tone and behavior during REM sleep, not epito be searching. Depending upon the area damaged, lepsy (Schenck et al., 1986). Before that announcement, the animal can proceed from head lifting to body rightwe had actually observed a case in a cat brought to our ing, forelimb support, and even walking (Hendricks clinic (Hendricks et al., 1989). We have since reported on et al., 1982). A subset with lesions extending into the other cases in cats, as well as in dogs (Hendricks et al., midbrain exhibited behavior resembling predatory 1989; Bush et al., 2004). attack. Later work demonstrated that this behavior A caveat is in order here. The cat with experimendepended, in part, on damage to fibers traversing the tally produced REM sleep without atonia does not lesion site from the central nucleus of the amygdala mimic exactly the clinical conditions in both humans (Zagrodzka et al., 1998). Amygdalar lesions made in and animals, for it depends on rather specific,

MOTOR CONTROL IN SLEEP localized, pontine lesions. Yet, it obviously served as a stimulus for studies into the pathophysiology of behavioral state control (Mahowald and Cramer Bornemann, 2005). I think it is important for clinicians to recognize that “models” of human disease can come in a variety of forms, from essentially identical diseases such as narcolepsy, to those such as REM sleep without atonia that provide unexpected insights. Terminology aside, the appearance of different behaviors during REM sleep without atonia reveals an important, normally masked, characteristic of REM sleep: a drive to move when the brain is “activated” that must be actively suppressed. For two reasons we postulated this drive: when awake, the cats with pontine lesions did not have excessive extensor tone, and they exhibited significantly increased exploratory behavior when measured in an open-field test (Morrison, 1979; Morrison et al., 1981). In an open-field test, the number of squares an animal enters during a set period is counted. Our animals did not simply pace back and forth in a perseverative manner: they went in a variety of directions. The pontine lesions, then, interrupt a mechanism that normally modulates the degree of movement both during wakefulness and REM sleep without affecting the cats in NREM sleep. This particular mechanism does not appear to be characteristic of NREM sleep, although occurrence of somnambulism in humans, which arises out of NREM sleep as a disorder of arousal (Broughton, 1968; Mahowald and Cramer Bornemann, 2005), indicates that there must be some drive to move in NREM sleep that is normally suppressed. No reports of sleepwalking occurring in quadrupeds have ever come to my attention, but it is difficult to believe that they do not occur. The mechanism released by pontine lesions, I suggest, resides at the midbrain–pontine junction (with inputs from the forebrain of course; e.g., Swanson et al., 1984; Mogenson, 1987; Rye, 1997), and continuous electrical stimulation here instigates locomotion in decerebrate cats placed on a moving treadmill. Shik and Orlovsky (1976) designated this area the mesencephalic locomotor region (MLR). The electrical stimulation obviously substitutes for the complex inputs from more rostral parts of the brain, both excitatory and inhibitory, that result in movement via the caudal reticular formation acting on a spinal motor generator. The MLR operates via multiple routes through the caudal brainstem, one of which is a laterally coursing “locomotor strip” included in Figure 51.4 (Mori et al., 1977; Reese et al., 1995). PPN neurons are not uniform in their activity during locomotion: some fired tonically with locomotion and ceased at termination; a second group fired tonically but decreased as locomotion ensued only to resume firing as locomotion was

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terminating; and a third group fired in bursts. The first two groups are assumed to regulate duration of a stepping episode, and the third, the frequency (Reese et al., 1995). Figure 51.4 (top) illustrates the combined force of direct inhibition of the spinal motor neurons and the withdrawal of facilitation of the spinal motor generator. The pontine lesions that induce REM sleep without atonia (Figure 51.4, middle) block these two processes, resulting in a hyperactive animal during wakefulness and REM sleep (Morrison et al., 1981). Injection of N-methyl-D-aspartate (NMDA) glutamatergic agonists in the PIA or NMC inhibitory area in decerebrate cats induced increased tone or stepping movements in decerebrate cats, whereas injection of nonNMDA agonists induced bilateral muscle tone suppression or atonia (Lai and Siegel, 1991). These workers suggest that in RBD there may be degeneration of nonNMDA receptors, shifting the balance toward the locomotor-promoting NMDA receptors. In cats with REM sleep without atonia, electrolytic lesions might shift the balance toward fibers exciting the NMDA receptors.

AN EXPLANATION FOR THE CHARACTERISTICS OF REM SLEEP Two cardinal signs of REM sleep are the presence of brain waves greatly resembling those of alert wakefulness and the presence of muscle atonia due to inhibition of the spinal motor neurons. (One might add the often overlooked suppression of homeostatic controls.) Thinking superficially – and teleologically – atonia during REM sleep makes perfect sense: not running around while dreaming is a good thing, and the negative effects on the body of a patient with RBD provide ample proof that this is so. Thinking of animals, the behavior of cats during REM sleep without atonia certainly could lead to harm were they not confined to a cage. To avoid such teleological thinking, I have developed a more mechanistic, evolutionary explanation for why REM sleep appears as it does: an activated brain in a paralyzed body (Morrison, 1983a). In order to survive in an unforgiving world, an individual must identify both positive and negative stimuli, for example food and an approaching predator. An unexpected or novel stimulus elicits the orienting reflex (Sokolov, 1963). The linkage between excitement and suppression of motor activity that seems to be shared by two grossly different behavioral states is an example of Nature’s parsimony and, therefore, efficiency. Why evolve two parallel systems when one (with some modifications depending on the particular demand) will do? After all, males use the same organ for reproduction and urination, with obvious modifications according

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A.R. MORRISON MEDULLARY INHIBITORY AREA

MOTOR NEURONS

PONS

LATERAL LOCOMOTOR STRIP

SPINAL LOCOMOTION GENERATOR

MEDULLARY INHIBITORY AREA

LESION

PONS

LESION

TO MUSCLES

LATERAL LOCOMOTOR STRIP

MOTOR NEURONS

TO MUSCLES

MOTOR NEURONS

TO MUSCLES

SPINAL LOCOMOTION GENERATOR

MEDULLARY INHIBITORY AREA

PONS

LATERAL LOCOMOTOR STRIP

SPINAL LOCOMOTOR GENERATOR

Fig. 51.4. Schematic representations of the brainstem systems proposed to account for the motor inhibition of normal rapid eye movement (REM) (top), the manner in which the pontine tegmental lesions might induce REM without atonia (middle), and the employment of the same systems during orienting in wakefulness (bottom). Excitatory influences are indicated by þ and inhibitory influences by . Interrupted lines signify blockage of an effect. The arrows in the bottom panel leading to the medullary inhibitory area the motor neurons and skeletal muscles are thinner to suggest that the effects are only strong enough to reduce the effectiveness of excitatory drives on motor neurons. Clearly, there is no atonia during orienting, although this can occur abnormally in narcoleptics. Adapted with permission from Morrison (1983b).

to use. The same muscles we employ to move us from one point to another serve to increase our body temperature by shivering when we are cold, and the lungs, chest muscles, and diaphragm that participate in respiration also help us to eliminate heat during panting. Our airway allows us to communicate as well. Why not assume, then, that the nervous system evolved to allow an animal to react in an automatic manner when the brain is very excited? And why not use the same mechanism whenever running about willy-nilly would be disadvantageous, such as during REM sleep? (Patients with REM sleep behavior disorder can tell us about the evolutionary disadvantage of not being paralyzed in REM sleep.) When we are awake, an unexpected stimulus is always potentially life threatening, so Nature has installed a little “look before you leap” program: the orienting reflex (Sokolov, 1963).

There is always a brief moment of hesitation as one orients the head toward the stimulus and rapidly assesses the situation before appropriate action is taken. This could be “run away”, “approach for closer inspection” or “dismiss as unimportant”, depending on the distance between an individual and the source of interest (Ratner, 1967). If one cannot escape, total behavioral arrest, or “playing possum”, may be the most prudent course of action (Ratner, 1967; Klemm, 2001). Recall from the Introduction the confounding of the “storms of inhibition” associated with the “whirlwinds of excitation” underlying the twitches and REMs to which Chase and Morales (1990) referred in describing the “motor control landscape” of REM sleep. The bouts of extra inhibition occur in association with pontogeniculo-occipital waves (PGO) waves recorded with deep electrodes in the lateral geniculate body of cats, which

MOTOR CONTROL IN SLEEP

845

EOG EEG LGN EMG

A

B 2.0 mv 0.1 0.2 0.1

C

D

Fig. 51.5. Characteristics of the behavioral states of (A) quiet wakefulness; (B) nonrapid eye movement (NREM) sleep; (C) transition from NREM to REM sleep; (D) REM sleep. EOG, eye movements recorded on the electro-oculogram; EEG, electroencephalogram; LGN, recording of pontogeniculo-occipital waves in the lateral geniculate body in C and D; EMG, electromyographic activity of the dorsal cervical muscles. Reprinted from Morrison (1979). #Elsevier.

appear spontaneously just prior to REM sleep and then throughout the episode (Figure 51.5). These waves can be elicited by sensory stimulation during REM sleep (Bowker and Morrison, 1976). We have argued that they are phasic signs of alerting that occur spontaneously during REM sleep (Bowker and Morrison, 1977). Using tones to elicit them, we later found that PGO waves evoked in W that were associated with orienting matched in amplitude the biggest waves occurring spontaneously during REM sleep (Sanford et al., 1993). Kohlmeier et al. (1997) demonstrated that somatic (sciatic nerve) and auditory (clicks) stimulation during carbachol-induced atonia would elicit a PGO wave at a threshold below effects that were seen on the membrane of masseteric motor neurons. They induced IPSPs in the motor neurons with higher stimulus intensities. There is, then, a mechanism to temper the excitation of alerting with accompanying motor neuronal inhibition no matter how slight the effect, as in the Kohlmeier et al. (1997) study. Thus, there is good reason to postulate that an “automatic” connection is made in the brain between high levels of excitation with the motor control systems described above that puts a “clamp” on action, however brief the latter might be. This clamp serves to maintain the atonia of REM sleep and is evidenced during the orienting reflex in W. The peculiar characteristics of narcolepsy convince me this is correct. A variety of unexpected stimuli and emotional situations can induce a cataplectic attack (Guilleminault, 1976). In nonafflicted individuals, such conditions lead

only to a brief hesitation with a slight “give” in the knees or a prolongation of the stance phase while walking that one can easily prove by personal experience. (Recall the medullary neurons found by Siegel et al. (1979) that can increase discharge in QW and are silent in AW.) The thin line extending from the pons to the medullary inhibitory area in the bottom section of Figure 51.4 represents the effect of brainstem inhibitory processes on spinal neurons during normal orientation. In the case of narcolepsy, the line would be thickened to equal that found in the top part of the figure, to represent the excess of inhibition that induces cataplexy. The complete atonia of cataplexy is an abnormal “add on” to behavioral arrest that results from the intrusion of abnormal inputs during emotional situations, such as those from the amygdala, basal ganglia, and hypothalamus (see Figure 51.4), with instability stemming from the loss of hypocretin cells (Siegel, 2004). Saper et al. (2005) have proposed that the hypocretin cells that facilitate noradrenergic and serotonergic neurons help to stabilize a flip-flop switch that shifts animals between wakefulness and sleep. In the absence of the former, as in narcolepsy, the switch is destabilized and rapid shifts into cataplexy can occur.

CONCLUDING REMARKS Motor control during wakefulness is a well studied, complex affair. This chapter demonstrates that such control during sleep is probably equally complex, only lacking the need to modulate movement of an

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individual through the external world that is frequently, but not always, generated by the conscious desires of the waking brain. When disease damages the multiple checks placed on organized movement during NREM or REM sleep, life-threatening events are always a possibility. Thus, a thorough understanding of the neural mechanisms responsible for motor control during sleep is a prerequisite to the development of ever more refined treatments. This brief review has presented the remarkable additions to our knowledge of motor control during sleep since Jouvet and Michel’s (1959) revealing discovery of complete atonia during REM sleep.

ACKNOWLEDGEMENTS Preparation of this chapter was partially supported by National Institutes of Health grant MH-72897. I take particular pleasure in acknowledging the assistance of the excellent original work and reviews of five of the leaders in the study of motor control in sleep: Michael Chase, Barry Jacobs, Ottavio Pompeiano, David Rye, and Jerry Siegel. Many other workers have also made significant contributions that could not be mentioned or cited in this brief, general chapter, and I apologize for not doing so. In addition, I thank Mark Mahowald for sharing his clinical insights. Finally, I owe a great debt to my various colleagues and my assistant of many years, Graziella Mann.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 52

NREM parasomnias ANTONIO ZADRA 1,2 * AND MATHIEU PILON 2 Department of Psychology, Universit de Montral, Montreal, Canada

1 2

Centre d’tude du Sommeil, Hpital du Sacr-Cˇur de Montral, Montreal, Canada

INTRODUCTION Parasomnias are undesirable physical or behavioral phenomena that occur during entry into sleep, within sleep, or during partial arousals from sleep (American Academy of Sleep Medicine, 2005). The focus of this chapter is confusional arousals, sleepwalking (somnambulism), and sleep terrors. These sleep disorders constitute the prototypic nonrapid-eye-movement (NREM) sleep parasomnias and are collectively termed “disorders of arousal” (Broughton, 1968) because of the autonomic and motor arousal that propels the patient towards partial wakefulness. A summary and comparison of the main features of NREM and REM sleep parasomnias are presented in Table 52.1. Disorders of arousal are more common in childhood than in adulthood and their prevalence rate decreases significantly with age. However, whereas the occurrence of NREM parasomnias in children is frequently viewed as a relatively benign and common event that will resolve spontaneously, these disorders often pose greater problems, including social inconvenience and sleep-related injury, in affected adults. In fact, injurious NREM sleep parasomnias in adults may be more prevalent than commonly believed (Schenck et al., 1989; Ohayon et al., 1999; Mahowald and Schenck, 2000c). The symptoms and manifestations of these NREM parasomnias can be considered along a spectrum. For instance, the patient’s affective expression can range from calm to extremely agitated, and the actual physical behaviors can range from simple and isolated actions (e.g., sitting up in bed, mumbling, fingering bed sheets) to complex behaviors (e.g., rearranging furniture, inappropriate sexual activity, playing a musical instrument, driving an automobile). Moreover,

an episode can be comprised of two overlapping disorders, such as a sleep terror followed by sleepwalking. Disorders of arousal share a number of characteristics. Most episodes arise from sudden but incomplete arousal from slow-wave (stages 3 and 4) sleep (Jacobson et al., 1965; Kavey et al., 1990; Espa et al., 2000) and sometimes from stage 2 sleep (Kavey et al., 1990; Zucconi et al., 1995; Joncas et al., 2002). Consequently, these parasomnias tend to occur in the first third of the sleep period when slow-wave sleep (SWS) is predominant. Episodes are generally characterized by misperception and relative unresponsiveness to external stimuli, mental confusion, automatic behaviors, and variable retrograde amnesia. This state is indicative of a high arousal threshold. A common genetic component is also suspected, as a positive family history is often reported by people with an arousal disorder (Hublin et al., 1997, 2001; Hublin and Kaprio, 2003). Factors that deepen sleep, such as intense physical activity (Vecchierini, 2001), hyperthyroidism (Ajlouni et al., 2005), fever (Dorus, 1979; Kales et al., 1979; Larsen et al., 2004), sleep deprivation (Rauch and Stern, 1986; Mayer et al., 1998; Joncas et al., 2002), and neuroleptics (Charney, 1979; Landry and Montplaisir, 1998) or medications with depressive CNS effects (Lee-Chiong, 2002; Mahowald, 2002), can facilitate or precipitate NREM parasomnias in predisposed individuals. Factors that fragment sleep, including sleepdisordered breathing (Guilleminault et al., 1998; Espa et al., 2002; Guilleminault et al., 2005a), periodic leg movement syndrome (Guilleminault et al., 2003), stress (Kales et al., 1980b; Klackenberg, 1982; Crisp et al., 1990; Ohayon et al., 1999), and environmental or endogenous stimuli (Gastaut and Broughton, 1965; Kales et al., 1966; Broughton and Gastaut, 1974), can

*Correspondence to: Antonio Zadra, Ph.D., Department of Psychology, Universite´ de Montre´al, C.P. 6128, succ. Centre-ville, Montreal, Quebec, Canada H3C 3J7. Tel: (514) 343-6626, Fax: (514) 343-2285, E-mail: [email protected]

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Table 52.1 Comparison of common features of NREM and REM sleep parasomnias

Time of night

Duration Autonomic activation Recall for the event Full awakening State after event Arousal threshold Reduced in sleep laboratory PSG findings Potential for injury/ violence

Somnambulism

Sleep terrors

Nightmares

RBD

First third to half of sleep period SWS May sit up in bed

First third to half of sleep period SWS Sits, screams. Agitated motor activity

Last half of sleep period REM Movements are rare and limited

Last half of sleep period REM without atonia Behavior that correlates with dream content

1–15 min Low Variable amnesia for the event Uncommon Confused/disoriented High Yes

First third to half of sleep period SWS Simple to complex movements. Possible ambulation 1–30 min Low to moderate Variable amnesia for the event Uncommon Confused/disoriented High Yes

1–10 min Moderate to extreme Variable amnesia for the event Uncommon Confused/disoriented High Yes

3–20 min None to moderate Vivid and detailed dream recall Common Fully awake and functional Low Yes

1–10 min Low to moderate Vivid and detailed dream recall Common Fully awake and functional Low No

Partial arousals from SWS Yes

Partial arousals from SWS Yes

Partial arousals from SWS Yes

REM No

Excessive EMG during REM Yes

EMG, electromyography; PSG, polysomnographic; RBD, REM sleep behavior disorder; REM, rapid eye movement; SWS, slow-wave sleep

A. ZADRA AND M. PILON

Sleep stage Associated activity

Confusional arousal

NREM PARASOMNIAS have similar effects. Hormonal factors may also influence the frequency with which women experience parasomnias, as sleep terrors and injurious sleepwalking can emerge premenstrually (Schenck and Mahowald, 1995b), and sleepwalking may decrease during pregnancy, particularly in primiparas (Hedman et al., 2002). Some researchers (Mahowald and Schenck, 1992, 1999, 2005) have cogently argued that a proper understanding of many parasomnias rests on the appreciation that sleep and wakefulness are not always mutually exclusive states and that various variables implicated in generation of wakefulness, REM sleep, and NREM sleep (the three primary states of being) may occur simultaneously, interact dynamically, or oscillate rapidly. It should also be noted that NREM parasomnia-related behaviors are not unlike the natural occurrence of clinically wakeful behavior during physiological sleep documented in the animal kingdom (Almanar and Ball, 1994; Rattenborg et al., 1999).

CONFUSIONAL AROUSALS Clinical features That people sometimes experience confused awakenings from deep sleep in which they appear to be partially awake and partially asleep was noted over 150 years ago – a condition termed “ivresse du sommeil” (French) or “sleep drunkenness”. Other terms used to describe this disorder include Schaftrunkenheit (German) and Elpenor syndrome (derived from the story of Elpenor, who broke his neck during such an episode in Homer’s The Odyssey). Confusional arousals, often seen in children, consist of mental confusion or confusional behavior during or following arousals from SWS. They can also occur upon attempted awakening from sleep in the morning or during daytime naps. An arousal will often begin with automatic movements (e.g., playing with bed sheets) and moaning or unintelligible vocalizations, and can progress to thrashing about in bed, violent behaviors towards the self or others, or inconsolable crying. Individuals usually appear confused with slow mentation and have poor reactivity to environmental stimuli; attempts to awaken the person are often unsuccessful and may be met with vigorous resistance. Most episodes last from a few to 15 minutes.

Prevalence Confusional arousals are common in infants and young children, and their prevalence in both male and female adults is approximately 3–4% (Ohayon et al., 1999, 2000).

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Pathophysiology Relatively little is known about the pathophysiology of confusional arousals. A familial pattern appears to exist in families of deep sleepers. Intensified sleep inertia (i.e., a feeling of grogginess after awakening accompanied by a temporarily reduced ability to perform even simple tasks) likely plays a role (Broughton, 2000). One study (Ohayon et al., 1999) of a representative sample in the UK found that people reporting confusional arousals were more likely than individuals without parasomnias to be diagnosed with a mood disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), mood disorder, to consume psychoactive drugs, and to be smokers. An association between confusional arousals and a mood disorder was found in a subsequent epidemiological study (Ohayon et al., 2000). It is possible that symptoms of insomnia or fragmented sleep, which are often associated with mood disorders, result in accumulated sleep deprivation and increased awakenings from NREM sleep, conditions known to facilitate the occurrence of arousal disorders. Similarly, shift or night workers are at higher risk of reporting confusional arousals (Ohayon et al., 2000). People with confusional arousals may also suffer from other sleep disorders, such as obstructive sleep apnea (Ohayon et al., 2000) or hypersomnia (Roth et al., 1972).

SOMNAMBULISM (SLEEPWALKING) Clinical features Like some other parasomnias, sleepwalking was once thought to be a behavioral manifestation of dreamingrelated processes. Sleepwalking is now considered a disorder of arousal involving a physiological dysfunction in the neural regulation of generalized cortical activation. Somnambulistic actions may be complex, such as dressing, playing a musical instrument, or driving a car, and may be performed with substantial dexterity; more often, however, they are mundane, stereotyped, and accompanied by a variable degree of amnesia for the episode. Far from being a benign condition, somnambulism can result in injury to the sleeper or to others. Adults suffering from somnambulism often consult due to a history of aggressive and/or injurious behavior during sleep (Rauch and Stern, 1986; Schenck et al., 1989; Moldofsky et al., 1995; Denesle et al., 1998). In a significant number of cases, patients report having suffered serious injuries (e.g., contusions, fractures to limbs, rib cage, multiple lacerations) and/or having attacked a bed partner during an episode (Kales et al., 1980c; Rauch and Stern, 1986; Kavey et al.,

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1990; Milliet and Ummenhofer, 1999). Furthermore, the number of legal cases of sleep-related violence is on the rise (Cartwright, 2000) and sleepwalking represents one of the leading causes of sleep-related injury (Pareja et al., 2000). In one polysomnographic investigation (Schenck et al., 1989) of 100 consecutive patients consulting for repeated nocturnal injury, 90% received one of two diagnoses: sleepwalking/night terrors (54%) or REM sleep behavior disorder (36%). Reported behaviors during somnambulism and/or agitated sleep terrors included running into walls and furniture, jumping out of windows, leaving the house, driving an automobile, wandering around streets, walking into lakes, climbing ladders, and wielding weapons such as loaded shotguns. A second laboratory investigation of 64 consecutive adult patients with sleepwalking or sleep terrors found that 40% reported a history of sleep-related violence leading to the destruction of property (e.g., breaking of walls, doors, windows, plumbing) or serious self-injury and a further 19% reported harmful but nondestructive behavior (Moldofsky et al., 1995). Similarly, a study of 50 chronic sleepwalkers found that 30% had injured themselves or others in the course of at least one episode (Guilleminault et al., 2005a). Moreover, the fact that the driving motor vehicles, sexual activity, suspected suicide, and even homicide and attempted homicide can occur during somnambulism raises fundamental questions as to the medicoforensic implications of these acts (Oswald and Evans, 1985; Mahowald et al., 1990, 2003, 2005; Broughton et al., 1994; Schenck and Mahowald, 1995a; Rosenfeld and Elhajjar, 1998; Kayumov et al., 2000; Mahowald and Schenck, 2000c; Shapiro et al., 2003).

Prevalence The yearly prevalence of somnambulism in children aged 6–16 years ranges from 4% to 17%, peaking at 11–12 years of age, and sleepwalking occurs in 1–4% of adults (Bixler et al., 1979; Klackenberg, 1982; Goldin, 1997; Hublin et al., 1997; Ohayon et al., 1999; Laberge et al., 2000). Although children with sleepwalking tend to outgrow the disorder during mid to late adolescence, somnambulism persists into adulthood in up to 25% of cases (Hublin et al., 1997). In addition, episodes can emerge in adulthood and increase in severity over time (Berlin and Qayyum, 1986; Kavey et al., 1990).

Pathophysiology The exact mechanisms that give rise to somnambulism remain unclear. Several general factors have been proposed, including increased psychopathology, genetics,

and deregulation of serotonergic systems. A number of atypical sleep parameters have also been described. The latter are covered in a dedicated section below (see Unusual sleep parameters).

PSYCHOPATHOLOGY Traditionally, the presence of somnambulism (with or without concomitant sleep terrors) in adulthood has been viewed as a sign of major psychopathology (Pai, 1946; Kales et al., 1980b; Soldatos et al., 1980). Epidemiological evidence suggests a higher prevalence of psychopathology among adult patients with arousal disorders (Ohayon et al., 1999), and psychopathology has been reported in subgroups of adolescents with sleep terrors and/or sleepwalking (Gau and Soong, 1999). However, several studies have shown that many adult patients do not have a DSM-based (American Psychiatric Association, 1994) Axis I psychiatric disorder, nor do they necessarily present with highly disturbed personality traits (Schenck et al., 1989, 1997; Mahowald and Schenck, 1999; Guilleminault et al., 2005a).

GENETICS Several studies have revealed a genetic contribution to sleepwalking. The prevalence of somnambulism is higher in children of parents with a history of sleepwalking, and about 80% of somnambulistic patients have one or more family members affected by the disorder (Abe and Shimakawa, 1966; Kales et al., 1980a; Hori and Hirose, 1995). Barkwin’s (1970) study of over 300 twin pairs found that monozygotic (MZ) twins are concordant for the disorder six times as often as dizygotic (DZ) twins. A population-based twin study of 1045 MZ and 1899 DZ pairs showed a considerable genetic effect in adulthood sleepwalking (probandwise concordance 5 times higher in MZ than in DZ pairs), although the effect in childhood sleepwalking was not as pronounced (probandwise concordance 1.5 times higher in MZ than in DZ pairs) (Hublin et al., 1997). HLA-DQB1 typing in sleepwalkers and their families indicates that somnambulism may be associated with excessive transmission of the HLA-DQB1*05 and *04 alleles (Lecendreux et al., 2003).

DEREGULATION

OF SEROTONERGIC SYSTEMS

Sleepwalking episodes are four to nine times more common in patients with Tourette syndrome or migraine headaches (Barabas et al., 1983, 1984; Giroud et al., 1987). These observations suggest that somnambulism may be associated with abnormalities in the metabolism of serotonin. That serotonin is involved

NREM PARASOMNIAS in the pathophysiology of sleepwalking has also been hypothesized on the basis that several factors that can precipitate sleepwalking (e.g., sleep-disordered breathing (SDB), certain drugs, fever) implicate the serotonergic system (Juszczak and Swiergiel, 2005).

Unusual sleep parameters Sleep architecture and normal cycling among sleep stages are preserved in adult somnambulistic patients. Nevertheless, a number of unusual sleep-related processes have been described including alterations in the cyclic alternating pattern (CAP), an increased number of sudden arousals from SWS, hypersynchronous delta waves, irregular buildup of slow-wave activity, and unique EEG characteristics prior to and during somnambulistic episodes.

CYCLIC

ALTERNATING PATTERN AND SLOW-WAVE

SLEEP AROUSALS

The CAP is a measure of NREM instability that expresses the organized complexity of arousal-related phasic events in NREM sleep (Terzano and Parrino, 2000; Terzano et al., 2001). In comparison with controls, patients with sleepwalking/sleep terrors show increases in the CAP rate (Zucconi et al., 1995). An increased CAP rate was also found children with chronic sleepwalking and concomitant sleep respiratory disorders (Guilleminault et al., 2005b). Similarly, polygraphic recordings have shown that, compared with controls, sleepwalkers experience a greater number of SWS arousals and brief microarousals (Halasz et al., 1985; Blatt et al., 1991; Espa et al., 2000). The data indicate that an increase in NREM sleep instability and arousal oscillation is a typical microstructural feature of SWS-related parasomnias. These results also suggest that, in addition to being a disorder of arousal, somnambulism is characterized by an inability to maintain stable and consolidated SWS.

HYPERSYNCHRONOUS

DELTA WAVES

One of the more controversial findings regarding the sleep EEG of patients with sleepwalking/sleep terrors is the presence of hypersynchronous delta activity (HSD), usually described as continuous high-voltage (>150 mV) delta waves occurring during SWS or immediately prior to an episode (Kales et al., 1966; Guilleminault and Silvestri, 1982; Kavey et al., 1990; Blatt et al., 1991; Broughton, 2000). Studies of HSD prior to sleepwalking or sleep terror episodes in adult parasomniacs have yielded mixed results (Kavey et al., 1990). Using a different approach to assess prearousal delta activity, one study found that most

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behavioral and nonbehavioral arousals from SWS in adult patients were not preceded by a delta-wave buildup and that only 15.5% were preceded by deltawave clusters (Schenck et al., 1998). The occurrence of HSD was recently assessed by our group (Pilon et al., 2006) with an array of measures over different EEG derivations during the NREM sleep of somnambulistic patients and controls during normal sleep, following sleep deprivation, and prior to somnambulistic episodes. We found that: (a) HSD was present in 80% of controls during baseline recording and in 90% after sleep deprivation; (b) when compared to control subjects, HSD occurred more frequently during sleepwalkers’ sleep EEG; (c) sleep deprivation increased HSD during stage 4 sleep in both groups; and (d) there was no evidence that somnambulistic episodes were immediately preceded by a buildup in HSD or by any HSD-related variables. Taken together, these findings reinforce the results from previous studies (Schenck et al., 1998; Pressman, 2004) in demonstrating that, regardless of how it is measured, HSD has low specificity for the diagnosis of NREM parasomnias. It is suggested that HSD is related to the expression of the homeostatic process underlying sleep regulation. This hypothesis is consistent with the finding that HSD is more frequent when sleep pressure is at its peak according to the twoprocess model of sleep (Borbe´ly and Acherman, 2000), and with studies reporting HSD and highamplitude delta waves during SWS of adults with SDB, another sleep-disordered population characterized by considerable sleep fragmentation and sleep deprivation (Himanen et al., 2004; Pressman, 2004). The potential neurophysiological mechanisms underlying HSD remain unknown. It can be argued, however, that HSD represents an increased activity of the neural structures involved in the regulation of delta activity during NREM sleep. Delta activity results from the progressive hyperpolarization of the thalamocortical and cortical neurons, and, as sleep advances, serves to protect the brain from incoming sensory stimuli in order to allow more deep sleep; spindles activity prevails at intermediate levels of hyperpolarization, whereas delta activity is seen at a high level of hyperpolarization (Steriade et al., 1993; McCormick and Bal, 1997; Merica and Fortune, 2004). Thus, HSD could reflect more hyperpolarized thalamocortical and cortical neurons compared with regular delta activity.

SLOW-WAVE

ACTIVITY

EEG slow-wave activity (SWA: spectral power in the 0.75–4.5-Hz band) is a quantitative measure of SWS dynamics and is considered an indicator of sleep depth

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or sleep intensity (Borbe´ly and Acherman, 2000). Gaudreau et al. (2000) investigated the power and dynamics of SWA in adult sleepwalkers and controls, and showed that sleepwalkers had significantly less overall SWA power, with the greatest difference occurring during the first NREM cycle. A similar reduction in SWA was also reported in two other studies of patients with sleepwalkers/sleep terror (Espa et al., 2000; Guilleminault et al., 2001). These data indicate that sleepwalkers’ frequent awakenings from SWS interfere with the normal buildup of their SWA and provide further evidence for an abnormality in these patients’ capacity to sustain stable SWS. Actual behavioral episodes, however, are immediately preceded by an increase in SWA (Espa et al., 2000) or low delta power (0.25–2.0 Hz) (Guilleminault et al., 2001), a process that may reflect cortical reaction to brain activation.

delta activity (pattern I) was more likely to accompany simple somnambulistic episodes than complex ones, and that it occurred only during events emerging from SWS as opposed to stage 2 sleep. There was no evidence of complete awakening during any of the episodes. Examples of patterns I and II are presented in Figures 52.1 & 52.2. Finally, one single-proton emission computed tomographic study during sleepwalking in a 16-year-old boy with a history of somnambulism suggests that episodes arise from the selective activation of thalamocingulate circuits and the persisting inhibition of other thalamocortical arousal systems (Bassetti et al., 2000). EEG during the episode showed diffused, high-voltage, rhythmic delta activity (i.e., pattern I). The authors supported the view of sleepwalking as reflecting a dissociated state consisting of motor arousal and persisting mind sleep.

EEG during behavioral episodes

SLEEP TERRORS

Original EEG investigations of experimentally induced somnambulistic episodes found that they could be described in terms of continuous and diffuse nonreactive alpha rhythms or by patterns of low-voltage delta and beta activity (Gastaut and Broughton, 1965; Broughton, 1968). More recently, the EEG associated with minor behavioral events in adult sleepwalkers was described as a pattern of stage 1 sleep without evidence of complete awakening (Guilleminault et al., 2001). Schenck et al. (1998) found that three postarousal EEG patterns characterized the first 10 seconds of most SWS arousals in adults with sleepwalking/sleep terrors: (I) diffuse rhythmic and synchronous delta activity (4 Hz), most prominent in bilateral anterior regions; (II) diffuse and irregular, moderate to high voltage delta and theta activity intermixed with, or superimposed by, alpha and beta activity; and (III) prominent alpha and beta activity, at times intermixed with moderate voltage theta activity. Irrespective of specific EEG patterns, delta activity was found to be present in 44% of the postarousal EEGs. We followed up on this study by assessing differences in observed postarousal EEG patterns across behavioral arousals from sleepwalkers as a function of sleep stage (Zadra et al., 2004). The two more frequently observed forms of postarousal activity were patterns II and III. These patterns were also the only two that occurred during stage 2 episodes. Delta activity was present in almost 50% of all episodes from SWS, and in 20% of those from stage 2. The distribution of principal postarousal EEG patterns was also investigated as a function of episode complexity. The results showed that diffuse rhythmic and synchronous

Clinical features Sleep terrors, also known as night terrors, are sometimes called “pavor nocturnus” in children. As outlined by Broughton (2000), the term sleep terror is preferable to night terror, because episodes can occur during daytime sleep or naps. Historically, sleep terrors have been confused with nightmares, a distinct REM sleep parasomnia (see Chapter 53 for details of REM sleep parasomnias). Gastaut and Broughton (1965) first observed polysomnographically that sleep terrors were not associated with REM sleep but rather occurred suddenly during SWS. Sleep terrors are characterized by a loud piercing scream or cry for help, intense autonomic activation (e.g., tachycardia, tachypnea, flushing of the skin, diaphoresis, mydriasis) inconsolability, and overwhelming anxiety or acute panic. Facial expressions often reflect intense fear. These reactions may be followed by agitated motor activity such as hitting the wall or running about as if reacting to imminent danger (Kales et al., 1980c). In fact, sleep terrors can be accompanied or followed by a sleepwalking episode (Fisher et al., 1973a; Nino-Murcia and Dement, 1987; Broughton, 2000). Somnambulism associated with sleep terrors may be more vigorous and frantic than a typical sleepwalking episode. At the end of a sleep terror, the person may awaken or simply return to sleep without being completely awakened. Although most sleep terrors are benign, the behavior may be violent and result in considerable injury (Hartmann, 1983; Rauch and Stern, 1986; Schenck et al., 1989), occasionally with medicoforensic implications relating to these acts (Mahowald et al., 1990,

NREM PARASOMNIAS

857

Fig. 52.1. Example of postarousal EEG pattern I during a behavioral episode from stage 4 sleep in a 19-year-old man. The EEG shows diffuse and rhythmic delta activity and is most predominant in the anterior regions.

Fig. 52.2. Example of postarousal EEG pattern II during a behavioral episode from stage 4 sleep in a 23-year-old woman. The EEG shows irregular delta and theta activity intermixed with faster activity.

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2005; Mahowald and Schenck, 2000b; Cartwright, 2004). Sometimes, family members of affected patients can suffer from psychological trauma related to the violent behaviors manifested during sleep terrors, even if they are not physically injured, as suggested in a recent case study (Baran et al., 2003). The incidence of sleep terrors in the sleep laboratory is lower than in the patient’s normal environment (Fisher et al., 1973a; Nino-Murcia and Dement, 1987; Broughton, 2000). However, sleep terrors can be induced precipitously in predisposed individuals by auditory stimulation during SWS (Fisher et al., 1973a; Schenck et al., 1989). This observation has led some researchers to suggest that episodes are not the culmination of ongoing sleep mentation. Although this may be true in many cases, precipitating dream imagery, ranging from a brief frightening image or thought to more elaborate dream-like mentation, has been noted, particularly in adults (Fisher et al., 1974; Schenck et al., 1989; Kahn et al., 1991). Although some of this mental content can be related to “postarousal” events (e.g., fear of dying associated with autonomic activation), there exist numerous examples of imagery occurring during “prearousal” events (Fisher et al., 1974).

Prevalence Sleep terrors usually begin in childhood or adolescence but may also emerge in adulthood and tend to persist longer in life than does sleepwalking (Kales et al., 1980c). Many children with sleep terror will report sleepwalking at a later age (Klackenberg, 1987). The overall prevalence of sleep terror in children range from 1% to 18% with a peak prevalence between the ages of 5 to 7 years (Simonds and Parraga, 1982; Klackenberg, 1982, 1987; Salzarulo and Chevalier, 1983; Vela-Bueno and et al., 1985; DiMario and Emery, 1987; Laberge et al., 2000; Schredl, 2001). Sleep terrors have been reported to persist in 7–36% of children affected during adolescence (DiMario and Emery, 1987; Laberge et al., 2000). The prevalence in the general adult population is about 2.2% (Ohayon et al., 1999). This prevalence declines gradually with age, and becomes about 1% at age 65 years and above (Ohayon et al., 1999). There are no significant gender differences in children (Laberge et al., 2000) and adults (Ohayon et al., 1999).

Pathophysiology Many parasomniacs present a history of both somnambulism and sleep terrors, and, as previously described, these two NREM parasomnias share many common features. Not surprisingly, factors considered as being operant in the pathophysiology of sleep terrors are similar to

those previously described for sleepwalking. Consequently, they are presented only summarily below.

PSYCHOPATHOLOGY As with somnambulism, sleep terrors in adulthood have been described in relation to various psychopathologies, but many studies have shown that such parasomnias can occur in otherwise mentally healthy individuals (Schenck et al., 1989; Espa et al., 2000; Schenck and Mahowald, 2000). That said, when compared to people with confusional arousals or sleepwalking, individuals reporting sleep terrors are the most likely to meet criteria for a DSM-IV disorder, particularly anxiety disorders (Ohayon et al., 1999).

GENETICS Although the exact mode of transmission remains uncertain, familial and twin studies suggest a significant genetic contribution to sleep terrors (Hallstrom, 1972; Debray and Huon, 1973; Kales et al., 1980a). Sleep terrors are also more frequent in families with a history of somnambulism, and vice versa (Kales et al., 1980a; Abe et al., 1984). These data and the clinical similarities between these two parasomnias suggest a common genetic predisposition and similar pathophysiological mechanisms. It has been suggested that sleepwalking is a more prevalent and less severe manifestation of the same substrate that underlies sleep terrors (Kales et al., 1980a).

ORIENTING

RESPONSE

The orienting response to auditory stimuli in patients with sleep terrors has been reported to be more intense and persistent than in normal subjects, suggesting a hyperexcitability of the nervous system in these patients (Rogozea and Florea-Ciocoiu, 1983, 1985). Furthermore, there appears to be an association between the severity of sleep terrors and the intensity of the responsiveness change (Rogozea and Florea-Ciocoiu, 1985).

Unusual sleep parameters As with sleepwalkers, patients with sleep terrors show normal sleep architecture and cycling among sleep stages (Schenck et al., 1989; Zucconi et al., 1995; Espa et al., 2000). Nevertheless, a number of unusual sleep-related processes have been identified in their sleep microstructure.

SLOW-WAVE

SLEEP AROUSALS

Compared with controls, patients with sleep terrors or a mixture of disorders of arousal (e.g., sleep terror and sleepwalking) show an increased number of arousals during SWS both in children (Benoit et al., 1978)

NREM PARASOMNIAS 859 and in adults (Broughton, 1991; Espa et al., 2000), et al. (1998) and described in the previous section on more SWS to wake transitions (Broughton, 1991), of sleepwalking also apply to sleep terrors. brief microarousals preceded by EEG slow-wave synCLINICAL VARIANTS chronization (Halasz et al., 1985), and in the number of CAP cycles (Zucconi et al., 1995). The resulting The behaviors manifested during an arousal disorder sleep fragmentation is viewed as interfering with norcan be relatively distinct and specialized. Two variants mal buildup of SWA, and one study showed that, comof NREM parasomnias involve sleep-related eating and pared with controls, SWA in patients with disorders of sleep-related sexual behaviors. arousal was significantly decreased and showed a slower rate of decay across NREM cycles (Espa Sleep-related eating disorder et al., 2000). As discussed previously, similar findings According to the International Classification of Sleep have been reported in adult sleepwalkers (Gaudreau Disorders (American Academy of Sleep Medicine, et al., 2000; Guilleminault et al., 2001). As suggested 2005), sleep-related eating disorder (SRED) consists of by Broughton (1991), these findings indicate the coexisrecurrent episodes of involuntary eating and drinking tence in patients with disorders of arousal of pressure during arousal from sleep with problematic consefor deep sleep and of a process resulting in repeated quences. SRED is classified under the “other parasomarousals during SWS. nia” section. Episodes typically occur during partial HYPERSYNCHRONOUS DELTA WAVES arousals from sleep during the first third of the night, with impaired subsequent recall (Whyte and Kavey, The presence of HSD has also been found to occur 1990; Schenck et al., 1991, 1993; Schenck and Mahowald, more frequently in the sleep EEG of patients with sleep 1994; Winkelman, 1998). Polysomnographic studies have terror than in controls (Halasz et al., 1985; Espa et al., associated SRED with a variety of underlying sleep dis2000). HSD activity, however, has a low specificity for orders, the most frequent of which is sleepwalking. the diagnosis of NREM parasomnias (Schenck et al., SRED may also be associated with restless leg syn1998; Pressman, 2004; Pilon et al., 2006). See the section drome, periodic limb movements of sleep, obstructive on sleepwalking for a more detailed account of HSD. sleep apnea, and circadian rhythm disorders (Schenck et al., 1993; Winkelman, 1998). Most of these sleep disEEG ACTIVITY PRIOR TO SLEEP TERRORS orders can precipitate NREM parasomnia episodes in Of the many findings reported in Fisher’s early studies predisposed individuals (Guilleminault et al., 2003, (Fisher et al., 1973a, 1974), one of the most salient is 2005a) and are known to increase arousals during sleep. that the severity of the sleep terror, as assessed by Although SRED can affect both sexes and all ages, heart rate increase and maximum heart rate after it is most common in young adult women (Schenck and arousal, is proportional to the duration of the precedMahowald, 1994). SRED affects up to 4% of college ing stage 3–4 sleep episode. This is true both for sponstudents (Winkelman et al., 1999) and can lead to contaneously occurring sleep terrors and for sleep terrors siderable weight gain (Schenck et al., 1993). A history induced experimentally by sounding a loud buzzer. of other parasomnias, especially sleepwalking, is also Consistent with these results, an EEG mapping study common (Winkelman, 1998). Although SRED is usuof a patient with chronic sleep terrors found that the ally not associated with the presence of waking eating EEG preceding sleep terrors contained significantly disorder, some patients present a history of current more delta power in central and frontal regions than or past daytime eating disorder such as anorexia nercontrol EEG sections, and that prearousal delta power vosa or bulimia (Schenck et al., 1991; Winkelman, was proportional to the sleep terror’s intensity (Zadra 1998), and SRED is reported more frequently in and Nielsen, 1998). Similarly, Espa et al. (2000) found patients with daytime eating disorders than in nonpsythat the time course of SWA on the central derivation chiatric populations (Winkelman et al., 1999). prior to behavioral episodes in patients with arousal SRED has been reported in association with medidisorder (sleepwalking, sleep terrors, or both) was precations such as zolpidem (Harazin and Berigan, ceded by an increase in SWA, with the main increase 1999; Morgenthaler and Silber, 2002; Schenck et al., occurring immediately prior to the episode. 2005) and triazolam (Menkes, 1992). Some medications have been reported to be effective for the EEG during sleep terrors treatment of SRED such as topiramate (Winkelman, The EEG activity during sleep terror is neither fully 2003), a combination of dopaminergic and opiate asleep nor fully awake (Fisher et al., 1973a). The three agents (Schenck and Mahowald, 2002a), or pramipexmain postarousal EEG patterns identified by Schenck ole (Provini et al., 2005).

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Sleep-related abnormal sexual behaviors Sleep-related abnormal sexual behaviors (SRASBs) consist of inappropriate sexual activity occurring without conscious awareness during sleep (Mahowald et al., 2005). Other terms proposed for these episodes include “atypical sexual behavior during sleep,” “sexsomnia,” and “sleep sex” (Wong, 1986; Buchanan, 1991; Fenwick, 1996; Rosenfeld and Elhajjar, 1998; Alves et al., 1999; Guilleminault et al., 2002; Shapiro et al., 2003). SRASB can range from sexual vocalizations or sexualized bodily movements to violent masturbation or sexual assaults, and have been reported as being markedly different from behaviors normally initiated during the patient’s waking state (Guilleminault et al., 2002; Shapiro et al., 2003). According to the International Classification of Sleep Disorders, 2nd edition (ICSD-2) (American Academy of Sleep Medicine, 2005), SRASB is classified in the Disorders of Arousal section as a clinical subtype of confusional arousal. One polysomnographic study found that disorder of arousals were the most frequent sleep disorders associated with SRASB, and that the condition could also occur in association with REMsleep behavior disorder (RBD) or NREM complex partial seizures (Guilleminault et al., 2002). SRASB may give rise to a variety of negative emotions and cognitions including feelings of embarrassment, guilt, shame, or depression, often carries interpersonal consequences (Guilleminault et al., 2002; Mangan, 2004), and has potential medicolegal implications (Guilleminault et al., 2002; Shapiro et al., 2003). The use of clonazepam, sometimes in association with psychotherapy or stress management, has been reported to be effective for the treatment of SRASB (Guilleminault et al., 2002).

NREM PARASOMNIAS ASSOCIATED WITH PRIMARY SLEEP DISORDERS Several lines of evidence indicate that in both children and adult populations sleep terrors and sleepwalking can be secondary to sleep respiratory events, such as obstructive sleep apnea (OSA) and upper airway resistance syndrome, or to other sleep disorders. Parentreported parasomnias in children with OSA suggest that sleep terrors and sleepwalking are more frequent in sleep-disordered children than in normative controls (Owens et al., 1997). Similar results were reported by Ipsiroglu et al. (2002). A population-based cohort study of preadolescent school-aged children showed that sleepwalking was significantly more prevalent in children with SDB (Goodwin et al., 2004). Guilleminault et al (2003) found that 49 of 84 (58%) prepubertal

children with chronic sleep terrors and sleepwalking also presented with SDB. Two other children presented with restless leg syndrome. Treatment of the precipitating sleep disorder may result in a disappearance of the disorder of arousal (Guilleminault et al., 2003). Similarly, a recent prospective study of 50 adults with chronic somnambulism found that many patients presented with SDB and that treatment of the SDB with continuous positive airway pressure or surgery controlled the sleepwalking (Guilleminault et al., 2005a). An association between adult sleepwalking and SDB has been noted by others (Ohayon et al., 1999; Espa et al., 2002).

NREM PARASOMNIAS ASSOCIATED WITH MEDICAL CONDITIONS Rarely, NREM parasomnias may develop as a result of medical or neurological conditions. De novo sleep terrors have been reported in association with a right thalamic lesion (Di Gennaro et al., 2004) and a brainstem lesion (Mendez, 1992). De novo somnambulism has been described in patients presenting with thyrotoxicosis caused by diffuse toxic goiter or Graves’ disease (Ajlouni et al., 2001, 2005). Disorders of arousal can also be triggered by medication. These include sedatives/ hypnotics (Mendelson, 1994; Harazin and Berigan, 1999), neuroleptics (Charney et al., 1979), lithium (Landry et al., 1999), minor tranquilizers, stimulants, and antihistamines (Huapaya, 1979; Mahowald and Schenck, 2000a).

DIAGNOSTIC CONSIDERATIONS The DSM-IV and ICSD-II clinical criteria for sleepwalking and sleep terrors are presented in Table 52.2. Diagnosis of NREM parasomnias can often be made based on a detailed history, including complete description of the time course and content of sleep-related behaviors. Given that variable retrograde amnesia characterizes disorders of arousal, descriptive information from family members or a bed partner can be particularly valuable. Similarly, home video recording may also be helpful in characterizing behavioral manifestations.

Use of polysomnography When case presentations involve violent or injurious behaviors, excessive daytime sleepiness, or associated medical or neurological conditions, more extensive evaluations, including polysomnographic study with an expanded EEG montage, may be required. An expanded electroencephalogram electrode array can help differentiate NREM parasomnias from sleep-related seizures

NREM PARASOMNIAS

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Table 52.2 Clinical criteria for sleepwalking and sleep terror disorder DSM-IV diagnostic criteria

ICSD-II diagnostic criteria

Sleepwalking disorder (307.46) A. Repeated episodes of rising from bed during sleep and walking about, usually occurring during the first third of the major sleep episode B. While sleepwalking, the person has a blank, staring face, is relatively unresponsive to the efforts of others to communicate with him or her, and can be awakened only with great difficulty

Sleepwalking disorder A. Ambulation occurs during sleep

C.

C.

On awakening (either from the sleepwalking episode or the next morning), the person has amnesia for the episode D. Within several minutes after awakening from the sleepwalking episode, there is no impairment of mental activity or behavior (although there may initially be a short period of confusion or disorientation) E. The sleepwalking causes clinically significant distress or impairment in social, occupational, or other important areas of functioning F. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition Sleep Terror Disorder (307.46) A. Recurrent episodes of abrupt awakening from sleep, usually occurring during the first third of the major sleep episode and beginning with a panicky scream B.

C.

Intense fear and signs of autonomic arousal, such as tachycardia, rapid breathing, and sweating, during each episode

Relative unresponsiveness to efforts of others to comfort the person during the episode D. No detailed dream is recalled and there is amnesia for the episode E. The episodes cause clinically significant distress or impairment in social, occupational, or other important areas of functioning F. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition

B.

Persistence of sleep, an altered state of consciousness, or impaired judgment during ambulation demonstrated by at least one of the following: i. Difficulty in arousing the person ii. Mental confusion when awakened from an episode iii. Amnesia (complete or partial) for the episode iv. Routine behaviors that occur at inappropriate times v. Inappropriate or nonsensical behaviors vi. Dangerous or potentially dangerous behaviors The disturbance is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder

Sleep Terror Disorder A. A sudden episode of terror occurs during sleep, usually initiated by a cry or loud scream that is accompanied by autonomic nervous system and behavioral manifestations of intense fear B. At least one of the following associated features is present: i. Difficulty in arousing the person ii. Mental confusion when awakened from an episode iii. Amnesia (complete or partial) for the episode iv. Dangerous or potentially dangerous behaviors C. The disturbance is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder

DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edn; ICSD-II, International Classification of Sleep Disorders, 2nd edn.

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as well as other sleep disorders such as RBD. Polysomnography is also required to identify primary sleeprelated disorders (e.g., SDB, periodic limb movement disorder) that may underlie the parasomnia. In all cases, continuous audiovisual monitoring is essential to document behavioral manifestations and to correlate videotaped events with polysomnographic characteristics. Diagnosing NREM parasomnias with objective instruments such as polysomnography can be difficult as episodes rarely occur in the sleep laboratory. Indirect evidence supporting a diagnosis can take the form of an increased frequency of arousals and microarousals from SWS, but these events are not specific to the arousal disorders. Two techniques that may increase the probability of recording more complex behavioral manifestations are sleep deprivation and the presentation of auditory stimuli during SWS. When compared to baseline recordings, one study found that 40 hours of sleep deprivation resulted in a fivefold increase in the number of somnambulistic episodes recorded in the sleep laboratory (Joncas et al., 2002). In addition, a significant increase in the complexity of the episodes recorded was observed during the recovery night. A subsequent study revealed that 25 hours of sleep deprivation was also effective in increasing both the frequency and the complexity of somnambulistic events recorded in the sleep laboratory (Pilon et al., 2005a). All but two of the 27 patients investigated in these studies had at least one behavioral episode during recovery sleep. The fact that none of the control subjects investigated in these studies experienced nocturnal behavioral manifestations in the laboratory demonstrates that sleep deprivation alone does not lead to somnambulistic episodes, but rather that it increases the probability of somnambulistic behaviors among those so predisposed. These results thus provide further evidence that sleep

deprivation can be a valuable tool that facilitates the polysomnographically based diagnosis of this sleep disorder, and suggest high sensibility for adult sleepwalkers. Early studies of a small sample of young sleepwalkers found that behavioral events could be induced by standing the child on his or her feet during SWS (Gastaut and Broughton, 1965; Kales et al., 1966; Broughton, 1968; Broughton and Gastaut, 1974). In one study, two episodes were triggered during a child’s SWS by calling his name (Kales et al., 1966). Similarly, sleep terrors can be precipitated in predisposed individuals by sounding a loud buzzer (Fisher et al., 1970, 1973a). It has been suggested that the probability of recording somnambulistic or sleep terror events can be further increased by simultaneously combining factors that deepen sleep (e.g., intense physical activity, sleep deprivation, neuroleptics) with those that fragment sleep (e.g., stress, environmental or endogenous stimuli (Broughton, 1991; Espa et al., 2000; Besset and Espa, 2001). One pilot investigation (Pilon et al., 2005b) assessed this hypothesis in eight adult sleepwalkers and five controls under controlled conditions by combining 25 hours of sleep deprivation with the presentation of auditory stimuli. As shown in Table 52.3, the auditory stimulations precipitated somnambulistic episodes in approximately 15% of the trials administered during sleepwalkers’ SWS at baseline and in 40% of the trials presented during their postsleep deprivation SWS. No somnambulistic episodes were induced in controls either during their SWS at baseline (0 in 24 trials) or after sleep deprivation (0 in 29 trials). These results support the hypothesis that the combination of sleep deprivation and external stimulation increases the probability of recording behavioral episodes in the sleep laboratory.

Table 52.3 Characteristics of induced somnambulistic events and of auditory stimulations administered during slow-wave sleep before and after 25 hours of sleep deprivation in eight adult sleepwalkers

Total number of induced episodes during SWS Number of patients experiencing at least one induced episode during SWS Mean (SD) frequency of induced episodes during SWS Mean (SD) number of auditory stimulations during SWS Success in inducing an episode with an auditory stimulation during SWS Mean (SD) intensity (in dB) of the auditory stimulations that induced behavioral episodes ns, Not significant; SWS, slow-wave sleep.

Baseline sleep

Recovery sleep

P

4 3/8 (38%) 0.5 (0.8) 3.5 (2.3) 4/28 (14%) 56.7 (11.5)

15 8/8 (100%) 1.9 (0.8) 4.6 (3.2) 15/37 (41%) 54.0 (12.4)

– <0.05 <0.05 ns <0.05 ns

NREM PARASOMNIAS

Differential diagnosis Disorders of arousal need to be distinguished from nightmare disorder, RBD, complex partial seizures, and nocturnal panic attacks. Nightmares are vivid and disturbing mental experiences that generally occur during REM sleep and often result in awakening (American Academy of Sleep Medicine, 2005). They can be distinguished from sleep terrors by their usual occurrence during the second half of the night, when REM is most prominent, and by the recall of detailed dream content. The degree of automatic activation (e.g., palpitations and dyspnea) is much greater during sleep terrors and there is an absence of mental confusion upon awakening from a nightmare as opposed to a sleep terror. Actual screaming or other intense vocalizations that can characterize sleep terrors are rare during nightmares. RBD is characterized by intermittent loss of REMsleep atonia and by the appearance of elaborate motor activity associated with dream mentation during REM sleep (Schenck et al., 1986; Schenck and Mahowald, 2002b). Patients usually have a vivid recall of the dreams, which appear to correlate with observed behaviors (Schenck and Mahowald, 2002b). RBD can be also be distinguished from NREM parasomnias by its usual occurrence during the second half of the night and by the absence of mental confusion upon awakening. However, some patients may have behavioral manifestations during both REM and NREM sleep with RBD occurring in combination with a disorder of arousal (Bokey, 1993; Kushida et al., 1995; Schenck et al., 1997). This a condition known as parasomnia overlap disorder (Schenck et al., 1997). Disorders of arousal and complex partial epileptic seizures share several clinical similarities (e.g., sudden onset, unresponsiveness, retrograde amnesia) and precipitating factors (e.g., sleep deprivation). Nocturnal frontal lobe epilepsy can be particularly difficult to differentiate from NREM parasomnias, especially in children (Zucconi and Ferini-Strambi, 2000). Complex partial seizures usually involve repetitive stereotypical behaviors and patients rarely return to bed. Epileptic seizures may occur in any sleep stages throughout the sleep period. Similar seizure activity may occur during daytime wakefulness. Sleep terrors and seizures may coexist in the same person (Tassinari et al., 1972). Approximately 50% of all patients with panic disorder have nocturnal panic attacks which are characterized by intense fear or discomfort accompanied by cognitive and physical symptoms of arousal (American Psychiatric Association, 1994). These attacks are comparable to panic attacks experienced in the daytime and they may sometimes be clinically similar to sleep

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terrors (Craske and Tsao, 2005). Nocturnal panic attacks usually occur in late stage 2 or early stage 3 sleep (Craske and Tsao, 2005) and, unlike many sleep terrors, patients do not become physically agitated or aggressive during the panic attack. Immediately after a nocturnal panic attack, patients are oriented, can vividly recall their attack, and usually have difficulty returning to sleep (i.e., suffer from insomnia); these features differ from those observed in patients with sleep terrors.

TREATMENT Several factors must be taken into account while considering treatment options for disorders of arousal. These include the frequency and chronicity of the episodes, the potential danger to the patient or to others, and the disruptive nature of the disorder for the patient, bed partner, or family. When the episodes are benign and not associated with harm potential, treatment is often unnecessary (Mahowald and Schenck, 1996). Reassuring the patient and significant others about the generally benign nature of the episodes and demystifying the events is sometimes sufficient. Efforts should be made to identify and avoid potential precipitating factors, such as sleep deprivation, stress, and environmental disturbances. Precautions should be taken to ensure a safe sleep environment for patients with sleep terrors or agitated somnambulism. Preventive measures can include the removal of obstructions in the bedroom, securing windows, sleeping on the ground floor, installing locks or alarms on outsides doors, covering windows with heavy curtains, using a nightlight, placing barriers in stairways, and removing all sharp or otherwise dangerous objects. As previously discussed, people reporting sleep terrors or somnambulism may suffer from SDB, including OSA and upper airway resistance syndrome. In these cases, treatment of the primary sleep disorder with nasal continuous positive airway pressure or surgical treatment for the SDB should result in the alleviation and control of the parasomnia.

Pharmacological treatments Generally, pharmacological agents should be considered only if the behaviors are hazardous or extremely disruptive to the bed partner or other household members (Nino-Murcia and Dement, 1987). Benzodiazepines (e.g., low doses of clonazepam or diazepam) and tricyclic antidepressants (e.g., imipramine) can be effective (Fisher et al., 1973b; Reid, 1975; Cameron and Thyer, 1985; Cooper, 1987; Schenck and Mahowald, 1996; Remulla and Guilleminault, 2004). Results of a randomized study in children with sleep terrors indicated

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satisfactory treatment with L-5-hydroxytryptophan (Bruni et al., 2004). Anecdotal reports suggest that melatonin may also be effective in children (Jan et al., 2004). However, pharmacotherapy does not always result in adequate control of NREM parasomnias such as sleepwalking (Guilleminault et al., 2005a).

Nonpharmacological treatments A variety of nonpharmacological treatments has been recommended for long-term management of NREM parasomnias. Hypnosis (including self-hypnosis) has received the most attention, and this relatively brief form of intervention has been found to be effective in both children and adults with sleep terrors or sleepwalking (Clement, 1970; Eliseo, 1975; Taboada, 1975; Reid and Gutnik, 1980; Reid et al., 1981; Gutnik and Reid, 1982; Koe, 1989; Hurwitz et al., 1991; Kohen et al., 1992). Other treatment options include psychotherapy (Kales et al., 1982) and progressive relaxation (Kellerman, 1979). Positive results have also been reported with scheduled or anticipatory awakenings in children with sleep terrors or sleepwalking (Lask, 1988, 1993; Tobin, 1993; Frank et al., 1997; Durand and Mindell, 1999; Durand, 2002). This technique involves briefly awakening the patient approximately 15–30 minutes prior to the expected episode. The procedure is repeated nightly for up to a month. Reports suggest that improvements can be maintained for several months after the end of the treatment and that the intervention may result in a significant reduction in the frequency of these parasomnias. Irrespective of which approach is adopted, treatment should include instructions on sleep hygiene and stress management. The aforementioned safety recommendations should also be provided.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 53

REM sleep parasomnias JACQUES MONTPLAISIR 1,2 *, JEAN-FRANC¸OIS GAGNON 1, 2, RONALD B. POSTUMA 1, 3, AND ME´LANIE VENDETTE 1, 4 1 Centre d’tude du Sommeil et des Rythmes Biologiques, Hpital du Sacr-Coeur de Montral, Universit de Montral, Montreal, Canada 2 3

Department of Psychiatry, Universit de Montral, Montreal, Canada

Department of Neurology, Montreal General Hospital, McGill University, Montreal, Canada 4

Department of Psychology, Universit de Montral, Montreal, Canada

INTRODUCTION Rapid eye movement (REM) sleep parasomnias are defined as disorders in which undesirable physical phenomena occur predominantly during REM sleep. REM parasomnias encompass abnormal sleep-related movements, behavior, emotions, and dreaming. Three conditions are commonly identified as REM sleep parasomnias, namely REM sleep behavior disorder (RBD), recurrent isolated sleep paralysis, and nightmare disorder (American Academy of Sleep Medicine, 2005). This chapter focuses on RBD as nightmares are treated separately elsewhere in this book.

REM SLEEP BEHAVIOR DISORDER Definition and description RBD is characterized by abnormal and often violent behaviors associated with dream mentation that cause sleep disruption and/or injuries to the patient or bed partner. It is accompanied by electromyographic (EMG) abnormalities in REM sleep, consisting of excess muscle tone and/or phasic EMG activity (American Academy of Sleep Medicine, 2005). RBD was formally identified as a distinct sleep disorder in humans by Schenck and coworkers in 1986.

BEHAVIORS Behaviors can range from simple motor activities such as laughing, talking, shouting, or excessive body and limb jerking to complex, seemingly purposeful and

goal-directed behavior, such as gesturing, punching, kicking, sitting up, leaping from bed, and running (American Academy of Sleep Medicine, 2005; Frauscher et al., 2007). Movements generally appear to act out the dream content: in two large series, dream-enacting behavior was present in 87% and 93% of nocturnal episodes (Schenck et al., 1993; Olson et al., 2000). Nocturnal behavior may have serious consequences, especially physical injuries to the patient or bed partner. In a large number of cases, medical attention is sought only after sleep-related injuries occurred. Common injuries include ecchymoses, lacerations, and fractures (Schenck et al., 1993). Severe injuries have been reported, including C2 vertebral fracture and subdural hematoma. Sleep-related injury was the reason for consultation in 79% of patients studied by Schenck et al. (1993), and was present in 96% of those studied by Olson et al. (2000). Therefore, we can conclude that RBD carries a significant risk for severe injury to both self and bed partner (Schenck and Mahowald, 2002). Sleep-related behavior may also cause severe sleep disruption for the bed partner and lead to major marital discord, mood changes, and even suicide attempts (Yeh and Schenck, 2004).

DREAMING Interestingly, a majority of patients report more vivid dreaming coincident with the onset of RBD (Schenck and Mahowald, 2002). A characteristic feature of RBD is the occurrence of specific and somewhat stereotyped dream content irrespective of individual psychological

*Correspondence to: Jacques Montplaisir, Centre d’E´tude du Sommeil et des Rythmes Biologiques, Hoˆpital du Sacre´-Coeur de Montre´al, Universite´ de Montre´al, Canada, E-mail: [email protected]

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profiles. Patients with RBD commonly report dreams of fighting in which they are usually defending themselves against attacking animals or unfamiliar individuals. Fear and anger are the most commonly associated emotions. It has been observed that the aggressiveness displayed during nocturnal behaviors contrasts with the often placid and mild-mannered daytime temperament (Schenck and Mahowald, 2002). This clinical observation was tested recently in a controlled study where dream characteristics and daytime aggressiveness were assessed in RBD patients and age- and sex-matched normal controls (Fantini et al., 2005a). This study confirmed that dreams of patients with RBD are characterized by an increased proportion of aggressive content, despite normal levels of daytime aggressiveness. The mechanism by which dream content is changed is unclear. It should be kept in mind that persons recall dreams much more reliably if they are awakened by them. In RBD, aggressive dreams are accompanied by excessive motor activity and are more likely to wake up the patient. Therefore, a proportion of this apparent difference in dream content between patients with RBD and control subjects may represent selective awakening.

POLYSOMNOGRAPHIC

RECORDING

REM sleep without atonia and increased phasic EMG activity in REM sleep Early studies reported a substantial loss of REM sleep muscle atonia in patients with RBD. For example, three large series reported that 92–100% of patients had some loss of REM sleep muscle atonia (Schenck et al., 1993; Sforza et al., 1997; Olson et al., 2000). However, these studies did not use any specific method to quantify REM sleep and REM sleep muscle atonia in patients with RBD (see the section on diagnosis, below). Changes in REM sleep in patients with RBD seem to be restricted to the excessive tonic and phasic motor activity (Figure 53.1). All other features of REM sleep, including REM latency, REM percentage, number of REM periods, and REM/nonREM cycling, are usually preserved. Slow-wave sleep Schenck et al. (1993) originally reported an increased proportion of slow-wave sleep (stages 3 and 4) in patients with RBD. In one series, 80% of patients over the age of 50 years had more than 15% of sleep time

Fig. 53.1. Polysomnographic recording of a typical patient with REM sleep behavior disorder (RBD) showing REM sleep without atonia. Rapid eye movements are present and the central lead shows desynchronized electroencephalographic activity, two features of REM sleep. Excessive muscle activity, which characterizes RBD, can be observed on chin and leg electromyographic leads. Modified from Gagnon et al. (2002b).

REM SLEEP PARASOMNIAS spent in slow-wave sleep (this was not associated with prior sleep deprivation). In the Mayo Clinic series, 33% of patients over the age of 58 years had more than 15% slow-wave sleep (Olson et al., 2000). These observations were confirmed in a controlled study of 28 patients with idiopathic RBD and 28 age- and sex-matched healthy volunteers, in whom both nocturnal sleep organization and EEG spectral analysis during sleep revealed increased time in slow-wave sleep and higher all-night delta power in patients with RBD in comparison with control subjects (Massicotte-Marquez et al., 2005). Periodic leg movements in sleep Another polygraphic characteristic of RBD is the presence of periodic leg movements in sleep (PLMS). Most of what is known about PLMS comes from the study of patients with the restless legs syndrome (RLS), in whom PLMS indices are strikingly increased. In a recent study of RBD and RLS, patients with RBD showed a mean PLMS index of 39.5 per hour of sleep, a value not significantly different from the mean PLMS index found in patients with RLS (Fantini et al., 2002). In this study, 70% of patients with RBD had a PLMS index greater than 10. This percentage is similar to the prevalence of PLMS previously reported in RLS and significantly higher than the prevalence rate found in healthy subjects of the same age (Fantini et al., 2004). One difference between the two groups was that in patients with RBD the higher PLMS index occurred mainly during REM sleep; this is most likely the result of the lack of motor inhibition during REM sleep in this condition, and may suggest that PLMS have a different pathophysiological basis in RBD. Also, PLMS were significantly less likely to be associated with microarousals in RBD compared with findings in patients with RLS. In addition, several studies have shown an autonomic activation, such as a transient tachycardia lasting approximately 10 seconds followed by a bradycardia in association with PLMS in patients with RLS (Fantini et al., 2002; Gosselin et al., 2003). A similar but markedly reduced-amplitude cardiac response and EEG response was found in patients with RBD (Fantini et al., 2002). This decreased cardiac and EEG response may suggest the presence of dysautonomia and/or reduced cortical reactivity in RBD (see the section on autonomic changes, below).

Diagnosis INTERNATIONAL CLASSIFICATION 2005

OF SLEEP

DISORDERS

Until recently, the diagnosis of RBD was based on clinical manifestations, namely the presence of limb or

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body movements associated with dream mentation, and at least one of the following: (1) harmful or potentially harmful sleep behaviors during sleep; (2) dreams that appear to be “acted out”; and (3) sleep behaviors that disrupt sleep continuity (American Sleep Disorders Association, 1997). Polysomnographic (PSG) observations of patients were not necessary for diagnosis. However, several authors have stressed the limitations of these criteria (Eisensehr et al., 2001; Gagnon et al., 2002a; Vignatelli et al., 2003; Consens et al., 2005; Schenck, 2005). RBD-like features can occur with other sleep conditions, such as obstructive sleep apnea syndrome, sleepwalking, night terrors, and sleep-related seizures. Therefore it is important to ensure that behavioral manifestations occur exclusively during REM sleep. Finally, polysomnography allows the detection of subclinical forms of RBD wherein REM sleep without atonia is seen in the absence of behavioral manifestations. In the second version of the International Classification of Sleep Disorders, PSG features are essential to establish the diagnosis (American Academy of Sleep Medicine, 2005). These diagnostic criteria are listed in Table 53.1. The first essential criterion is the presence of REM sleep without atonia, that is the EMG finding of excessive amounts of either sustained or intermittent elevation of submental EMG activity or excessive phasic submental or limb EMG twitching. The second criterion is the presence of either sleeprelated injurious or disruptive behaviors by history, or abnormal REM sleep behaviors documented during PSG recording. Time-synchronized video recording is essential for helping establish the diagnosis of RBD Table 53.1 Diagnostic criteria for REM sleep behavior disorder (International Classification of Sleep Disorders) 1.

Presence of REM sleep without atonia: electromyographic finding of excessive amounts of sustained or intermittent elevation of submental electromyographic tone or excessive phasic submental or (upper or lower) limb electromyographic twitching 2. At least one the following is present: ● Sleep-related injurious, potentially injurious, or disruptive behaviors by history ● Abnormal REM sleep behaviors documented during polysomnographic monitoring 3. Absence of electroencephalographic epileptiform activity during REM sleep unless RBD can be clearly distinguished from any concurrent REM-related seizure disorder 4. The sleep disturbance is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder

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during polysomnography. The last two criteria are exclusion criteria, namely the absence of epileptiform activity during REM sleep and the presence of other sleep disorders, medical or neurological disorders that could better explain the sleep disturbance.

SLEEP

LABORATORY DIAGNOSIS OF

RBD

One limitation of these new criteria is the absence of a validated and universally accepted method for scoring REM sleep in RBD. Assessing REM sleep without atonia by using standard criteria is impossible – muscle atonia is an essential defining criterion for REM sleep (Rechtschaffen and Kales, 1968), and therefore REM sleep cannot be identified formally in the presence of tonic EMG activity. Lapierre and Montplaisir (1992) developed a scoring method for REM sleep based on EEG and EOG alone (Table 53.2). As muscle atonia is deficient in RBD, REM sleep is scored without requiring submental EMG atonia. In this method, the occurrence of the first rapid eye movement is used to determine the onset of the REM sleep period. The termination of the REM sleep period is identified either by the occurrence of specific EEG features of a different sleep stage (K-complexes, sleep spindles, EEG signs of arousals), or by the absence of rapid eye movements for three consecutive minutes. Then, tonic and phasic components of REM sleep are scored separately. Each epoch is scored as tonic or atonic depending on whether tonic chin EMG activity is present for more or less than 50% of the epoch duration. Phasic EMG density is also scored from the submental EMG recording, and is expressed as the percentage of mini-epochs (2 or 3 seconds depending on epoch duration of 20 or 30 seconds)

Table 53.2 Scoring method for RBD (Lapierre and Montplaisir, 1992) 1.

REM sleep is scored on the basis of EEG and EOG alone Onset of a REM sleep period ¼ occurrence of the first rapid eye movement ● Termination of a REM sleep period ¼ occurrence of a specific EEG feature indicative of another stage (K-complex, sleep spindle, or EEG sign of arousal) or absence of rapid eye movements during three consecutive minutes 2. Atonia: each epoch is scored as tonic or atonic depending on whether tonic chin EMG activity (>10 mV) is present for more or less than 50% of the epoch 3. Phasic events: percentage of 2- or 3-second mini-epochs of REM sleep with phasic EMG activity (EMG bursts <5 seconds and four times the amplitude of background EMG) ●

containing phasic EMG events. Those phasic EMG events are defined as any burst of EMG activity lasting 0.1–5 seconds with an amplitude exceeding four times the background EMG activity. It was shown recently that the short EMG bursts (less than 100 milliseconds) are not more frequent in patients with RBD compared with normal controls, and therefore these EMG activities are not included in the scoring (Eisensehr et al., 2003a). This method has been used subsequently to select patients with RBD in several research programs (Gagnon et al., 2002a; Rompre´ et al., 2004; Gagnon et al., 2004, 2006a). A similar method was used recently to assess 17 patients at risk for secondary to neurodegenerative diseases and 6 normal controls (Consens et al., 2005). The tonic and phasic measures combined together were found to be higher in patients with clinically defined probable or possible RBD. However, this study used the Rechtschaffen and Kales’ criteria for scoring REM sleep, the limitations of which were described above. Further studies are needed to validate PSG methods for diagnosing and assessing severity in RBD.

DIFFERENTIAL

DIAGNOSIS

RBD is a relatively rare condition and largely unknown to most physicians; therefore it is not surprising that it is often misdiagnosed and mistreated. A complaint of nocturnal disrupting behaviors is the major clinical feature of several other conditions, such as primary and secondary disorders of arousal, dreaming, and panic disorders. Primary arousal disorders include nocturnal confusional arousals, sleepwalking, and night terrors. In contrast to RBD, sleepwalking and night terrors are more frequent in children and rarely appear de novo in middle-aged or elderly individuals. Primary arousal disorders are also characterized by confusion and retrograde amnesia upon awakening at the time of nocturnal episodes; these phenomena are not seen in patients with RBD. Polysomnography reveals that the nocturnal spells of arousal disorders arise out of stages 3 and 4 slow-wave sleep and not from REM sleep; therefore they typically take place early during the night when these sleep stages are more abundant. Secondary disorders of arousal include obstructive sleep apnea and nocturnal epilepsy. Recently, Iranzo and Santamaria (2005) studied 16 patients presenting with unpleasant dreams and dream-enacting behaviors in addition to severe obstructive sleep apnea. The sleep laboratory investigation revealed neither loss of REMsleep muscle atonia nor increased chin EMG phasic activity. Continuous positive airway pressure therapy eliminated the abnormal nocturnal behaviors. These

REM SLEEP PARASOMNIAS 873 cases illustrate the importance of recording patients in with age-matched controls (Winkelman and James, the laboratory to accurately diagnose RBD. Nocturnal 2004). The authors concluded that individuals taking epilepsy may also mimic symptoms of RBD (Manni these antidepressants may be at increased risk of develet al., 2007). As for obstructive sleep apnea syndrome, oping RBD. Antidepressant agents can also induce polysomnography will be mandatory to make the diagRBD and/or REM sleep without atonia in patients with nosis (obstructive sleep apnea syndrome and nocturnal parkinsonism (Onofrj et al., 2003), depression (Schenck epilepsy are discussed in detail elsewhere in this et al., 1992), or narcolepsy (Guilleminault et al., 1976; volume). Bental et al., 1979; Schenck and Mahowald, 1992; Attarian et al., 2000). The development and the exacerPrimary and secondary RBD bation of RBD have also been reported with noradrenergic medications, such as bisoprolol (Iranzo and RBD may be associated with a great variety of medical Santamaria, 1999). conditions or with the use of various psychotropic medications (Gagnon et al., 2006b, 2006c). Therefore Narcolepsy and RBD RBD has been divided into primary and secondary forms (American Academy of Sleep Medicine, 2005). RBD can be a manifestation of narcolepsy (Schenck and Mahowald, 1992; Olson et al., 2000; StiasnyKolster et al., 2005; Dauvilliers et al., 2007; Mattarozzi PRIMARY RBD et al., 2008). A recent study using mailed questionPrimary or idiopathic RBD is diagnosed when none of naires revealed that 68% of patients who regularly the conditions listed below is present. Secondary RBD experienced cataplexy, sleep paralysis, hypnagogic has been classified into acute and chronic subtypes hallucinations, and automatic behavior had RBD, comdepending on the time course of clinical manifestations pared with 14% of those who rarely or never experi(American Academy of Sleep Medicine, 2005). enced these symptoms (Nightingale et al., 2005). This association could be expected as both narcolepsy and ACUTE SECONDARY RBD RBD are two forms of REM sleep dyscontrol (state– boundary dysregulation). Acute RBD is usually associated with intoxication or withdrawal from psychotropic substances. Caffeine abuse, tricyclic antidepressants, biperidin, and monoamine oxidase inhibitors have been reported to be associated with RBD. Withdrawal from alcohol or from medications such as meprobamate, pentazocine, barbiturate, and nitrazepam can also trigger episodes of acute RBD (for review, see Mahowald and Schenck, 2005).

CHRONIC

SECONDARY

RBD

Chronic secondary RBD may occur during long-term use of medications (drug-induced RBD) or in association with narcolepsy and several other neurological conditions. Drug-induced RBD RBD and/or REM sleep without atonia have been reported in patients taking cholinesterase inhibitors for Alzheimer’s disease (AD) (Carlander et al., 1996; Ross and Shua-Haim, 1998) and in patients taking monoamine oxidase inhibitors (Akindele et al., 1970; Louden et al., 1995) or tricyclic antidepressants (Passouant et al., 1972; Besset, 1978; Niiyama et al., 1993). One recent controlled study showed that patients taking newer serotonergic agents (fluoxetine, paroxetine, citalopram, sertraline, and venlafaxine) had more activity in the submental EMG recording compared

RBD and neurodegenerative disorders RBD is particularly frequent in neurodegenerative disorders characterized by intraneuronal deposition of a-synuclein (synucleinopathies), such as Parkinson’s disease (PD), multiple system atrophy (MSA), and Lewy body dementia (LBD) (see chapter on PD and neurodegenerative disorders). The presence of REM sleep without atonia was first noted in PD in the late 1960s (April, 1966; Stern et al., 1968; Traczynska-Kubin et al., 1969), long before the recognition of RBD as a clinical entity. Since then, several studies have also reported behavioral manifestations of RBD in these patients. Based on clinical diagnostic criteria, 15–60% of patients with PD have been estimated to have symptoms of RBD (Comella et al., 1998; Scaglione et al., 2005; De Cock et al., 2007a; Gjerstad et al., 2008). In a sleep laboratory study, one-third (11 of 33) of patients with PD had RBD based on PSG criteria (Gagnon et al., 2002a). REM sleep without atonia but without behavioral manifestations (subclinical RBD) was noted in 8 additional patients. Therefore, REM sleep without atonia may be present in more than 50% of patients with PD. In PD, the presence of hallucinations and delusions is associated with a higher prevalence of RBD (Pacchetti et al., 2005).

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Several studies have shown a very high association between RBD and MSA (Plazzi et al., 1997; Tachibana et al., 1997; Iranzo et al., 2005a). In a sleep laboratory study of 19 patients with MSA, RBD was detected in 100% (Vetrugno et al., 2004). Therefore, RBD appears to be more prevalent in MSA than in PD. The higher prevalence of RBD in MSA may result from a distribution of neurodegeneration that is usually more widespread in MSA and includes severe atrophy of pontine structures known to be involved in maintaining muscle atonia during REM sleep. RBD is also very common in patients with LBD (Boeve et al., 1998, 2001; Ferman et al., 1999). Recently, brain histopathology of 15 patients with RBD associated with dementia or parkinsonism revealed the presence of Lewy body disease in 12 patients and MSA in 3, suggesting that the discovery of RBD in a patient with dementia may indicate the presence of an underlying synucleinopathy (Boeve et al., 2003a). Several studies have also looked for RBD in patients with other neurodegenerative disorders. Numerous cases of REM sleep without atonia and some reports of RBD have been documented in progressive supranuclear palsy (Laffont et al., 1979a, b, 1988; Pareja et al., 1996; Sforza et al., 1997; Olson et al., 2000; Rompre´ et al., 2004; Arnulf et al., 2005; De Cock et al., 2007b). REM sleep without atonia and RBD in association with AD (Gagnon et al., 2006a) and corticobasal degeneration (Kimura et al., 1997; Wetter et al., 2002; Gatto et al., 2007) have also been described, but these reports are sparse and, especially given the high prevalence of AD, may represent chance associations.

Idiopathic RBD as an indicator of presymptomatic Parkinson’s disease As more patients with so-called idiopathic RBD are studied over time, it is becoming increasingly clear that more than 50% will eventually develop neurodegenerative disorders, especially PD. For example, Schenck et al. (1996) found that a parkinsonian syndrome developed in 38% of 29 patients initially diagnosed with idiopathic RBD after 5 years of follow-up. Seven years later, 65% of patients from the same cohort had developed a parkinsonian syndrome (Schenck et al., 2003). Conversely, RBD is frequent in PD (Comella et al., 1998; Gagnon et al., 2002a; Iranzo et al., 2005a), where it often precedes by several years the appearance of the first motor symptoms (Olson et al., 2000; Iranzo et al., 2006). As patients with RBD are at risk of developing PD, recent studies have looked at a variety of potential early markers of PD in patients with idiopathic RBD who were free of parkinsonism.

OLFACTORY

AND COLOR VISION DYSFUNCTION

Significant abnormalities in olfactory discrimination have been described in the earliest stages of PD (Katzenschlager and Lees, 2004; Ponsen et al., 2004). A recent staging system of PD by Braak et al. (2003) has indicated that the olfactory bulb degenerates before the substantia nigra pars compacta is involved, suggesting that these abnormalities may be present before motor manifestations are evident. Several studies have reinforced this hypothesis. For example, a study of asymptomatic relatives of patients with PD revealed that olfactory impairment was correlated with a decline in presynaptic binding to the dopamine (DA) transporter, as measured by 123I-FP-CIT SPECT (123I-labelled N-(3-fluoropropyl)-2b-carbomethoxy-3b(4-iodophenyl)nortropane single-photon emission computed tomography) (Ponsen et al., 2004). A prospective study from the Honolulu Study of Aging found that persons in the highest tertile of olfactory function at baseline were at lower risk of developing PD (Ross et al., 2005). Recently, three different groups have found olfactory dysfunction in patients with idiopathic RBD, in the absence of clinical parkinsonism (Fantini et al., 2005b; Stiasny-Kolster et al., 2005; Postuma et al., 2006). Color vision abnormalities have also been demonstrated in patients with PD (Bu¨ttner et al., 1995; Diederich et al., 2002; Mosimann et al., 2004). Although this deficit of color discrimination has been known for more than 10 years, there is still controversy as to whether it is present early in the disease and whether it is primary or secondary to motor requirements of the tasks used to assess it. Recently, a significant loss of color vision discrimination was reported in idiopathic RBD without parkinsonism, supporting the hypothesis that color vision dysfunction is an early and possibly presymptomatic marker of PD (Postuma et al., 2006). Olfactory and color discrimination impairments are closely correlated to the motor abnormalities detected in idiopathic RBD, suggesting the same underlying disease process (Postuma et al., 2006).

AUTONOMIC

CHANGES

Autonomic dysfunction is common in PD and may occur early in the disease course (Chaudhuri, 2001). In a recent study, patients with idiopathic RBD had a higher prevalence of symptoms and signs of orthostatic hypotension, erectile dysfunction, and constipation, compared with normal controls (Postuma et al., 2006). A reduction of tonic and phasic heart rate variability has also been observed during sleep and wakefulness in several patients with RBD (Ferini-Strambi et al., 1996). In addition, patients with RBD have a lower cardiac and EEG

REM SLEEP PARASOMNIAS response in association with PLMS (Fantini et al., 2002). Moreover, a reduction of cardiac 123I-MIBG (123Ilabelled meta-iodobenzylguanidine) uptake, consistent with the loss of sympathetic terminals, and an absence of REM-related cardiac and respiratory responses have also been reported in idiopathic RBD (Miyamoto et al., 2006; Lanfranchi et al., 2007). These results suggest the presence of a dysfunction of the autonomic system and of cortical reactivity to internal stimuli in idiopathic RBD, similar to those found in PD. Autonomic dysfunction in PD is probably due to degeneration of postganglionic neurons in the peripheral autonomic ganglia, and this may be the case in RBD. However, it is possible that autonomic changes seen in RBD may be also related to dysfunction of preganglionic structures in the lower brainstem, as is seen in MSA.

OTHER SIMILARITIES BETWEEN RBD AND PARKINSON’S DISEASE Additional abnormalities were reported in RBD, similar to those found in PD. These include subtle abnormalities on quantitative motor testing, EEG spectral analysis, and changes in cognitive performances. In a recent study of 25 patients with idiopathic RBD, subtle motor manifestations, usually bradykinesia, were frequent (Postuma et al., 2006). Significant differences were found between RBD and controls for the alternate tap test and the timed up-and-go test (i.e., quantitative motor indices), but between-group differences were less dramatic for quantitative motor testing than for color vision and olfaction (Postuma et al., 2006). Slowing of the waking EEG has been documented in nondemented patients with PD (Neufeld et al., 1988; Soikkeli et al., 1991). Subsequently, slowing of the waking EEG, characterized by an increase in theta power in frontal, temporal, and occipital brain areas, was found in idiopathic RBD without parkinsonism (Fantini et al., 2003a). Compared with healthy controls, patients with idiopathic RBD also had a decrease in the posterior dominant frequency, an EEG characteristic often noted in PD. Recently, EEG spectral analysis was reassessed in nondemented patients with PD with and without RBD (Gagnon et al., 2004). Only patients with associated RBD showed slowing of the EEG; patients with PD without RBD did not have any EEG abnormalities. Moreover, cerebral blood flow abnormalities, similar to those observed in PD and LBD, have been reported in idiopathic RBD (Caselli et al., 2006; Mazza et al., 2006). Neuropsychological studies of patients with PD and LBD show a cognitive profile characterized by visuospatial constructional abnormalities, verbal and

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nonverbal learning impairment predominantly affecting retrieval processes, and executive dysfunction (Emre, 2003; McKeith et al., 2004). Similar, but milder, impairment of verbal and nonverbal learning, visuospatial constructional abilities, and attention/executive functions has been found in patients with idiopathic RBD (Fantini et al., 2003a; Ferini-Strambi et al., 2004; Massicotte-Marquez et al., 2008; Terzaghi et al., 2008). In patients with PD, the presence of RBD may be a risk factor for cognitive impairment (Sinforiani et al., 2006; Vendette et al., 2007; Marion et al., 2008). The high prevalence of abnormalities on ancillary testing raises the question of the validity of the diagnosis of idiopathic RBD. The term “idiopathic” implies that the patient has not met the criteria for a neurodegenerative disorder, but it must be understood that a significant proportion of these patients may have incipient neurodegenerative disease, especially a synucleinopathy. Although we continue to classify these patients as having idiopathic RBD, further follow-up will help to define which of these patients have truly idiopathic RBD, and which have RBD as an early manifestation of neurodegeneration. On the ancillary tests described above, there is substantial heterogeneity among patients with RBD. In other words, patients with RBD can be divided into subsets: one group tends to score normally on all domains and another has abnormalities in multiple domains. This may suggest that, pathophysiologically, RBD is not homogeneous. Diagnostic testing may, in the future, be able to separate these patient groups and allow more targeted interventions.

Treatment of RBD To our knowledge, there are no randomized, doubleblind, placebo-controlled studies of any treatment for RBD. There are numerous reports of case series of RBD treated with a variety of medications, but these have important methodological limitations and few have included PSG assessments (Gagnon et al., 2006b). Clonazepam, a sedating benzodiazepine, is considered the treatment of choice for RBD. Two large case series have reported substantial improvement in a majority of patients treated with clonazepam (Schenck et al., 1993; Olson et al., 2000). In a study of 90 patients, clonazepam was found to be beneficial in 90% of patients (Schenck et al., 1993). The initial dose was 0.5 mg at bedtime. In several patients, the dose needed to be increased to 1 or 2 mg. In most cases, a suppression of problematic sleep behaviors and nightmares was reported during the first week of treatment. Sustained efficacy was reported during long-term administration of up to 17 years (Mahowald and

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Schenck, 2005), although some degree of tolerance did occur. After an initial period of marked suppression of disrupting sleep motor activity lasting weeks or months, moderate amounts of limb twitching frequently re-emerged along with sleeptalking and more complex behaviors; nevertheless the medication continued to control the problematic and vigorous motor activity. PSG recordings have revealed that clonazepam suppresses behavioral manifestations and decreases phasic EMG activity without restoring REM sleep muscle atonia (Lapierre and Montplaisir, 1992). The mechanism of action of clonazepam is unclear but it likely results from its serotonergic properties (Lapierre and Montplaisir, 1992; Mahowald and Schenck, 2005). This hypothesis is based on observations made in animals where selective destruction of brainstem serotonergic neurons produced a disinhibition of REM sleep phasic activity and triggered hallucinatory behaviors, whereas the administration of serotonin inhibited motor activity in several experimental designs (Green et al., 1976; Fleisher et al., 1979). However, clonazepam is ineffective in approximately 10% of patients (Schenck et al., 1993; Olson et al., 2000). In addition, some patients experience serious side-effects, such as an increased risk of confusion and falls in elderly individuals (Woods and Winger, 1995) and a worsening of sleep-related respiratory disturbances in patients with obstructive sleep apnea syndrome (Schuld et al., 1999). Therefore, alternative treatments must be considered. There has been no systematic study of other benzodiazepines in RBD. Kunz and Bes (1997) fortuitously discovered the beneficial effect of melatonin on RBD when treating a 64-year-old patient for sleep-onset insomnia. Subsequently, they conducted an open-label trial of six consecutive patients with RBD over a 6-week period with 3 mg melatonin given 30 minutes before bedtime (Kunz and Bes, 1999). They reported a dramatic clinical improvement in five of the six patients within a week that extended for weeks or months beyond the end of treatment. A second polysomnogram performed 6 weeks after the beginning of treatment showed a significant restoration of REM sleep muscle atonia without any significant reduction of phasic motor activity. This initial observation was confirmed in a study of 15 idiopathic RBD patients treated with 3–9 mg melatonin (Takeuchi et al., 2001). Thirteen patients improved but only 20% (3 of 15) of the patients achieved a 75% suppression of RBD. These authors also noted a nearly threefold suppression of REMsleep tonic activity after melatonin therapy. More recently, Boeve et al. (2003b) looked at the efficacy of melatonin in 14 patients with RBD associated with neurological conditions. The coexisting neurological

findings/disorders were LBD (7), mild cognitive impairment with mild parkinsonism (2), MSA (2), narcolepsy (2), and PD (1). The reasons for using melatonin in these cases were: incomplete response of RBD to clonazepam in six patients, existing cognitive impairment in five patients, intolerable side-effects with clonazepam in two patients, and presence of severe obstructive sleep apnea syndrome and narcolepsy in one patient. Seven patients continued to use clonazepam at 0.5–1.0 mg/night; RBD was controlled in six patients, significantly improved in four, and initially improved but subsequently returned in two; no improvement occurred in one patient, and increased RBD frequency/severity occurred in one patient. The effective melatonin doses were 3 mg in two patients, 6 mg in seven, 9 mg in one patient, and 12 mg in two patients. Five patients reported side-effects, which included morning headaches (2), morning sleepiness (2), and delusions/hallucinations (1); these symptoms resolved with decreased dosage. The mean duration of follow-up was 14 (range 9–25) months; eight patients experienced continued benefit with melatonin beyond 12 months of therapy. In this series, persistent benefit with melatonin beyond 1 year of therapy occurred in most, but not all, patients (Boeve et al., 2003b). However, the findings from these studies suggest that melatonin may be less potent than clonazepam. In summary, melatonin can be considered as an alternative therapy in both idiopathic and secondary RBD but long-term controlled trials are needed to ascertain the efficacy of melatonin in this condition. The mechanism of action of melatonin in RBD is still unknown; it appears that melatonin restores REMsleep muscle atonia, whereas clonazepam exerts its therapeutic effect by suppressing phasic motor activity. Another drug family was shown to produce therapeutic benefit in RBD. Indeed, some studies of acetylcholinesterase inhibitors (donepezil and rivastigmine) demonstrated increased sleep quality and reduced motor events in patients with idiopathic RBD (Ringman and Simmons, 2000) and in patients with RBD associated with LBD (Grace et al., 2000; Maclean et al., 2001; Massironi et al., 2003). However, neither of these studies used PSG recordings to confirm treatment efficacy. Other studies of patients with RBD associated with LBD did not find any change in the frequency or severity of RBD symptoms with donepezil (Boeve et al., 2003b; Massironi et al., 2003). Other medications have been used to treat RBD. Based on the strong association between RBD and PD, dopaminergic agents have been considered as a treatment of RBD. Pramipexole, a D2 receptor agonist with a high affinity for D3 receptors, was shown to reduce the intensity and the frequency of clinical

REM SLEEP PARASOMNIAS motor events reported by patients and to decrease the number of simple motor manifestations seen on PSG video recordings (Fantini et al., 2003b; Schmidt et al., 2006). The REM sleep phasic EMG activity was not changed, and there was a paradoxical increase in REM sleep tonic EMG activity. This effect of pramipexole was not found in RBD associated with PD (Iranzo et al., 2005b). Another study reported an increase in both REM sleep phasic and tonic EMG activity after treatment with levodopa in patients with PD (Garcia-Borreguero et al., 2002). A major component of the treatment strategy is to provide the patient with a safe environment. Injury to the patient or bed partner is the most common reason that brings patients to consultation. Therefore, the treatment program should start with a discussion with the patient and the bed partner on the risk of accidents, indication of sleeping in different beds, and safety measures such as removal of dangerous objects in the room, protection of the windows, placement of cushions around the bed, or putting the mattress on the floor. These recommendations are important even in treated patients, because cases of injury have been reported in patients successfully treated for RBD.

Physiopathology in animals and humans Animal studies using various methodological approaches (electrophysiology, lesions, and neuropharmacology) have shown that REM sleep muscle atonia results from the interaction of several neuronal systems located in the brainstem. These structures include the substantia nigra, the ventral mesopontine junction, the tegmental laterodorsal and pedunculopontine nuclei, the locus coeruleus–subcoeruleus complex, and the sublaterodorsal, raphe, gigantocellularis, paramedian, and magnocellularis nuclei (Rye, 1997; Gagnon et al., 2002b; Chase and Morales, 2005; Siegel, 2005; Boeve et al., 2007a; Fuller et al., 2007). Bilateral tegmentopontine lesions in animals can produce both a loss of muscle atonia and the presence of motor behaviors during REM sleep (Jouvet and Delorme, 1965; Henly and Morrison, 1974; Trulson et al., 1981; Hendricks et al., 1982; Friedman and Jones, 1984; Webster et al., 1986), a model for human RBD. Recently, lesions at the ventral mesopontine junction in the cat or lesions of the sublaterodorsal nucleus in the rat produced an increase of motor activity during REM sleep (Lu et al., 2006; Lai et al., 2008). To produce RBD in animals, two different systems must be involved: the atonia system and the locomotor system. Lesions to the atonia system will produce only REM sleep without atonia, a phenomenon frequently

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encountered in neurodegenerative diseases and thought to be a form of incomplete RBD. To produce RBD in animals, the lesions should also involve the system that normally suppresses the brainstem motor generators during REM sleep. Animal studies indicated a colocalization of both the locomotor and atonia systems operating during REM sleep (Lai and Siegel, 1990). Therefore, RBD may result from a dysfunction in these two systems, such as either a loss of REM sleep atonia, excessive locomotor drive, or both (Lai and Siegel, 1990). Neuropathological analysis and imaging studies of patients with RBD, whether or not associated with a neurodegenerative disorder, have also started to provide answers. Only 12 cases of RBD with autopsy that included examination of the brainstem have been published so far. The definite diagnoses were LBD in five cases (Schenck et al., 1997; Boeve et al., 1998; Turner et al., 2000; de Brito-Marques et al., 2003), MSA in four (Benarroch and Schmeichel, 2002), incidental Lewy bodies in two (Uchiyama et al., 1995; Boeve et al., 2007b), and idiopathic PD in another (Arnulf et al., 2000). Mild or severe histopathological anomalies (i.e., Lewy bodies, neuronal loss, depigmentation, or gliosis) were reported in the locus coeruleus– subcoeruleus complex and in the substantia nigra for all patients. Anomalies have been found less severely or less consistently in the dorsal raphe, dorsal vagus, gigantocellular reticular, and pedunculopontine nuclei. Magnetic resonance imaging revealed ischemic lesions in pontomesencephalic regions in three patients with RBD (Culebras and Moore, 1989). Other studies have also suggested that tumor, ischemic infarction, lesions related to multiple sclerosis, or surgery in the pontine region may trigger RBD (Kimura et al., 2000; Plazzi and Montagna, 2002; Zambelis et al., 2002; Provini et al., 2004; Tippmann-Peikert et al., 2006). However, neuroimaging is negative in most patients with RBD (Olson et al., 2000). Similarly, proton magnetic resonance spectroscopy (1H-MRS), revealed no anomalies on several metabolic measures (N-acetylaspartate, creatine, choline, and myoinositol) in the brainstem of patients with idiopathic RBD (Iranzo et al., 2002), or between patients with PD with and without RBD (Hanoglu et al., 2006). SPECT showed a reduction in striatal dopamine transporters in patients with idiopathic RBD (Eisensehr et al., 2000). A reduced density of striatal dopaminergic terminals has also been shown with positron emission tomography (Albin et al., 2000). In addition, there appeared to be a continuum of reduction in striatal dopamine transporters on SPECT from patients with subclinical RBD to clinical RBD, and finally to

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PD (Eisensehr et al., 2003b). Moreover, a significant correlation was found between the percentage of REM sleep muscle atonia and striatal dopaminergic transmission, but not with thalamic cholinergic transmission (Gilman et al., 2003). It remains unclear, however, whether the dysfunction of the nigrostriatal dopaminergic system is the primary cause of RBD or an epiphenomenon. In conclusion, a dysfunction of one or several neural pathways originating in the brainstem (nigrostriatal dopaminergic neurons, noradrenergic/cholinergic neurons of the locus coeruleus–subcoeruleus complex, serotoninergic neurons of the raphe nucleus, glutamatergic neurons of the sublaterodorsal nucleus, or cholinergic neurons of the pedunculopontine nucleus) is likely responsible for the pathogenesis of RBD (Rye, 1997; Gagnon et al., 2002b, 2006c; Boeve et al., 2007a).

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 54

Isolated motor phenomena and symptoms of sleep R. VETRUGNO, F. PROVINI, AND P. MONTAGNA* Department of Neurological Sciences, University of Bologna Medical School, Bologna, Italy

INTRODUCTION Sleep identifies a natural and healthy, temporary, and periodical state of rest, with suspension of the sensorial functions of the organs of sense, as well as those of the voluntary and rational soul. Several motor phenomena, however, occur during sleep, both physiological and pathological. The International Classification of Sleep Disorders, second edition (ICSD-2) (American Academy of Sleep Medicine, 2005), lists sleep disorders within eight categories: I. Insomnias II. Sleep-related breathing disorders III. Hypersomnias of central origin not due to a circadian rhythm sleep disorder, sleep-related breathing disorder, or other cause of disturbed nocturnal sleep IV. Circadian rhythm sleep disorders V. Parasomnias VI. Sleep-related movement disorders VII. Isolated symptoms, apparently normal variants, and unresolved issues VIII. Other sleep disorders. Some periodic and aperiodic phenomena of sleep are included within different categories of the ICSD-2, without a unifying classification scheme. Here, these will be described with their salient characteristics and distinguishing features, ranging from simple movements or symptoms of sleep up to more complex behaviors classified within the parasomnias.

PHYSIOLOGICAL AND EXCESSIVE FRAGMENTARY HYPNIC MYOCLONUS Myoclonus is part of normal sleep physiology representing a state-related paradoxical motor excitation.

Physiological fragmentary (or partial) hypnic myoclonus (PFHM) PFHMs was first described by De Lisi in 1932 as sudden, arrhythmic, asynchronous, and asymmetrical brief twitches involving various body areas, in particular distal limb and facial muscles, occurring during sleep. Such electromyographic (EMG) activity in humans shows an inverse relationship with the degree of sleep EEG synchronization (Dagnino et al., 1969), prevailing equally during relaxed wakefulness (nonrapid-eyemovement (NREM) sleep stage 1) and during rapideye-movement (REM) sleep (Montagna et al., 1988). The muscle discharges of PFHM appear as isolated or bursts of motor unit action potentials with or without visible movement (Figure 54.1). They must originate in the muscle endplate (Buchthal and Rosenfalck, 1966) but are modulated by brainstem regions implicated in motor control during sleep. The motor inhibition typical of REM sleep is related to state-dependent activity of the pontine nucleus pontis oralis which, by exciting cells of the medullary nucleus reticularis gigantocellularis, inhibits the alpha motoneurons (Moruzzi, 1972). A physiological escape from these state-related motor inhibition hypothetically accounts for the PFHM, which is probably caused by descending volleys within the reticulospinal system impinging upon the spinal alpha motoneurons during REM sleep. Indeed, destruction of the reticulospinal tract in animals abolished the myoclonic activity that remained unchanged by lesioning the dorsal roots, red nucleus, or pyramidal tracts (Gassel et al., 1964). In humans, PFHM represents a “simple” motor phenomenon during sleep, present mostly during stage I of NREM sleep and during REM sleep, in apparent contrast with experimental animals which show the highest peak of hypnic myoclonic activity during REM sleep

*Correspondence to: Pasquale Montagna, M.D., Professor of Neurology, Department of Neurological Sciences, University of Bologna Medical School, Via U. Foscolo 7, 40123 Bologna, Italy. E-mail: [email protected]

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R. VETRUGNO ET AL. C3–A2 O2–A1 R EOG L EOG Mylohyoideus R orbicularis oculi L orbicularis oculi R masseter L masseter R orbicularis oris 50 µV

1s

L orbicularis oris L tibialis anterior

Fig. 54.1. Physiological fragmentary hypnic myoclonus during stage 1 NREM sleep involving face and limb muscles. EOG, electro-oculogram; R, right; L, left.

(Gassel et al., 1964). No PFHM was recorded from patients with complete peripheral nerve lesions or with spinal paraplegia. PFHM, absent on the affected side of patients with chronic ischemic hemiparesis and increased in patients with Parkinson’s disease and Wilson’s disease, was normally present in patients with tabe dorsalis in whom muscle proprioception input was probably abolished (Dagnino et al., 1969). A supraspinal origin of PFHM is therefore implicated by its absence in muscles that are completely paralyzed because of a peripheral nerve, spinal, or pyramidal lesion, its increase in extrapyramidal diseases, and by the fact that it remains unaffected by lesions of the dorsal roots that abolish muscle spindle afferent activity.

Excessive fragmentary hypnic myoclonus (EFHM) EFHM has been reported as a pathological enhancement of PFHM in which small myoclonic twitches and fasciculations are present throughout sleep and associated with sleep apnea, excessive daytime drowsiness, and insomnia (Broughton and Tolentino, 1984; Broughton et al., 1985; Lins et al., 1993). EFHM may cause small movements of the fingers, toes, and/or corners of the mouth, without gross displacements

across a joint space. Similar motor activity during sleep has been reported in patients with restless legs syndrome (Coccagna et al., 1966) (Figure 54.2), in extrapyramidal syndromes (Tassinari et al., 1965), and in patients with REM sleep behavior disorder (Mahowald and Schenck, 2000), obstructive and central sleep apnea, narcolepsy, periodic limb movements during sleep and fatigue (Broughton et al., 1985). EFHM may also present as an isolated motor phenomenon during relaxed wakefulness, NREM, including stages III and IV, and REM sleep in which “quiver” movements recur throughout the body, affecting primarily the hands and face with some degree of sleep fragmentation. The twitches may occasionally awake the patient. They are absent during wakefulness and EEG–EMG back-averaging does not show any cortical potentials related to the twitches (Vetrugno et al., 2002). These data suggest a selective impairment of motor control during sleep. However, the exact origin and significance of EFHM remain unclear and despite the myoclonus being a common finding in polysomnography, it is often asymptomatic. EFHM is now classified in the VII section of the ICSD-2 (Isolated symptoms, apparently normal variants, and unresolved issues) that lists sleep-related symptoms that are in the borderline between normal and abnormal sleep.

ISOLATED MOTOR PHENOMENA AND SYMPTOMS OF SLEEP

885

C3–A1 O2–A1 Cz–A1 R EOG L EOG Mylohyoideus R wrist extensor R tibialis anterior L wrist extensor L tibialis anterior ECG Intercostalis Oronasal resp. Thoracic resp. Abdominal resp. Plethysmogram Systemic arterial 150 pressure (mmHg) 100 SaO2 (%)

50 100 80 60

50 µV 1s

Fig. 54.2. Excessive fragmentary hypnic myoclonus during stage 2 NREM sleep in a patient with restless legs syndrome. EOG, electro-oculogram; ECG, electrocardiogram; resp., respirogram; SaO2, oxygen saturation; R, right; L, left.

HYPNIC JERKS (SLEEP STARTS) Hypnic jerks, or sleep starts, are normal physiological events occurring at the transition from wakefulness to sleep, often associated with sensory phenomena, such as a feeling of falling, unexplained alarm or fear, inner electric shock or light flash (Oswald, 1959; Gastaut and Broughton, 1965). An outcry can occasionally accompany the jerks, which are usually associated with autonomic activation (tachycardia, irregular breathing, and sudomotor activation). Jerks consist of nonstereotyped, abrupt, and brief flexion or extension movements, generalized, or, more frequently, segmental and asymmetrical with neck and/or limb muscles involvement. Usually EMG complexes last less than 250 milliseconds and are associated with K-complexes and vertex sharp waves on the EEG (Figure 54.3). Hypnic jerks occasionally occur during light sleep, causing a brief arousal. Fatigue, stress, and sleep deprivation may facilitate the occurrence of the hypnic jerks, which may be misdiagnosed as myoclonic seizures. Sleep starts may occur without any motor activity with only visual, auditory, or somesthetic sensory phenomena. Purely sensory sleep starts without a body jerk have been described occurring exclusively at onset of sleep (Sander et al., 1998). The exploding head syndrome may also represent a variety of purely sensory sleep starts, even though it is classified amongst the “Other parasomnias” in ICSD-2. It was first described by Armstrong-Jones (1920) as a “snapping of the brain”

and is characterized by the sensation lasting some seconds that an explosive noise has occurred in the head, which wakens the individual from sleep. Patients describe this sensation variously as a terrifying “loud bang” or a “shotgun- or bomb-like explosion” (Pearce, 1989), the most common age of onset being over 50 years. The attacks may have variable frequency, up to more than one per night, for a few weeks or months, with possible prolonged or total remissions. Polysomnographic studies have documented the occurrence of these attacks during all sleep stages, including REM sleep (Sachs and Svanborg, 1991), and during the passage from wakefulness to sleep (Pearce, 1989). Another related phenomenon at sleep onset, probably representing a variant of sensory sleep starts, is the blip syndrome in which patients experience momentary sensations of impending loss of consciousness particularly when relaxed, without any obvious cardiac, cerebral vascular, or epileptic basis (Lance, 1996). It has been suggested that sleep starts with combined sensory, motor, and autonomic components represent dissociated elements of sleep during which “twilight” phenomena arise. A possible basis for these motor–autonomic–sensory phenomena is thought to be a delay in the reduction of activity in selected areas of the brainstem reticular formation as the patient passes from wakefulness to sleep (Mahowald et al., 1998). Hypnic jerks represent a normal accompaniment of sleep.

886

R. VETRUGNO ET AL. Cz–O2 Mylohyoideus R masseter R SCM

R biceps brachialis L biceps brachialis R pectoralis L pectoralis R rectus abdominis R TL paraspinalis L rectus abdominis L TL paraspinalis R rectus femoris L rectus femoris R tibialis anterior R gastrocnemius ECG

2s

TA respirogram

Fig. 54.3. Hypnic jerk in a normal subject at the transition from wakefulness to sleep, with abrupt neck, trunk and limb muscles involvement. SCM, sternocleidomastoideus; TL, thoracolumbar; ECG, electrocardiogram; TA, thoracoabdominal; R, right; L, left.

Intensified hypnic jerks, however, may cause sleep fragmentation and insomnia, a condition recognized since 1890 by Weir Mitchell (Mitchell, 1890; Broughton, 1988).

PROPRIOSPINAL MYOCLONUS AT THE WAKE^SLEEP TRANSITION Propriospinal myoclonus (PSM) describes jerks that involve muscles innervated by many different segments of the spinal cord, myoclonic activity spreading up and down the cord via supposed propriospinal pathways from a more restricted source (Brown et al., 1991). PSM has been reported associated with infective myelitis (de la Sayette et al., 1996), cervical trauma (Fouillet et al., 1995), pharmacological treatments (ciprofloxacin, cannabis, interferon-a) (Benatru et al., 2003; Lozsadi et al., 2004; Post et al., 2004), syringomyelia (Nogues, 2002), and multiple sclerosis (Kapoor et al., 1992), but in many cases it remains idiopathic. PSM may progress into a severe and potentially fatal “myoclonic status” (Manconi et al., 2005). In some patients PSM displays a striking relationship with vigilance level, as, independently of posture, it recurs in a semirhythmic fashion only during relaxation and drowsiness preceding sleep onset. This has been termed PSM at the wake–sleep transition

(Montagna et al., 1997; Vetrugno et al., 2001b). Patients complain of sudden involuntary axial jerks occurring every night and impeding falling asleep. The spontaneous jerks remain restricted to the prehypnic wake period when the EEG alpha activity spreads to involve the anterior brain regions, but disappear as soon as spindles and K-complexes begin on the EEG. Sometimes PSM reappears during intrasleep wakefulness and upon awakening in the morning. Mental and sensory stimulations (simple arithmetic exercises or making a fist) during relaxed wakefulness stop the jerks concomitantly with the disappearance of the EEG alpha activity and independently of any postural changes. Findings on neurological examination, neurophysiological investigation (EEG back-averaging, somatosensory evoked potentials, transcranial magnetic stimulation motor-evoked potentials), and spinal and cranial magnetic resonance imaging (MRI) are usually normal. The myoclonic jerks occur as flexion or extension movements with prominent axial muscles involvement, may be single or repetitive, with or without agonist–antagonist relationship, and with EMG discharges lasting 100–300 milliseconds (Figure 54.4). In some of the jerks, myoclonic activity may be confined to the abdominal muscles, as in spinal segmental myoclonus, but usually the jerks spread at about 7–8 m/s up and down the cord to involve muscles in the legs and

ISOLATED MOTOR PHENOMENA AND SYMPTOMS OF SLEEP

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F3 C3 O1 R L EOG Mylohyoideus R SCM R intercostalis R rectus abdominis R TL paraspinalis R rectus femoris R tibialis anterior ECG TA respirogram 2s

Fig. 54.4. Propriospinal myoclonus at the wake–sleep transition: quasi-periodic recurrence of axial jerks during wake–sleep transition occurring at a time when alpha activity is evident on anterior EEG leads. EOG, electro-oculogram; SCM, sternocleidomastoideus; TL, thoracolumbar; ECG, electrocardiogram; TA, thoracoabdominal; R, right; L, left.

C3–A2 O2–A1 Mylohyoideus R orbicularis oculi R masseter R SCM R deltoideus L deltoideus R biceps brachialis L biceps brachialis R diaphragm R intercostalis R rectus abdominis R TL paraspinalis R rectus femoris L rectus femoris R tibialis anterior L tibialis anterior 1s ECG

Fig. 54.5. EEG–EMG recordings of propriospinal myoclonus at sleep onset showing a rostrocaudal propagation of muscular activity starting in the right intercostalis muscle (dotted line). SCM, sternocleidomastoideus; TL, thoracolumbar; ECG, electrocardiogram; R, right; L, left.

neck (Vetrugno et al., 2000) (Figure 54.5). PSM may be spontaneous or triggered by stimuli. As a consequence of the slow conduction velocity of spinospinal pathways along which EMG activity supposedly spreads,

significant jitter occurs from jerk to jerk and among single muscles involved in the same jerk. There is no associated EEG abnormality routinely searched or by back-averaging. PSM at sleep onset has also been found in patients with a long history of restless legs syndrome (Vetrugno et al., 2005). In these cases, PSM jerks arise during relaxed wakefulness but give way with the appearance of spindles and K-complexes on the EEG to typical periodic limb movements during sleep with characteristic EMG activity limited to leg muscles. The occurrence of PSM only during relaxed wakefulness indicates that the predormitum and postdormitum periods represent peculiar states with intrinsic mental and neurophysiological characteristics (Critchley, 1955; Braun et al., 1997; Montagna and Lugaresi, 1998). Reduced sleep-related spinal inhibition during the wake to sleep transition may result in activation of several motor generators, including those associated with PSM. These state-dependent modulatory influences on motor control set PSM into motion, probably by releasing a spinal generator responsible for PSM. Benzodiazepines – clonazepam (0.5–2 mg/day at bedtime) in particular – may reduce their intensity and frequency, but usually do not abolish the jerks of PSM at sleep onset.

BENIGN SLEEP MYOCLONUS OF INFANCY Described for the first time in 1982 by Coulter and Allen, benign sleep myoclonus of infancy is a movement disorder with a self-limited course characterized by myoclonic jerks occurring only during sleep and presenting in the first month of life (Coulter and Allen, 1982; Di Capua et al., 1993; Vaccario et al., 2003). Movements are absent during wake and stop when the child is woken. A spontaneous resolution

888 R. VETRUGNO ET AL. occurs around the third or fourth month of life, feet also become cramped. The cramps can last for a always before the first year of age (Di Capua et al., few seconds or up to 10 minutes, but the soreness 1993; Noone et al., 1995; Caraballo et al., 1998). may linger. The cramps can affect persons in any age Affected children show no increased risk of developing group, but they tend to occur in middle-aged and older subsequent epileptic seizures (Caraballo et al., 1998; individuals, and cause recurrent awakenings from Vaccario et al., 2003) and are otherwise healthy sleep associated with painful leg sensations; the disnewborns with normal psychomotor development and comfort is relieved by local massage, movement, or no neurological deficits. heat. Studies show that about 25–50% of adults, espeSome 30% of the jerks of benign myoclonus of cially subjects aged 80 years or more, experience nocinfancy involve the whole body, 20% the abdominal turnal leg cramps (Naylor and Young, 1994; Abdulla or proximal muscles, and 50% the arms or the legs. et al., 1999). They often involved the whole limb, but on occasion Polysomnographic recordings show increased EMG prevail in the distal segments (Resnick et al., 1986). activity in the affected leg and associated awakening Ankle dorsiflexion myoclonus was described in the (Saskin et al., 1988). EMG studies suggest that cramps first two infants reported. The jerks frequently occur result from spontaneous firing of groups of anterior in clusters repeating at one per second (Resnick horn cells followed by contraction of several motor et al., 1986), last 40–300 ms, being briefer when occurunits at rates of up to 300 Hz (Miller and Layzer, ring in clusters, and persist from several seconds to 90 2005), but a distal origin in the intramuscular motor minutes. Only one reported case exhibited prolonged nerve terminals is also possible (Jansen et al., 1990). jerks lasting for 12 hours, mimicking status epilepticus Muscle cramps are a common consequence of vigor(Turanli et al., 2004). ous exercise and are more frequent in patients with The movements are present during all sleep states, peripheral vascular disease (Abdulla et al., 1999). Neveralthough with higher frequency during NREM sleep theless, in many cases nocturnal leg cramps occur inde(Resnick et al., 1986), but they do not awake the infant. pendently of arterial circulation abnormalities as an No EEG correlates are noted and the EEG is normal idiopathic condition (Jansen et al., 1990). Medications during and after the episodes (Resnick et al., 1986). (diuretics, nifedipine, b-agonists, steroids, lithium), Benign neonatal myoclonus may be triggered by noise some medical conditions (uremia, diabetes, thyroid (Daoust-Roy and Seshia, 1992) and especially by rocking disease, hypomagnesemia, hypocalcemia, hypokalemia, (Alfonso et al., 1995). The major differential diagnosis continuous motor unit activity syndromes such as of benign sleep myoclonus of infancy is, of course, with neuromyotonia), and pregnancy (Hertz et al., 1992) are epilepsy and particularly with two myoclonus epilepsy associated with nocturnal leg cramps. Nocturnal cramps syndromes that can occur in the neonatal period: infanin some cases may be a familial condition with an autotile spasms and benign infantile myoclonus (Lombroso somal dominant pattern of inheritance (Lazzaro et al., and Fejerman, 1977; Kellaway et al., 1983; Donat and 1981; Jacobsen et al., 1986; Ricker and Moxley, 1990). Wright, 1992). Benign sleep myoclonus of infancy can Nocturnal leg cramps should not be confused with be distinguished from these conditions by history or by restless legs syndrome, which is characterized by an the observation of repetitive myoclonic limb jerks that urge to move during repose and in the evening with or occur only during sleep and stop upon awakening, by without a crawling sensation that is relieved by walking a normal EEG and neurological examination, and by a or moving around. Although uncomfortable, restless sustained normality on follow-up. legs syndrome usually does not involve cramping. ConThe mechanism of benign sleep myoclonus of ditions that mimic cramps include simple muscle strain, infancy is unknown. It has been hypothesized to result dystonias, ischemic or neuropathic claudication, nerve from a benign disturbance of the brainstem control of root disease, and PLMS. Muscle cramps are a feature sleep (Coulter and Allen, 1982) or from transient immaof many myopathic and neuropathic conditions in which turity or imbalance of the serotonergic system (Resnick they are not usually restricted to the nighttime or neceset al., 1986). Genetic factors might play a role, because sarily to the legs. Although various medications, includthis disorder has been described in siblings (Dooley, ing vitamins of the B group and vitamin E, calcium 1984; Tardieu et al., 1986; Vaccario et al., 2003). blockers, potassium, magnesium citrate, gabapentin, and botulinum toxin may be effective, the most successful treatment is quinine sulfate (Man-Son-Hing et al., NOCTURNAL LEG CRAMPS 1998; Butler et al., 2002; Miller and Layzer, 2005). Nocturnal leg cramps are sudden, involuntary contracQuinine, however, carries a high risk of hepatic and tions of the calf muscles that occur during the night or blood toxicity (Jung, 2004). Some patients also respond while at rest. Occasionally, muscles in the soles of the to local massage and leg movement.

ISOLATED MOTOR PHENOMENA AND SYMPTOMS OF SLEEP

RHYTHMIC MOVEMENT DISORDERS Rhythmic movement disorder (RMD) is a group of stereotyped, repetitive movements involving large axial muscles, usually of the head, neck, and trunk, and sometimes also the legs, which typically occur immediately before sleep onset and are sustained into light sleep. Also known as jactatio capitis or corporis nocturna, headbanging, headrolling, bodyrocking, bodyrolling, rythmie du sommeil, the term RMD is preferred as different body areas may be involved in the movement activity. Rhythmic body movements may occur in any stage of sleep, including REM sleep, but most often during drowsiness persisting into light sleep (American Academy of Sleep Medicine, 2005). In the more common form of RMD, at least one of the following types of movement is present: the head is forcibly moved in a back and forward direction (headbanging type); the head is moved laterally while in a supine (lying on the back, face up) position (headrolling type); the whole body is rocked while on the hands and knees (bodyrocking type); the whole body is moved laterally while in a supine position (bodyrolling type). The stereotypic, repetitive movements occur with a frequency of 0.5–2.0 Hz and persist for a few minutes to many hours during sleep. RMD is common in children, sometimes as a semivoluntary behavior utilized as a sleep-inducing aid, usually resolving by about 4 years of age (Klackenberg, 1971), but it may rarely persist into adulthood (Happe et al., 2000). RMD isolated to REM sleep has occasionally been reported in children (Walsh et al., 1981; Gagnon and De Koninck, 1985; Stepanova et al., 2005) and unusually persists into adult life (Anderson et al., 2006). It is also possible that RMD may appear de novo during adulthood. RMD may be associated with other disorders such as anxiety, attention deficit disorders, and autism, and occasionally skull injuries can occur in patients with associated intellectual impairment or autistic syndromes. The treatment of RMD usually involves reassurance, but protective headgear may sometimes be necessary, particularly in children with learning disabilities. Benzodiazepines, levodopa or dopamine agonists, and tricyclic antidepressants have been tried with variable success. The association of RMD with longlasting restless legs syndrome, although reported by Morgan in 1967 and emphasized by Walters in 1988, is still underrecognized. RMD may also occur in restless legs syndrome of recent onset (Lombardi et al., 2003). Rhythmic feet movement, also called hypnagogic foot tremor, occurring during presleep wakefulness and light sleep may be considered a new kind of RMD arising in adults, in some cases associated with

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insomnia (Broughton, 1988), sleep apnea, PLMS, and restless legs syndrome (Wichniak et al., 2001). Hypnagogic foot tremor presents as rhythmic, oscillating movements of the whole foot or toes, occurring usually bilaterally but asynchronously in both legs at varying frequencies, between 0.5 and 3 Hz, with a mean duration of the EMG bursts of 500 ms and without a substantial sleep-disturbing effect (Figure 54.6). Brief activations of the tibialis anterior in one leg alternating with similar activation in the other leg, socalled alternating leg muscle activation (ALMA), have also been described. Such activations, similar to rhythmic feet movements while falling asleep, occur at a frequency of 1–1.5 Hz, each lasting up to 0.5 s, with sequences of several to 20 seconds and recurring in all sleep stages but particularly during arousals (Figure 54.7). ALMA has been described in patients with sleep apnea, PLMS, those taking antidepressant medication (Chervin et al., 2003), and with restless legs syndrome (Vetrugno et al., 2005).

SLEEPTALKING Sleeptalking (somniloquy) is one of the most common parasomnias and consists of verbal vocalization during sleep ranging from mumbled nonsense to coherent sentences, but without awareness of the event. The utterances may be brief, infrequent, and devoid of any emotional stress, or they may include long speeches. Somniloquy can sometimes be evoked by conversation with a predisposed sleeping individual. Multilingual or dominant bilinguals patients always use the dominant language during somniloquy episodes (Gastaut and Broughton, 1965; Pareja et al., 1999), and balanced bilinguals (those who have equal proficiency in both languages) may sleeptalk in either of the two languages (Pareja et al., 1999). Somniloquy occurs during NREM as well as REM periods (Rechtschaffen et al., 1962); in general, 20–25% of speeches are associated with REM sleep and 75–80% with NREM sleep (Arkin et al., 1970), but some individuals are more productive in REM sleep. Somniloquy occurs spontaneously, but in some instances it may be precipitated by factors such as febrile illness or emotional stress. Somniloquy is common in both children and adults (Horne, 1992). About half of the children aged 3–13 years present somniloquy at least once a year, but less than 10% every night (Reima˜o and Lefe´vre, 1980; Simonds and Parraga, 1982; Laberge et al., 2000). Adair and Bauchner (1993) reported that somniloquy was more prevalent in children aged 4–5 years, but other studies have found no effect of age on the prevalence of somniloquy (Reima˜o and Lefe´vre, 1980; Simonds and Parraga, 1982; Laberge et al., 2000). Somniloquy is

890

R. VETRUGNO ET AL. C3–A2 Cz–A1 O1–A2 R EOG L EOG Mylohyoideus R orbicularis oculi R orbicularis oris R masseter R SCM R biceps brachialis L biceps brachialis R tibialis anterior L tibialis anterior Oronasal resp. Thoracic resp. ECG Plethysmogram Systemic arterial pressure (mmHg)

150 100 50 SaO2 100 80 (%) 60

50 µV

1s

Fig. 54.6. Hypnagogic foot tremor occurring during presleep wakefulness on the left tibialis anterior muscle. EOG, electrooculogram; SCM, sternocleidomastoideus; resp., respirogram; ECG, electrocardiogram; SaO2: oxygen saturation; R, right; L, left. C3–A2 O2–A1 Mylohyoideus

R orbicularis oculi R masseter R SCM R deltoideus L deltoideus R biceps brachialis L biceps brachialis R diaphragm R intercostalis R rectus abdominis R paraspinalis

500 µV

R rectus femoris L rectus femoris R tibialis anterior L tibialis anterior ECG 10 s

1s

Fig. 54.7. Sequence of alternating leg muscle activation occurring on the right and left tibialis anterior muscles at a frequency of 1.5 Hz, each lasting about 0.5 s. SCM, sternocleidomastoideus; TL, thoracolumbar; ECG, electrocardiogram; R, right; L, left.

indeed reported by 24% of normal adults (Ohayon et al., 1997). There is no apparent sex difference, even though in one study somniloquy was more common in boys (Laberge et al., 2000). Preadolescents and adolescents sleeping badly present a higher incidence of

somniloquy than the subjects who sleep well (Kahn et al., 1989; Manni et al., 1997). Children with sleepdisordered breathing and children with chronic headache are more likely to sleeptalk (Smeyers, 1999; Goodwin et al., 2004).

ISOLATED MOTOR PHENOMENA AND SYMPTOMS OF SLEEP Somniloquy is usually an isolated phenomenon occurring in otherwise healthy subjects (Arkin, 1966), but it may be one of the clinical features accompanying obstructive sleep apnea syndrome (OSAS), sleepwalking (somnambulism), and sleep terrors (pavor nocturnus) (Gastaut and Broughton, 1965; Broughton, 1968), and REM sleep behavior disorder (RBD) (Schenck et al., 1987). There is a strong association between sleepwalking, night terrors, and somniloquy (Kales et al., 1980; Simonds and Parraga, 1982; Abe et al., 1984; Laberge et al, 2000), which suggests a common genetic background. Children are indeed likely to sleeptalk if one or both parents have a parasomnia such as sleepwalking (Abe et al., 1984). Somniloquy may be a prodrome of RBD (Pareja et al., 1996), but it usually represents a benign condition that resolves spontaneously.

CATATHRENIA (NOCTURNAL GROANING) Catathrenia, from the Greek kat a yr  noB (like a groan), is a rare idiopathic condition characterized by high-pitched, monotonous, irregular groans that occur during prolonged expiration in sleep (Vetrugno et al., 2001a). The hallmark of catathrenia is that deep inspiration is followed by protracted expiration during which a sound is produced, repetitively recurring during NREM and especially REM sleep. Patients are unaware, but typically parents and bed partners are troubled and alarmed by the nocturnal noise that occurs very often, if not every night. The patients do not have respiratory distress or anguished expression

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during the groaning, or any abnormal motor behavior or recall of vivid dream. Coaxed to change posture during sleep, they may transiently stop to groan, only to start again later on the same night. Physical and neurological examinations, laboratory and otolaryngological investigation including static and dynamic vocal cord endoscopic evaluation and neck and cranial computed tomography and MRI are generally normal, and no mood disturbance has been identified. On polysomnographic examination, the groaning usually starts 2–6 hours after falling asleep, and occurs during NREM and REM sleep, lasting 2–20 seconds and repeating in clusters for 2 minutes to 1 hour, many times per night, with the patient lying in any position in bed. A slight decrease in heart rate and arterial blood pressure with moderately positive intraesophageal pressure but no EMG activation of the diaphragm and intercostal muscles occurs during each expiratory groaning, which ends usually with a snort followed by a rebound in heart rate and arterial blood pressure, and without significant oxygen saturation variability, SaO2 remaining normal at 95–98% (Vetrugno et al., 2001a) (Figure 54.8). During the groaning, the patients remain still and an EEG arousal irrespective of a change of posture often marks the end of a groaning episode. Treatment with benzodiazepines, antidepressants, or dopamine agonists has been unsuccessful or refused (Pevenargie et al., 2001; Vetrugno et al., 2001a; Oldani et al., 2005), and nasal continuous positive airway pressure has been proposed as an option to treat this condition (Iriarte et al., 2006; Guilleminault et al., 2008). The origin of this nocturnal groaning remains unexplained and the long-term

C3–A2 O2–A1 Cz–A1 R EOG L EOG Mylohyoideus ECG Microphone Intercostalis Diaphragm Oral resp. Thoracic resp. Abdominal resp. Intraesophageal 0 pressure (cmH2O) −40 Systemic 200 arterial pressure 100 (mm Hg) 0 100 SaO2 50 % 0

4s

Fig. 54.8. Nocturnal groaning (catathrenia) arising during REM sleep. Groaning sounds (microphone) lasting 20–28 seconds follow one another in cluster during prolonged expiration, associated with slightly decreased heart rate and arterial pressure, and without appreciable SaO2 modification. EOG, electro-oculogram; resp., respirogram; SaO2, oxygen saturation; R, right; L, left.

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prognosis unknown, as the normal wake laryngoscopic investigation cannot rule out a functional sleep-related obstruction of the upper airway during expiration.

SLEEP-RELATED LARYNGOSPASM A laryngospasm is a spasm of the throat. Sleep-related laryngospasm refers to episodes of abrupt awakenings from sleep with an intense sensation of inability to breathe and stridor. If a laryngospasm occurs during sleep, the patient will typically wake up choking and jump out of bed, clutching the throat and rushing in panic to the bathroom or a window with acute fear of suffocation. Episodes last anywhere from a few seconds to five minutes. Patients typically experience laryngospasm only two or three times per year; the result is similar to a single episode of apnea, but these patients do not have apnea. Drinking water usually speeds the relaxation of throat muscles. Often patients with sleep-related laryngospasm have evidence of gastroesophageal reflux and respond to antireflux therapy (Thurnheer et al., 1997). Patients who suffer frequent attacks are afraid to go to sleep at night. The infrequent, erratic and almost exclusively nocturnal occurrence and short duration of the attacks makes them hard to observe and to capture on polysomnography (Aloe and Thorpy, 1995). The differential diagnosis includes sleep-related neurogenic hyperventilation, nocturnal bronchial asthma, epilepsy manifesting as laryngospasm (Mahowald and Schenck, 1993), the sleep-related choking syndrome, the sleep-related abnormal swallowing syndrome, and nocturnal panic attacks (American Academy of Sleep Medicine, 2005).

SLEEP-RELATED CHOKING SYNDROME This is a rare disorder. Unlike sleep-related laryngospasm, which usually only occurs two or three times a year, this condition causes the individual to have choking episodes almost every night, and sometimes several times in one night. This causes the individual to wake up with feelings of anxiety, fear, and even impending death. It is different from nightmares or night terrors, because the fear is always associated with the choking. These individuals do not suffer from sleep apnea (Thorpy and Aloe, 1989; American Academy of Sleep Medicine, 2005).

SLEEP-RELATED ABNORMAL SWALLOWING SYNDROME People with this rare disorder have inadequate swallowing of their saliva with aspiration while sleeping. Saliva builds up in the mouth, then flows down the throat and is breathed into the lungs, the sleeper coughing,

choking, and briefly arousing or completely waking up from sleep. Polysomnographic studies show brief episodes of coughing and gagging (Guilleminault et al., 1976; American Academy of Sleep Medicine, 2005).

SLEEP-RELATED NEUROGENIC TACHYPNEA Sleep-related neurogenic tachypnea is a rare condition that was considered only as a proposed sleep disorder in the ICSD-1 but was excluded from the ICSD-2. It is characterized by a sustained respiratory rate occurring at sleep onset, maintained throughout sleep, and reversing immediately upon awakening. This disorder has been described in a few patients, associated with multiple sclerosis, lateral medullary syndrome, and benign intracranial hypertension (Broughton et al., 1988; Wilmer and Broughton, 1989). A patient with chronic sleeprelated neurogenic tachypnea after head injury has been reported recently with polysomnographic documentation of the condition (King et al., 2005). Notably, tachypnea during sleep has been reported as a polysomnographic finding in patients with multiple system atrophy (Vetrugno et al., 2004).

SLEEP HYPERHIDROSIS (NIGHT SWEATS) In sleep hyperhidrosis, more commonly known as “night sweats”, profuse sweating occurs during sleep and requires the patient to change the bedclothes (Geschickte et al., 1966; Lea and Aber, 1985; Smetana, 1993). The sweating can cause an awakening because of the discomfort due to sweat sleepwear, and the patient may have to arise. Excessive daytime sweating may or may not be present. Excessive sweating during sleep may occur at any age, but most commonly in early adulthood. Some patients may have a lifelong tendency to sweat excessively during sleep, whereas in other patients it is a self-limited condition. Although uncomfortable, isolated nighttime sweating is not usually a sign of a serious underlying medical condition. Polysomnography with quinizarin powder, which turns purple on contact with sweat, can be performed to demonstrate the affected body areas. Examinations are, however, aimed at revealing associated symptoms that enter into the differential diagnosis such as febrile illness, infections, menopause, diabetes insipidus, obstructive sleep apnea, gastroesophageal reflux disease, pregnancy, anxiety, medications, drug or alcohol abuse, hyperthyroidism, pheochromocytoma, cancer (especially lymphoma), hypothalamic lesions, epilepsy, cerebral and brainstem strokes, cerebral palsy, chronic paroxysmal hemicrania, spinal cord infarction, head injury, familial dysautonomia (Viera et al., 2003), primary hyperhidrosis,

ISOLATED MOTOR PHENOMENA AND SYMPTOMS OF SLEEP 893 and unilateral hemihidrotic hyperhidrosis in patients long the night. Hallucinations consist of well-delineated, confined to bed (Vetrugno et al., 2003). Idiopathic night realistic, vivid, detailed, relatively immobile, silent, ususweats are at present classified in the group of miscellaally multicolor, and often oddly distorted images of peoneous secondary parasomnias in ICSD-2. ple or animals, and occur several times a week. Described in 12 patients, mostly women (Silber et al., 2002, 2005), the age of onset of symptoms varied from 5 to 80 years NOCTURNAL PANIC ATTACKS (mean 40.2 years). The etiologies were different: idioPanic episodes arising during sleep are common, and may pathic hypersomnia, b-adrenergic antagonists, dementia result in a sense of anxiety about falling asleep with a with Lewy bodies, visual loss from macular degeneracomplaint of insomnia. Nocturnal panic attacks occur in tion, anxiety disorder, and depression. No patient had 30–50% of patients with diurnal panic, but episodes arissymptoms suggesting psychosis. In only four patients, ing exclusively from sleep appear to be rare (Hauri et al., complex nocturnal visual hallucinations were the only 1989; Rosenfield and Furman, 1994; Schredl et al., 2001). parasomnia, whereas in the others they occurred together During sleep studies, patients with nocturnal panic with sleepwalking, sleeptalking, RBD, sleep paralysis, attacks do not usually report a dream. The episodes occur and lucid dreams. The hallucinations occurred immediduring NREM sleep, particularly at the transition from ately after an arousal from NREM sleep (Kavey and stage 2 to stage 3, and, in contrast to patients with sleep Whyte, 1993; Silber et al., 2005) and the EEG during terrors, patients with nocturnal panic attacks are awake the episodes showed alpha rhythm without epileptic and hyperalert during the episode (Stein et al., 1993; activity. Landry et al., 2002). Nocturnal panic attacks should be Complex visual hallucinations are also seen in differentiated from the sleep terrors, nocturnal seizures, pathological states such as Charles Bonnet syndrome sleep apnea, and sleep-related abnormal swallowing, (exclusively visual, well-formed hallucinations of peochoking, and laryngospasm. ple, places, and things, but devoid of emotional or threatening contents; they do not interfere with normal mental functions and occur in otherwise intact, SLEEP-RELATED HALLUCINATIONS elderly individuals with usually binocular visual loss), Sleep-related hallucinations are included in this chapter peduncular hallucinosis (striking visual images occabecause they may represent an isolated symptom of sionally accompanied by tactile and auditory hallucinasleep (witness the hypnagogic hallucinations of drowstions, often of prolonged duration with disturbed sleep iness), and also because they are often associated in and related to brainstem or thalamus lesions; patients the motor manifestations, as, for example, in sleep usually have insight into the hallucinations and cope paralysis (see below). Sleep-related hallucinations are with them well without features of paranoia or psychihallucinatory experiences, principally visual, that occur atric disturbance), delirium tremens (variable, brief or at sleep onset (hypnagogic hallucinations) or on awakusually almost continuous visual, occasionally polymoening from sleep (hypnopompic hallucinations). The dal, hallucinations with autonomic disturbances, motor term hypnagogic hallucinations was coined by Maury agitation, and confusion), Parkinson’s disease and in 1848 to describe his own vivid hallucinations in the Lewy body dementia (often in the evening and rarely state of drowsiness, just before sleep. Sleep-related polymodal, lasting some minutes usually with prehallucinations are often vivid and terrifying, and are served insight, and related to widespread cortex and also recalled clearly; they are not perceived as dreams. brainstem lesions, patients being not unconscious but Up to one-third of normal individuals may experience normal or drowsy), migraine (simple visual, much rarer these hallucinations (Ohayon, 2000), anywhere from complex, hallucinations, the initial region of visual once in a lifetime to most nights, but they are particuabnormality being usually near the fixation point, and larly common in the narcolepsy–cataplexy syndrome. the brilliant and flickering scintillations surrounding Vivid hallucinatory experiences are often associated the negative scotoma making “fortifications” figures with sleep paralysis, a temporary period of paralysis or spectra), schizophrenia (complex visual hallucinaexperienced prior to falling asleep or waking from tions usually in color and with auditory components, REM sleep (Cheyne, 2005). Both hypnagogic and hypwith animals and figures, but often with a delusional nopompic hallucinations are more common in younger or hyper-religious character), epilepsy (usually brief, persons and occur slightly more frequently in women stereotyped, and fragmentary, with or without other than in men (Ohayon, 2000). seizure manifestations such as experiential phenomComplex nocturnal visual hallucinations represent ena, altered awareness, motor activity, and automaa well-defined syndrome characterized by nocturnal tisms, often due to posterior temporoparietal lesions, visual hallucinations that occur upon waking during patients being normal between episodes) (Teunisse

894 R. VETRUGNO ET AL. et al., 1996; Manford and Andermann, 1998; Barnes few seconds to several minutes. The muscle power and David, 2001; Williams and Andrew, 2005). returns to normal either spontaneously or if the indiAlice in Wonderland syndrome is a peculiar disvidual tries hard to move or is touched by another order in which the symptoms are remarkably similar person. The attacks leave no sequelae. Hallucinatory to the distortion in body image and shape as experiexperience (visual hallucinations, unusual bodily sensaenced by the main character in Lewis Carroll’s, 1865 tions including floating and feeling of pressure on the novel, and first described in 1955 by the English psychibody, sensing the presence of others, feeling external atrist John Todd. The patients have the feeling that pressure on the chest, and hearing footsteps or odd their entire body or parts of it have been altered in sounds) can commonly accompany sleep paralysis, shape and size, and usually experience visual hallucinacausing fear and making such episodes particularly tions with impaired perception of time and place (also alarming (Cheyne et al., 1999). known as Lilliputian hallucinations). The majority of Sleep paralysis is such a vivid experience that it has patients with the syndrome have a family history of been incorporated into popular folklore in many parts migraine headache or have overt migraine themselves of the world, and may be interpreted as a supernatural and, perhaps not coincidentally, Lewis Carroll himself experience, a nocturnal visitation of demons and devils, suffered from severe migraine. in a culturally distinct manner (Hinton et al., 2005). The visual imagery in the nightmares and RBDs These cultural interpretations include “Kanashibari” in occurs during sleep and not after waking, and is clearly Japan (Fukuda et al., 1987), “ghost oppression phenomerecognized by the patients as dreaming. Sleep terrors non” in Hong Kong, China (Wing et al., 1999), “Old arise out of NREM sleep, but patients recall little Hag” in Newfoundland (Ness, 1978), “uqumangirniq or imagery and appear terrified and confused during the aqtuqsinniq” among Inuit (Laws and Kirmayer, 2005) events. “bedridden by the witch” among African Americans in A number of factors have been invoked to explain the USA, and visitation by tokoloshis (spirit of anceswhy complex hallucinations occur during sleep. Low tors) among black South African people (Gangdev, ambient illumination may play a role, as the images van2004). In general, stress, anxiety, panic disorder, sleep ish upon switching on the light. In most form of hallucideprivation or irregular or disturbed sleep–wake nosis, however, including the Charles Bonnet syndrome, rhythm appear to precipitate attacks in some patients; hallucinations are most prominent at the end of the day, ISP can be associated with the use of anxiolytic drugs, which would support the importance of arousal and even after consideration for the concurrence of menbrainstem activity (Manford and Andermann, 1998). tal disorders. Estimates of the prevalence of isolated ISP vary, depending on the sample under study and the ethnic, SLEEP PARALYSIS genetic, and cultural experience (reported prevalences Sleep paralysis is one of the cardinal symptoms of the of sleep paralysis can be changed by the terminology “narcoleptic tetrad” (Yoss and Daly, 1957): about 60% used) (Fukuda, 1993). Prevalence has been estimated as of people with narcolepsy experience sleep paralysis 6–62% in the general population (Dahlitz and Parkes, either rarely or frequently (even daily). However, 1993; Ohayon et al., 1999), 18% in the elderly (Wing recurrent isolated sleep paralysis (ISP), i.e., not assoet al., 1999), and 29% among college student samples ciated with narcolepsy, is one of the lesser known (Cheyne et al., 1999). Increased rates of ISP occur in and often benign forms of parasomnia. adults reporting history of childhood sexual abuse and ISP consists of brief episodes of transient inability in individuals meeting criteria for post-traumatic stress to move when falling asleep (hypnagogic or predormidisorder (Ohayon and Shapiro, 2000). The frequency tal form) or, more usually, when wakening up, either of ISP may vary from a single attack in a lifetime to during the night or in the morning (hypnopompic or attacks every night. The age of onset of ISP is usually postdormital form). Characteristically all of the skelearound the teens, and gender does not seem to be a factal muscles are virtually “paralyzed”, resulting in tor. The occurrence of sleep paralysis in some families inability to move the limbs, trunk, and head, or to raises the possibility of a genetic mechanism (Dahlitz speak; respiratory and ocular movements remain intact and Parkes, 1993; Wing et al., 1999). and consciousness is clear. Eye fluttering, moaning, It has been suggested that sleep paralysis consists of numbness or tingling of the limbs, palpitation or sweatdissociated REM sleep activities that occur in full ing, and a sensation of struggling to move may be awareness: sleep paralysis occurs if awareness alone experienced during an episode, and also a feeling of returns to the wake mode but muscle tone and perceppressure on the chest and difficulty breathing despite tion continue in REM mode (Hishikawa, 1976). Videonormal respiration function. ISP usually lasts from polysomnographic recordings during sleep paralysis

ISOLATED MOTOR PHENOMENA AND SYMPTOMS OF SLEEP document the characteristics of the dissociative state characterized by mixed EEG patterns of REM and wake, abundant alpha activity and atonia of antigravitational muscles. Sleep position and timing appear to influence rates of sleep paralysis, with higher rates in individuals sleeping in the supine position and in patients reporting paralysis at the beginning and in the middle of sleep compared with those reporting episodes when waking up at the end of sleep (Buzzi and Cirignotta, 2000; Dahmen and Kasten, 2001; Cheyne, 2002; Girard and Cheyne, 2006). The differential diagnosis of sleep paralysis includes: atonic generalized epileptic seizures (they occur during daytime and EEG shows epileptic abnormalities); drop attacks (they occur during wakefulness and in patients with vertebrobasilar vascular insufficiency); cataplexy (which does not occur at sleep onset and is a reaction to, rather than a cause of, emotional experience); familial hypokalemic periodic paralysis (which often occurs on awakening but lasts hours or days, is associated with low serum potassium levels during attacks, and is easily reversed by correcting the hypokalemia); dissociative or psychotic states (in which observation of the patient’s movements during sleep can be conclusively diagnostic of psychogenic paralysis). In particular, difficulty waking up, for example because of intense fatigue, should not be mistaken for sleep paralysis. Occasionally, the symptoms associated with sleep paralysis may be mistaken for a psychotic state. It is possible for sleep paralysis to be the first presenting feature of the narcolepsy syndrome if the excessive daytime sleepiness has not been recognized or is concealed. If sleep paralysis is frequent, serotoninergic agents seem to represent the most effective agents for treatment; in particular, amitriptyline has been used in conjunction with L-tryptophan as a precursor of brain 5-hydroxytriptamine (5HT, serotonin) (Snyder and Hams, 1982).

STATUS DISSOCIATUS The concept of status dissociatus (SD) defines a clinical condition in which elements of one state of being (wakefulness, NREM sleep, and REM sleep) persist or are pathologically recruited into another state (Mahowald and Schenck, 1991, 2001). This condition is thus characterized by a breakdown of state-determining boundaries, in which every manifestation represents a “switching error” (Mahowald and Schenck, 2001). Polygraphically, SD is often characterized by the simultaneous admixture of elements of wakefulness, REM and NREM sleep, so as to make recognition of the proper wake or sleep stage difficult or even impossible.

895

The definition of SD is a broad one, but it is useful in the clinic, as it brings together under one concept several sleep disorders variously classified under different headings. The elemental forms of SD are cataplexy (intrusion of REM sleep muscle atonia into wakefulness), hypnagogic and hypnopompic hallucinations (dream mentation occurring during sleep), NREM parasomnias such as confusional arousals (wakefulness motor behavior occurring during deep sleep), REM parasomnias such as RBDs (persistence of muscle tone during REM sleep), and sleep paralysis (the persistence of REM sleep muscle atonia into wakefulness). Symptomatic SD has been reported after brain lesions, such as surgery for tegmental pontomesencephalic cavernoma (Provini et al., 2004) and paramedian thalamic syndromes (Montagna et al., 2002). The most complex forms of SD are characterized from a behavioral point of view by frequent muscle twitching (resembling excessive fragmentary myoclonus), diffuse and sometimes massive myoclonic jerks, vocalization, and complex motor behaviors associated with reports of dream-like mentation (Cochen et al., 2005). Agrypnia excitata, a syndrome characterized by prominent loss of slow-wave sleep and abnormal REM sleep without atonia, associated with autonomic and motor hyperactivity (Lugaresi and Provini, 2001; Montagna and Lugaresi, 2002), has been also viewed as a particular instance of SD.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 55

Sleep bruxism 1

N. HUYNH 1, G.J. LAVIGNE 1, 3 *, K. OKURA 1, 2, D. YAO 3, AND K. ADACHI 1, 3 Facult de Mdecine Dentaire, Universit de Montral, and Hpital Sacr Cur de Montral, Montreal, Canada 2

Institute of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan 3

Faculty of Dentistry, University of Toronto, Toronto, Canada

INTRODUCTION Rhythmic masticatory muscle activity (RMMA), defined as repetitive jaw muscle contractions (three or more at 1 Hz frequency), is frequently observed during sleep (Lavigne et al., 2001a). Approximately 60% of normal subjects exhibit this activity in the absence of tooth grinding during sleep, whereas RMMA is occasionally associated with tooth-grinding noise in patients with sleep bruxism. Most patients diagnosed with sleep bruxism have frequently been told by their sleep partners that they grind their teeth during sleep. Patients may complain of waking up during the night or in the morning with a sensation of stiffness in the jaw, known as clenching. In addition, patients may experience jaw muscle and joint pain, headaches, and their teeth may become sensitive to cold or heat and/or may become damaged by forceful jaw muscle contractions (Lavigne et al., 2005, 2008). Two recent position papers have proposed that sleep bruxism is a movement disorder and a centrally regulated condition (Lobbezoo and Naeije, 2001a; De Laat and Macaluso, 2002). More recently, the second edition of the International Classification of Sleep Disorders (ICSD) moved the description of sleep bruxism from the category “parasomnia” to “sleep-related movement disorders” (American Academy of Sleep Medicine, 2005b). Sleep bruxism is described primarily alongside conditions with “relatively simple and stereotyped movements that disrupt sleep” such as “periodic limb movement disorders”; conversely, parasomnias include conditions that are “undesirable events that accompany sleep”. Sleep bruxism does not disrupt the patient’s sleep (it is more a problem for the sleep partners), and as such is probably not a pure “undesirable

event” such as rapid eye movement (REM)-sleep behavior disorder (RBD) or sleep terrors. It is important to distinguish between clenching while awake from tooth grinding during sleep, as both conditions probably have a different etiology and pathophysiology. In the absence of any medical or sleep disorders, use of medication or recreational drugs, sleep bruxism is classified as primary and as a “sleeprelated movement disorder”. It is also classified as secondary if a concomitant history of the following medical or psychiatric disorders is associated with recent tooth-grinding episodes: Epilepsy, Parkinson’s disease, sleep apnea or upper airway resistance, oromandibular or cervicofacial myoclonus, oral tardive dyskinesia or dystonia, Huntington’s disease, cerebellar hemorrhage, coma, Rett syndrome, depression, anxiety disorders, etc. (Kato et al., 2001b; Lavigne et al., 2005). It is obvious that the same label is applicable to tooth grinding while awake (no evidence during sleep, to date) resulting from the use of medication or recreational drugs: cocaine, ecstasy, most selective serotonin reuptake inhibitors (SSRIs), haloperidol, flunarizine (calcium blocker), or other antiarrhythmia medications (Lavigne et al., 2003).

EPIDEMIOLOGY AND GENETICS The prevalence of self-reports of sleep bruxism stands at 8% in the adult population. Age seems to be an important variable, as tooth grinding is reported at 14% in children whereas in older people it is reported at 3% (Lavigne and Montplaisir, 1994; Laberge et al., 2000; Ohayon et al., 2001). Gender differences are also reported for clenching while awake: among the 20% of the population that is aware of this reactive motor

*Correspondence to: G. Lavigne, Faculte´ de Me´decine Dentaire, Universite´ de Montre´al CP 6128, succ Centre ville, Montreal, Canada H3C 3J7. Tel: 514-343-2310, Fax: 514-343-2233, E-mail: [email protected]

902 N. HUYNH ET AL. behavior, women predominate. By contrast, it is not (Lobbezoo et al., 1997). Use of haloperidol and other clear whether tooth grinding–sleep bruxism is gender dopaminergic antipsychotic medications can also trigdominant, although a recent report suggests that males ger tooth grinding, but this seems to be dominant while may be more at risk of occasional grinding (Baba et al., awake, as no study has reported tooth grinding during 2004). A clear genetic heritability pattern is not strongly sleep in these patients (for a review see, e.g., Winocur supported by the literature (Lavigne et al., 2008). Studet al., 2003). Similarly, antidepressive medications ies in twins have revealed that environmental factors of the SSRI family also seem to be a risk factor for make an important contribution, and heterogeneity is sudden tooth clenching with occasional grinding, again most likely present (Hublin et al., 1998). while awake; no evidence is available for sleeping subjects (for a review see, e.g., Winocur et al., 2003). The absence of polysomnographic data with antipsyRISK FACTORS chotic medications and SSRI prevents the possibility Based on common belief, it would seem that episodes of of making any firm cause-and-effect statement regardintense workload or strong familial demands are imporing sleep bruxism. Patients using recreational drugs tant risk factors associated with tooth grinding. One (e.g., cocaine or Ecstasy) may complain of jaw lock, paper has suggested that clenching–grinding may be an reduction in the freedom of jaw movement, temporal example of persistent activation of fear circuitry (Bracha headache, and jaw clenching. et al., 2005). Another report from a survey made in the Evidence of epileptic seizures in relation to tooth general population highlighted that anxiety seems to be grinding was not found in our population of patients more prevalent in adults who grind their teeth (Ohayon with sleep bruxism, but was found in one of our control et al., 2001). In a case–control study of a large sample subject who was unaware of any episode of epileptic (1399 adults), an odds ratio of 5 (confidence interval seizure while awake. However, a recent paper reported 2.8–8.8) was estimated for self-reported bruxism and a patient presenting rhythmic tooth grinding in relation continual stress (it is unknown whether the subjects were to temporal seizures while awake and asleep (Meletti awake or asleep) (Ahlberg et al., 2004). The collection of et al., 2004). We recommend that a full electroencephurine in patients with and without reported bruxism alographic (EEG) recording be requested for patients revealed higher levels of epinephrine and dopamine, presenting with both sleep bruxism–tooth grinding a finding associated with stress (Clark et al., 1980; and tooth tapping, frequent with faciomandibular myoVanderas et al., 1999). A biological investigation of a limclonia, to rule out epileptic activity (Kato et al., 1999a; ited sample of 24 patients who were aware that they Vetrugno et al., 2002). Moreover, faciomandibular ground their teeth, of whom the majority complained myoclonia may simulate epileptic seizures during of morning headaches, suggests that anxiety and vulnersleep due to oral biting (Montagna, 2004). Caution is ability to psychosomatic disorders were dominant charnecessary when interpreting data from electrodes in acteristics (Bader et al., 1997). However, other studies the frontal and temporal positions, because artifacts in which an “ecological validation” (e.g., assessments produced by the temporal muscle contractions of made in tandem with real-life events) was attempted bruxism can mimic the scoring of electromyographic using recordings of muscle activity made during stress(EMG) brief events during an epileptic spike. Parallel ful events or with a “vigilance motor task” have not recording of EMG from masseter muscles with a video supported a direct cause-and-effect relationship between of the face is useful for further discrimination of anxiety and sleep bruxism (Pierce et al., 1995; Major signals. et al., 1999). Another indirect factor is a type A personalTen years ago, a case report suggested that sleep ity, a highly goal- or success-oriented attitude (Pingitore bruxism and RBD could be concomitant (Tachibana et al., 1991; Kato et al., 1999b; Major et al., 1999). As a et al., 1994). In our group of scientist–clinicians, result, biological investigations into the “cause and Montplaisir and Gagnon have investigated sleep motor effect” link are rather disappointing; this in itself may activity in a large population of patients with RBD withbe due to the heterogeneous causes of bruxism. out finding evidence of tooth grinding (unpublished Reports of “secondary” tooth grinding, following observation). However, in a survey of violent behavior the use of medications or “recreational” drugs, can during sleep, Ohayon et al. (1997) reported an increased be found in the literature (for a review see, e.g., incidence of sleep bruxism. At this time, in the absence Winocur et al., 2003). L-Dopa, a catecholamine preof video and polygraphic recording, it is difficult to concursor, was reported to trigger sleep bruxism in one clude that violent behavior in sleep is associated with patient with Parkinson’s disease (Magee, 1970). ConRBD and sleep bruxism, although chewing-like moveversely, a recent controlled study revealed that L-dopa ments similar to bruxism can probably be observed in reduced sleep bruxism motor activity by about 30% the absence of reports of tooth grinding.

SLEEP BRUXISM 903 Less than 10% of our patients with sleep bruxism masseter muscle hypertrophy as an indirect indicator of presented periodic limb movements during sleep (5 to a clenching habit (e.g., repetitive isometric jaw clench); 10 events in tibialis muscle per hour of sleep). Again, and (4) examination of the magnitude of tooth wear that interpretation of this statement needs to be weighted needs to be taken into consideration along with the presagainst other factors: in patients in their forties it is ence of gastric reflux, xerostomia, or wear due to dentospossible to find concomitant sleep bruxism and perikeletal malocclusion. Tooth wear needs to be correlated odic limb movements during sleep, as the prevalence with a current report of active grinding from a sleep of both are within the 8–12% range (Lavigne and partner, parent, and even condominium neighbors. The Montplaisir, 1994). following need to be looked for as they may be secondary signs that are among risk factors for sleep breathing anomalies or disorders that may also increase the probaDIAGNOSIS bility of tooth grinding: deep palate (ogival shape) and/or A diagnosis of sleep bruxism and its pathognomonic retrognathia (short mandibular bone) with large tongue/ “gold standard” – currently tooth grinding – is reached macroglossia, long uvula, or soft palate. following patient interview, clinical examination, and Confirmation of an unusual oromandibular motor ambulatory or sleep laboratory recordings. These activity can be made using several tools: (1) sound recordings are necessary in cases where nocturnal activrecording (e.g., a voice-activated recorder placed next ity may be associated with sleep epilepsy, sleep apnea, to the pillow at bedtime); (2) video and sound home insomnia, or pain. recording (focus on head and face) with a black light The clinician investigating a patient complaining of in the room; (3) portable EMG recording with video bruxism will first need to gather a history of awareness and sound at home; (4) laboratory recordings with of jaw clenching and/or tooth grinding. The history audio and video recordings, EMG recording of at least needs to be corroborated by a sleep partner (usually one masseter muscle plus electroencephalogram, leg, complaining that they are awakened by a noise like EMG, or sensor and respiratory activity sensors to rule stones grinding or a wooden floor cracking), to confirm out concomitant sleep disorders such as periodic limb that tooth grinding is present. The interview will include movement during sleep, apnea/snoring, insomnia/pain, questions about the use of medications such as SSRIs, sleep epilepsy/tooth tapping. Be aware that, in the antipsychotics (e.g., haloperidol), or recreational drugs absence of audio–video recordings, specific assess(e.g., Ecstasy, cocaine), as it has been suggested that ment of jaw muscle EMG is weak as approximately these substances may increase the probability of clench30% of oromotor activities during sleep are not ing while awake and tooth grinding (e.g., Winocur specific to sleep bruxism (Dutra et al., 2009). et al., 2003). Moreover, concomitant complaints of In accordance with recent revised ICSD criteria pain in the jaw muscles, temporomandibular dysfunc(American Academy of Sleep Medicine, 2005a; Walters tion (e.g., jaw movement limitation and joint sound), et al., 2007), the criteria used most frequently to score and headaches (mainly temporal) are indicators of sleep bruxism are adapted from those suggested in jaw clenching while awake and bruxism while asleep. literature (Reding et al., 1968; Ware and Rugh, 1988). A Reports of tooth fracture or tooth sensitivity are also bruxism episode is scored positive if, in the presence of noted, because both clenching and tooth grinding may tooth-grinding noise, at least three EMG events occur, be triggering factors. In the presence of diurnal comor a burst lasts 0.5 s or more, or one contraction lasts plaints of sleepiness, jaw muscle pain or fatigue upon 2 s or more (Lavigne et al., 1996; Rompre´ et al., 2007). awakening, morning headache, gastric reflux during EMG episodes with tooth grinding, confirmed with sleep, we recommend ruling out sleep apnea–hypopnea audio–video recordings, are then classified by pattern and upper airway resistance syndrome (the last is furinto phasic or rhythmic event (three or more bursts), ther described below). tonic-sustained (one episode lasting more than 2 s) or The clinical examination includes: (1) head and neck mixed (if both patterns are seen together) (Figure 55.1). muscle palpation to rule out pain; joint palpation and If the contraction lasts less than 0.25 s and the video consound (with stethoscope) to rule out temporomandibular firms rapid jerk-like contractions, a diagnosis of isolateddisorders or other joint pain or pathology (e.g., osteoarfragmentary myoclonus is made in the absence of any thritis); estimation of mandibular opening and lateral evidence of sleep-related epilepsy (Kato et al., 1999b). movements; (2) examination of mucosa to identify tooth We used research-scoring criteria and high cutoff grooving or ridging on the cheeks and the side of the values in selected patients with a regular history of tongue suggestive of a concomitant oral habit; (3) qualtooth-grinding EMG oromotor activities during sleep ity of salivation, because in the absence of saliva the in most of our previous publications in order to invesrisk of tooth wear may be increased; identification of tigate further the putative mechanism(s) of the genesis

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EEG 1

ECG 2 EMG (suprahyoid − opening muscle)

3

EMG (left masseter − closing muscle) EMG (right masseter − closing muscle)

4

Swallowing 5

L -MAS

R -MAS

Phasic bursts

Tonic bursts

Mixed bursts

Fig. 55.1. Example of a polygraphic recording of a healthy young patient with sleep bruxism in our sleep laboratory with the sequence of physiological events (1–5) associated with rhythmic masticatory muscle activity sleep bruxism. Taken during sleep stage 2, surface electrodes include: an electroencephalogram (EEG) (C3A2), an ECG, one suprahyoid–chin electromyogram (EMG), and two masseter muscle EMGs (left and right) for sleep bruxism assessment over nonspecific oral activities. As for the two masseter muscle EMGs, there are different kinds of sleep bruxism burst: phasic (three or more bursts), tonic (each burst of 2 s or more), and mixed bursts (tonic and phasic). For each burst, the EMG is 10–20% or more of the voluntary contraction, whereas each burst must last for at least 0.25 s or it is considered to be myoclonia. Note: The two big inspiratory breaths are not illustrated; this occurs at the junction of sequence 3 and the onset of sequence 4 (for more details see Khoury et al., 2008).

of sleep bruxism. The use of a cutoff of 4 EMG episodes per hour of sleep (termed the “brux index”) in patients with a current history of tooth grinding, allowed “frequent” sleep bruxers to be distinguished from those with fewer sleep-bruxism motor episodes who had concomitant complaints of pain and headaches, and from controls (Rompre´ et al., 2007). With such research criteria we were able to distinguish frequent sleep bruxers from controls (Lavigne et al., 1996, 2001b). Interestingly, a recent cluster analysis of polysomnographic data collected from 100 patients with sleep bruxism and positive tooth grinding (studied for two nights in the sleep laboratory), based on the frequency of sleep-bruxism RMMA episodes, revealed the existence of three groups of patients with

sleep bruxism: low frequency with a median (range) of 2.1 (0.1–4.5); moderate frequency with a median of 5.7 (4.3–9.8); and high frequency with a median of 9.6 (5.9–15.2). Importantly, patients with sleep bruxism with the lowest frequency of RMMA commonly reported concomitant morning pain, whereas this was reported less frequently in patients with high-frequency sleep bruxism (Rompre´ et al., 2007). It is important to recognize the night-to-night variability of the oromotor EMG brux index, found to be in the 25% range, and the variability of episodes with tooth-grinding noise, which is much higher – over 50% (Lavigne et al., 2001a). A total brux time index has also been suggested as a practical measure (van der Zaag et al., 2005), but its night-tonight variability is unknown at this time.

SLEEP BRUXISM 905 Again, we reiterate that when patients present with bruxism became associated in the literature with stress daytime sleepiness, headaches upon awaking in the or anxiety in “healthy” subjects without neurological or morning, or gastroesophageal reflux it is important to psychiatric disorders (e.g., Kato et al., 2001b; Lavigne rule out sleep apnea or upper airway resistance synet al., 2005). The discovery of REM sleep in the middrome, because breathing problems during sleep may be 1950s gave rise to the suggestion that sleep bruxism concomitant with sleep bruxism (see previous chapters and tooth grinding might be associated with sleep in this volume for further information and Miyawaki arousal (Tani et al., 1966; Reding et al., 1968; Satoh et al., 2003a; Okamoto et al., 2003). In the presence of and Harada, 1973). tooth tapping, present in 10% of our tooth-grinding In fact, in young patients, the primary sleep bruxpatient sample, oromandibular myoclonus was found – ism, most RMMA events are observed in light sleep brief and sudden jaw muscle contractions lasting for stages 1 or 2, with about 10% in REM sleep (Miyawaki less than 0.25 s (Kato et al., 1999b). As a familial form et al., 2003a). However, more events can be noted in of this activity has been reported, and sleep-related epiREM sleep of older patients or in presence of medical lepsy is a possible concomitant finding, a neurological or psychiatric problems (Ware and Rugh, 1988; Bader examination with full EEG montage is recommended et al., 1997). (Vetrugno et al., 2002; Meletti et al., 2004). However, Contrary to initial observations made in the absence as described above, the clinician has to be aware that, of controls, recent controlled investigations have failed in the presence of tooth grinding and a possible epileptic to demonstrate that sleep bruxism is associated with a event, electrodes at the temporal muscle level may give dopaminergic “pathological” process or with the presfalse signals due to artifacts on the EEG signal caused ence of EEG K-complexes (Magee, 1970; Satoh and by the contraction (O’Donnell et al., 1974; Veerasarn Harada, 1973; Lobbezoo et al., 1996; Lavigne et al., and Stohler, 1992). 2001c, 2002). However, the original suggestion that sleep arousal mechanisms may be associated (e.g., facilitatory window) with the onset of sleep bruxism PATHOPHYSIOLOGY motor activity is supported by few recent studies. It There is no definitive evidence supporting a simple pathhas been demonstrated that most sleep-bruxism motor ophysiology for the genesis of sleep bruxism. Recent events occur within cyclical activation during sleep, reviews on this topic are informative (Kato et al., called a microarousal, consisting of a 3–10-s increase 2001b, 2003b; Lobbezoo and Naeije, 2001b; Lavigne in brain activity, heart rate acceleration, and a rise in et al., 2003, 2005, 2007, 2008; Winocur et al., 2003). muscle tone (e.g., a cyclic alternating pattern that tends Historically, the literature demonstrates that tooth grindto appear every 20–40 s) (Zucconi et al., 1995; Okura ing may be associated with: (1) some neurological and et al., 1996; Bader et al., 1997; Macaluso et al., 1998; psychiatric disorders; (2) the influence of peripheral Kato et al., 2001a; Lavigne et al., 2003). factors on motor control and reflexes such as dental Our laboratory further demonstrated the presence of micromorphology, called occlusal interferences; (3) the a physiological sequence of activation before the onset interaction with some neurotransmitters such as dopaof sleep bruxism–tooth grinding: (a) at
8 to 4 min, mine, or with the release of catecholamines in urine, an increase in sympathetic–cardiac dominance (no. 1 in including epinephrine and norepinephrine; and (4) some Figure 55.1); (b) at
4 s, a rise in EEG brain activity mechanisms related to sleep arousal. (no. 2 in Figure 55.1); (c) at
1 s, the start of tachycardia; At the beginning of the 20th century, tooth grinding and (d) at
0.8 s, a major increase in the muscle tone of in patients with brain damage of various causes was suprahyoid muscles with initiation of two big breaths described under the term “bruxomanie” (Marie and (sequence no. 3 in Figure 55.1) (Kato et al., 2001a; Huynh Pietkiewicz, 1907). The observation of tooth grinding et al., 2006a; Khoury et al., 2008). Finally, RMMA and in patients with Parkinson’s disease, epilepsy, and some sleep bruxism (sequence no. 4 in Figure 55.1) occur, with brain damage has prompted the emergence of a role either phasic or tonic contractions in jaw-closer muscles for dopamine and the upper brainstem in the genesis and tooth grinding, which are followed by swallowing of spontaneous jaw movements associated with tooth (sequence no. 5 in Figure 55.1) in over 60% of these grinding (for a review see, e.g., Lavigne et al., 2005). episodes (Miyawaki et al., 2003b). Further study revealed In the mid-1960s, occlusal tooth surface interference that, in patients with sleep bruxism, experimentally was thought to be primarily responsible for the initiinduced microarousals were associated with tooth grindation of tooth grinding. Although this hypothesis ing (Kato et al., 2003a). Furthermore, the administration remains popular in some clinical circles, it suffers of a cardioactive a-agonist medication, clonidine, at from a lack of strong evidence showing a cause-andbedtime decreased the autonomic cardiac activation and effect relationship (Tsukiyama et al., 2001; Okeson, the number of sleep bruxism episodes by 60% in compar2003). As described above, in the mid-1960s, sleep ison to placebo administration, without reducing the

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frequency of microarousals (Huynh et al., 2006b). This last finding supports the hypothesis that sleep bruxism occurs within arousal, probably by an independent mechanism that can be linked to autonomic–cardiac excitability and respiration. The exact mechanism or the “cause and effect” explanation for the genesis of RMMA sleep bruxism remains to be demonstrated. The study of sleep in animals is also of interest in developing an understanding of the mechanism that may be associated with a sudden phasic or tonic increase in the muscle tone of jaw muscles. It has been clearly shown that during sleep the level of activity in masseter muscle motoneurons is reduced (Chase and Morales, 2005), that hypocretin/orexin is a neurotransmitter involved in vigilance and the level of jaw muscle tone during sleep (Peever et al., 2003), and that rhythmic jaw movement is controlled by the brainstem center, Open

Before sleep

the central pattern generator (CPG) neuronal network (e.g., Lavigne et al., 2003). Activation of the CPG neuronal network by descending cortical inputs is responsible for the alternating pattern between agonist and antagonist muscles. However, as both opener and closer jaw muscles contract simultaneously during sleep, rather than alternating as they do when food is chewed, we hypothesized that the CPG is isolated from upper brain influences such as those in the cortical masticatory area (Lavigne et al., 2003; Huynh et al., 2004). A recent study in sleeping Macaca fascicularis revealed that rhythmic jaw muscle activity, observed while the animal was awake, disappeared during sleep (Adachi et al., 2005); when the cortical threshold to evoke rhythmic jaw movement was increased 10-fold, only a very slow opening was observed, and as soon as the animal awoke the threshold returned to previous values (Figure 55.2). After sleep

Sleep

Pattern of RJMs Close A 1400

10 mm : ICMS 1 sec Sleep

Before sleep

After sleep

1200 3

Mean of thresholds

1000 5

: number of sessions

3

5

800

600

400

5

3

200

0 B

Time (30 min/divisioin)

Fig. 55.2. The patterns of intracortical microstimulation (ICMS) that induced rhythmical jaw movements (RJMs) and the effect of sleep on the threshold of ICMS that induced RJMs in Macaca fascicularis. (A) ICMS of threshold intensity induced RJMs signals, recorded by a magnet sensing motion detector, were averaged to obtain the pattern of jaw movements in each experimental period (“before sleep”, “sleep”, and “after sleep”; see below). (B) MeanSEM of normalized ICMS thresholds for inducing RJMs in five nights. ICMS threshold was obtained when inducing RJMs every 60 min (“before sleep”). The monkey was then allowed to sleep in a dark and silent environment during which the ICMS thresholds inducing RJMs (“sleep”) were investigated every 30 min. The monkey was awakened by a lighted environment, whereupon ICMS thresholds inducing RJMs (“after sleep”) in 30-min intervals were investigated. (From Lavigne et al., 2007. #Elsevier.)

SLEEP BRUXISM These data suggest that spontaneous rhythmic jaw activity during sleep, of a kind similar to the activity of sleep bruxism, is generated at the brainstem level. However, the trigger of this spontaneous activity seems to facilitate influences with repeated or clustered sleep arousal during the cyclic alternating pattern of sleep that is known to occur 6 to 15 times per hour of sleep in young healthy adults (Boselli et al., 1998). The sleep of otherwise healthy subjects with tooth grinding is relatively normal in terms of macrostructure and sleep efficiency. However, some patients without snoring or sleep apnea do complain of morning pain and headache. As described above, in a recent analysis of subjects with a history of tooth grinding, we found that those who complained about pain in their jaw muscles seemed to have a lower “brux index” than frequent grinders (Lavigne et al., 1997; Rompre´ et al., 2007). Upper airway resistance syndrome is defined as an inspiratory effort that does not reach full amplitude and is characterized by patients’ report of morning headaches and daytime sleepiness in the absence of clear sleep apnea (see Chapter 26 for definition). The influence of the so-called upper airway resistance needs to be ruled out in patients with morning headache and sleep bruxism. The literature regarding a possible association between respiratory disturbance and sleep bruxism is difficult to interpret due to the lack of any standardized scoring criteria for sleep bruxism, and because most studies have not been designed to investigate the role of apnea and hypopnea (an extreme condition with specific clinical and sleep scoring features) in patients with sleep bruxism (see previous chapters on apnea in this volume). Historically, the first evidence of an association came from a study based on the scoring of bruxism-like motor activity at the level of the masseter muscle in patients with sleep apnea without any clear information regarding a clinical history of tooth grinding (Okeson et al., 1991). It was found that 65% of apnea and hypopnea events included some activity in the jaw muscle of patients with sleep-disordered breathing, who were matched with controls of the same age and sex (all males). This observation is at first not surprising, as sleep apnea and hypopnea are widely recognized to trigger sleep arousals and awakenings. Furthermore, a rise in muscle tone is a main feature of sleep arousals. In contrast, another study with different criteria to score masseter muscle contractions showed that jaw activity was rarely observed in sleep apnea; less than 14.4% of apnea or hypopnea events ended with a contraction in the masseter muscle (Sjoholm et al., 2000). The prevalence of bruxism (not further defined as being wake clenching type versus sleep tooth-grinding

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type) in a sleep breathing-disordered population was reported to be between 30% and 50% (Gold et al., 2003). Moreover, the literature suggests that breathing disturbances may contribute to an increased probability of sleep arousal and, by consequence, may facilitate the probability of the occurrence of tooth grinding. The association between airway disturbances, sleep bruxism, and headache is further supported by a study showing that in a sample of 24 patients with sleep bruxism (aged 23–63 years), 65% reported frequent morning headaches, but a clear diagnosis of apnea and hypopnea was made in only 4 of the sample (Bader et al., 1997). In children with a previous history of sleep-disordered breathing, such as snoring and apnea-like disturbances, the prevalence of bruxism/ tooth grinding decreased from 45.6% before to 11.8% after surgical removal of tonsillar hyperplasia (DiFrancesco et al., 2004). An investigation of upper airway resistance syndrome in patients complaining of tooth grinding and morning pain with headaches is probably an avenue to consider when managing tooth grinding.

MANAGEMENT It is important to clarify that, to our knowledge, there is no treatment that eliminates sleep bruxism and associated tooth grinding. As reported above, the high level of night-to-night fluctuation or variability in the incidence of tooth grinding should be kept in mind during clinical interviews (Lavigne et al., 2001a). It is not rare that a clinician receives a false impression that tooth grinding has disappeared, when in reality a patient has been sleeping alone for a given period or is passing through a “smoother” period of life (e.g., less pressure load). All these factors need to be taken into account. The term sleep bruxism “consequence management” seems more appropriate than “treatment” due to the cyclic nature of signs and symptoms, lack of curative therapy, and the low level of long-term follow-up evidence. Our advice to clinicians for selecting the most appropriate strategy for treating a patient is to reassess the main complaint – the motive for the consultation. Two recent reviews are useful: one is a critical review of available drug treatments (both beneficial and harmful effects) and the other is a comparison based on number needed to treat (NNT) (Table 55.1) of the most valuable treatment to be used in future randomized controlled trial (RCTs) or in the meantime, until evidence-based information becomes available (for reviews see, e.g., Winocur et al., 2003) and Huynh et al. (2006c).

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Table 55.1 Summary of the number needed to treat (NNT) estimation for various treatments that can be used and further tested in sleep bruxism management Treatment

n

Oral devices MAD* 13 Occlusal* 23 Palatine* 9 Experimental pharmacological treatments Clonidine* 16 L-Dopa* 10 Bromocriptine* 7 Propranolol* 10 Tryptophan 8

NNT

Reference

2.17 (1.37 to 5.25) 3.83 (1.87 to
69.41) 4.50 (1.58 to
5.31)

Landry et al. (2006) Dube et al. (2004), Landry et al. (2006) Dube et al. (2004)

3.20 (1.67 to 37.25) 10.00 (3.50 to
11.64) 1 (2.53 to
2.53) 1 (2.55 to
2.55)
8.00 (9.60 to
2.82)

Huynh et al. (2006b) Lobbezoo et al. (1997) Lavigne et al. (2001c) Huynh et al. (2006b) Etzel et al. (1991)

Values in parentheses are 95% confidence intervals. The NNT is the number of patients that need to be treated with a specific treatment in order for one patient to receive a benefit or harm in comparison with placebo. The NNT could not be calculated for all published trials because raw individual data and data from baseline nights were needed. As the included studies had a crossover design, the NNT was calculated accordingly. The NNT is calculated as the reciprocal of the absolute risk difference. A NNT value from 0 to 4 is considered beneficial. If the NNT is negative, the treatment has worsened sleep bruxism. In case of a null treatment, the NNT is infinite. MAD, mandibulary advancement device. *Studies done in the authors’ sleep laboratory. (Adapted from Huynh et al., 2006c. #Quintessence.)

If the patient complains about noise reported by a sleep partner or is anxious about tooth damage or wear Patients are first instructed in relaxation techniques and in the common habits of sleep hygiene. These include abdominal respiration and mental imagery for further relaxation, and avoiding a heavy meal in the evening or intense physical exercise. So far, to our knowledge, no study has investigated the effectiveness of these approaches on sleep bruxism. Cognitive– behavioral treatment is also an important tool used in insomnia management, but there is little evidence available regarding its efficacy in the case of sleep bruxism. A dental device called a bite splint or oral guard, which is adapted to either the maxillary or mandibular arches, is the recognized procedure used to prevent the annoying effect of grinding sounds. The device protects teeth from damage and attenuates the grinding noises. It is important to reiterate that, although these devices reduce tooth damage and grinding noise, the jaw muscle contractions remain present or can even become more frequent in some patients. Another point to take into consideration is the fact that most studies have been conducted on a short-term basis; more recent studies suggest that over a 2–4-week period the initial reduction in the number of bruxism episodes/hour of sleep tends to return to baseline levels (Dube et al., 2004; Harada et al., 2004; van der Zaag et al., 2005). Modest patient compliance is also another

limitation associated with such oral devices: approximately 50% of patients with tooth grinding were still using the splint after 1 year (Dube et al., 2004). Reasons include discomfort with the device, snoring, hypersalivation, problems with “self-image”, etc. The use of a dental splint may be contraindicated in patients with a history of frequent snoring or sleep apnea; in an open study design we noticed that 50% of patients with a clear diagnosis of sleep apnea presented an increase in their index of respiratory disturbance during sleep (Gagnon et al., 2004). Consequently, the use of dental splints needs to be monitored if a patient reports sleep apnea concomitantly with tooth grinding.

Complaints of tooth grinding and morning jaw muscle pain including headaches In these cases we recommend first that upper airway resistance and other sleep anomalies be ruled out by a qualified physician. Next, the condition of the patient’s health and medication use need to be assessed; some medications may exacerbate respiratory disturbances (e.g., propranolol, opioids) and alter sleep quality. Note that it is important to improve sleep quality and reduce pain because it is known that a night of poor sleep is frequently followed by a day with more pain, and a day with intense pain may be followed by sleep of poor quality (e.g., Lavigne et al., 2005). In mild cases, the first line of approach might be short-term use of a muscle relaxant; meprobamate, diazepam, lorazepam, and clonazepam are among those

SLEEP BRUXISM used. Only clonazepam (1.0 mg at bedtime) has been demonstrated to reduce sleep bruxism; however, the same group also presented other medical conditions such as anxiety, insomnia, and leg movement disorders (Saletu et al., 2005). According to our clinical experience, we prefer the use of 0.5 mg in the early evening for a short period (1 to 3 nights per week, to prevent morning grogginess and risk of dependence). The use of tricyclic antidepressants (e.g., amitriptyline) has no noticeable effect on sleep bruxism (for a review see, e.g., Winocur et al., 2003). By contrast, the use of SSRIs may increase reports of clenching and tooth grinding while awake (for a review see, e.g., Winocur et al., 2003). Furthermore, use of a dopaminergic medication, such as L-dopa, had a mild effect, whereas bromocriptine has no effect (Lobbezoo et al., 1997; Lavigne et al., 2001c). Recent experimental trials designed to prevent the autonomic cardiac activation preceding sleep bruxism (as described in the Pathophysiology section above) failed to show any effect for propranolol (120 mg at bedtime), a beta-blocker, although a moderate dose of clonidine (0.3 mg at bedtime), an a-agonist, decreased the frequency of sleep bruxism episodes by 60% (Huynh et al., 2006b). Care must be taken if clonidine is used in normotensive patients: they may experience hypotension in the morning, a side-effect noted in 20% of our patient sample. Before final recommendations can be made, the effects of clonidine and its safety need to be tested in a RCT employing a dose–response curve design. Other medications such as flurazepam, buspirone, and gabapentin have been reported to reduce sleep bruxism in some patients, but lack of RCT evidence reduces our enthusiasm for recommending the use of these medications (Winocur et al., 2003). The use of drugs such as botulinum toxin may appear seductive due to their rapid administration, and high advertising and marketing strategies. However, clinicians should be warned that no RCT has yet been performed for sleep bruxism–tooth grinding; the botulinum toxin does travel toward the central nervous system, and the harmful or beneficial effects of this medication will remain unknown until companies provide evidence (Lavigne et al., 2005). Other devices currently under investigation for managing sleep bruxism include an oral splint on a single dental arch with a vibratory system that is activated when the patient bites the device. However, this system may trigger an arousal and an awakening that may disrupt sleep (Nishigawa et al., 2003). We recently completed two experimental RCTs using mandibular advancement appliances (e.g., protrude lower jaw to “open” the airway or prevent its collapse during sleep). The frequency of RMMA sleep bruxism per hour of

909

sleep was significantly reduced (Landry et al., 2006). In patients presenting with both sleep bruxim–tooth grinding and sleep apnea–hypopnea, it may be wise to use “stronger” mandibular advancement appliance, because the broken part may be aspirated in lungs. (Biofeedback systems using an EMG sensor and sound alarm were popular in the past; however, their low popularity may be explained by the sleep arousals and disruption of the bed partner’s sleep triggered by the sound; Kato et al., 2001b.) Use of hypnosis has also been proposed, but this technique lacks long-term follow-up and control for other relaxation strategies (Kato et al., 2001b). It also remains to be verified whether hypnosis is a beneficial treatment for only a specific instance or whether its effects last over time. In one case it was reported that the use of a continuous positive airway pressure (CPAP) device was beneficial in a patient suffering from sleep apnea and tooth grinding (Oksenberg and Arons, 2002). According to our experience, no clear effect of CPAP was observed in a few cases of patients with tooth grinding.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 56

Restless legs syndrome and periodic leg movements in sleep CHRISTOPHER J. EARLEY 1 *, RICHARD P. ALLEN 1, AND WAYNE HENING 2 (DECEASED) 1 Department of Neurology, Johns Hopkins University, Baltimore, MD, USA 2

Department of Neurology, University of Medicine & Dentistry of New Jersey – Robert Wood Johnson Medical School, New Brunswick, NJ, USA

INTRODUCTION

Diagnostic criteria for RLS in adults

Restless legs syndrome (RLS) when first described by Willis in 1672 was apparently considered to be rare and, given the apparent delayed onset of RLS morbidity largely to those aged over 50 years and the relatively short lifespan of 17th century Europeans, it may indeed have been a relatively uncommon problem. Although there are scattered references to conditions likely to be RLS throughout 19th and 20th century literature, Karl Ekbom provided the first comprehensive clinical description and diagnostic criteria for the condition (Ekbom, 1945, 1960). He emphasized the distinctive sensory discomforts, sometimes painful, that were provoked by rest and enhanced later in the day and into the night, disrupting sleep. Patients found rest problematic and experienced an urge to move that was relieved with movement. In the past 20 years there has been a growing clinical awareness of RLS with significant advances in diagnosis, treatment, epidemiology, genetics, and pathophysiology. These advances are the focus of this chapter. This chapter is about RLS; periodic leg movement in sleep (PLMS) will be discussed as it relates to RLS.

In 1994, the International Restless Legs Syndrome Study Group (IRLSSG) was the first to develop an international consensus on the diagnostic criteria for RLS (Walters et al., 1995). These original criteria were updated in 2002 to clarify some concepts and provide more explicit operational definitions for the RLS diagnoses at a workshop at the National Institutes of Health in Washington, DC (Allen et al., 2003). The workshop set out four diagnostic criteria, three supportive features, and three associated features, which are discussed below.

DIAGNOSIS AND CLINICAL FEATURES The diagnosis of the RLS is a clinical one. There are no diagnostic laboratory tests and even sleep laboratory studies can only help confirm a diagnosis. Diagnosis is made on the basis of the patient’s description of symptoms and of the factors that modulate them (Table 56.1).

THE

FOUR DIAGNOSTIC CRITERIA

The four criteria (see Table 56.1) can be divided into two groups: the first criterion, which specifies the core symptom of RLS, an unpleasant urge or need to move, and the last three criteria, which indicate the key factors that modify symptoms. The typical symptom of RLS is an akathisia or restlessness experienced within the leg. This akathisia is usually associated with unpleasant or uncomfortable sensations, which may be steady, fluctuating, or pulsatile. This sensation can be felt anywhere within the leg, although symptoms in the lower leg are more common than those in the upper leg; relatively few patients have symptoms confined to the feet. In some patients, the symptoms can extend beyond the legs to the arms (Michaud et al., 2000) and, less commonly, to other body regions including the pelvis, trunk, shoulder girdle, and genitals. The sensation is typically deep in

*Correspondence to: Christopher J. Earley, Neurology and Sleep Medicine, Johns Hopkins University, Asthma and Allergy Bldg 1B-82, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA. Tel: 410-550-1044, Fax: 410-550-3364, E-mail: [email protected]

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Table 56.1 Key clinical features for the diagnosis of restless legs syndrome (RLS) Clinical feature I.

Diagnostic features

II.

Supporting features

III.

Associated features

Clinical finding 1. 2. 3. 4. 1. 2. 3. 1. 2. 3.

Urge or need to move the legs, usually accompanied by unpleasant sensations Symptoms are worse or exclusively present at rest (i.e., lying, sitting) There is at least partial and temporary relief of symptoms by activity Circadian pattern – symptoms maximal in evening/night Periodic limb movements Family history of RLS Response to dopaminergic medications Generally chronic course, often progressive Sleep disturbance and its consequences Normal neurological examination in idiopathic cases

Modified from the International RLS Study group published consensus on clinical definition (Allen et al., 2003).

the limb, but not often felt within the joints. Although the sensations can be influenced by leg posture or applied sensations such as massage, the leg is not typically sensitive or tender; signs of inflammation, swelling, or other physical abnormalities are not usually observed. Patients provide a wide variety of descriptions of the symptoms, such as creepy, crawly, shock-like, bubbling, itchy, buzzing, or flowing, but almost invariably qualify them as annoying or often very unpleasant. Some cannot describe the sensations, perhaps because there is not a common term for the phenomena. In some cases (up to one-third), patients will indicate that the sensations are painful, especially if the symptoms are severe. Some patients have no obvious sensations beyond the need to move. In moderate to severely affected individuals, this need is “overwhelming” and the individuals cannot conceive of not moving in response to the discomfort. Confinement, as in an airplane, can aggravate symptoms and make them even more distressing. RLS is quiescegenic, that is, symptoms of RLS are evoked by rest (Criterion 2): they increase with both physical and mental relaxation and inactivity. In this regard, RLS is increased by the very situations that promote sleepiness in those without RLS. In contrast, those situations that increase arousal and include activity tend to suppress RLS symptoms (Criterion 3). Physical movement, strong cutaneous stimulation (heat, cold, scratching, massage), or mental activity, especially with strong emotional components, can reduce RLS as they reduce sleepiness. Patients almost invariably discover for themselves that various activities reduce symptoms, and will acknowledge this if questioned. Finally, symptoms of RLS follow a circadian rhythm with peak symptoms around midnight and a relatively protected period early in the day (morning) (Hening et al., 1999; Trenkwalder et al., 1999; Michaud

et al., 2004). This may be altered in those with abnormal circadian rhythms. Where this is due in part to the tendency for activity to subside later in the day, studies have shown that the circadian rhythm exists independent of activity level (Hening et al., 1999; Trenkwalder et al., 1999; Michaud et al., 2004), suggesting a true circadian rhythm. This rhythm – similar to that of pain sensitivity – is not merely subjective or related to voluntary movement, because involuntary leg movements show the same pattern, during both wakefulness and sleep (Trenkwalder et al., 1999; Michaud et al., 2004).

SUPPORTIVE

CRITERIA FOR DIAGNOSIS OF

RLS

The three supportive criteria include the presence of PLM (see Periodic limb movements, below), therapeutic response to dopaminergic (DAergic) agents (see Dopaminergic agents, below), and a family history of the disorder (see Familiality, below). None of these is needed for diagnosis; nevertheless, in some cases, they can help elucidate difficult diagnoses.

ASSOCIATED

FEATURES

The most important associated feature is sleep disturbance. In individuals with mild RLS, sleep may not be disturbed. The second common finding is a progressive course. This may be quite prolonged over decades, or relatively brief (see Phenotypes, below). Progressive RLS is most common in patients who seek medical attention, however; many individuals with mild RLS may not progress, and even when relatively severe patients may have sustained remissions (Walters et al., 1996). The third finding is the absence of clearcut signs of other neurological diseases in patients with idiopathic RLS. If RLS has been induced by another

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP disorder or a common comorbidity is present, there may be signs of that disorder.

Periodic limb movements and periodic leg movement disorder The uncomfortable sensations seen with RLS can also be associated with involuntary spasms or jerks, designated periodic limb movements (PLMs). Although most of these movements occur during sleep, they can also occur with the subject awake, when they are termed “period limb movements in wake” (PLMW). The use of PLMs to support the diagnosis of RLS has been investigated, but only in select populations. PLMs are repetitive movements that typically recur at intervals of 10–40 seconds (Figure 56.1). They were first noted during the sleep state – termed periodic limb movements in sleep (PLMS) – but initially called nocturnal myoclonus by Lugaresi and his group, who first characterized them and associated them with RLS (Lugaresi et al., 1968, 1986). They are detected by recording leg movement (actigraphy) or leg muscle activation (electromyography, EMG). The usual

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recording method is to apply surface EMG electrodes during polysomnography (PSG) to one or both of the anterior tibialis muscles, which are involved in most of these movements. Movements, however, can involve a wide range of leg muscles (Provini et al., 2001; de Weerd et al., 2004) as well as the arms (Chabli et al., 2000). Phenomenologically, the movements are generally of a flexion type and the individual movements of a series tend to resemble one another. The movements can be quite varied, however, and shift from side to side or vary in intensity, duration, or distribution from one night to another, or even within a single night. PLMS are rather broadly defined by the pattern of their occurrence (Coleman et al., 1980). A current definition indicates that they should occur in a series of four movements, with onset-to-onset intervals of between 5 and 90 seconds, individual durations of 0.5–5 seconds, and an amplitude of at least one-quarter of a voluntary movement of the big toe (American Academy of Sleep Medicine, 2005) It has been proposed that for PLMs that occur during wake (PLMW), the duration limit should be increased to 10 seconds (Michaud et al.,

Fig. 56.1. Series of periodic limb movements in a sleeping patient. These occur almost exclusively in the left leg. Burst at arrow shows several initial high-amplitude brief components. Middle burst in the record is prolonged, consistent with an arousal leading to prolonged movement. After this burst, there is an altered EEG rhythm and EMG activity spreading to the chin and right leg, as well as altered respiratory rhythm. (Chin EMG has respiratory artifacts through tracing.) Note the approximate, but not exact, periodicity. Top four traces: EEG from vertex (top two traces) and occiput (third and fourth traces), referenced to the opposite ear. Fifth and sixth traces: left and right EOG (electro-oculogram). Seventh trace: chin EMG. Eighth trace: ECG. Ninth and tenth traces: left and right tibialis anterior EMGs. 11th trace: oral air flow. 12th and 13th traces: thoracic and abdominal respiratory effort. Bottom trace: sound recording. Trace superimposed on abdominal effort is a displaced oximeter tracing indicating oxygen saturation. Entire record is 160 seconds long; thick vertical lines indicate 16-second divisions.

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2001). Unfortunately the current operational definition is arbitrary and probably both too narrow (setting rigid limits) and too broad (including frequent movements that are by no means periodic), and a revision of these criteria is currently in progress. Excessive PLMS have also been proposed as an independent cause of sleep disturbance. It has been argued that, in some cases, the presence of only PLMS without wake-time symptoms might represent a forme fruste of RLS, which has been referred to as periodic leg movement disorder (PLMD) (Allen et al., 2003). In favor of such a disorder, PLMS can be associated with arousals or awakening, disruptions in the sleep state, which potentially could cause sleep complaints (Carskadon et al., 1982). Nevertheless, a number of authors have argued that such a disorder rarely, if ever, exists. According to the current standards (American Academy of Sleep Medicine, 2005), the diagnosis of PLMD is warranted only if no other sleep–wake disorder (including RLS) is present and can account for the symptoms. Thus, PLMS in RLS do not constitute PLMD. Furthermore, more modern PSG techniques have found that PLMS are often associated with sleep-related breathing disorders, such as the upper airway resistance syndrome (Exar and Collop, 2001). The large numbers of PLMS, such as those in the elderly (Mosko et al., 1988; Carrier et al., 2005), which cannot be associated with any sleep complaint, should also be considered (Nicolas et al., 1998). PLMS are also increased in several neurological conditions, such as narcolepsy, rapid eye movement (REM)sleep behavior disorder, and Parkinson’s disease. PLMS occur commonly in healthy adults over the age of 45 years, and those over 60 years old showed a high rate of PLMS, averaging more than 20 PLMS/hour (Pennestri et al., 2006). Because PLMS are nonspecific, there is still ongoing debate about the value of treating them (Allen et al., 2003). It has been reported that treating PLMS may not alleviate such complaints as excessive daytime somnolence (Montplaisir et al., 2000b). Some have even argued that it is not useful to record leg movements during sleep studies (Mahowald, 2001). In some cases symptomatic PLMS (PLMD) may exist and require treatment. The problem is knowing when PLMS is causing the symptoms or whether it is simply an epiphenomenon coexisting with other sleep-related problems.

Diagnosis of RLS in children The diagnosis of RLS in preadolescent children can be quite difficult. Children may not have the verbal facility to describe symptoms properly. Moreover,

the manifestations of RLS in children may be different from those in adults. As a result, there is now a set of proposed diagnostic criteria for RLS in children that grade diagnoses as definite, probable, or possible (Table 56.2) (Allen et al., 2003). The key to a definite diagnosis is finding all four diagnostic features (see above) plus additional supportive evidence: either the presence of actual verbalized leg discomfort or at least two of three additional features. These are drawn from the supportive (PLMs, positive family history) or associated (sleep disturbance) features of adult RLS. Probable RLS can be found for children who lack one of the diagnostic features (aggravation later in day) or require observational reports from parents because the child is unable to explain symptoms. In either case, diagnosis is supported by definite RLS in a first-degree relative (sibling, parent). Possible RLS occurs when criteria for definite or probable RLS are lacking. These children have sleep disturbance and PLMS that is not associated with sleep-related breathing (Picchietti and Walters 1999). Again, the child must have a definitely affected first-degree relative. Thus, diagnosis in children relies heavily on two of the three supportive criteria for adult RLS diagnosis (PLMs, family history). The boundary between childhood and adult RLS is not exact. Once a child can give a suitably accurate account of symptoms, an adult diagnosis may be possible. This should occur early in adolescence or around the age of 12 years for most children.

Diagnosis in the cognitively impaired Although a definite diagnosis is unlikely to be feasible, a possible RLS diagnosis may be suspected when there is one or preferably several of the following present: a prior history of RLS, symptoms responsive to DAergic medications, evidence of restlessness predominantly at night with attempts to move or to apply counterstimuli (pressing, rubbing, hitting), or evidence for common disorders causing secondary RLS (low ferritin, renal failure, diabetes, neuropathy, or radiculopathy) (Allen et al., 2003).

Objective measures of disease The objective measures used to assess RLS have primarily been based on the PSG study or the suggested immobilization test (SIT) (Brodeur et al., 1988). There is a typical pattern of PSG study found in patients with RLS: delayed sleep onset, excessive movement artifact (resulting in epochs scored as movement time) – sleep fragmentation, and increased wake after sleep onset leading to reduced sleep efficiency – but the main measure derived from the PSG study has been number of PLMs or the PLM index (PLMs/hour). Sometimes

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Table 56.2 Criteria for the diagnosis of restless legs syndrome in children Diagnostic category I.

Definite RLS

Criteria ● ●

or

● ●

II.

Probable RLS

● ●

The child meets all four essential adult criteria for RLS and The child relates a description in his or her own words that is consistent with leg discomfort (The child may use terms such as oowies, tickle, spiders, boo-boos, want to run, and a lot of energy in my legs to describe symptoms. Age-appropriate descriptors are encouraged) The child meets all four essential adult criteria for RLS and Two of three supportive criteria for the diagnosis of RLS in children are present: 1. Sleep disturbance for age 2. A biological parent or sibling has definite RLS 3. The child has a polysomnographically documented PLMS index of
5 per hour of sleep The child meets all four essential adult criteria for RLS, except criterion 4 (the urge to move or sensations are worse in the evening or at night than during the day) and The child has a biological parent or sibling with definite RLS

or*

●

III.

Possible RLS or “at risk” for RLS

● ● ●

The child is observed to have behavior manifestations of lower-extremity discomfort when sitting or lying, accompanied by motor movement of the affected limbs; the discomfort has characteristics of adult criteria 2, 3, and 4 (i.e., is worse during rest and inactivity, relieved by movement, and worse during the evening and at night); and The child has a biological parent or sibling with definite RLS The child has periodic limb movement disorder (for the childhood definition, please see text) and The child has a biological parent or sibling with definite RLS, but does not meet definite or probable childhood RLS definitions (as outlined above)

*This last probable category is intended for young children or cognitively impaired children who do not have sufficient language to describe the sensory component of RLS. Modified from the International RLS Study Group published consensus on clinical definition (Allen et al., 2003).

this is also partitioned to focus on those PLMS associated with arousals. As PLMs are common in a wide variety of conditions, including aging, the absence of PLM may be more telling than the presence. It has been found recently that the index of PLM while awake (PLMW/hour of wake during PSG) is perhaps a more discriminating measure than any other (Michaud et al., 2002b) on the PSG. But a recent study noted that high rates of PLMW during the night’s sleep occurred for children and young adults up to about age 30 years (Pennestri et al., 2006). Thus, this measure to support the diagnosis of RLS should be considered mostly for those over 30 years of age, but it may be particularly helpful then as in the older age groups the normal level of PLMS/hour is very high, limiting its use to support the RLS diagnosis. Montplaisir and his group have devoted particular effort to establishing a laboratory diagnosis. They have developed the SIT, in which subjects sit comfortably with legs extended for 40 minutes to 1 hour, during which time they are not allowed any distracting activity and are instructed to stay as still as possible. PLMs are recorded and the level of sensory discomfort is measured, typically on a visual analog scale.

For diagnostic purposes, the SIT is conducted shortly before bedtime when RLS symptoms are likely to be greater. In an evaluation of different measures from the PSG and SIT, the group found that a combination of the index of PLMW during the PSG and the summed sensory discomfort during the SIT best discriminated RLS patients from controls, with a sensitivity of 88% and a specificity of 100% in their sample (Michaud et al., 2002b). Whether this would also discriminate patients with RLS from those with other sleep disorders, or those with milder RLS from controls, remains unknown. Their results, however, point to the specific measures that are more distinctive in patients with RLS.

Differential diagnosis In the differential diagnosis of RLS, two types of condition need to be distinguished: those that present with restlessness and a desire to move, and those that occur with leg discomfort. Arthritic conditions, myalgia, and arterial or venous insufficiency rarely cause confusion, because they generally do not satisfy the diagnostic criteria for RLS. Leg cramps should

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be easily discriminated from RLS by the patient’s description of contracted or knotted muscle and severe pain. Peripheral neuropathy, especially small-fiber neuropathies, can mimic the features of RLS. Most neuropathies should include sensory or motor findings or laboratory findings on EMG or nerve conduction studies. As peripheral neuropathy is a possible cause of RLS, the two conditions may also coexist and it may be almost impossible to disentangle them. Even a therapeutic trial with a RLS medication may not be conclusive, because it is possible that the peripheral neuropathy could also conceivably respond. If treatment is successful, the differentiation is less critical for management, but these remain among the most difficult patients to diagnose definitely. Conditions associated with akathisia, anxiety, or some other psychiatric disturbance generally do not have specific symptoms related to the limbs, but may otherwise mimic RLS. The similarity of the symptoms between these conditions and RLS leads to considerable error in epidemiological surveys asking people whether they have RLS symptoms (Hening et al., 2009). It is therefore important that the clinician carefully evaluates the patient to exclude these conditions that can mimic RLS. Generalized and drug-induced akathisia (the inability to remain still) is often difficult to discriminate from RLS. With this type of akathisia, leg sensations are less common and the restlessness is usually generalized. Also there is no strong circadian rhythm, and movement provides no clearcut relief (Walters et al., 1991). Generalized akathisia, however, is primarily drug induced. Therefore, if symptoms started after treatment with a dopamine (DA) antagonist, centrally acting antihistamine, or antidepressant, drug-induced akathisia (or drug-induced RLS) may be the diagnosis and the treatment is removal of the offending drug. Another condition, hypotensive akathisia (Cheshire, 2000), can mimic RLS by causing vague leg discomforts and restlessness. This akathitic condition, however, occurs almost exclusively with subjects in the sitting position and is relieved by lying down, which would be very unusual in RLS. Because PLMS may not be apparent to the patient, it is unlikely that the patient will be able to give a history of PLMs (Hilbert and Mohsenin, 2003). The patient’s bed partner may contribute some history of leg movements occurring during sleep, as they may be the unintended target of these movements. However, the diagnosis will usually require a sleep study (Polysomnography Task Force, American Sleep Disorders Association Standards of Practice Committee, 1997) for documentation of the limb movements and exclusion of other conditions. The full array of disorders that cause abnormal motor activity at night should

be included in the differential diagnosis of PLMS, but if these can be excluded by history then leg activity monitors provide an alternative diagnostic procedure. The leg activity monitors allow for multiple nights of recording reducing the type II error associated with the relatively high internight variability of PLMS.

Standardized diagnostic interview As RLS is a clinical diagnosis based on the patient’s medical history and subjective report of symptoms, a clinical interview is required. Considerable effort has been spent developing and validating a telephone interview (the Hopkins Telephone Diagnostic Interview) (Hening et al., 2009). More recently this has been adapted for clinical use and is available, named after its primary author, as the Hening Clinical Diagnostic Interview for RLS. This is available along with a training video in its use from Dr Richard Allen at the Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

CLINICAL CONSEQUENCES A survey of two RLS focus groups and a qualityof-life (QoL) impact survey of 392 patients with RLS produced four primary areas to be considered for identification of specific adverse effects of RLS: sleep, mood state, social functioning, and daily functioning (Atkinson et al., 2004). When asked to identify aspects of daily functioning that were significantly disturbed by their RLS, patients reported a negative impact on mood (51%), lack of energy (48%), and disturbance of normal daily activities (40%) (Allen et al., 2005). Abetz et al. (2004) evaluated 85 patients with RLS as outpatients, diagnosed by expert RLS clinicians. The Short Form 36 (SF-36W) scores of these patients were markedly lower (P < 0.001) than the normative data (Ware et al., 1993) for all eight of the SF-36W scale scores. The largest differences were for the “vitality/ energy” and “role limitations due to physical problems (role physical)” scales, with RLS scores at about half or below the normative scores. The “mental health” score showed the least difference, with RLS scores about 10% lower than the normative values. The RLS scores were reduced by about 20–40% for all the other scales: physical functioning, bodily pain, general health, social functioning, and role limitations due to emotional problems (role emotional). In that study, patients provided a subjective rating of the severity of their RLS and, on the basis of these ratings, were divided into approximately equally sized groups with mild, moderate, and severe RLS. Patients who reported mild RLS showed scores significantly lower than the normative values for all the scales except for the three mental health

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP scores (social functioning, role emotional, and mental health). Those who reported moderate and severe RLS showed consistently large decreases in all of the QoL scores, particularly for the vitality and role physical scales. Allen et al. (2005) evaluated QoL for a US population-based sample of those who on telephone interview met diagnostic criteria for RLS, had symptoms at least twice a week, and reported them as being at least moderately distressing. This level of RLS symptoms was judged by experts to indicate that medical intervention should be considered. These subjects, referred to as “RLS sufferers”, comprised 2.7% of the general population surveyed in that study, and most (94%) had not been treated for or given a diagnosis of RLS. Their SF-36W scores on each of the eight scales were significantly (P < 0.05) below the age- and sex-adjusted norms for the USA. The larger differences were for vitality/energy, role physical, and bodily pain. The smaller differences were for the three mental health-related scales (social functioning, role emotional, and mental health). These studies when taken together identify four specific problems for patients with RLS: sleep disturbance, decreased energy/alertness in the day, mood disturbance, and problems with activities of daily living.

Sleep disturbance Sleep disturbance can be profound for those with untreated and moderately severe RLS. Allen and Earley (2001) found reduced sleep efficiency on a PSG (median 60%, range 2–91%) in a consecutive series of 31 patients with RLS. In another consecutive series of 133 patients with RLS Montplaisir et al. (1997) also found on PSG that sleep efficiency was reduced on average by 75.0  18.9%. Both studies found that the more severe the RLS symptoms, the greater the reduction in the sleep efficiency. Specific questions used to elicit the patient’s subjective evaluation of sleep showed that 85% reported difficulty falling asleep, 86% reported difficulty staying asleep, and 34% reported excessive daytime sleepiness (Montplaisir et al., 1997). Three separate studies with samples of 12–16 patients with RLS and age- and sex-matched controls showed that patients with RLS had statistically significantly increased arousal with PLMS and wake after sleep onset, and significantly decreased total sleep time and sleep efficiency (Montplaisir et al., 1998; Saletu et al., 2000a, b; Garcia-Borreguero et al., 2004). Although the sleep latencies were on average longer for RLS, this did not reach statistical significance. A much larger study (Michaud et al., 2002b), comparing 100 patients with RLS with 50 matched, healthy community controls, found the same significant differences as in the three

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smaller studies, but also observed significantly longer sleep latency for the patients with RLS (mean  26.6  32.4 versus 16.0  12.6, P < 0.006). Overall, the sleep disturbance produced by RLS involves mainly reduced total sleep time and sleep efficiency, and increased arousals due to PLMS. Sleep latency tended to be somewhat longer for patients with RLS. Of interest is that about 10–15% of patients with RLS seeking treatment at a clinic have apparently normal sleep and no specific sleep complaint (Allen et al., 2005). In a large population-based survey limited to those defined as an “RLS sufferer”, 24.5% reported no significant sleep difficulty (Allen et al., 2005). Thus moderate to severe RLS produces a profound sleep loss occurring every night, but milder RLS has less effect on sleep and in many cases no significant sleep disturbance.

Decreased alertness and fatigue A survey of patients seen in primary care practice (Hening et al., 2004) found that 10% of those with RLS reported problems with daytime exhaustion/ fatigue. Alertness in the day was evaluated objectively for 12 selected patients with RLS compared with that in 12 matched controls, and showed significantly increased simple reaction time for a computer key press in response to repeated visual stimuli. Scores on a standard Gru¨nberger alphabetic cancellation test, however, showed no difference on its measures of either attention or concentration (% errors). The subjects with RLS in this study also rated themselves subjectively on a visual analog scale as having more drowsiness than did the controls (Saletu et al., 2000a). However, when evaluated for frank sleepiness, 31 patients with RLS not receiving treatment had Epworth Sleepiness Scale scores very similar to those of 33 matched controls (mean  SD 5.9  4.5 versus 5.1  2.1) (Saletu et al., 2002). Similar findings were demonstrated in large population-based epidemiological studies: sleepiness during the day was reported as more common for those with RLS symptoms (Ulfberg et al., 2001a, b; Bjorvatn et al., 2005). The sleepiness in the day, although increased, was relatively mild, as the Epworth Sleepiness Scale scores were not significantly increased for those with RLS (Ulfberg et al., 2001a, b). Thus, RLS appears to produce some decreased alertness but not much frank sleepiness.

Mood disturbance Lower mental health scores (Berger et al., 2004) and depression/depressive mood (Ulfberg et al., 2001a; Sevim et al., 2003; Bjorvatn et al., 2005) have been

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reported in epidemiological studies to be more common in RLS than in nonRLS cases. Using the structured Munich-Composite International Diagnostic Interview (M-CIDI) (Wittchen, 1994), mood was evaluated in a consecutive series of 130 patients with RLS compared with a large community control group (n ¼ 2265). The patients with RLS showed higher 12-month rates (odds ratio with 95% confidence interval) for depressive disorder (2.6, 1.5–4.4), panic attacks (2.9, 1.4–5.4), panic disorder (5.2, 2.4–11.3), and generalized anxiety disorder (3.7, 1.8–7.4). In most cases (>60%), the mood disorder occurred after the RLS developed. Despite the excellent diagnostic methods, there are two problems with the study. First, patients with RLS were slightly older than the comparison group (mean  SD 55.3  8.2 versus 42.3  13.1) and there was no consideration of an age correction in the analyses. Second, the gender balance was about the same in both populations, but the RLS sample was only 55% female. This seems unusually low for a consecutive case series of patients with RLS and there is no explanation of this somewhat unusual sample characteristic. Nonetheless, the differences are striking and the rates in patients with RLS are remarkably high. Depression in the past year was reported by 18% of patients with RLS, compared with 9% of the controls. Generalized anxiety and panic disorder were each reported to have occurred in the previous year by 9% of patients with RLS, compared to 2.3% and 2.1%, respectively, of controls. These rates did not differ between patients with RLS treated mostly with DAergic medications and those not treated, suggesting that the standard treatments are not effective in reducing this aspect of RLS morbidity. It is, however, not known how much the increased occurrence of mood disorders with RLS results from the symptoms of RLS, for example the sleep deprivation, which should improve with treatment, or from some overlap of biological factors causing these disorders. These high rates apply to those with RLS seeking treatment; presumably, milder RLS will not show the same high rates of mood disturbance.

Problems with daily functioning and health Reduced physical health scores (Sevim et al., 2003; Berger et al., 2004), social isolation (Ulfberg et al., 2001a, b), and increased heart problems or history of myocardial infarction (Ulfberg et al., 2001a; Berger et al., 2004) have been reported in epidemiological studies to be more common in RLS than in nonRLS cases. Most of the reports in which activities of daily living are reported to be disrupted suggest that disturbance in alertness, memory, or cognition underlies this primary

complaint (Atkinson et al., 2004; Allen et al., 2005). Some of these problems may stem from the sleep loss associated with more severe RLS. Apart from documenting subjective reports in surveys, only one study has focused on the expected cognitive consequences of sleep loss. In that study, 16 patients with RLS who were treatment-free for at least 14 days were compared with 15 matched controls. The patients with RLS showed a 20% decrease in verbal fluency scores and a 40% increase in complex trail-making time, but did not show any difference in more general cognitive measures, i.e., colored progressive matrices (Pearson et al., 2006). This pattern matches that seen for one night of sleep deprivation (Durmer and Dinges, 2005). Unfortunately, chronic (14 days) sleep restriction studies similar to the sleep loss experienced by the patients with RLS in this study have not been done. Such a comparison would be necessary to understand the degree to which patients with RLS are affected by the sleep loss.

Summary RLS adversely affects QoL in all dimensions measured by the SF-36W but, in particular, leads to reduced vitality and energy, and also to increased limitations of normal life activities because of physical problems. RLS has been further documented to reduce total sleep time and sleep efficiency, increase fatigue in the daytime, and impair aspects of cognitive functioning known to be sensitive to sleep loss. These adverse effects on daily function are proportional to the severity of RLS symptoms. There is also an association between RLS and both depressive and anxiety disorders, but, unlike the other conditions consequent to RLS, there is no clear indication that this association is related to RLS severity or improved with treatment of RLS.

ASSOCIATED CONDITIONS AND SECONDARY FORMS OF RLS RLS, like many other syndromes or medical conditions, can be divided into primary and secondary forms. There are insufficient population-based studies to know the extent to which secondary causes contribute to the total prevalence of RLS. A substantial number of case reports and clinical series, however, together with a few scientifically sound studies, suggest at least three conditions that may worsen or induce RLS symptoms: iron deficiency, pregnancy, and renal failure with dialysis. These three conditions are discussed with several other less clearly associated conditions. In the final analysis, it appears from review of the data that the large majority of patients have RLS as an idiopathic form unrelated to some of the secondary causes mentioned below.

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Iron deficiency In the early 1950s, Nordlander was the first to note the high prevalence of iron deficiency among his RLS clinical population (Nordlander, 1954). He assumed its causal relation to RLS when the treatment of the iron deficiency improved symptoms (Nordlander, 1953). Later, Ekbom (1960) reported a 24.6% prevalence of iron deficiency in his RLS population and, like Nordlander, assumed iron deficiency to be a contributing factor when symptoms improved with iron supplementation (Ekbom, 1970). A relation between iron status and RLS severity was subsequently shown by two independent studies. O’Keeffe et al. (1994) showed in an elderly population that decreasing serum ferritin concentration was negatively correlated (r ¼ 0.53) with RLS symptoms. Sun et al. (1998), by retrospective review of a consecutive series of patients with RLS who presented to an outpatient sleep disorders center, also found a significant correlation between serum ferritin levels and symptom severity (r ¼ 0.43), and between serum ferritin levels and PSG-derived sleep efficiency (r ¼ 0.48). Of interest is that PLMS on a PSG did not correlate with serum ferritin concentration. A question posed by the results is whether disease severity is related to iron insufficiency/deficiency or to body iron stores in general. In O’Keefe’s study (O’Keeffe et al., 1994), the majority of patients had ferritin values below 50 mg/l, suggesting that they had very low body iron stores or were even iron deficient. In Sun’s study (Sun et al., 1998), there was a broader range of ferritin values, although the large majority were below 100 mg/l. When the analysis included only those with ferritin levels of 50 m/l or less, the ferritin–severity correlation was improved (r ¼ 0.51), whereas there was no significant correlation for those with ferritin levels above 50 mg/l. Therefore, the results support a relation between very low or deficient iron status and disease severity. If the question is reversed and we ask how many people with iron deficiency are likely to develop RLS, it is a little more difficult to answer. Ekbom reported, without giving any details, a 24% prevalence of RLS symptoms among those with iron deficiency (Ekbom, 1960). Aspenstroem (1964) reported on the prevalence of RLS in a clinical population of patients (64 women and 16 men) with iron deficiency anemia. He found that about 48% of the women and about 25% of the men had symptoms consistent with RLS. As the blood donor population is at risk for developing iron deficiency, a high prevalence of RLS in that population would be expected. Of the 946 consecutive blood donors who answered a questionnaire about sleep habits, which included symptoms of RLS, 15% of males and 25% of females had RLS symptoms

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(Ulfberg and Nystrom, 2004). Women in this study who had blood indices consistent with iron deficiency had a prevalence of RLS of almost 38% (Ulfberg and Nystrom, 2004). Thus it appears that, in various clinical populations in which iron deficiency is high, the prevalence RLS is two to four times higher than that found in a general population. If iron deficiency is a contributing factor in RLS then how prevalent is iron deficiency as a cause of RLS in the general population? Berger et al. (2002) carried out a cross-sectional examination of several measures of iron metabolism and RLS in an elderly population in southern Germany, and found a 10% prevalence of RLS. The odds ratio of having RLS based on quintiles of serum ferritin were all between 1.0 and 1.2, none of which was outside the 95% confidence range. Other indices of iron status (percentage iron saturation, transferrin receptor, and serum iron) also showed no significant change in risk with diminishing iron status. As noted above, however, the relation between systemic iron status and RLS is probably restricted to iron deficiency, not systemic iron status in general. The lowest quintile range for males in this study was a ferritin level below 117 mg/l, which is likely to include many without iron deficiency. However, this study did not have sufficient power to make any definitive conclusions other than that iron deficiency is not likely to be a major cause of RLS in the general population. A similar population-based study in Tyrol, however, found that iron deficiency as indicated by increased levels of soluble transferrin receptor was associated with a significantly increased risk of RLS (Hogl et al., 2005). Thus, unless the population surveyed is large enough and has enough iron deficiency, iron status is not likely to be detected as a risk factor for RLS. Nonetheless, some subpopulations of patients with RLS have an iron deficiency that appears to be a cause, or at least an aggravator, to the symptoms, and as such should be identified and treated appropriately. Low iron status has also recently been reported in children who have demonstrated a significant number of PLMS during sleep evaluations (Simakajornboon et al., 2003). Some relation between low iron and RLS or attention-deficit/hyperactivity disorder in children is currently an area of active clinical interest (Sever et al., 1997; Konofal et al., 2004).

Pregnancy Ekbom was the first to note the increased prevalence (11.3%) of RLS during pregnancy and that it reached a peak in the last half or third trimester (Ekbom, 1945, 1960). Women with pre-existing RLS often reported an exacerbation of the symptoms during

922 C.J. EARLEY ET AL. pregnancy (Ekbom, 1945). Three large, relatively well(Hui et al., 2000). One Boston-based study reported designed, studies have since substantiated Ekbom’s that the prevalence of moderate to severe RLS among original findings. In a London-based clinic survey of patients on dialysis was 20% (Winkelman et al., 1996). 500 women presenting in the last trimester of pregSeveral studies have found a higher prevalence of RLS nancy, the prevalence of RLS was found to be 19% among women on dialysis compared with men (Goodman et al., 1988). In a population of 16,528 preg(Miranda et al., 2001; Siddiqui et al., 2005), and among nant Japanese women, 19.9% were reported to have Caucasian compared with nonCaucasians patients on RLS (Suzuki et al., 2003). In a northern Italian populadialysis (Kutner and Bliwise 2002; Filho et al., 2005). tion of 606 pregnant women, 26.6% were affected Several studies have tried to relate the presence of with RLS symptoms (Manconi et al., 2004a). The peak RLS in patients on dialysis to various risk factors prevalence in all three studies was found in the last triincluding pre-existing diseases, primary cause of renal mester. In British (Goodman et al., 1988) and Italian failure, coexisting clinical conditions (e.g., polyneuro(Manconi et al., 2004a) studies, 3% and 10%, respecpathy, hypertension, cardiac failure), current hemoglotively, of the total population surveyed had RLS sympbin level, iron status, renal conditions, number and toms before pregnancy. Thus, about 16–17% of those duration of dialyses, and prescribed medications (Winsurveyed developed RLS during pregnancy. Of those kelman et al., 1996; Collado-Seidel et al., 1998; Kutner who developed symptoms, about 95% had resolution and Bliwise, 2002; Gigli et al., 2004; Filho et al., 2005; of the symptoms after delivery, with the majority havSiddiqui et al., 2005). All of these studies had a relaing remittance in the first few weeks postpartum tively small sample size for the number of analyses (Goodman et al., 1988; Manconi et al., 2004a). that were being performed: 20 to 50 independent The etiology of RLS during pregnancy remains analyses, usually without any correction for multiple unknown and poorly studied, but a metabolic hypotheanalyses. For every positive association reported in one sis involving iron and folate has been suggested (Manstudy, there are one if not two papers reporting either coni et al., 2004a). Ekbom (1945, 1960) noted a high no change or the opposite finding. Several studies that incidence of low iron and low folate levels in women have looked at the relation between iron status and with RLS during pregnancy. One study noted that RLS have failed to find an association (Collado-Seidel pregnant women with RLS had significantly lower et al., 1998; Miranda et al., 2001; Filho et al., 2005; Sidhemoglobin values than pregnant women without diqui et al., 2005). Unfortunately, with dialysis, serum RLS (Manconi et al., 2004a). Another study found that iron, ferritin, transferrin receptor, and total iron-binding the average red blood cell folate concentration in pregcapacity lose validity as determinants of “utilizable” nant women was lower for patients with RLS than in body iron stores. Although body iron may be increased into those without RLS (Botez and Lambert, 1977). with chronic dialysis, it is not readably available for Unfortunately, direct measures of iron status were use. There are no good laboratory studies to determine not evaluated in either of these studies. the amount of available or “utilizable” iron present under chronic disease conditions. Irrespective of the inconclusive nature of associated End-stage renal disease and dialysis risk factors for RLS, the syndrome per se is associated The reported prevalence of RLS in a dialysis populawith increased mortality and morbidity among patients tion is quite variable. Some limitations of these studies on dialysis; the more severe the RLS, the higher the have been the criteria used by the authors to define mortality rate (Winkelman et al., 1996; Unruh et al., RLS, as about one-third of the studies gave no criteria 2004). Of potential relevance to this finding is that by which the diagnosis of RLS was made (Kavanagh low iron levels have been shown be a predictor of moret al., 2004). In those studies where appropriate diagtality and morbidity (Kalantar-Zadeh et al., 2004, nostic RLS criteria were at least reported, the preva2005). Therefore, one interpretation of the finding is lence of RLS was as low as 6.6% in an Indian that RLS may be a symptom of the low iron status, population (Bhowmik et al., 2003) and as high as which is a predictor of poor outcome. As it appears 68% in a Caucasian American population (48% for that improved iron status also improves outcomes for the African American population in this study) (Kutner patients on dialysis (Kalantar-Zedah et al., 2005), the and Bliwise, 2002). A Brazilian population had a prevnext step is to see whether it also reduces the prevaalence of about 15% (Filho et al., 2005), an Italian poplence of RLS. ulation 21.5% (Gigli et al., 2004), a German population A causal relationship between renal failure or dialy23% (Collado-Seidel et al., 1998), a Chilean population sis and the enhanced prevalence of RLS is strongly 26% (Miranda et al., 2001), a UK population 45.8% supported by the effects seen in patients with renal (Siddiqui et al., 2005), and a Chinese population 62% transplants. One study of 11 patients who developed

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP RLS while on dialysis found complete remission of RLS symptoms within a few weeks of renal transplantation (Winkelmann et al., 2002b). RLS symptoms returned in 3 of 11 patients in association with transplant failure (Winkelmann et al., 2002b). A large cross-sectional study of patients with renal transplants found the frequency of reported RLS symptoms (4.8%) to be within the predicted range for the general population (Molnar et al., 2005). Declining transplant function (glomerular filtration rate, GFR) was strongly predictive of increasing frequency of reported RLS symptoms: with GFR above 60 ml per min per 1.73 m2, RLS prevalence was less than 3%, and with GFR below 15 ml per min per 1.73 m2, RLS prevalence was greater than 22% (Molnar et al., 2005). The prevalence of RLS also increased with increasing comorbidities and with declining serum iron levels (Molnar et al., 2005).

Neuropathy It has been generally accepted that polyneuropathy is a potential secondary cause of RLS. Only one peerreviewed study has examined the frequency of RLS cases in a clinical population with polyneuropathy (Rutkove et al., 1996). This study reported a frequency of 5.2%, which is no greater than the estimated prevalence for the population at large. Studies that have looked at the frequency of neuropathy within the RLS clinical population, however, tend to suggest it is increased. Iannaccone et al. (1995) evaluated 8 patients with RLS and found that all had normal nerve conduction in the lower limbs, 5 had neuropathic findings by EMG, and all 8 had axonal neuropathy on nerve biopsy. Polydefkis et al. (2000) evaluated 22 consecutive patients with RLS for evidence of large- and small-fiber neuropathy. Standard EMG and nerve conduction studies were used to evaluate large-fiber neuropathy; skin biopsy with semiquantitative assessment of epidermal fiber density was used to assess smallfiber neuropathy. They found that 8 of the 22 patients had findings consistent with some degree of neuropathy. Three had mild large-fiber neuropathy (decreased sural nerve amplitudes), and the other five had, at a minimum, skin biopsy changes consistent with smallfiber neuropathy. The authors also found that smallfiber neuropathy was more likely to occur in patients with RLS whose symptoms started late in life and who did not report a family history of RLS. O’Keefe (2005) found that, among 80 consecutive patients with RLS, neuropathy was present in 16.5% of those whose symptoms started after the age of 64 years, in 11.5% of those whose symptoms started between the ages

923

of 50 and 64 years, and in no patient whose symptoms started before age 50. The diagnosis of neuropathy was based on bilateral distal sensory nerve symptoms with or without signs that clearly were distinguishable from RLS symptoms. Finally, Ondo and Jankovic (1996) reported on a nonconsecutive series of 41 patients with RLS who had EMG/NC studies; 14 of the patients had underlying neuropathy (mixed type) and only half showed clinical signs of a neuropathy. Patients with neuropathy had a much more rapid progression of symptoms than those without neuropathy. In summary, neuropathy may play a role in RLS, particularly in those with late-onset RLS or with rapid progressive of RLS. To answer the question of whether polyneuropathy increases the risk for RLS or what role neuropathy may play in the pathology of RLS, studies with better design and substantially more scientific rigor are required.

Parkinson’s disease (PD) Three studies of RLS among patients with PD have used adequate criteria for RLS diagnosis. Tan et al. (2002) reported no RLS in 125 consecutive patients with PD in Singapore. This was noted to match the low population prevalence of RLS in Singapore (Tan et al., 2001). Krishnan et al. (2003) found 10 patients with RLS in a sample of 126 consecutive patients with PD seen in the clinic in India. This prevalence of 7.9% was significantly higher than the 0.8% for a healthy population matched for gender and age to the patients with PD in that study. Ondo et al. (2002) used a diagnostic questionnaire followed by an interview to identify patients with RLS in 303 consecutive cases seen in the movement disorders clinic in Texas. They found 63 with RLS (20.8% prevalence). In reviewing the patients’ histories, these authors found no relation with general patient demographics or to types of treatment. They reported that low serum ferritin levels were associated with an increased risk of RLS in this PD population. PD preceded the RLS symptoms in about 85% of the patients. The prevalence of RLS occurring independently of PD treatment was about 3%, which approximates the expected prevalence before the usual age of onset of PD. Thus, these studies as a whole suggest some possible relation between PD treatments and expression of RLS symptoms, rather than any clear indication of PD increasing the risk of RLS. Clearly, however, PD does not protect from RLS.

Other conditions Two studies have reported a high frequency – 29% (Abele et al., 2001) and 45% (Schols et al., 1998) – of RLS symptoms in patients with spinocerebellar ataxia.

924

C.J. EARLEY ET AL.

One report suggests that the prevalence of RLS is increased in Charcot–Marie–Tooth (CMT) type II (37%) but not in CMT type I (Gemignani et al., 1999). Finally, there is a single report suggesting that patients with positive rheumatoid factor or SSA/SSB antibodies have a high frequency (25%) of RLS (Ondo et al., 2000). These single studies, however, are insufficient to validate or substantiate the degree to which these are potential secondary causes of RLS.

Prevalence in American and European population surveys Table 56.3 lists the eight published general population surveys of RLS prevalence in Europe and North America, representing all of the published studies from a Medline search as of August 2005 that used criteria close to the current diagnostic standards (Allen et al., 2003). The commonly quoted study of RLS prevalence in a population-based sample from Kentucky has been omitted because the one question used to identify RLS in that study did not include relief with movement (one of the four basic diagnostic criteria) and it required a sleep disturbance (not part of the basic diagnostic criteria) (Phillips et al., 2000). That study, with its limited diagnostic criteria, not surprisingly reported an aberrant RLS-positive response rate of 19.4% for occurrence at any frequency, about twice as high as rates reported from studies that included more complete diagnostic criteria. There are four factors that should be considered in understanding the data in Table 56.3.

EPIDEMIOLOGY Prior to the International Restless Legs Syndrome Study Group (Walters et al., 1995) and the National Institutes of Health (NIH) workshop (Allen et al., 2003) consensus on diagnostic criteria for RLS, epidemiological studies of RLS often did not have well defined criteria; moreover, those that were available would not have been acceptable by current standards. This section, therefore, includes only those published reports that used the currently accepted IRLSSG diagnostic criteria for RLS. It will also consider only population-based surveys with an adequate sample size of at least 100. The prevalence of RLS in special clinical populations has been discussed above.

GENDER

DIFFERENCES

In all of these studies, RLS occurred more commonly among women than men; in most studies the male prevalence was about half that for females.

Table 56.3 General population-based surveys from America and Europe

Reference

Location

n

Age range (years)

Bjorvatn et al., 2005*

2005


18

4107

20–79

Telephone interview Interview

Ho¨gl et al., 2005{ Ulfberg et al., 2001b Ulfberg et al., 2001a Tison et al., 2005*

Norway– Denmark North-east Germany South Tyrol Sweden Sweden France

701 140 2608 10,263

50–89 18–64 18–64
18

Interview Q Q Interview

Allen et al., 2005

EU þ USA

15,391


18

Interview}

Sevim et al., 2003{

Mersin, Turkey

3234


18

Interview

Berger et al., 2004

Method

Minimum symptom frequency

Prevalence (% of population) All

Females

Males

Any lifetime

11.5

13.4

9.4

Any current

10.6

13.4

7.6

Any lifetime Any current Any current Any lifetime Any past 12 months
weekly{ Any lifetime
weekly
2/week þ distress Any past month

10.6 – – 9.1 8.5

14.2 11.4 – – 10.8

6.6 – 5.8 – 5.8

4.5 7.2 5.0 2.7

5.5 9.0 6.2 3.7

3.2 5.4 2.8 1.7

3.2

3.9

2.5

*Diagnosis did not require leg paresthesia other than urge to move. {Diagnosis included self-report of restlessness. {Estimated after adjustment for sample lost before obtaining frequency data. }Interview was face-to-face in Europe and by telephone in the USA. Q, questionnaire completed by subject.

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP This degree of higher prevalence for females occurs at all levels of severity of RLS. The exceptions are the studies from Norway–Denmark (Bjorvatn et al., 2005) and Turkey (Sevim et al., 2003), in which the male prevalence, although relatively higher, was still only 65–70% that for females.

TIMEBASE

FOR OCCURRENCE OF SYMPTOMS

The German (Berger et al., 2004) and Swedish (Ulfberg et al., 2001a, b) surveys asked about current symptoms, where as the other surveys asked about lifetime occurrence. Lifetime occurrence would be expected to be slightly higher and, indeed, the French survey (Tison et al., 2005) reported an increase in prevalence of 0.6% for lifetime compared with the past year: 93% of the subjects who reported ever having had RLS symptoms had experienced them within the past year. Conversely, about 7% of adults reporting ever having symptoms either had RLS symptoms less than once a year or, more likely, had a current remission of symptoms lasting more than a year. This may differ with age, but, on the whole, once the RLS symptoms start, they appear almost always to continue. Thus, the difference of lifetime versus current symptoms is small enough to have little impact on these prevalence estimates.

FREQUENCY-BASED

OCCURRENCE OF SYMPTOMS

Frequency provides one dimension of symptom severity and the wide variation in frequency reflects the very wide variation reported for severity of RLS symptoms. Two of the studies provide prevalence estimates for those with at least weekly symptoms that are remarkably close to each other, at 4.5–5% of the general population or about 60% of all those reporting RLS symptoms (Allen et al., 2005; Tison et al., 2005). One study based on expert opinion defined a group whose RLS would be severe enough to be considered for medical treatment (Allen et al., 2005). Their criteria were RLS symptoms occurring at least twice weekly plus causing moderate or extreme distress. The 2.7% prevalence of these RLS “sufferers” provides one estimate of the potential number of RLS patients to be managed in the medical system. This is still a sizeable number of patients, but only about one-third of all with RLS symptoms and somewhat closer to the clinical experience. It appears that about two-thirds of patients with RLS have symptoms mild enough not to warrant medical attention. This was partly confirmed in the study from Norway and Denmark, where 66% of those reporting RLS symptoms indicated the symptoms were not severe enough to involve a doctor (Bjorvatn et al., 2005).

DIAGNOSTIC

925

METHODS AND CRITERIA

The two Swedish studies relied upon subject-completed questionnaires. Those studies had a reasonable response rate of 65–70% of the questionnaires returned, and their prevalence estimates of 11% for females and 6% for males approximate the results from the interview studies for concurrent or lifetime prevalence (average 12.2% for females and 7.0% for males). Thus, the different methods did not produce an obvious distortion of the prevalence estimates, although clearly the interview data should be considered more accurate. The nature of the RLS diagnostic criteria also varied. Although some of these studies claim to be based on the old IRLSSG diagnostic criteria, in fact most are closer to the updated NIH IRLSSG criteria. The older criteria required a symptom of “motor restlessness”. The only studies to include that criterion in their definitions were the questionnaires used in Sweden (Ulfberg et al., 2001a, b) and the small study of older adults from Tyrol (Hogl et al., 2005). The other studies essentially took the same course recommended by the NIH workshop and used the diagnostic criteria of relief with movement and onset with rest, with no mention of the somewhat ambiguous term “restlessness”. Another interesting diagnostic issue involves the differences between most of these studies and the official diagnostic criteria regarding the sensory disturbance of RLS. Almost all of these studies required that the subjects report some sort of paresthesia in the legs associated with the urge to move, but the IRLSSG diagnostic criteria include paresthesias only as commonly occurring, not as a necessary part of the diagnosis. Only the studies from France (Tison et al., 2005) and Norway–Denmark (Bjorvatn et al., 2005) correctly relied upon the urge to move, without the paresthesias. The supplementary data available online for the French study (Tison et al., 2005) shows that the 12-month prevalence decreased from 8.5% to 7.8% when paresthesias were a requirement for the diagnosis. Thus, about 8% of all those with RLS symptoms within the past year reported an urge to move without any disagreeable or unpleasant leg sensations. Although this is clearly a small difference, it can and should be avoided in future by using criteria more faithful to the established diagnosis for RLS.

AGE

DIFFERENCES

Age contribution to prevalence was evaluated in all of the studies listed in Table 56.3, except for the two Swedish studies. RLS prevalence increased significantly with age for four of the remaining six studies. It did not increase significantly in the Tyrol study (Hogl et al., 2005), but that population was limited to

926 C.J. EARLEY ET AL. those aged over 50 years and had a small sample size; GEOGRAPHY both factors obscure age effects. The Turkish study Table 56.3 has been ordered by decreasing prevalence also failed to find any significant effect of age on rates and there is some suggestion of increased RLS prevalence (Sevim et al., 2003), although the popprevalence in the Scandinavian countries, with lower ulation size of 3234 was marginal for finding an age prevalence in other populations, many of which are effect, given both the low prevalence of RLS (3.2%) included in the EU þ USA sample. The different methand the younger average age in this sample (43.3 years ods used in each of these studies complicate any such compared with the average age of over 55 years for interpretation of the data. The striking difference is patients with RLS in most other studies). Increasing the lower prevalence for Turkey (Sevim et al., 2003). age correlated significantly with increasing prevalence The Turkish survey unfortunately asked about sympof RLS for all of the larger studies with more than toms occurring in the past month and thus has a differ220 subjects reporting RLS symptoms. ent timebase from that of the other studies. Although The pediatric criteria for RLS diagnosis (Allen this complicates comparison, it remains noteworthy et al., 2003) has now been used in a large general popthat the values for 1-month prevalence for Turkey are ulation survey of 10,523 families in the UK and the about 33% lower than the weekly rates from the French USA. The prevalence of RLS in that survey was 1.9% and EU þ USA studies. It seems likely that the prevafor 8–11 year olds and 2.0% for 12–17 year olds. Modlence is somewhat lower in Turkey than in most of erate to severe RLS (“RLS sufferers”) was reported Europe or the USA. for 0.5% of the 8–11 year olds and 1.0% of the 12–17 year olds. There was no gender difference in the pediPrevalence in other geographical population atric population (Picchietti et al., 2007). Thus,, RLS surveys increases significantly from childhood to young adult There have been few studies of RLS prevalence in populife (from 2% to 5%) and approximately doubles from lations that were not predominantly from European desyoung to old adult life (about 5–6% for those under 30 cendents; these include those in Asia, including India. and 12–14% for those aged 45–65 years) (Berger et al., None has been done in Africa or among natives of the 2004; Bjorvatn et al., 2005; Tison et al., 2005). This Americas. Two reports of RLS prevalence in Asia, one expected age increase from childhood until later life from Korea (Kim et al., 2005) and the other from Japan occurred even more dramatically for more severe (Kageyama et al., 2000), were both based only on the RLS (“RLS sufferers”) (Allen et al., 2005; Picchietti occurrence of leg sensations and the urge to move, withet al., 2007). For the population of RLS sufferers conout the other three essential diagnostic criteria for RLS. sidered likely to benefit from medical treatment, prevThe two studies by Tan et al. (2001), the Korean study alence increases more than fourfold from childhood to by Cho et al. (2008). and the rural Japanese study by older adult life (0.5% for very young children, 1% for Nomura et al. (2008), however, used the full diagnostic adolescents and those under 30, about 4–5% for those criteria, as did the small case–control studies from India 60–79 years old). This greater age increase for the (Bhowmik et al., 2003; Krishnan et al., 2003). These are “sufferers” compared with all RLS probably reflects listed in Table 56.4. the slowly progressive worsening of the RLS sympTan et al. (2002) used direct clinical interviews in toms noted to occur in those with early onset RLS two clinic-based populations: one included 157 subjects (before age 45) (Allen and Earley, 2000). The increasfrom those participating in a healthy elderly (>55 ing prevalence with age continues until the last ageyears) screening, and the second (Tan et al., 2001) period evaluated, and in all four studies providing full included 1000 consecutive subjects over the age of 21 age evaluation there was an unexpected decrease in years presenting to a primary healthcare center. Only prevalence for the oldest age cohort (
80 years for one RLS case was reported in each of these populathe EU þ USA, 70–79 years for the northern Germany tions (prevalence 0.6% and 0.1% respectively). Both study, and >64 years for the French study). These of the two studies from India used healthy populations studies noted that this decrease in the oldest age selected to match a patient population. Krishnan et al. groups may be a statistical artifact of the smaller sam(2003) selected 128 healthy controls to match the age ple size in this group, but it remains striking that all and sex of a population of patients with Parkinson’s four of the studies that evaluated changes by age disease, and reported only one with RLS (0.8%). The cohort found the same decrease. At this point, howactual age and sex distribution of these controls was ever, the prevalence of RLS in those aged over 70 not specified in the paper, but presumably was close years remains to be better established. Aside from this to that for the patients with PD in the study (mean oldest age group, the studies show the expected consisage 57.9 years, 89.8% male). Bhowmik et al. (2003) tent increase in RLS prevalence with age.

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP

927

Table 56.4 Restless legs syndrome (RLS) surveys from Asia and India that used full International Restless Legs Syndrome Study Group diagnosis of RLS

Reference

Location

n

Mean  SD age (years)

Male : female ratio

Tan et al., 2002 Tan et al., 2001

Singapore Singapore

157 1000

64.2  7.3 41  14.9

69 : 88 480 : 520

Krishnan et al., 2003 Bhowmik et al., 2003 Cho et al., 2008 Nomura et al., 2008

India India Korea Rural Japan

128 99 5000 2824

57.9  10.0* 43.7  11.2 Range 20–69 52.9  17.8

115 : 13* 32 : 67 2470 : 2530 1223 : 1601

Population basis Healthy, >55 years Consecutive cases, primary care clinic Match Parkinson’s patients Kidney donors Adult population Adults in rural town

Prevalence (% of population) 0.6 0.1 0.8 0.0 7.5 1.8

These studies used direct clinical interviews of the subjects and asked about any lifetime symptoms. *Values were not given in the paper but were estimated assuming they matched those of the Parkinson’s patients in the study.

selected 99 healthy controls who had volunteered as kidney donors and were undergoing pretransplant evaluation (mean age 43.7 years, 32% male), and reported that none met the diagnostic criteria for RLS. Both of these last two studies suffered from potential experimenter bias against finding RLS diagnosis, because the study design did not use blinded diagnoses and expected to see lower RLS in the controls. Both the study by Cho et al. (2008) and that by Nomura et al. (2008) were population based. The study of 1000 consecutive case series reported by Tan et al. (2001) and both the Korean (Cho et al., 2008) and the Japanese (Nomura et al., 2008) studies met reasonable criteria. Thus the prevalence of RLS appears to be very low (<1%) in Singapore, about 2% in rural Japan, and about 8% in Korea. The geographical differences are interesting, with the Korean population showing about the same prevalence as Europe and North America. The other three studies are included in Table 56.4 largely because they are the only studies available that used appropriate diagnostic criteria. Their results provide some support for a low prevalence of RLS in Asia, including India, but, as noted, not in Korea. Clearly, these prevalence differences need to be confirmed by a study using identical techniques and adequate RLS diagnoses in both a European and Asian or Indian population.

Prevalence in primary care settings Two studies have used the NIH-modified IRLSSG criteria to define RLS occurrence in a family care setting. One study evaluated RLS by using a screening questionnaire followed by an interview of those identified as having RLS (Nichols et al., 2003). All patients presenting over 1 year to a single medical office in a rural setting in northwestern USA were asked to complete

the questionnaire. This area had been identified previously by a questionnaire as potentially having a high prevalence of RLS. RLS diagnoses were confirmed medically in 24% of 2099 patients entered into the study; symptoms were reported to occur weekly for 15.3% and more than three times a week for 6.6% of the population. RLS prevalence was higher for women than men (27.9% versus 19.9%), and increased with age from ages 18 to 59 years and then decreased for ages 60–93 years. A multinational study gave an RLS diagnostic questionnaire to all patients attending one of 182 primary care offices during a 2-week period, adjusted to meet the schedule of the local clinic (Hening et al., 2004). The study covered the USA, France, Germany, Spain, and the UK, with approximately equal numbers of patients screened in each country. Lifetime prevalence of RLS at any frequency was reported to be 11.1% of 23,052 patients screened, and the prevalence for symptoms at least once a week was 9.6%. RLS with frequent (two or more times a week) and at least moderately distressing symptoms was estimated to occur in 3.9% of the population. These values are similar to, but slightly higher than, those in the general population study from Europe and the USA (see Table 56.3). These studies indicate that, among patients already being seen in primary care offices, RLS is slightly more common, but otherwise has the same characteristics as seen in the general population.

Summary RLS has an overall prevalence of 7–11% in Europe and the USA, but is lower in Turkey and much lower in most of Asia, although apparently not in Korea. The male : female ratio of occurrence of RLS is about

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1 : 2 for adults over 30 years, but there is no sex difference for young adults under 30 years, nor for children. This may reflect the effect of pregnancy, because the prevalence of RLS is the same for adult nulliparous women as in men (Berger et al., 2004). RLS prevalence increases with age up to about 65–70 years, and may then decrease somewhat. Prevalence of RLS symptoms severe enough to be considered for medical treatment is about 3% of North Americans and Europeans, with a strong age effect increasing from less than 1% for those under 30 to more than 4% for those over 50 years. RLS is associated with both sleep, mental and physical health problems, and, in particular, depression, insomnia, and daytime fatigue, but not profound sleepiness.

PHENOTYPES AND GENETICS Most studies of RLS have focused on the presence or absence of the disorder. Nevertheless, determining whether a person has RLS may not be straightforward. Must symptoms be frequent (once a month, once a week, or daily?); persist over some period (such as 3 months or more); or is even a single symptomatic episode sufficient to make a diagnosis? Moreover, as RLS can occur at different ages over the lifespan, when can it definitively be stated that a person is free of RLS? These issues remain unresolved and challenging, but, despite their difficulty, some important advances have been made in the field.

Phenotypes The major distinction in RLS has been between idiopathic and secondary RLS (see the discussion of secondary RLS above). Phenomenologically, there has been no clearcut distinction between the subjective complaints of those with idiopathic or secondary RLS, although in some cases the laterality of symptoms may relate to some underlying unilateral pathology, such as a root lesion (Walters, 1996). The one major difference has been in uremic RLS: uremic patients have more PLMs than patients with idiopathic RLS (Wetter et al., 1996). A major factor separating these different forms of RLS may be the age at which symptoms start. Patients with a family history tend to have a younger age of onset than do those with either secondary or sporadic forms of RLS (Winkelmann et al., 2000; Bassetti et al., 2001). Sporadic cases may, in fact, represent cryptic secondary forms, as suggested by one study which found that late-onset sporadic cases very frequently had signs of subclinical nerve damage (Ondo and Jankovic, 1996). These distinctions based on age of symptom onset led Allen and colleagues to propose

that in idiopathic RLS there were two phenotypes, denoted as “early” and “late” onset with a division at 45 years of age (Allen and Earley, 2000). The earlyonset RLS phenotype, in contrast to the late-onset phenotype, was more likely to have a family history of RLS, slower progression of symptoms, and a weaker relationship to iron status – patients with late-onset RLS showed a stronger relation between decreased serum ferritin levels and severity of symptoms. In recent work it has now been shown that patients with early, but not late, onset have a deficiency in brain iron that is more pronounced the earlier the onset of symptoms (Earley et al., 2005b). Another potential phenotypic factor is the association of RLS with PLM. Whereas almost all patients with RLS have at least five PLMs/hour during sleep, not every patient has such movements (Montplaisir et al., 1997). Although no specific studies have been performed in patients without PLMs, the results of genetic studies (see below) have suggested that there may be a distinctive phenotype with RLS and PLM, or sometimes PLM alone. Other variable aspects of clinical features in RLS might be the basis for different phenotypes, for example distribution of symptoms (within the leg or beyond the leg), rate of progression, timing of symptoms (evening versus later in the night), or quality of discomfort (creepy-crawly versus shock-like versus painful). However, these clinical features have not been investigated systematically. In the future, genetic factors may help to delineate specific phenotypes associated with major genetic determinants.

Familiality and segregation analysis Familiality is the degree to which a disease is increased within families of affected individuals. Although many familial disorders have a genetic basis, this is not required; common environment can also explain such clustering. Segregation analyses examine the pattern of those affected in pedigrees (family trees) to determine which model of disease transmission, genetic or not, most closely fits the observed distribution of cases.

FAMILIALITY Three clinical series have found that almost two-thirds of patients were aware of affected relatives (Ondo and Jankovic, 1996; Walters et al., 1996; Montplaisir et al., 1997). Familiality also increases with lower age of onset in patients (Winkelmann et al., 2000). In a preliminary study based on interviews of patients with RLS and controls, it was found that first-degree relatives of the patients were five times more likely to be affected

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP with RLS (Allen et al., 2002). In an ongoing case– control family study with blinded expert diagnosis of family members, the relative risk (l) of first-degree relatives was found to be closer to 3 (Hening et al., 2003). In both studies, the relative risk for family members was higher for patients with younger age of onset, consistent with the picture of younger-onset patients as being more likely to have familial RLS.

SEGREGATION

ANALYSIS

The pattern of apparent inheritance in RLS has long been suggested to be through a major dominant gene, with the trait passing from generation to generation and with transmission through both males and females with approximately 50% of children affected (Walters et al., 1990). This suggestion has now been at least partially confirmed by two segregation analyses performed on the families of patients with RLS (Winkelmann et al., 2002a; Hening et al., 2005). In both studies, a commingling analysis found that ages of onset could be broken down into two distributions, with age-cut points (where an individual with that age of onset had an equal chance of being in either distribution) of 30 and 26.3, respectively. One study, however, found that only the group with the younger age of onset fitted a genetic model (Winkelmann et al., 2002a), whereas in the other study all families (n ¼ 76) could be fit with a genetic model (Hening et al., 2005). Both studies found that a major dominant gene with full penetrance best explained the pattern of affected individuals, although the suggested gene frequency was much higher in the USA study and close to the expected frequency of RLS in the population (see above). In the USA study, the age of onset was also examined to see whether genetic factors might control this age (Hening et al., 2005). The results were not compatible with a major gene model, but suggested that complex genetic influences as well as environmental ones controlled age of onset.

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specific inheritance pattern – but confirmed in two families, using a dominant model). Although initially present only in selected families, two of the linkages have been confirmed in other countries: 12q in Iceland (D. Rye, personal communication from) and 14q in Canada (Levchenko et al., 2004). This confirmation is important because many linkages found in common diseases restricted to one population fail to be confirmed in other populations and may turn out to be spurious. In these genetic studies, the association of RLS symptoms with PLM has proven to play an important role. Families demonstrating linkage in both Canada (Desautels et al., 2005) and Italy (Bonati et al., 2003) have been those with high frequencies of PLM. Furthermore, in Iceland linkage is stronger to a phenotype with increased PLM (15% of affected lacking subjective symptoms of RLS) than to RLS defined purely by subjective symptoms (D. Rye, personal communication). Whatever the resulting implications for phenotyping of RLS, this finding argues that the underlying physiologies of RLS and PLM are likely to overlap substantially. Another genetic approach is to examine candidate genes selected from prior knowledge about the disorder. In RLS, genes coding significant molecules in the DA and iron pathways have been examined for possible mutations, because of the presumed involvement of these pathways in RLS (see section on Pathophysiology below). This approach has largely been unrevealing (Desautels et al., 2001b; Li et al., 2003). In one association uncovered, the rapid acetylator form of monoamine oxidase A was associated with RLS in women, but not in men (Desautels et al., 2002). Although this approach has so far not given major results, it is still possible that additional candidate genes related to DA, opioid, or iron metabolism may be affected in RLS.

Genetics: association studies Genetics: linkage studies and candidate genes Although no specific genes affecting RLS have yet been uncovered, RLS has been linked to specific chromosome regions where causal genes may be located. Three linkage studies have discovered three different chromosomal regions that are likely to influence RLS: 12q in Quebec (Desautels et al., 2001a), 14q in north Italy (Bonati et al., 2003), and 9p in southern USA (Chen et al., 2004). These studies used different inheritance models: recessive (although dominant models worked almost as well: G. Rouleau, personal communication), dominant, nonparametric (i.e., assuming no

Three recent associations studies have found strong genetic affects for RLS. Two studies identified essentially the same common variant, an intron of BTBD9 on chromosome 6p21, as highly associated with RLS (Stefansson et al., 2007; Winkelmann et al., 2007). The particular RLS allele on this gene was strongly associated with increased PLMS/hour and with lower serum ferritin levels (Stefansson et al., 2007). One of these two studies identified two other intronic variants closely related to RLS: one in MEIS1 on chromosome 2p and the other in MAP2K5 and LBXCOR1 on chromosome 15q (Winkelmann et al., 2007). A more recent study identified a fourth area in PTPRD on

930 C.J. EARLEY ET AL. chromosome 9p (Schormair et al., 2008). These three understand whether the brain could selectively be defistudies identified ten possible risk alleles for RLS in cient in iron, even in the face of otherwise normal body four separate areas of the chromosomes. It is imporiron stores. tant to recognize that these genetic associations are The first of these studies was a cerebrospinal fluid common in the general population, but more common (CSF) evaluation of ferritin and transferrin in a cohort in patients with RLS. Thus they are not useful for diagof 16 patients with idiopathic RLS and 16 age- and sexnosis of RLS. This is consistent with the evidence from matched controls. Subjects had to have ferritin levels twin studies, that RLS heritability is only about 0.60 above 50 mg/l. Although both groups had almost identi(Chen et al., 2004). However, they seem likely eventucal and normal serum ferritin and serum transferrin ally to inform about the pathology of RLS. values, patients with RLS had significantly diminished CSF ferritin and increased transferrin (Earley et al., Summary 2000b). The results suggest that, even with normal systemic iron stores, patients with RLS have diminished Studies to date have established that RLS is a familial brain iron stores. Identical results have recently been disorder and that some component of that familial reported by Mizuno et al. (2005) in a Japanese populaaggregation is due to genetic factors. RLS is clearly tion of patients with RLS. Using special magnetic associated with allelic variations on at least four areas resonance imaging (MRI) techniques (Ma and Wehrli, of the genome. Like most common disorders, however, 1996) that allow quantification of the iron concentraRLS is a complex disorder, with multiple genetic and tion (“iron index”) in the brain, Allen et al. (2001) environmental factors increasing the risk of RLS. Its performed brain MRIs on five patients with RLS and estimated heritability of 0.6 (Chen et al., 2004) denotes five age-matched controls as part of a preliminary the importance of considering RLS as a result of envistudy. They found that the patients had a significantly ronmental and genetic interaction. Understanding that decreased substantia nigra (SN) iron index compared interaction may be very important for developing betwith the control group. They also found a significant ter treatments and even possible interventions. correlation (r ¼ 0.69) between the decreasing SN iron index and increasing RLS severity as assessed by the PATHOPHYSIOLOGY Johns Hopkins RLS Severity Scale. Transcranial Doppler ultrasonography can also be used to quantify iron in The role of iron metabolism the brain owing to the echogenicity of the tissue Studies have shown a strong relationship between (increases with increasing iron concentration) (Zecca declining systemic iron status (serum ferritin) and et al., 2005). Using this technique, Schmidauer et al. increasing RLS severity, and have reported improve(2005) demonstrated that patients with RLS had hypoements in RLS symptoms with iron treatment in chogenicity in the SN compared with that in agethose with iron deficiency (Ekbom, 1945; O’Keeffe matched controls. The findings were interpreted as et al., 1993, 1994; Sun et al., 1998) (see above). reduced iron in the SN of RLS subjects. Taken together, these findings tend to implicate a role Autopsy studies of patients with RLS are mostly for systemic iron deficiency state (serum ferritin level supportive of the brain iron deficiency model of RLS. <50 mg/l) in some cases of RLS. The larger question The focus of these studies has been on the SN, because is whether altered iron metabolism, beyond the sysof the prior MRI findings and because of the sugtemic iron-deficient condition, can be implicated in gested relationship between the DAergic system and RLS (Earley et al., 2000a). RLS. In brains from seven patients with RLS, general Nordlander first recognized the association between neuropathological evaluation found no abnormalities iron deficiency and RLS, but took this a step further by (Connor et al., 2003). Evaluations for underlying evaluating the effects of iron treatment on those with Alzheimer, Parkinson, and Lewy body disease were negnormal serum iron levels (Nordlander, 1954). Twentyative. Specifically, there was no indication of neuronal two patients with RLS and normal serum iron levels cell loss or gliosis in the SN. Five control brains of simireceived multiple intravenous doses of iron until symplar age and with relatively disease-free findings on neutoms resolved; 21 of them had complete resolution of ropathology were used to compare to the findings in the RLS symptoms. On the basis of his clinical experience RLS group. Specialized histological assessment of iron and these findings, Nordlander was the first to propose and related proteins demonstrated that in patients with the iron deficiency hypothesis of RLS, and stated: “it is RLS, the cells in the SN showed markedly diminished possible. . .that there can exist an iron deficiency in the iron concentrations (Connor et al., 2003). Levels of tissues in spite of normal serum iron” (Nordlander, H-ferritin, which functions more as an iron transport 1954). This hypothesis has been investigated to protein (Testa, 2002), were significantly diminished,

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP 931 whereas the concentration of L-ferritin, which functions relevance in differentiating RLS into two subpopulaprimarily as a iron storage protein (Testa, 2002), was tions for which pathology may differ (Allen and unchanged compared with controls. Transferrin levels Earley, 2000). This was raised in part by the finding were significantly increased, whereas the transferrin of increased small-fiber neuropathy in small subgroup receptor (TfR) appeared to be unchanged or decreased. of patients with RLS in whom RLS symptoms develop Two reviewers with four-point rating of the degree of late in life (Polydefkis et al., 2000). The implication is staining obtained these semiquantitative data from a that the neuropathy in these cases may be the primary blinded review of slides. The changes in iron and related cause. As those with neuropathy also had late-onset proteins were consistent across all seven RLS brains. RLS, the question is raised of whether age at onset The decrease in tissue iron with a concomitant decrease defines different pathologies (Ondo and Jankovic, in H-ferritin and increase in transferrin are indicative of 1996; Polydefkis et al., 2000). Two studies have iron-deficient state in the SN of these RLS brains. attempted to address the question of whether earlyMore quantitative methods (immunoblot analysis) and late-onset RLS differ with respect to brain iron of assessing iron-related proteins were performed in metabolism. One study analyzed CSF and found that neuromelanin cells, which were isolated by using laser patients with early-onset (n ¼ 15) but not those with capture microscopy techniques. Neuromelanin cells late-onset (n ¼ 15) RLS had significantly lower CSF obtained from four RLS and four control brains ferritin compared to sex-matched and age-appropriate demonstrated significantly decreased H-ferritin, norcontrols (n ¼ 22) (Earley et al., 2005b). A second study mal L-ferritin, and markedly increased transferrin examined SN and nine other brain regions by MRI and levels (Connor et al., 2004). An unexpected finding demonstrated that 22 patients with early-onset RLS was significantly decreased TfR. With iron defihad a significantly decreased SN iron index compared ciency, TfR should be increased in parallel with transwith that in 39 controls, whereas 19 patients with lateferrin. As TfR synthesis is controlled primarily onset RLS showed no difference to controls (Earley through control of TfR mRNA stability (Testa, et al., 2005a). The late-onset RLS group did have sig2002), further studies have focused on that aspect nificantly increased iron in the putamen (P < 0.009) of iron regulation. and pons (P < 0.005); although, after Bonferroni corTfR is directly controlled by iron through specific rections for multiple comparisons, the changes were iron regulatory proteins (IRPs) (Testa, 2002). The IRPs marginally nonsignificant (Earley et al., 2005a). can bind to one of five iron responsive elements (IRE,) One of the more interesting findings from the CSF found at the 50 end of TfR mRNA (Testa, 2002). ferritin studies was the strong and significant correlaBy binding to the IRE, the IRP stabilizes the TfR tion between CSF ferritin and the age at which sympmRNA and thus permits continued TfR synthesis toms started (r ¼ 0.64): the earlier the symptoms (Testa, 2002). To complicate the picture further, there started, the lower the CSF ferritin. All subjects had are two IRPs (IRP1 and 2), which appear to have disdaily symptoms; the majority had moderate to severe tinct physiological roles (Pantopoulos, 2004). IRP2 is symptoms and were on average in their seventh decade essential for the development/survival of the animal. of life, yet CSF ferritin correlated with none of these Iron deficiency leads to increased synthesis or factors. The correlation remained significant and decreased degradation of the protein (Pantopoulos, strong for early-onset RLS (r ¼ 0.65) but lost signifi2004). IRP1 knockouts show no obvious abnormality cance in the late-onset RLS group. Early-onset RLS is of red blood cell production or of storage of iron (Panassociated with a slowly progressive worsening of topoulos, 2004). With diminished cellular iron, cytosymptoms over 20–30 years. To the degree that sympsolic aconitase loses its iron residues and converts to toms are related to brain iron status, the changes may IRP1 (Testa, 2002). The equilibrium is reversed with reflect an underlying progressive change in brain iron. increased cellular iron. Therefore, to understand the Notably, iron in the SN is relatively low before adolesbasis for the low TfR in the face of low iron found cence and then progressively increases in humans up to in RLS brains, IRP1 and 2 and aconitase activity were about 50 years of age. The mechanism behind this late evaluated in the neuromelanin cells (Connor et al., developmental change in SN iron may be relevant to 2004). Cell extracts from RLS brains showed signifiearly-onset RLS: its absence would create a relative cantly increased IRP2, which would be expected but progressive iron insufficiency in the SN compared under the iron-deficient conditions, but also showed with levels in those with a normal mechanism. significantly decreased total IRP1 activity. Aconitase The studies suggest that those with early-onset RLS activity was also decreased. have relatively diminished brain iron, at least in the SN. There is reason to believe that phenotypic classificaOf note, all of the autopsy data presented above were tion of RLS into early- and late-onset RLS may have from brains of patients with early-onset RLS (Connor

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et al., 2003, 2004). If altered iron metabolism underlies late-onset RLS, then it probably differs from that seen in the early-onset disorder. Two studies have shown an excellent and significant correlation between CSF ferritin and serum ferritin in controls (r ¼ 0.72–0.89) and RLS (r ¼ 0.46–0.65), but the slope of the regression line was significantly lower for RLS cases (Earley et al., 2000b; Mizuno et al., 2005). Thus, for the same value of serum ferritin, the CSF ferritin would be lower in RLS than in controls. The findings may also be interpreted by considering that to achieve “normal” CSF ferritin, patients with RLS need to have substantially higher serum ferritin levels. Although this latter interpretation does imply cause and effect (“relatively” low systemic iron stores resulted in low brain iron stores), there are some data to support it. As already stated, Nordlander (1954) showed, by increasing systemic iron stores via intravenous iron treatment, that RLS symptoms would remit even in patients with “normal” iron levels. Studies have also shown that when symptoms return after intravenous iron treatment there is a concomitant and significant drop in serum ferritin (Earley et al., 2005c). Slower rates of ferritin decline were associated with longer symptom-free periods (Earley et al., 2005c). Importantly, despite Nordlander’s success in treating RLS with intravenous iron, the only other study of such iron therapy showed benefits in only 7 of 10 patients (Earley et al., 2004). A major criticism of both studies is that they were open label. Randomized, blinded trials would better define the efficacy of intravenous iron treatment. However, it would be equally helpful to ascertain whether different phenotypes or indicators of systemic or brain iron status can differentiate responders from nonresponders. In addition, do markers of brain iron status (CSF, MRI, transcranial Doppler) change with treatment response? This would help to answer the question of cause and effect with respect to the systemic and brain iron relationship. The overall results clearly define a role for brain iron deficiency in at least some patients with RLS, whether produced by systemic iron deficiency or by altered iron metabolism. The exact mechanisms by which the resultant brain iron deficiency occurs and how it leads to RLS symptoms remain speculative. Even in the scenario where systemic iron deficiency can be shown to cause RLS, it does not explain why many people with iron deficiency do not develop the syndrome. We know from animal studies that sex, strain, and area of interest determine the level of iron in the brain under systemic iron-deficient conditions (Morse et al., 1999). Studies in mice have also shown that, within recombinant inbred strains with normal dietary iron intake, the amount of iron in the midbrain

can vary across strains by a factor of 3 (Jones et al., 2003). Thus, independent of any change in systemic iron status, several genetic factors operate to determine “resting” brain levels of iron (Jones et al., 2003). It is not unreasonable, therefore, to assume that similar genetic determinants operate under human conditions as well, to create the conditions for RLS. The autopsy data give a general view of the brain’s iron status in its final days, and therefore it is difficult to know what is cause and/or effect. Does the cellular iron initially decrease and then the cell is unable to compensate (increase TfR) because of inadequate IRP1–aconitase synthesis? Is the IRP1–aconitase synthesis inadequate, leading to reduced TfR and thus reduced iron? Given the highly complex nature of iron regulation, it is more than likely that several metabolic defects will be found.

The role of the dopaminergic system Although it is commonly stated that RLS stems from a central DAergic abnormality, the data supporting this claim are somewhat limited and conflicting. As will be discussed, the best support comes from pharmacological studies, with limited support from hormonal and brain imaging studies.

PHARMACOLOGICAL

STUDIES

The pharmacological studies provide a picture consistent with a DAergic abnormality in RLS. Levodopa and all DA agonists evaluated to date produce an immediate and dramatic reduction of all the primary motor and sensory symptoms of RLS. The effective doses of these medications are significantly less than that for Parkinson’s disease. In contrast to the efficacy of DA agonists, DA antagonists have been reported to induce RLS-like symptoms or segmental akathisia (Blom and Ekbom, 1961; Ratey and Salzman, 1984) or to exacerbate existing symptoms (Ekbom, 1960). Both of these points are not without controversy. Whether DA antagonist-induced akathisia is truly similar to RLS has been debated (Walters et al., 1991; Lang, 1993; Sachdev, 1995; Poewe and Hogl, 2004). One study found that 76% of patients with RLS versus 18% without RLS developed akathisia when given metoclopramide intravenously for acute migraine management (Young et al., 2003). This suggests that if the two symptom complexes (RLS and akathisia) are not the same, at least they appear to share a common biological risk. Two recent studies explored the degree to which DA antagonists worsen RLS symptoms by using PLM during a SIT as a primary measure of RLS. Tribl et al. (2005) titrated intravenous apomorphine to achieve

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP therapeutic benefits in nine patients with RLS and then, while they were still receiving continuous infusion, attempted to block the benefits with naloxone or metoclopramide. Neither naloxone nor metoclopramide was able to block the effects of apomorphine significantly in terms of either symptom severity or PLM. There were several methodological problems, however. First, the sample size was small. Also, it was unclear whether the pharmacodynamics between continuous infusion of a very high-affinity DA1/DA2 receptor agonist (apomorphine) could be compared with single dose of a medium-affinity, selective DA2 receptor antagonist (metoclopramide) in the brain. Winkelmann et al. (2001) gave metoclopramide (10 mg intravenously), placebo, and naloxone to six drug-naive patients with RLS and found no significant difference between the treatment groups for reported symptom severity. Nevertheless, five of six patients had at least some increase in PLM with metoclopramide compared with their placebo response. The dose of metoclopramide used in this study may not have been adequate to produce a more dramatic effect on the PLM and the sensory symptoms (Bateman et al., 1979). That RLS symptoms are DA responsive is well supported by the literature, but the question remains whether the DAergic system has a direct role in causing the symptoms. The pharmacological support rests primarily on whether one believes that RLS and druginduced akathisia have a common biological pathway.

HORMONAL

STUDIES

Prolactin release is directly inhibited by DA through the activation of the tuberoinfundibular system. Sleep and drowsiness increase prolactin release and the amplitude of the prolactin pulse (Spiegel et al., 1994). There is also an intrinsic circadian rhythm producing a smaller effect independent of the sleep–wake state, which mildly decreases prolactin about 8 hours after the temperature nadir (Waldstreicher et al., 1996). Therefore, various measures of prolactin release have been used by several investigators to assess the role of the DAergic system in RLS. Wetter et al. (2002) measured plasma prolactin levels every 20 minutes for 24 hours in 10 treatmentnaive patients with RLS and 8 matched controls. They reported no differences in prolactin levels or in the frequency or amplitude of prolactin pulses. Of critical importance in interpreting the results is that 10-minute sampling intervals are considered to be the minimum needed for accurate measurement of prolactin amplitude and pulsatility (Veldman et al., 2001). Winkelmann et al. (2001) measured plasma prolactin every 15 minutes after an intravenous infusion of 10 mg

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metoclopramide in 8 treatment-naive patients with RLS. Prolactin levels increased 18-fold after the metoclopramide infusion. The authors compared their results to a reported set of “normal” controls (Volavka et al., 1980) and, based on this normative data set, values in patients with RLS were considered not to be different. The prolactin increases in this study, however, were two to three times greater than those reported for other control data sets, and therefore could be interpreted as suggesting an increased sensitivity to DA2 receptor antagonists in RLS (Bateman et al., 1978; Greenspan et al., 1990). Garcia-Borreguero et al. (2004) evaluated the prolactin response after administration of 200 mg levodopa at either 11 am or 11 pm for 12 RLS and 12 age- and sex-matched controls. A significant difference between the groups in the response to the morning levodopa dose was not found. Patients with RLS did show a greater decrease in prolactin at the 11 pm dose compared with controls, but this was significant at only one of the multiple timepoints. Total prolactin over the duration of the trial (area under the curve) did not differ significantly between RLS and control subjects. The amount of the prolactin decrease correlated significantly with the patients’ baseline PLMS/ hour. The authors interpreted their findings as indicating an increased sensitivity of the DA postsynaptic receptors at night but not in the morning. Overall, the results with prolactin have been suggestive of a relative increase in tuberoinfundibular DAergic sensitivity in the evening at the time of RLS symptoms. These data do not indicate whether the putative change in sensitivity of the DAergic system results from changes at the postsynaptic receptor, from changes in availability of DA, from changes in the metabolism of levodopa, or, perhaps, from a combination of these factors.

IMAGING

STUDIES

Several small imaging studies of the striatal DA system in patients with RLS have been performed. Two studies of [18F]fluoro-L-DOPA (FDOPA) uptake in the caudate and putamen both showed significant decreases. Ruottinen et al. (2000) compared nine drug-naive patients with RLS with 27 matched controls and showed that FDOPA uptake was 88% of the control values in the caudate and 89% in the putamen (P < 0.05 for both areas). Turjanski et al. (1999) reported a similar mild reduction in FDOPA uptake for 13 patients with RLS (5 on current L-dopa treatment for RLS) in comparison with to age-matched historical controls that was statistically significant only for putamen (P ¼ 0.04) and not for the caudate.

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Turjanski et al. (1999) also evaluated these same 13 patients using [11C]raclopride positron emission tomography (PET), and reported significantly reduced D2 binding in the caudate (P ¼ 0.01) and putamen (P ¼ 0.008). They also reported that there were no differences in any of the imaging studies between untreated and treated patients with RLS. Single-photon emission computed tomography (SPECT) studies have produced inconsistent results. Eisensehr et al. (2001) evaluated 14 drug-naive and 11 L-dopa-treated patients with RLS compared with 10 matched controls by using SPECT imaging and reported no differences between the groups for either DA transporter or D2 receptor binding. Tribl et al. (2004) performed SPECT studies in 14 treated subjects with RLS who were off their medications and in 10 matched controls, and reported no difference in striatal DA transport. Michaud et al. (2002c), however, compared 10 drug-naive patients with RLS to 10 matched controls evaluated with SPECT and showed no differences for DA transporter binding, although there was a significant (P ¼ 0.006) average 7% decrease in D2 receptor binding. Given the decreased binding in the more precise PET studies, it seems unlikely these data represent a type I error. One interesting difference between the Michaud et al. study and other SPECT studies was the timing of the test: in the Michaud et al. study the imaging covered the afternoon and early evening, whereas the other studies were all performed earlier in the day. It is possible that the differences are small, creating a problem for type II error, or that imaging later in the day would reveal more clearly the DA abnormality with RLS. Overall, these studies suggest some relatively small abnormality in the striatal DA system, providing limited support for the concept of a central DA abnormality in RLS. But, again, reduced binding or uptake provides relatively little information about the nature of the abnormality, if it is present at all.

and 11 control subjects, and reported no significant differences for HVA, BH4, neopterin, or several other DA-related measurements. Two studies, however, have reported a surprising increase in 3-O-methyldopa in the CSF of patients with RLS compared with controls (Earley et al., 2006; Allen et al., 2009). This increase was associated with more severe RLS, increased PLMS/hour, and increased HVA (Allen et al., 2009). This suggests a possible hyperdopaminergic state for RLS.

CEREBROSPINAL

CORTICAL

FLUID STUDIES

There have been two studies of DA metabolites and related proteins in CSF. Earley et al. (2001) evaluated CSF samples taken about 10 am from 16 patients with RLS who had been without medication for 2 weeks versus 14 control subjects. They reported no significant differences for the DA metabolite homovanillic acid (HVA) and, after correction for age differences, also no significant difference for neopterin, although tetrahydrobiopterin (BH4) was significantly increased in the RLS group (P < 0.01). Stiasny-Kolster et al. (2004c) evaluated CSF samples obtained in the evening (6–8 pm) from 22 mostly untreated patients with RLS

SUMMARY Apart from the pharmacological data, evidence supporting a DAergic abnormality is rather meager. What data we have show an interesting pattern. If there is DAergic system pathology in RLS, then it appears to have a significant circadian feature, with mild abnormalities occurring only later in the day or in the early morning. Thus, the DA pathology in RLS, if present, appears not to be a static, fixed abnormality, but rather a dynamic one requiring consideration of those factors contributing to the daily cycling of the DA system. It also appears to involve increased, not decreased, presynaptic DA activation.

Anatomical localization of pathology Somewhat independent of the question of what mechanisms (iron? DA?) may be involved in RLS is the question of what part of the nervous system is involved. As discussed in the preceding sections, PET/ SPECT, MRI, and autopsy studies have suggested that the nigrostriatal pathway may be involved, at least with regard to iron and DA. This does not exclude the possibility that other neurotransmitters or other regions (whether or not iron or DA related) may play a role. There are various studies that indicate cortical, subcortical, or spinal mechanisms may be involved in the RLS. These are reviewed in this section.

Four studies (Entezari-Taher et al., 1999; Tergau et al., 1999; Quatrale et al., 2003; Stiasny-Kolster et al., 2003) have used transcranial magnetic stimulation (TMS) to evaluate cortical motor inhibitory/excitatory mechanisms in idiopathic RLS subjects (Barker et al., 1985). Controls for all of these studies were effectively age matched. Table 56.5 gives a summary of the four major variables, as measured from a muscle in the foot, that were found to be positive in at least two of the four studies. The duration of the cortical silent period (CSP), a commonly measured TMS index, was assessed in all four of these studies. It is considered

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Table 56.5 Relevant RLS subject characteristics and methods and results of four studies with transcranial magnetic stimulation (TMS)

No. of patients Male  female ratio Mean  SD age (years) Prior treatment Drug-free period Time of testing CSP ICI ICF PSP

Tergau et al., 1999

Entezari-Taher et al., 1999

Quatrale et al., 2003

Stiasny-Kolster et al., 2003

18 13  5 63.1  10.8 61% >1 day “Late afternoon” NS Decreased Decreased ND

10 NP 52  9 NP >2 days NP Decreased ND ND NS

15 NP 60.5  25.4 0% NP 9 am NS Decreased Increased NS

15 10  5 55.5  9.3 100% >2 days 8 am NS ND ND ND

8 pm Decreased ND ND ND

TMS results are given as not significant (NS) or as significantly changed (increased or decreased) compared with control values; some procedures were not done (ND) in some of the studies. NP, information not provided; CSP, cortical silent period; ICI, intracranial inhibition; ICF, intracranial facilitation; PSP, peripheral silent period.

to reflect the excitability of inhibitory neurons projecting on to the pyramidal cells in the motor cortex (Haug et al., 1992; Kukowski and Haug, 1992). The second two indices were the paired-pulse TMS intracortical inhibition (ICI) and intracortical facilitation (ICF), which are measures of the inhibitory or excitatory intracortical network, respectively (Kujirai et al., 1993; Kammer et al., 2001). The fourth measure is the duration of the peripheral silent period (PSP), which reflects only the spinal inhibitory mechanisms that are affecting the motor response. As summarized in Table 56.5, two studies (EntezariTaher et al., 1999; Stiasny-Kolster et al., 2003) found a decrease in the CSP for RLS subjects compared with controls, whereas the other two studies found no difference. Two studies found a diminished ICI (Tergau et al., 1999; Quatrale et al., 2003); one also found a decreased ICF (Tergau et al., 1999), whereas the other found an increased ICF (Quatrale et al., 2003). The other two studies did not evaluate these indices. Only two of the four studies looked at the PSP, and found no significant difference between patients with RLS and controls (Entezari-Taher et al., 1999; Quatrale et al., 2003). One study showed that treatment with levodopa normalized the CSP changes in patients with RLS (Stiasny-Kolster et al., 2003). Of significance to these findings is that pergolide, which is an effective treatment for RLS (Earley et al., 1998), results in lengthening of the CSP and enhancement of ICI in normal subjects, an effect which is opposite to that seen with RLS (Ziemann et al., 1996). Although results were somewhat different across the studies, all four studies concluded that patients

with RLS show increased cortical–motor excitability or “disinhibition”. The failure to find significant changes in the PSP suggests that changes in cortical motor excitability are not related to spinal motor changes. The reason for the differences among studies is unclear, but may reflect differences in RLS population, prevalence of previously treated subjects, timing of the study, and differences in procedures. A recent study found that CSP varies across the menstrual cycle (Smith et al., 1999). As many of the patients in the RLS studies were women, did this affect the results? When off medication, patients with RLS are likely to lose sleep, so were there effects of sleep loss on the TMS indices? Issues such as these need to be addressed before the results can be interpreted properly. A study of movement-induced EEG beta oscillations by characterizing premovement event-related desynchronization (ERD) or postmovement event-related synchronization (ERS) reported increased cortical excitability in RLS (Schober et al., 2004). A single brisk movement of the right index finger was the movement event. None of the RLS patients had received DAergic treatment and the controls were matched for age and sex. The results demonstrated no differences between RLS and control subjects in the preparatory phase of the movement (ERD), but there was an enhanced magnitude of induced beta oscillations in the postmovement recovery phase (ERS). The interpretation was that the enhanced beta oscillations reflect the “higher need for cortical inhibition due to increased. . .excitation of the cortical area” (Schober et al., 2004). A parallel question to that of cortical motor excitability is whether PLMs originate in the cortical area.

936 C.J. EARLEY ET AL. Using standard EEG techniques, Lugaresi et al. (1986) from the spinal cord. One study (de Mello et al., found no premovement cortical EEG activation before 2004) reported the benefits of levodopa in treating a sleep-related PLM event. An independent study the PLMs associated with complete spinal cord transecreported the absence of Bereitschaftspotential in the tions. Notably, the 40% reduction in PLMs seen with EEG during wake in patients with RLS after a leg levodopa was relatively small compared with the movement (Trenkwalder et al., 1993). A cortically 90–100% reduction seen in patients with RLS taking based origin for the PLM was therefore not supported levodopa (Brodeur et al., 1988; Kaplan et al., 1993; by these two studies. Movement-induced EEG beta Benes et al., 1999). In addition, in the patients with spioscillations, by characterizing the ERD, however, can nal cord transections, physical activity of the legs more accurately assess the pre-EMG events. When a resulted in a subsequent reduction in PLMs equal to voluntary leg movement, an involuntary leg moveor greater than that achieved with levodopa (de Mello ment caused by the RLS symptoms, and intermittent et al., 1999, 2002, 2004). Although physical activity passive leg movements of the same leg were assessed, may reduce or eliminate RLS symptoms while the beta ERD were found to be present prior to the RLSactivity is occurring, there is no indication that PLMs associated leg movements and the voluntary leg moveduring sleep would be reduced. Indeed, clinical experiments, but not the passive leg movements (Rau et al., ence suggests that physical activity during the day is 2004). The study demonstrates that cortical activation likely to make the RLS symptoms or the PLMs at night does occur before the movement of the leg with RLS worse. Finally, PLMs in sleep are seen in association and that the movements appear to be “voluntary” in with many disorders that have nothing to do with nature. This is not surprising given the clinical picture RLS: apnea, drugs, narcolepsy, aging, and Parkinson’s of RLS, where the primary symptom is the urge to disease (Ancoli-Israel et al., 1991; Askenasy, 2001; move to legs, which occurs prior to movement. UnforDhanuka and Singh, 2001; Allen et al., 2005; Carrier tunately, this study did not address the basis of PLMs et al., 2005). Therefore, PLMs in sleep are simply an as they occur in sleep. electrophysiological phenomenon for which there are many different causes, and are not necessarily indicaSUBCORTICAL tive of RLS. Only one study has provided reasonable data to sugThe findings of a functional MRI (fMRI) study indicate gest a relationship between RLS and spinal processes that activation of the thalamus and cerebellum is asso(Bara-Jimenez et al., 2000). Ten subjects with idiociated with the development of the sensory symptoms pathic RLS, who were off medication for at least 5 of RLS, whereas activation of the red nucleus and the days before the study, and 10 controls were evaluated. brainstem may be important in generating the periodic The primary measure was the spinal cord flexor reflex motor movements that follow the sensory component (FR); studies were done at night with subjects awake or (Bucher et al., 1997). The area of the thalamus that asleep. The study found no differences in the FR in was activated on fMRI appears to be the dorsal medial patients with RLS and no difference between RLS thalamus. The dorsal medial thalamus functions as a patients and controls while awake (Bara-Jimenez relay nucleus between the basal ganglia and the prefronet al., 2000). Patients with RLS did demonstrate a tal cortex, and has been noted in primates to have signifgreater spatial spread of the FR and a lower threshold icant DAergic inputs (Sanchez-Gonzalez et al., 2005). while asleep compared with controls. The authors conWhether activation is a result of an underlying primary cluded that patients with RLS have “enhanced spinal thalamic change, or related to ascending or descending cord excitability” during sleep (Bara-Jimenez et al., inputs, is unclear. Of relevance is that voxel-based 2000). These findings do not exclude the possibility MRI morphometric analysis of the thalamus has shown of supraspinal processes as the basis for a change in an increased volume of the pulvinar in patients with the spinal excitability. RLS (Etgen et al., 2005). The significance of this is The findings are interesting, but have yet to be unclear, but it does suggest that a primary thalamic proreproduced by an independent group. It is of concern cess may be involved in RLS. that the patients with RLS were not completely matched with the control population, primarily with SPINAL respect to sleep loss. The patients with RLS had poor The primary basis for assuming a spinal process in sleep efficiency and frequent awakenings, most likely RLS is the reported findings of PLM in patients with due to the severe PLMS (mean rate of 96 PLMS/hour) complete spinal cord transections. This implies that (Bara-Jimenez et al., 2000). It is surprising that the the generator for PLM is in the spinal cord and, by findings were found only during sleep and not during association, suggests that RLS symptoms may evolve the wake period, as RLS is clearly a “wake time”

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP phenomenon and not a sleep-dependent disorder (Allen et al., 2003). PLMs during wake will persist with little change as the subject transitions into and finally enters sleep (Montplaisir et al., 1998). The quality of sleep and the number of arousals during sleep were not controlled for in this study. Therefore, the most likely interpretation of the results is that the CNS (spinal or supraspinal) in these patients with RLS during sleep is more activated than in controls because of the frequent arousals and sleep fragmentations associated with active PLM. On the basis of the EMG recruitment pattern of PLMS, a recent study postulated “an abnormal hyperexcitability of the entire spinal cord” (Provini et al., 2001). Although the postulated spinal cord hyperexcitability was very speculative, the study similarly failed to take into account the effects that PLM and increased arousals per se would have on EMG recruitment patterns of PLMS.

SUMMARY Some degree of cortical–motor excitability may play a role in RLS. This may involve the cortical–subcortical motor axis. There are insufficient data to support a primary role for spinal cord mechanisms. Unfortunately, RLS is primarily a sensory disorder, not a motor disorder (Allen et al., 2003). The studies with EEG signal analysis clearly demonstrate a preparatory change in the premotor cortex with leg movements. If there is increased cortical motor excitation then that may predict only the degree to which a motor response is likely to happen, in response to this urge to move. As has been demonstrated in studies with the SIT, there is a variable degree to which patients exhibit leg movements in response to the sensory component (Michaud et al., 2002a; Birinyi et al., 2005). The degree of cortical excitability may define that boundary between the actual urge to move and the potential to have the leg jump involuntarily. The fMRI study was the only study that related the sensory symptoms to specific CNS activation (thalamus and cerebellum); beyond that, the data are insufficient to be certain where the primary source of the sensory symptoms lies.

Table 56.6 Suggested dose ranges of common RLS medications Drug type I.

II.

THERAPEUTICS The management of RLS depends on a number of factors such as the severity and frequency of symptoms, any aggravating conditions, the timing of symptoms, the age or clinical status of the patient, and the history of prior treatment. Medications that can provoke RLS include all DA blockers (antipsychotics, many antiemetics and antinausea compounds, metoclopramide), most antidepressants (except bupropion), and centrally

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active antihistamines (diphenhydramine). Treating underlying conditions (iron deficiency or anemia, uremia) can often alleviate RLS. Caffeine and alcohol ingestion, especially late in the day, loss of sleep, lack of exercise or excessive exercise may all increase RLS symptoms. Patients can be warned to avoid these potential aggravators and to practice good sleep hygiene (using bed only for sleep and intimacy, avoiding alerting activities near bedtime, keeping a regular sleep–wake cycle, having a quiet and dark bedroom) (Stepanski and Wyatt, 2003). In addition, patients can employ techniques they may have discovered themselves in order to alleviate symptoms, including brief activity before bedtime, warm baths or cold showers, or massage; when having to sit, patients can use alerting mental activities (video games, use of a computer, needlework) to reduce symptoms. These general recommendations are not based on the scientific literature, but from broad clinical experience (Buchfuhrer and Gunzel, 2009). For moderate to severe symptoms, DAergic medications are the agents of choice, and management of some patients will also require use of opioids, anticonvulsants, and sedative hypnotics. Practical clinical guidelines for use of drugs in the treatment of RLS can be found in two recent publications (Earley, 2003; Silber et al., 2004) and Table 56.6 gives suggested starting and maximum doses for the various agents, which are discussed below.

III. IV.

Drug name

Dopaminergic

Levodopa (with decarboxylase inhibitor) Ropinirole Pramipexole Pergolide Cabergoline Opioid Codeine (usually in compound) Propoxyphene hydrochloride Oxycodone Hydrocodone Tramadol Methadone Anticonvulsant Gabapentin Sedative–hypnotic Clonazepam Flunazepam

Modified from Earley (2003).

Dose range (mg) 50–200

0.25–3.0 0.125–1.0 0.05–0.5 0.5–4.0 30–180 100–600 5–20 5–30 50–300 5–20 300–3600 0.5–2.0 15–60

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Dopaminergic agents These medications are effective at dose ranges considerably below those used to treat Parkinson’s disease (Table 56.6). Within the generally healthier population of patients with RLS and with low-dose treatment, some of the major complications of DAergic therapy in Parkinson’s disease are quite rare, including dyskinesias, psychosis, hallucinations, and sleep attacks. Nevertheless, DAergic agents may induce either insomnia or daytime sleepiness.

LEVODOPA The first DAergic agent to be studied in RLS was levodopa (with a decarboxylase inhibitor) (Akpinar, 1982; Montplaisir et al., 1986). Levodopa, combined with either carbidopa or benserazide, has been tested extensively (for a review of the literature on levodopa in RLS see Chesson et al., 1999; Littner et al., 2004), including controlled trials, but no large-scale multicenter trials. For short-term use, it is well tolerated by most patients and the typical DAergic side-effects (nausea, gastrointestinal upset, light-headedness, headache, mental side-effects) are often fewer than those associated with agonists. One issue is the relatively short half-life of regular levodopa formulations, which can lead to the re-emergence of symptoms late in the sleep period as drug levels decline. This can be improved by using a sustained-release formulation (Collado-Seidel et al., 1999; Trenkwalder et al., 2003). Other strategies to increase duration of action include the addition of catechol-O-methyltransferase (COMT) inhibitors, but this has not been studied formally. In any case, the more sustained-release preparations did not resolve the issue of augmentation (see below).

DOPAMINE

AGONISTS

There is a major chemical division of DA agonists between those with ergotamine structure (bromocriptine, pergolide, cabergoline, lisuride) and those without (nonergotamine: ropinirole, pramipexole, rotigotine). The ergotamine agonists have been associated with intrathoracic fibrotic disorders including cardiac valvulopathy (Danoff et al., 2001; Horvath et al., 2004), which suggests a degree of caution and monitoring when using these agents. Ropinirole was the first DA agonist to be approved for moderate to severe idiopathic RLS by the Food and Drug Administration in the USA. The several phase III multicenter, parallel, double-blind trials conducted before approval showed subjective benefit (Trenkwalder et al., 2004a; Walters et al., 2004), and in one study notable suppression of PLM (Allen et al.,

2004). QoL also improved. Onset of benefit was evident within 1 week. Pramipexole has been shown in several studies to improve symptoms and sleep, and markedly reduce PLM (Montplaisir et al., 1999; Stiasny-Kolster and Oertel, 2004). Long-term studies have shown that therapeutic benefit can be maintained for years (Montplaisir et al., 2000a; Silber et al., 2003; Winkelman and Johnston, 2004). Side-effects tend to be mild. Larger-scale studies have been conducted, but the results not yet published; conference presentations indicate that the results are positive. Rotigotine is given in a continuous-release patch formulation (Mucke, 2003). It is currently under investigation for use in both Parkinson’s disease and RLS. Initial studies indicate that is also likely to be a useful agonist for treatment of RLS (Stiasny-Kolster et al., 2004b). Pergolide was the first agonist extensively studied and shown to be effective for treatment of RLS (Earley and Allen, 1996; Silber et al., 1997; Staedt et al., 1997; Earley et al., 1998; Winkelmann et al., 1998; Wetter et al., 1999; Stiasny et al., 2001; Trenkwalder et al., 2004b). As a result, it was accepted as a “standard” for treatment in the 2004 American Academy of Sleep Medicine practice parameters for the management of RLS (Littner et al., 2004). Cabergoline has been reported to be an effective treatment, with relatively little provocation of augmentation (Stiasny et al., 2000; Zucconi et al., 2003; Benes et al., 2004; Stiasny-Kolster et al., 2004a). It has been studied more extensively in Europe than in the USA. Because of its long half-life, cabergoline provides sustained coverage with once-daily dosing. A variety of other agonists have been tried in small studies in RLS: acute treatment with subcutaneous apomorphine (Tribl et al., 2005), talipexole (Inoue et al., 1999), piribedil (Evidente, 2001), bromocriptine (Akpinar, 1987; Walters et al., 1988), and dihydroergocryptine (Tergau et al., 2001). Although all studies were successful, further exploration is needed for these agents to find a place in the RLS pharmacopoeia. Of note, there have been no head to head comparisons of agonists for the treatment of RLS (and, in general, comparative therapeutic studies have been rare in RLS). Therefore, comparison of agents is at best imprecise; details of studies and sampling are sufficiently varied that there is no standard protocol against which results can be compared.

OTHER

DOPAMINERGIC AGENTS

Other agents active on the DAergic system include amantadine, which has been studied as an add-on medication for RLS (Evidente et al., 2000), and deprenyl,

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP a monoamine-B inhibitor, which has been reported to reduce PLMS (Grewal et al., 2002). These have not been as effective as medications that act more directly on the DAergic system.

REBOUND

AND AUGMENTATION

Rebound and augmentation provide two major limitations to DAergic therapy. Rebound is related to the short half-life of medications, particularly regular levodopa formulations. The short half-life leads to the reemergence of symptoms late in the sleep period or early morning as drug levels decline (Guilleminault et al., 1993). There is a suggestion that this is not merely resumption of symptoms (and increase in PLM) expected by the decreased effectiveness of the medication as blood levels fall, but rather an actual exaggeration of symptoms provoked by the drug. Although rebound is, in a sense, a re-emergence of symptoms, augmentation is the advance of symptoms to an earlier time (Allen and Earley, 1996). Augmentation should be viewed as an iatrogenic worsening of the patient’s RLS. The key feature of augmentation is that symptoms begin to occur earlier in the day than before treatment was begun (Allen et al., 2003). In general, one measure of severity of RLS is the duration of symptoms experienced by patients; as this duration increases, symptoms tend to occur earlier in the day– night cycle. This feature is assessed by the Johns Hopkins RLS Severity Scale, which categorizes patients by time of onset of their symptoms (Allen and Earley, 2001). In addition to this shift in the timing of symptoms, augmentation includes an intensification of symptoms, a reduced latency at rest to onset of symptoms, an increased lag before medications become effective, and a spread of symptoms to other body parts. Tolerance is a related condition: it does not involve a change in the severity of RLS, but an increased need for higher doses of medication to achieve a similar therapeutic effect (Winkelman and Johnston, 2004). Although conceptually distinct, these two phenomena may co-occur or be difficult to distinguish in specific cases. Augmentation tends to be more severe the higher the dose of medication and, perhaps in relation to this, the greater the general severity of symptoms. More than 50% of patients on long-term levodopa therapy may develop augmentation (Allen and Earley, 1996). Among the more studied agonists, augmentation with pergolide and pramipexole appears to be in the range of 15–30% (Earley and Allen, 1996; Silber et al., 1997; Silber et al., 2003; Winkelman and Johnston, 2004), whereas that with cabergoline may be still lower (Zucconi et al., 2003; Benes et al., 2004; Stiasny-Kolster et al., 2004a).

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This finding with cabergoline – which has a very extended half-life, permitting once-daily dosing – has led to the suggestion that agents with a longer half-life may be less likely to induce augmentation. This could be related to relatively stable rather than widely fluctuating blood levels. Augmentation appears to be a phenomenon tightly associated with DAergic therapy of RLS. Despite clinical reports of occasional cases of augmentation associated with other classes of agent, there have been no published reports.

Opioids and related agents There is much greater clinical experience with opioids than that reported in the literature. One open-label trial of various opioids (Hening et al., 1986) and one double-blind study of oxycodone (Walters et al., 1993) found that these agents can relieve both waking symptoms and sleep problems of patients with RLS. A double-blind trial found that 200 mg propoxyphene was less potent than levodopa in relieving RLS, although PLMS were reduced (Kaplan et al., 1993). Strong opioids such as methadone have been reported as effective in treating patients in whom the DA agonists were no longer effective (Ondo, 2005). Opioids can also work over sustained periods, both as combination and as monotherapy (Walters et al., 2001). One concern is the development or aggravation of sleep-related respiratory disturbances. Tramadol was found to be effective in a limited study of RLS (Lauerma and Markkula, 1999). Tramadol has a mixed action: it is a m-opioid receptor agonist and a serotonergic and noradrenergic uptake transporter blocker. Clinical experience suggests that tramadol may cause augmentation of RLS (Earley, 2003), which would make it unique among the nonDAergic agents used in RLS.

Anticonvulsants Although carbamazepine was the first anticonvulsant tested in RLS (Telstad et al., 1984) and was thereby recognized for the treatment of RLS (Chesson et al., 1999), gabapentin has been more accepted by RLS experts based on recent studies (Happe et al., 2001; Garcia-Borreguero et al., 2002; Micozkadioglu et al., 2004). It is generally well tolerated – although somnolence and ataxia can occur – and can be used for treatment of daily RLS. Doses can approach those used for treatment of seizures (up to 1800–3600 mg per day). Other anticonvulsants have also been shown to be beneficial in RLS or PLMD. Studies provide some support for the use of valproic acid (Ehrenberg et al., 2000; Eisensehr et al., 2004) and lamotrigine (Youssef

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C.J. EARLEY ET AL.

et al., 2005), suggesting that still other anticonvulsants may also be useful in RLS.

Sedative–hypnotics agents Although benzodiazepines, notably clonazepam, were the first drugs tested for RLS in the modern era, they have assumed a rather subsidiary role in modern practice. They may be used for intermittent symptoms, for PLMD alone, for those with mild sleep-period symptoms, or for combination therapy, especially to reduce sleep-related symptoms, which may persist with other forms of therapy (Silber et al., 2004). Whereas the classes of medications discussed above seem to act to suppress RLS more directly, sedative hypnotics appear in contrast to enhance sleep, thus indirectly improving RLS. Despite the need for concern about potential somnolence and mental clouding with the use of benzodiazepines, especially long-acting drugs such as clonazepam, at least one study has found that they can be effectively and safely used long term in sleep disorders, even in the elderly (Schenck and Mahowald, 1996). Nonbenzodiazepine sedative–hypnotic agents, such as zolpidem, zaleplon, and now eszopiclone, have also been used in RLS for the same purpose, but so far there are no publications supporting their efficacy.

Other agents A variety of other agents have been reported in small studies to be helpful in RLS, especially in the 1980s (for a review see Walters and Hening, 1987). One agent worth mentioning is clonidine, an a agonist, which has been useful primarily for waking symptoms (Wagner et al., 1996).

Special populations SECONDARY RLS –

IRON DEFICIENCY AND UREMIA

One specific strategy in dealing with secondary RLS is to alleviate the underlying symptoms. Oral iron supplementation can improve RLS symptoms associated with iron deficiency (O’Keeffe et al., 1994). Intravenous iron supplementation is potentially more efficient and effective (Earley et al., 2004), but requires further investigation before routine use. In uremia, dialysis does not appear to benefit RLS (Molnar et al., 2005), although transplantation is helpful (Winkelmann et al., 2002b). Improving the iron status of uremic patients through erythropoietin (Benz et al., 1999) or intravenous iron (Sloand et al., 2004) has been reported to be helpful. Although studies are limited, most medications for primary RLS appear to work well in uremic RLS (Trenkwalder et al., 1996), including DAergic, opioids, anticonvulsants (Thorp et al., 2001),

sedative–hypnotics (Read et al., 1981), and clonidine (Ausserwinkler and Schmidt, 1989).

PREGNANCY Treatment of RLS in pregnancy is done cautiously (Earley, 2005). Most medications used for RLS have not been studied extensively in pregnancy and many can cause birth defects. Iron treatment may be helpful, as pregnancy is a period of high iron stress. Opioids may be among the less risky medications, but most treatment should be deferred until the third trimester, when RLS is most likely to be a problem (Manconi et al., 2004a, b). Sleep disruption can be a risk factor for pregnancy complications, so treatment should be seriously considered if RLS is severe (Earley, 2005).

CHILDREN There has been relatively little investigation of the treatment of RLS in children. Behavioral measures and caffeine restriction have been recommended. Iron deficiency may be common (Kotagal and Silber, 2004) and correction can reduce symptoms (Kryger et al., 2002). Two small studies found that DAergic agents can help childhood RLS or PLMD (Walters et al., 2000; Martinez and Guilleminault, 2004), including that associated with attention-deficit/hyperactivity disorder (Walters et al., 2000).

THE

ELDERLY

There have been no specific studies (except for those of iron therapy: O’Keeffe et al., 1994) in the elderly, but many studies have accepted patients up to 75 or 80 years old. Therefore, treatment in the elderly is generally the same as that for younger adults. The one additional issue is the greater likelihood of comorbid disorders. These may require modification of RLS therapy to avoid issues of drug interactions.

PLMD Recent studies have not focused on PLMD. Many studies of RLS treatment, however, include measures of PLM as indices of therapeutic success, and all classes of medications, most notably the DAergic agents, have been found to suppress PLM. Because PLMs are so sensitive to DAergic agents, low-dose levodopa or low-dose DA agonists should improve RLS. Sedative– hypnotics may also provide adequate relief.

Summary The treatment of restless legs and PLMD involves several classes of medication, especially DAergic agents, opioids, anticonvulsants, and sedative–hypnotics.

RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS IN SLEEP Treatment should be tailored to the severity of the condition, presence of waking discomfort, previous treatment response, underlying conditions, and special populations depending on age or pregnancy. A major therapeutic problem has been rebound and augmentation seen with higher-dose levodopa therapy and, to a lesser extent, with DA agonists. Most patients can receive substantial benefit from treatment, which can provide relief over a period of years.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 57

Molecular neurobiology of circadian rhythms FRED W. TUREK * AND MARTHA HOTZ VITATERNA Department of Neurobiology & Physiology, Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL, USA

INTRODUCTION Over the past three decades, remarkable progress has been made in elucidating the physiological substrates that underlie the generation of 24-hour rhythms in mammals. Such rhythms are now known to be produced by a circadian system with a “master” biological clock located in the bilaterally paired suprachiasmatic nuclei (SCN) of the hypothalamus that acts to coordinate oscillators in tissues throughout the organism. More recently, it has been recognized that individual cells and tissues are capable of producing sustained rhythms in isolation, and the SCN directly or indirectly coordinates rhythmic processes throughout the body. These rhythms are the result of oscillations in the expression of a core set of interrelated circadian genes. This chapter describes the genes expressed in the SCN (and other oscillators) and the proteins they encode which are responsible for this daily rhythmicity. Readers not familiar with some of the terms used in genetics research should refer to http://www.biology-text.com/ and http://www.biochem. northwestern.edu/holmgren/Glossary/Definitions/Def-A/ Index-A.html, which contain a glossary of terms used in genetics.

THE MASTER NEURAL CIRCADIAN CLOCK Evidence has accumulated since the early 1970s that the SCN is the site of the master circadian pacemaker in mammals. Early studies demonstrated that destruction of the SCN abolishes circadian oscillations in the plasma concentration of cortisol (Moore and Eichler, 1972) and in locomotion and drinking (Stephan and Zucker, 1972). Normal circadian rhythms can be restored to a SCN-lesioned animal by transplantation

of fetal SCN tissue, but not by transplantation of fetal tissue from other regions of the brain (Lehman et al., 1987). Transplant into a SCN-lesioned animal of fetal SCN tissue obtained from a mutant animal with an abnormally short circadian period (i.e., 20–22 hours) confers the short period of the donor to the host animal (Ralph et al., 1990), indicating that the properties of the rhythm are determined by the SCN rather than other tissues or brain regions. A number of other lines of evidence also point to the SCN as the site driving or controlling circadian behavior for mammals (Rosenwasser and Turek, 2005). Recent studies of rhythms in gene expression have indicated that persistent rhythms can be observed in tissues throughout the organism, even in tissue explants kept in culture for extended periods of time (Yamazaki et al., 2000; Yoo et al., 2004). The phases of these peripheral tissue rhythms differ from that of the SCN, but nonetheless appear to be coordinated by the SCN. In SCN-lesioned animals, these peripheral rhythms persist but no longer exhibit the consistent phase relationship to one another as seen in unlesioned animals (Yoo et al., 2004). How the SCN communicates and coordinates oscillations throughout the body is not well understood. Although some outputs of the SCN are clearly neuronal in nature (e.g., neural control of pineal melatonin rhythm), circadian information also arises as a neurohormonal or diffusible signal (Silver et al., 1996). One such signal may be the peptide transforming growth factor a (TGFa), which was identified in a screen for SCN factors that might inhibit locomotor activity; when infused into the third ventricle, TGFa inhibits locomotor activity. Mice with targeted mutations of the epidermal growth factor receptor (the receptor

*Correspondence to: Fred W. Turek, Department of Neurobiology & Physiology, Center for Sleep and Circadian Biology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3520, USA. Tel: 847-467-6512, Fax: 847-467-4065 E-mail: fturek@ northwestern.edu

952 F.W. TUREK AND M.H. VITATERNA likely to bind TGFa) also have disrupted activity gene expression and protein synthesis were identified rhythms (Kramer et al., 2001). as being central to the generation of circadian Even before the circadian molecular core machinoscillations. ery had been identified at the cellular level, there were The period gene of the circadian clock several lines of evidence to indicate that oscillations were intrinsic to individual SCN neurons. Blockade The first circadian clock gene in animals, called period, of action potentials by injection of tetrodotoxin into denoted with the symbol per, was discovered in 1971 the SCN did not stop the circadian oscillator, although in Drosophila using a forward genetic approach blockade does prevent inputs and outputs from being consisting of chemically inducing random mutations transmitted to and from the SCN (Schwartz et al., in the genome, and detecting those mutations that 1987). In addition, synaptogenesis in the SCN occurs affected circadian rhythms by screening the progeny after the development of circadian rhythms (Moore of the mutagenized individuals for altered rhythmicity and Bernstein, 1989). These two findings demonstrate (Konopka and Benzer, 1971). This approach has the that the oscillations do not depend on communication advantage that no assumptions are made about the between SCN neurons. Indeed, the periods of individual nature of the genes or gene products involved, but is SCN cells studied in slices vary widely, and the circadian based on the presumption that there exist genes that, period of an animal appears to reflect the mean of the when mutated, will alter rhythms in a detectable manperiods of many SCN neurons (Liu et al., 1997). Finally, ner. At the time, this presumption of the existence of individual, dissociated SCN neurons in culture demonsingle genes that regulate a complex behavior was strate oscillations with periods that differ from cell to considered radical, but eventually was proven to be a cell, indicating that these neurons possess an intrinsic defining moment in the field of circadian rhythms as oscillatory mechanism (Welsh et al., 1995). The remainit led the way for the discovery of other clock genes der of this chapter focuses on the mechanism by which in flies and mammals. individual cells generate oscillations with a period of Initially, three alleles of the per gene were identified about 24 hours. by the process of mutagenesis and screening. These alleles had either no apparent rhythm in eclosion (emerGENE EXPRESSION UNDERLIES THE gence from the pupal case) or locomotion, or had CIRCADIAN OSCILLATOR either long (e.g., 29 hours) or short (e.g., 19 hours) perHow do individual cells generate rhythmic activity with iods for the rhythms of eclosion and locomotor activity a period of about a day? Many pacemaker neurons (Konopka and Benzer, 1971). It is important to note generate oscillatory activity, such as rhythmic patterns that the finding of three alleles with three different of action potentials, and these relatively rapid oscillaphenotypes made it possible to have confidence in the tions can be explained by the concerted action of a conclusion that the per gene encodes a protein that is small number of ion channels. However, the much a clock component. Had only an arrhythmic mutant slower oscillations of the individual SCN neurons are been found, then an alternative explanation could be not likely to involve the same mechanisms. In fact, proposed whereby the lack of circadian behavior was the finding that nonneuronal tissues can produce sussecondary to another primary defect that did not lie tained circadian rhythms, as well as the prevalence of in the clock itself. It should be noted that the approach circadian rhythms in plants and unicellular organisms, of mutagenesis and screening has also been successful were early findings that argued against a coordinated in identifying circadian clock genes in other organisms neural process underlying circadian rhythm generation. such as Neurospora crassa (Dunlap, 1996), plants (Millar Indeed, it appears that the synthesis of proteins by et al., 1995), and cyanobacteria (Kondo et al., 1994). SCN neurons is central to the mechanism for the genHowever, a discussion of these important findings is eration of 24-hour rhythms. The initial evidence for outside the scope of the present review. this is that application of protein synthesis inhibitors The importance of the per gene as a central circain the region of the SCN shifts the circadian phase of dian clock component was confirmed by the rescue activity of animals by an amount and in a direction of the mutant phenotype after introduction of the that depends upon the time at which the inhibition is wild-type allele of the per gene into mutant flies imposed (Inouye et al., 1988; Takahashi, 1995). A simi(Bargiello et al., 1984; Zehring et al., 1984). The level lar shift in the phase of vasopressin release from of the mRNA transcript encoded by the per gene was explanted SCN also results from inhibition of protein shown to oscillate in a circadian fashion (Hardin synthesis (Watanabe et al., 1995). Thus, even before et al., 1990) as a result of transcriptional regulation circadian clock genes were discovered in mammals, (Hardin et al., 1992), and the levels of the PER protein

MOLECULAR NEUROBIOLOGY OF CIRCADIAN RHYTHMS were shown to lag the per mRNA levels (Edery et al., 1994a, b). In fact, shifts in the circadian phase can be evoked by the induction of PER protein under the control of a noncircadian promoter (Edery et al., 1994a, b). Thus, many lines of evidence indicate that the per gene encodes a protein that is a clock component. Three orthologs of the per gene, mPer1, mPer2, and mPer3, have now been identified in the mouse, and their mRNA levels have also been shown to oscillate with a circadian period (Albrecht et al., 1997; Shearman et al., 1997; Sun et al., 1997; Tei et al., 1997; Zylka et al., 1998).

The mammalian Clock gene As no mammalian orthologs (genes with both functional and sequence homology) to Drosophila circadian clock genes had been identified by the early 1990s, and no other genes in mammals had been identified as even possible candidate circadian clock genes in genetically accessible organisms, we initiated a mutagenesis and screening program in mice in an effort to identify

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mammalian circadian clock genes. For this, we used the C57BL/6J mouse strain, in which the activity rhythm of wild-type mice shows robust entrainment to a light–dark cycle, and has a circadian period with very little individual variability between 23.6 and 23.8 hours under free-running conditions in constant darkness (DD) (Figure 57.1). In our initial screen for dominant or semidominant mutations of over 300 progeny of mutagen-treated mice, we found one animal that had a free-running period of about 24.8 hours, more than six standard deviations longer than the mean (Vitaterna et al., 1994). In the homozygous condition this mutation results in a dramatic lengthening of the period to about 28 hours, which is often followed by the eventual loss of circadian rhythmicity (i.e., arrhythmicity) after about 1–3 weeks in DD. The affected gene was mapped to mouse chromosome 5 and named Clock (Vitaterna et al., 1994; King et al., 1997a, b). We cloned the Clock gene by a combination of genetic rescue and positional cloning techniques. Clock/Clock mutant mice were phenotypically rescued by a bacterial

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C Fig. 57.1. Activity records of mice. Each record is double-plotted according to convention, so that each day’s data are presented both to the right and beneath the day preceding. Times of wheel-running activity are indicated by black. On days 1–6, mice were maintained under a 12-hour light–12-hour dark cycle. Mice were then transferred to continuous darkness by allowing lights to go out at the usual time but remain off through the remaining days of data collection shown. (A) Activity record of a wild-type C57BL/6J mouse, with a free-running period of approximately 23.7 hours. (B)Activity record of a Clock/þ heterozygote C57BL/6J mouse, with a free-running period that lengthened over time to approximately 24.8 hours. (C) Activity record of a homozygous Clock/Clock mutant C57BL/6J mouse, with a free-running period of approximately 28 hours. #Elsevier.

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artificial chromosome (BAC) transgene that contained the Clock gene, allowing for functional identification of the gene (Antoch et al., 1997). The Clock gene encodes a transcriptional regulatory protein with a basic helix–loop–helix DNA-binding domain, a PAS dimerization domain, and a Q-rich transactivation domain. The mutant form of the CLOCK protein (CLOCK D19) lacks exon 19, a portion of the activation domain found in wild-type protein, and thus, although it is capable of protein dimerization, transcriptional activation is diminished or lost. The PAS domain is so named because of the genes originally identified with this protein dimerization domain, per, ARNT, and sim. Clock mRNA is expressed in the SCN as well as other tissues, but has not been found to oscillate in a circadian fashion (King et al., 1997a, b); although subsequently its dimerization partner was found to oscillate.

Interactions of Clock with period and Bmal1 genes The presence of the PAS dimerization domain in CLOCK protein suggested that it may form a heterodimer similar to that of PER and the protein product of another Drosophila clock gene, timeless, TIM (Huang et al., 1993). A screen for potential partners for the CLOCK protein using the yeast two-hybrid system revealed that a protein of unknown function, BMAL1 (brain and muscle ARNT-like 1), was able to dimerize with the CLOCK protein (Gekakis et al., 1998). Next, the ability of this heterodimer to regulate transcription was tested using a reporter construct based on the upstream regulatory elements of the per gene. The per gene of Drosophila contains an upstream regulatory element, the “clock control region”, within which is contained a sequence needed for positive regulation of transcription, the so-called E-box element (CACGTG) (Hao et al., 1997). CLOCK–BMAL1 heterodimers were found to activate transcription of the mPer gene in a process that requires binding to the E-box element (Gekakis et al., 1998). However, CLOCK △19 mutant protein was not able to activate transcription, consistent with the finding that exon 19, which is skipped in Clock mutant animals (King et al., 1997a, b), is necessary for transactivation. Thus, CLOCK protein interacts with the regulatory regions of the per gene to allow transcription of the per mRNA and eventual translation of PER protein. A similar activation of transcription of the tim gene by the CLOCK– BMAL1 heterodimer also occurs (Darlington et al., 1998). However, this positive regulation alone will not produce an oscillation in per mRNA levels, which is known to be responsible for the oscillation in PER

protein levels (Hardin et al., 1992). The finding that the Clock mutation dramatically decreases the expression of per genes also confirms the positive regulation of CLOCK–BMAL1 on per transcription in situ (Shearman and Weaver, 1999; Vitaterna et al., 2006). Creation of mice harboring a null allele of Bmal1 (also referred to as MOP3) demonstrated the critical role of this gene in circadian rhythm generation. These mutant mice, while being able to entrain to the light– dark cycle, become arrhythmic immediately upon release in constant darkness (Bunger et al., 2000). Mice with null mutations of mPer1, mPer2, or mPer3 display altered circadian periods (Bae et al., 2001; Zheng et al., 2001), whereas mice with both mPer1 and mPer2 null mutations also lose rhythmicity. mPer3 null mutant mice exhibit only a subtle alteration in rhythmicity, and mPer1/mPer3 or mPer2/mPer3 double mutants are not substantially distinct from the mPer1 or mPer3 single mutants. These findings suggest there may be some compensation of function among the different mammalian per genes, and point to the importance of mPer1 and mPer2, in particular, in the generation of circadian rhythms. Recently, additional actions of the CLOCK–BMAL1 heterodimer have become clear. Although Clock mRNA does not oscillate, its protein’s nuclear versus cytoplasmic localization does (Kondratov et al., 2003). By studying the intracellular localization of CLOCK and BMAL1 in fibroblasts of mouse embryos with mutations in different Clock genes, and ectopically expressing the proteins, it was found that nuclear accumulation of CLOCK was dependent on formation of the CLOCK–BMAL1 dimer, as was phosphorylation of the complex and its degradation (Kondratov et al., 2003). Other PAS domain-containing proteins failed to affect the localization of CLOCK, indicating that these posttranslational events are specific to the CLOCK–BMAL dimer.

THE CRYPTOCHROMES Cryptochromes are blue light-responsive flavoprotein photopigments related to photolyases, so named because their function was cryptic when first identified. In mammals, two cryptochrome genes, Cry1 and Cry2, have been identified, and were found to be highly expressed in the ganglion cells and inner nuclear layer of the retina and the SCN (Miyamoto and Sancar, 1998), and their mRNA expression levels oscillates in these tissues. Targeted mutant mice lacking Cry2 exhibit lengthened circadian period, whereas mice lacking Cry1 have a shortened circadian period and mice with both mutations have immediate loss of rhythmicity upon transfer to constant darkness

MOLECULAR NEUROBIOLOGY OF CIRCADIAN RHYTHMS (Thresher et al., 1998; Van der Horst et al., 1999; Vitaterna et al., 1999). Thus, like the mammalian period genes, the cryptochrome genes appear to have both distinct (given their opposite effects on circadian period) and compensatory (given that either gene can sustain rhythmicity in the absence of the other) functions. Because of their expression pattern, the cryptochromes were initially thought to be the long-unidentified mammalian circadian photoreceptors, and thus light responses were examined in characterizing the null mutants. Cry2 mutant mice exhibit altered phaseshifting responses to light pulses (Thresher et al., 1998). Cry1/Cry2 double mutants exhibit impaired light induction of mPer1 in the SCN, whereas light induction of mPer2 in double mutants remains (Okamura et al., 1999; Vitaterna et al., 1999). Neither mPer1 nor mPer2 exhibits persistent oscillations in expression in the SCN in constant conditions in Cry1/Cry2 double mutants (Okamura et al., 1999; Vitaterna et al., 1999). Thus, although the cryptochromes are not the mammalian circadian photoreceptor, they do appear to play a central role in the generation of circadian signals. Further evidence for a central clock function is the finding that the cryptochromes appear to share a number of regulatory features with the period genes. In Clock mutant mice, the mRNA levels of Cry1 and Cry2 are reduced in the SCN and in skeletal muscle (Kume et al., 1999), suggesting that the cryptochromes also are induced by CLOCK–BMAL1 transactivation. Using mammalian (National Institutes of Health (NIH) 3T3 or COS7) cell lines, CRY1 and CRY2 were found by coimmunoprecipitation to interact with mPER1, mPER2, and mPER3, leading to nuclear localization of the CRY–PER dimer as indicated by cotransfection assays with epitope-tagged proteins (Kume et al., 1999). Luciferase assays indicate that CRY–CRY and CRY–PER complexes were capable of inhibiting CLOCK–BMAL1 transactivation of mPer1 or vasopressin transcription (Kume et al., 1999). Thus, the CRYs as well as the PERs are capable of a negative feedback function, inhibiting CLOCK–BMAL1-induced transcription.

TIMELESS How is the level of the PER protein regulated by the circadian clock? The first hint came from the identification of the timeless gene, tim, which when mutated produces abnormal circadian rhythms in Drosophila (Sehgal et al., 1994). The levels of the mRNA encoded by the tim gene oscillate with a time course that is indistinguishable from that of per mRNA (Sehgal et al., 1995). The levels of the TIM protein lag behind

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those of tim mRNA by several hours (Hunter-Ensor et al., 1996), similar to the finding with per mRNA and PER protein. The PER and TIM proteins form heterodimers (Gekakis et al., 1995) that are transported to the nucleus (Saez and Young, 1996). The finding that the heterodimer is transported to the nucleus suggested that it might be involved in the regulation of transcription of the per or tim genes. Indeed, recent experiments have shown that the transcription of the per and tim genes is repressed by the PER–TIM protein heterodimer (Darlington et al., 1998). This finding is important because it demonstrates that the production of mRNA encoded by a clock component gene, the delayed accumulation of the encoded protein, and later feedback to the clock gene’s promoter in the nucleus are able to explain the basic features of the circadian clock in Drosophila. However, PER–TIM interactions are not sufficient and the basic mechanism does not become clear until one adds interactions with other clock genes. In experiments using a luciferase reporter assay, the luminescent luciferase protein was expressed under the control of the promoter regions of the Drosophila per and tim genes. It was found that the fly homolog of Clock, dClock (Allada et al., 1998), was capable of driving expression of luciferase (Darlington et al., 1998) in cells that have high endogenous levels of the Drosophila homolog of BMAL1, CYC (cycle). The effect of the PER–TIM heterodimer on the ability of the dCLOCK–CYC heterodimer to drive the transcription of the per and tim genes was tested by cotransfecting the encoding genes into the cells that expressed the luciferase reporter gene. Indeed, it was found that expression of both per and tim genes was reduced by their own protein products. This negative feedback has recently been found for a mammalian heterodimer consisting of homologs of the TIMELESS and mPER1 proteins (Sangoram et al., 1998). Whether the identified mammalian tim homolog (Sangoram et al., 1998; Tischkau et al., 1999) actually represents an orthologous gene has been called into question (Gotter et al., 2000). This issue has been difficult to resolve, as gene targeting to create a null mutant results in early embryonic lethality. Differences in results obtained by different groups examining the oscillation of mTim expression could result from both a full-length and a truncated protein being expressed, with only the full-length form oscillating (Barnes et al., 2003). Antisense oligodeoxynucleotides directed against Timeless in rat SCN slice preparations disrupt neuronal oscillations in vitro, suggesting that a role in rhythmicity may exist (Barnes et al., 2003). However, a true functional homology of Timeless in mammals with the fly gene remains to be demonstrated.

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THE TAU MUTATION The tau mutation of the hamster arose spontaneously in a laboratory stock (Ralph and Menaker, 1988). The mutation is semidominant and shortens the period from 24 to 22 hours in heterozygotes, and to 20 hours in homozygotes. This mutation has been of great importance for several reasons. (1) The mutation predated the Clock mutation and demonstrated that single gene mutations could profoundly alter the circadian clock in mammals, just as in flies and Neurospora. (2) Tau mutants display several other physiological phenotypes such as alteration of the responses of males to photoperiod length (Shimomura and Menaker, 1994) and effects of the estrous cycles in females (Refinetti and Menaker, 1992), providing further insight into the importance of the circadian clock for other biological cycles. (3) The evidence that the SCN is indeed the site of the master circadian oscillator (see above) was demonstrated unequivocally using transplantation of the SCN that employed the tau mutation. These manipulations also gave rise to the evidence necessary to conclude that the tau mutation encodes a protein that is a clock component. Unfortunately, the genetic tools needed for cloning this important and interesting gene were not available for the hamster, and thus its molecular identity could not be determined by conventional genetic mapping/positional cloning. Nevertheless, using as ingenious approach, Lowrey and colleagues (2000) were able to identify a genomic region of conserved synteny (a grouping of genes together on a chromosome) in hamsters, mice, and humans that encompassed the tau mutation. Tau was thus identified as being a mutation in the Casein Kinase 1 epsilon (CK1e) gene, the mammalian ortholog of the Drosophila doubletime gene, which had previously been identified as a component of the fly circadian clock. Sequencing of the gene identified a point mutation that leads to altered enzyme dynamics and autophosphorylation state. In vitro assays demonstrated that CK1e can phosphorylate PER proteins, and that the tau mutant enzyme is deficient in this ability. Thus, CK1e may lead to degradation of PERs, slowing the accumulation of PER in the nucleus and thus slowing the repression of CLOCK–BMAL1 production.

rhythmic transcription of Bmal1, with an antiphase relationship to the Pers, an orphan nuclear receptor, Reverba, was identified. Its promoter region contains three E-boxes and transcription is thus positively regulated by CLOCK and BMAL1 (Preitner et al., 2002). Its transcription is negatively regulated by the PERs and CRYs and is at a minimum when mPER2 is at a maximum, and it is constitutively expressed at intermediate levels in Cry1/Cry2 or Per1/Per2 double knockouts. REVERBa protein appears to drive the circadian oscillation in Bmal1 transcription: the Bmal1 promoter includes two RORE sequences (enhancer sequences that recognize members of the REV-ERB and ROR orphan nuclear receptor families), and Bmal1 expression is drastically reduced in Rev-erba null mutants (Preitner et al., 2002). Thus, Rev-erba may act to link the positive and negative regulatory signals of other clock genes to the transcription of Bmal1. The differences between the phase of Cry1 mRNA rhythms relative to other clock genes whose transcription is enhanced by CLOCK– BMAL binding to E-boxes may also be attributable to Rev-erba. The Cry1 gene has three candidate REVERB/ROR binding sites (Etchegaray et al., 2003); in vitro assays indicate that REV-ERBa binds to two of these sites. Luciferase reporter assays indicate that REV-ERBa protein can inhibit transcription of Cry1 through binding at these two sites. There also is evidence of regulation of clock gene transcription via rhythms in acetylation of H3 histone: CRY proteins may inhibit H3 acetylation (Etchegaray et al., 2003), and the Per1, Per2, and Cry1 promoters have rhythms in H3 acetylation, as well as rhythms in RNA polymerase II binding. These promoter rhythms are in phase with mRNA levels. P300, a histone acetyltransferase, immunoprecipitates together with CLOCK in liver nuclear preparations, with a peak at circadian time (CT) 6 and minimum at CT 18 (Etchegaray et al., 2003). P300 may be part of the CLOCK–BMAL1 coactivator complex; a Per1 promoter-driven luciferase reporter assay indicates that CRY proteins can disrupt this. Hence, inhibition of histone acetylation by P300 provides a potential separate mechanism by which CRY proteins can preclude CLOCK–BMAL1 transactivation of Per and Cry genes.

ADDING MORE LOOPS TO THE CYCLE

A MOLECULAR MODEL FOR THE CIRCADIAN CLOCK

Although the negative feedback of PER and CRY proteins on their own CLOCK–BMAL1-induced transcription constitutes a form of negative feedback, and may be sufficient to explain the oscillations in expression of mPer and Cry genes, the rhythmic expression of Bmal1 with an opposite phase is not explained by this feedback. In searching for regulatory elements producing the

Our current knowledge of the molecular genetic interactions of circadian clock genes provides for a basic mechanism involving multiple feedback loops of clock proteins on transcription of clock genes. These core interactions are summarized in Figure 57.2. These and other suspected circadian clock gene interactions are listed in Table 57.1.

MOLECULAR NEUROBIOLOGY OF CIRCADIAN RHYTHMS Cytoplasm

Nucleus

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Undoubtedly additional clock genes will be part of the mechanism, and additional transcriptional, translational, and post-translational interactions among these genes and their proteins are expected to be identified.

Clock Bmal1

RORE

OTHER GENES AND MUTATIONS E

Rev-erba

CK Iε P

Pers

E

E

Crys

Fig. 57.2. Molecular model of the core circadian oscillator. CLOCK and BMAL1 proteins (light grey) form heterodimers in the cytoplasm and, upon nuclear entry, bind to E-box promoter elements in the Rev-erba, Per, and Cry genes to drive transcription of these genes. REV-ERBa (white) binds to a retinoic acid-related orphan receptor response element (RORE) to inhibit transcription of Bmal1. PER proteins are phosphorylated by CK1e (casein kinase 1E; triangle), possibly leading to its degradation. PER and CRY proteins form heterodimers (dark grey) and enter the nucleus to repress CLOCK–BMAL1-driven transcription of Rev-erba, Per, and Cry genes. #Elsevier.

Four additional mammalian genes have been proposed to play roles in the circadian system, because mutations in these genes result in alterations in circadian rhythms. The Rab3a gene was identified in a mutagenesis screen (earlybird) based on an advanced phase angle of entrainment and shortened circadian period. Null mutant mice display a similar phenotype (Kapfhamer et al., 2002). The DBP gene has E-box elements in its promoter, and exhibits robust oscillations in expression in the SCN and the liver. DBP null mutant mice display alterations in circadian period as well (Lopez-Molina et al., 1997). NPAS2 is another basic helix–loop–helix PAS family member that forms heterodimers with BMAL1. Null mutant mice for this gene display alterations in the pattern of their activity rhythms (Dudley et al., 2003). Mice that lack the peptide receptor vasoactive intestinal peptide receptor 2 show abnormal entrainment and disrupted rhythms, indicating that vasoactive intestinal peptide signaling in the SCN may be necessary

Table 57.1 Ten steps to build a circadian pacemaker Step

Action

Effect CLOCK is phosphorylated and CLOCK–BMAL1 dimers enter the nucleus Positive and rhythmic drive of expression of these circadian genes CRY–CRY and CRY–PER dimers enter the nucleus

6

CLOCK and BMAL1 form protein heterodimers. CLOCK–BMAL1 bind to E-box enhancer elements of Pers, Crys, and Rev-erba PER and CRY proteins form homodimers and heterodimers in the cytoplasm PER is phosphorylated by CK1e PER–CRY and CRY–CRY repress CLOCK–BMAL1-driven transcription of Pers and Crys PER–TIM can repress Per transcription

7

PER–CRY repress Rev-erba transcription

8

REV-ERBa enhances Bmal1 and represses Cry1 transcription CRY proteins inhibit H3 histone acetylation by P300 The histone acetyltransferase P300 works together with CLOCK–BMAL in promoting mPer1, mPer2, and Cry1 transcription

1 2 3 4 5

9 10

PER protein is degraded, nuclear accumulation is slowed Negative feedback of PER and CRY proteins on their own transcription Mammalian timeless may have function orthologous to Drosophila tim, acting in a negative feedback Rev-erba is regulated by negative feedback of PER–CRY, resulting in a similar oscillation in expression REV-ERBa modulation of transcription produces different phases in expression of Bmal1 and Cry1 CRY proteins can modulate transcription via modulations in histone acetylation H3 histone acetylation rhythms in the promoter regions of mPer1, mPer2, and Cry1 may regulate timing of the transcription of these genes

958 F.W. TUREK AND M.H. VITATERNA for normal expression and coordination of rhythms may have greatly diversified as humans successfully (Harmar, 2003). Although these genes should be considinvaded and adapted to such extreme environments ered as possible mammalian clock genes because their as polar regions, deserts, and high mountains that mutations affect expression of circadian rhythms, their required changes in the phase relationship of daily life roles in the circadian timekeeping mechanism remain to the harsh, but often predictable, changes in the daily equivocal. Further studies are needed to define their environment. With so many clock genes (at least 10 and roles, if any, in the core molecular circadian clock. In counting), and their possible allelic variations, it may any case, although the story of clock genes is certainly well be that there are many circadian genotypes (and not complete, it now appears that the core of the mamassociated phenotypes) in the human population. malian molecular clock has been identified. Linking circadian genotype with human circadian phenotypes in the modern world may provide for a much deeper understanding of health and disease. DisCIRCADIAN CLOCK GENES IN HUMANS orders of circadian temporal organization come in The discovery of circadian clock genes in mice led two general varieties: those imposed by the lifestyle almost immediately to the search for homologous of the individual (e.g., jetlag and shiftwork) and those genes in humans. In addition to searching for human that arise from endogenous alterations in normal orthologs of the murine clock genes based on sequence rhythmicity (Turek et al., 1994; Czeisler et al., 1999). similarities, a number of laboratories attempted to Elucidating the genetic basis of human circadian link specific clock gene alleles with two of the major rhythmicity holds the promise for new therapeutic recognized altered circadian phenotypes in humans, approaches for both the “voluntary” and the “involundelayed sleep phase syndrome (DSPS) and advanced tary” disruption of normal circadian function. It will sleep phase syndrome (ASPS), either in large populaalso be of great interest, both from a scientific as well tions or in small families demonstrating genetic linkas a medical perspective, to determine whether the age with these syndromes. DSPS has been associated expression of human clock genes is altered under variwith a dominant mode of inheritance (Alvarez et al., ous pathophysiological conditions or in advanced age. 1992; Ancoli-Israel et al., 2001) and has been linked The effects of aging are of particular interest because to polymorphisms in circadian clock and related genes it has been associated with abnormal circadian timeincluding hPER3, arylalkylamine N-acetyltransferase, keeping (Turek et al., 2001). and hCLOCK (Takahashi et al., 2000; Iwase et al., The potential richness of the circadian genotype for 2002; Archer et al., 2003; Hohjoh et al., 2003). Simihuman health and disease takes on possible special siglarly, several families have also been identified in nificance in view of the relatively recent discovery that, which ASPS shows a clear autosomal dominant mode although the SCN circadian clock may be the master of inheritance (Jones et al., 1999; Reid et al., 2001; pacemaker, most, if not all, tissues/organs of the body Satoh et al., 2003), with a genetic polymorphism in may contain the molecular circadian clock machinery, hPER2 being identified in one ASPS family (Toh and that hundreds if not thousands of “clock-controlled et al., 2001). Katzenberg et al. (1998) found that subgenes” may be under circadian control (Panda et al., jects with a preference for “eveningness” based on 2002). This multioscillatory nature of the circadian the Horne–Ostberg test carried a specific allele of timing system may require very fine timing for normal hCLOCK, but subsequent studies did not find such physiological function and it is likely that different allelinkage (Iwase et al., 2002; Robilliard et al., 2002). lic forms of the circadian clock genes may have evolved The finding that different circadian phenotypes may for tissue/organ-specific, as well as whole organism, be linked to different circadian clock genes and/or be phase preference for internal synchronization of the due to different allelic forms of any given clock gene multitude of circadian rhythms, as well as for external may be the rule and not the exception. Indeed pre synchronization with the physical environment. Humans “molecular era” findings that DSPS may increase at in modern society rarely live in the temporal lifestyle northern latitudes (Lingjaerde et al., 1985), and that a in which their circadian clock genes/alleles evolved. human psychiatric disorder linked to human rhythms, Although there is for good reason a great interest in seasonal affective disorder (SAD), is also associated how human metabolic genes, that evolved over millions with latitude, raises the intriguing possibility that of years to survive a feast-and-famine way of life, are throughout human evolution there may have been subnow influencing feeding behavior and metabolism in a tle changes in human clock genes that enabled humans modern society of plenty, it may well be of similar to fine-tune their temporal relationship to the environimportance to understand how humans are attempting ment as they migrated into multiple environmental to navigate our 24/7 modern society with circadian habitats on earth. Indeed, our circadian clock genome genes adapted for another time.

MOLECULAR NEUROBIOLOGY OF CIRCADIAN RHYTHMS

CONCLUSIONS The core circadian oscillator is autonomous to individual neurons of the SCN and is the result of the daily oscillation in the levels of several clock component proteins. The basis for this oscillation in mammals, as in other organisms, lies in rhythmic feedback regulation of transcription of the genes encoding these proteins. The levels of the PER and CRY proteins alter the rate of transcription of their own genes. This alteration is achieved by inhibition of the enhancement of transcription that results from binding of the CLOCK–BMAL1 heterodimer to the E-box element of the promoter region of the Per and Cry genes. Additional interactions between circadian clock proteins may slow the time course of this feedback, achieving the near 24-hour interval: the phosphorylation of PER by CK1e may lead to its degradation, and the association with BMAL1 appears needed for CLOCK to be present in the nucleus. Rhythmic transcription of Bmal1 appears to result from regulation via REV-ERBa, itself regulated by E-box elements. Finally, it appears that rhythms in histone acetylation contribute to the circadian expression pattern of some core circadian genes. Additional genes have been identified based on altered circadian rhythms in mutants, although the roles of these genes in the circadian system remain to be determined. It is of interest that the majority of the core genes have been identified in mice or in flies by forward genetics, in which mutations were induced in the genome randomly and those mutations that specifically affect the circadian oscillator were identified with carefully crafted circadian phenotypic screens. Now that these clock component genes and proteins have been identified, it will be easier to find the proteins that serve the input and output pathways of the circadian oscillator, and to identify the components that are out of order in disease states that affect circadian rhythms. It is fortuitous that the unraveling of the molecular basis for circadian rhythmicity is occurring at a time when the biomedical research community, as well as the general public, is becoming aware of the importance of normal circadian timekeeping for human health, safety, performance, and productivity.

ACKNOWLEDGEMENTS Preparation of this manuscript was in part supported by NIH cooperative agreement U01 MH 61915, and grant numbers R01 AG 18200, P01 AG11412, R01 HL 59598, and R01 HL 69988-01A1. Figures and some text have been reproduced with permission of WB Saunders Publishing.

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MOLECULAR NEUROBIOLOGY OF CIRCADIAN RHYTHMS Robilliard DL, Archer SN, Arendt J et al. (2002). The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects. J Sleep Res 11: 305–312. Rosenwasser AM, Turek FW (2005). Physiology of the mammalian circadian system. Section 4 – Chronobiology: sleep and the circadian clock. In: MH Kryger, T Roth, W Dement (Eds.), Principles and Practices of Sleep Medicine. WB Saunders, New York, pp. 351–362. Saez L, Young MW (1996). Regulation of nuclear entry of the Drosophila clock proteins period and timeless. Neuron 17: 911–920. Sangoram AM, Saez L, Antoch MP et al. (1998). Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK– BMAL1-induced transcription. Neuron 21: 1101–1113. Satoh K, Mishima K, Inoue Y et al. (2003). Two pedigrees of familial advanced sleep phase syndrome in Japan. Sleep 26: 416–417. Schwartz W, Gross RA, Morton MT (1987). The suprachiasmatic nuclei contain a tetrodotoxin-resistant circadian pacemaker. Proc Natl Acad Sci U S A 84: 1694–1698. Sehgal A, Price JL, Man B et al. (1994). Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 263: 1603–1606. Sehgal A, Rothenfluh-Hilfiker A, Hunter-Ensor M et al. (1995). Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation. Science 270: 808–810. Shearman LP, Weaver DR (1999). Photic induction of Period gene expression is reduced in Clock mutant mice. Neuroreport 10: 613–618. Shearman LP, Zylka MJ, Weaver DR et al. (1997). Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron 19: 1261–1269. Shimomura K, Menaker M (1994). Light-induced phase shifts in tau mutant hamsters. J Biol Rhythms 9: 97–110. Silver R, LeSauter J, Tresco PA et al. (1996). A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382: 810–813. Stephan FK, Zucker I (1972). Circadian rhythm in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A 69: 1583–1586. Sun ZS, Albrecht U, Zhuchenko O et al. (1997). RIGUI, a putative mammalian ortholog of the Drosophila period gene. Cell 90: 1003–1011. Takahashi JS (1995). Molecular neurobiology and genetics of circadian rhythms in mammals. Annu Rev Neurosci 18: 531–553. Takahashi Y, Hohjoh H, Matsuura K (2000). Predisposing factors in delayed sleep phase syndrome. Psychiatry Clin Neurosci 54: 356–358. Tei H, Okamura H, Shigeyoshi Y et al. (1997). Circadian oscillation of a mammalian homologue of the Drosophila period gene. Nature 389: 512–516. Thresher RJ, Vitaterna MH, Miyamoto Y et al. (1998). Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282: 1490–1494.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 58

Circadian rhythm sleep disorders KATHRYN J. REID * AND PHYLLIS C. ZEE Department of Neurology, Northwestern University Medical School, Chicago, IL, USA

INTRODUCTION Circadian rhythm sleep disorders occur when there is a misalignment between the timing of sleep and the 24-hour social and physical environment. A diagnosis of a circadian rhythm sleep disorder can be made when this misalignment is persistent or recurrent, resulting in insomnia, excessive daytime sleepiness, and impaired daytime function. The clinical diagnosis of circadian rhythm sleep disorders is based on published clinical criteria from the second edition of the International Classification of Sleep Disorders (ICSD-2) (American Academy of Sleep Medicine, 2005) and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) (American Psychiatric Association, 2000). This chapter discusses circadian rhythm sleep disorders including their clinical presentation, diagnosis, prevalence, pathophysiology, and treatment.

CIRCADIAN RHYTHMS Circadian rhythms are self-sustaining rhythms that persist in the absence of external time cues. In humans, the intrinsic circadian period is close to, but not exactly, 24 hours (Czeisler et al., 1999). In order to adapt to the outside environment, circadian rhythms are strongly influenced by external time cues such as the light–dark cycle and physical and social activity (Aschoff et al., 1971; Czeisler et al., 1986; Honma et al., 1995; Buxton et al., 1997; Baehr et al., 2003). Circadian rhythms are generated by the suprachiasmatic nucleus (SCN), a paired structure located in the anterior hypothalamus (Moore and Eichler, 1972; Stephan and Zucker, 1972; Ralph et al., 1990; Moore, 1997). The SCN is the central pacemaker for the body. It is responsible for synchronizing many biological processes to the external environment, as well as

maintaining the temporal organization of these processes to one another. The basic molecular mechanism by which SCN neurons generate and maintain a selfsustaining rhythm is via an autoregulatory feedback loop. Within this loop, oscillating circadian gene products regulate their own expression through a complex system of transcription, translation, and post-translational processes (Reppert and Weaver, 2002). Most cells within the body express the molecular mechanisms responsible for circadian regulation. In fact, many organ tissues have been shown to express endogenous cycling for multiple days when removed from the host organism (Takata et al., 2002; Yoo et al., 2004). In this context, the SCN may be thought of as a central pacemaker responsible for coordination and regulation of clock machinery found throughout the body. The human sleep–wake cycle is regulated by a complex interaction between the endogenous circadian (process C) and homeostatic (process S) processes as well as environmental factors (Borbely, 1982; Borbely and Achermann, 2000). The circadian clock (process C) promotes wakefulness during the day and facilitates the consolidation of sleep during the night (Wever, 1979; Czeisler et al., 1980; Zulley et al., 1981; Edgar et al., 1993; Dijk and Czeisler, 1994). In humans, there is a biphasic circadian rhythm of alertness (Richardson et al., 1982). In most individuals there is a dip in alertness occurring at around 2–4 pm in the afternoon, followed by a robust increase in alertness lasting through the early to mid-evening hours, and then declining to lowest levels between 4 and 6 am in the morning. Maximum alertness occurs in the early evening hours when the drive for sleep is also highest (Carskadon and Dement, 1975, 1977; Strogatz et al., 1987; Dantz et al., 1994; Boulos et al., 1995). The homeostatic process (S) regulates the amount and depth of sleep. Process S accumulates as a function

*Correspondence to: Kathryn J. Reid, Ph.D., Department of Neurology, Northwestern University Medical School, 710 N. Lake Shore Drive, 11th Floor Abbott Hall, Chicago, IL 60611, USA. Tel: (312) 503 1528, E-mail: [email protected]

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of prior wakefulness, and currently sleep is the only known way to reduce this homeostatic drive after extended wakefulness (Borbely, 1980; Dijk et al., 1989, 1990). Alignment between the circadian drive for alertness and the homeostatic drive for sleep is required for optimal sleep and waking function.

DELAYED SLEEP PHASE TYPE (DELAYED SLEEP PHASE SYNDROME) Clinical presentation and diagnosis Delayed sleep phase type (DSPT) is characterized by a 3–6-hour delay in the major sleep period compared with desired or conventional sleep times. Bedtimes are typically between 1 and 6 am, with wake times in the late morning or early afternoon (Weitzman et al., 1981; American Academy of Sleep Medicine, 2005). Patients with DSPT typically present with complaints of chronic sleep-onset insomnia and difficulty waking in the morning. Patients also report feeling most alert in the evening and most sleepy in the morning, and may report excessive daytime sleepiness, particularly in the morning. Diagnosis is based on a detailed clinical history (Table 58.1); however, a sleep log or wrist activity monitoring for 7–14 days should also be used to determine the timing and stability of the habitual sleep period (Figure 58.1A). A detailed history of work and psychosocial responsibilities is also useful to determine the impact of these factors on the timing and opportunity for sleep. Patients may have difficulty maintaining early morning work or school times, and, due to the delayed bedtime, may experience chronic sleep deprivation. Patients with DSPT also typically have a delay in other circadian rhythms such as core body temperature and dim-light melatonin onset (DLMO) (Shibui et al., 1999; Watanabe et al., 2003). These measures Table 58.1 Diagnostic criteria: delayed sleep phase type I.

II. III.

IV.

The major sleep period is delayed in relation to the desired sleep and wake times, and is associated with a complaint of difficulty falling asleep or waking at the desired time. When sleep is at the preferred time it is normal for age, but with a stable delay. Sleep log or activity monitoring (with a sleep log) for at least 7 days demonstrates a stable delay in the timing of the sleep period. The sleep disturbance should not be better explained by another current sleep, medical, neurological, mental, substance or medication use disorder.

of circadian phase can be useful to confirm a delayed phase. Patients with DSPT will typically report being evening types, also referred to as “owls” on circadian preference questionnaires (Chang et al., 2003). However, these questionnaires are not the same as a clinical diagnosis of a circadian rhythm sleep disorder but rather a self-rating of preference for sleeping or conducting activities at a particular time of day (Horne and Ostberg, 1976; Zavada et al., 2005). They can be a useful tool in identifying a circadian rhythm sleep disorder as patients tend to have extreme preference as determined by the questionnaires. Scores on these questionnaires have also been associated with physiological differences in circadian phase, genetics, and sleep homeostasis (Duffy et al., 1999; Archer et al., 2003; Mongrain et al., 2004, 2006a, b).

Prevalence DSPT is the most common circadian rhythm sleep disorder with an estimated prevalence in the general population of 0.13–0.17% (Schrader et al., 1993). This disorder appears to be more common among adolescents, with a prevalence of 7–16% (Pelayo et al., 1988; Regestein and Monk, 1995; Mercer et al., 1998; Garcia et al., 2001) and is believed to make up 5–10% of chronic insomnia cases reported in sleep clinics (Weitzman et al., 1981).

Pathophysiology There have been several mechanisms proposed to account for the chronic delay in sleep observed in patients with DSPT. These mechanisms include either an alteration to the internal circadian system and/or behavioral factors that precipitate and perpetuate the delay. Several physiological mechanisms have been proposed to explain DSPT, including an unusually long endogenous circadian period, altered sensitivity to photic input, genetic alterations, an altered internal phase relationship between sleep and other circadian rhythms, and alterations to the homeostatic sleep process. A longer circadian period has been described for adolescence and those reporting an eveningness preference on circadian preference questionnaires (Duffy et al., 2001). A long endogenous circadian period may have an altered phase angle of entrainment, delaying sleep in relation to the external light–dark cycle. There is evidence that the internal phase angle between sleep and other circadian rhythms is altered in DSPT. Patients with DSPT have been shown to have a greater interval between core body temperature nadir and sleep offset (Uchiyama et al., 2000a; Watanabe et al., 2003). An altered response to photic

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C Fig. 58.1. Representative rest–activity cycles in patients with circadian rhythm sleep disorders recorded with wrist activity monitoring. Actograms are double plotted in clock hours. (A) Delayed sleep phase type has a sleep time of approximately 4–6 am and a wake time of between 10 am and 2 pm. (B) Advanced sleep phase type has a sleep time of approximately 8–10 pm and a wake time of about 5 am. (C) Free-running type has a rest–activity cycle that is progressively delayed each day.

input during the night has also been reported in DSPT; specifically, patients with DSPT have a hypersensitivity in the suppression of melatonin due to light exposure during the night (Aoki et al., 2001). It has also been suggested that DSPT may result from an unusually “small” advance portion of the light phase– response curve (PRC) (Weitzman et al., 1979; Czeisler et al., 1981b). Although DSPT is believed to be a disorder of the circadian system, there is evidence that the homeostatic process may be altered in these individuals. Studies have shown that there are alterations in slow-wave

activity (Watanabe et al., 2003) and in sleep propensity in response to sleep deprivation (Uchiyama et al., 1999, 2000b). It has been suggested that poor sleep recovery perpetuates the inability of patients with DSPT to reset their sleep phase (Uchiyama et al., 2000b). Therefore, it is likely that both alterations in circadian timing and impaired sleep recovery contribute to symptoms of insomnia and excessive sleepiness in DSPT. Alterations in the molecular circadian clock system have been reported in DSPT. Polymorphisms in several circadian clock genes have been identified, including: CKIepsilon, hPer3, arylalkylamine N-acetyltransferase,

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HLA and Clock (Takahashi et al., 2000; Ebisawa et al., 2001; Iwase et al., 2002; Archer et al., 2003; Hohjoh et al., 2003; Takano et al., 2004; Pereira et al., 2005). Exactly how these alterations in gene function lead to DSPT has not been fully demonstrated. In addition there has been no reported genetic characterization of the one reported familial case of DSPT (Ancoli-Israel et al., 2001). Behavioral factors likely also play a role in precipitating and perpetuating DPST (Takahashi et al., 2000). As a result of later wake times, patients with DSPT have less light exposure during the phase-advancing portion of the light PRC (Ozaki et al., 1996). In addition, due to the later bedtimes, patients with DSPT have more light exposure in the phase-delay portion of the light PRC.

Treatment Treatment for DSPT has been aimed at realigning the sleep–wake cycle with the external environment to achieve the desired sleep time. Three main strategies have been used to treat DSPT, including: (1) behavioral manipulations of the sleep–wake cycle, (2) bright light exposure, and (3) melatonin administration. The earliest reported behavioral manipulation of the sleep–wake cycle for treatment of sleep disorders advanced wake times by 5 minutes every 2 days (Regestein, 1976). Other studies advanced wake times by different amounts on a daily or weekly schedule, including a 1.5-hour advance following a night of sleep deprivation once a week (deBeck, 1990). These attempts to reset the sleep phase of patients with DSPT, by advancing sleep time, have been largely unsuccessful. Chronotherapy is a behavioral treatment in which the sleep time is progressively delayed by 3 hours until a final earlier bedtime schedule is achieved and maintained. This approach has been shown to be effective, although difficult to achieve (Czeisler et al., 1981a). Bright light can be used to phase-shift the circadian clock (Lewy, 1983; Lewy et al., 1984; Czeisler et al., 1986, 1989) and is the most commonly used treatment for DSPT. The impact of bright light exposure on the phase of circadian rhythms can be predicted by the human PRC. Practice parameters for the use of bright light in the treatment of sleep disorders have been published by the American Academy of Sleep Medicine (Chesson et al., 1999). Bright light in the early morning hours will result in a phase advance of circadian rhythms. Exposure to 2 hours of morning bright light (2500 lux) for 2 weeks in conjunction with evening light avoidance resulted in an advance of the core body temperature rhythm, earlier sleep times, and greater morning alertness (James et al., 1990; Rosenthal et al., 1990).

While bright light therapy can be successful, patients with severe DSPT may find it exceedingly difficult to rise early enough to administer light in the phaseadvance portion of the light PRC (Regestein and Monk, 1995). If patients wait until they wake to administer the light treatment, phase shifts will be reduced. Exogenous melatonin administration can also be used to phase-shift the circadian clock (Lewy et al., 1992) and has been a relatively effective treatment for DSPT (Oldani et al., 1994; Nagtegaal et al., 1998; Mundey et al., 2005). Due to the limited number of clinical studies using a variety of doses and times of administration, there is currently no standard approach for the treatment of DSPT with melatonin. However, evidence suggests that melatonin administered relative to the DLMO is most effective (Mundey et al., 2005). A combination therapy using morning bright light and early evening melatonin may be more efficacious in creating a phase advance than either alone, although clinical data are lacking. Other pharmacological and combination therapies have met with some degree of success. Vitamin B12 is thought to enhance the light sensitivity of the circadian clock, and has been used to phase-advance circadian rhythms in DSPT and free-running type (Kamgar-Parsi et al., 1983; Okawa et al., 1990; Ohta et al., 1992). However, a large study of 50 patients with DSPT using vitamin B12 in a double-blind placebo-controlled design showed no significant changes in sleep, and daytime mood or drowsiness (Okawa et al., 1997). Use of a combination approach including chronotherapy, bright light, triazolam and vitamin B12 (Ohta et al., 1992; Okawa et al., 1998) has also shown some success. Several factors should be taken into consideration when treating patients with DSPT; these include the severity of the disorder, school schedule, work obligations and social pressures, comorbid psychopathologies, and, most importantly, the patient’s ability and willingness to comply with the treatment plan (Thorpy et al., 1988; Ohta et al., 1992; Regestein and Pavlova, 1995). With these factors in mind, an individualized treatment plan should be developed to increase the chance of success.

ADVANCED SLEEP PHASE TYPE (ADVANCED SLEEP PHASE SYNDROME) Clinical presentation and diagnosis Advanced sleep phase type (ASPT) is characterized by a stable 3–6-hour advance of the major sleep–wake period compared with desired or conventional sleep times. Habitual or involuntary bedtime is typically between 6 and 9 pm, and wake time between 2 and 5 am.

CIRCADIAN RHYTHM SLEEP DISORDERS Patients report sleepiness in the late afternoon or early evening but often stay awake longer than desired in order to participate in family or social activities. They also report early-morning awakening insomnia or sleep maintenance insomnia; if bedtime is delayed and wake time is earlier than desired, sleep duration is reduced and patients may be chronically sleep deprived. When sleep is at the desired time, it is typically normal for age (American Psychiatric Association, 2000; American Academy of Sleep Medicine, 2005). Diagnosis of ASPT is based on history according to the clinical criteria outlined in the ICSD-2 (American Academy of Sleep Medicine, 2005) (Table 58.2). Patients report sleep onset and wake times earlier than desired with complaints of evening sleepiness and early morning awakening. Sleep diary and activity monitoring for at least 7 days demonstrates a stable advance of the sleep period (see Figure 58.1B). The use of other circadian markers such as core body temperature and dim-light melatonin onset can also be useful for confirmation of an advanced circadian phase (Reid et al., 2001; Reid and Zee, 2005). Patients with ASPT typically report being morning types or “larks” on circadian preference questionnaires such as the Horne and Ostberg morning–eveningness questionnaire (Reid et al., 2001; Satoh et al., 2003).

Prevalence The prevalence of ASPT is estimated to be quite low in the general population (Schrader et al., 1993; Ando et al., 1995) and tends to increase with age. The reduction in the reported numbers of ASPT may be due to several reasons; the most likely is that advanced sleep phase, unless extreme, does not hinder daily functioning to the same degree as a delayed sleep phase as it conforms more to societal schedules and norms.

Table 58.2 Diagnostic criteria: advanced sleep phase type I.

II. III.

IV.

The major sleep period is advanced in relation to desired sleep and wake times, and is associated with a complaint of an inability to stay awake or remain asleep until the desired time. When sleep is at the preferred time it is normal for age, but with a stable advance. Sleep log or activity monitoring (with a sleep log) for at least 7 days demonstrates a stable advance in the timing of the sleep period. The sleep disturbance should not be better explained by another current sleep, medical, neurological, mental, substance or medication use disorder.

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Pathophysiology Several mechanisms have been proposed to account for the chronic advance in sleep observed in patients with ASPT, although the exact cause is yet unknown. A genetic and familial component to ASPT has been reported by several researchers (Reid et al., 2001; Toh et al., 2001; Satoh et al., 2003) and in familial cases appears to be transmitted via an autosomal dominant mode of inheritance (Reid et al., 2001; Toh et al., 2001; Satoh et al., 2003). Polymorphisms in molecular clock genes such as hPer2 and CKIdelta have been linked to familial cases of ASPT (Toh et al., 2001; Xu et al., 2005). This type of polymorphism has subsequently been shown to result in alterations in phosphorylation of proteins within the molecular clock system (Toh et al., 2001; Xu et al., 2005). Potential physiological or behavioral causes of ASPT could be a shorter circadian period (Jones et al., 1999), or early morning light exposure in the phase-advance portion of the human PRC to light, due to early morning wakening, which may exacerbate or result in a chronically advanced phase.

Treatment Treatment for ASPT is aimed at realigning the sleep– wake cycle with the external environment to achieve the desired sleep time. Bright light exposure in the evening phase delays the human circadian system and has been the most commonly used treatment for ASPT. Several studies have shown improvements in sleep, including sleep efficiency and self-reported sleep duration, and a delay in core body temperature following evening bright light exposure over several consecutive nights (Campbell et al., 1993; Lack and Wright, 1993). However, as light treatment must be continued on a chronic basis to maintain the phase delay, compliance with light therapy can be difficult in practice (Campbell et al., 1993; Lack and Wright, 1993). Melatonin taken in the morning should result in small phase delays and could be useful in the treatment of ASPT; however, its effectiveness in ASPT has not been demonstrated. It should also be noted that, due to its hypnotic effects, melatonin may result in residual daytime sleepiness when taken in the morning. Behavioral approaches such as chronotherapy have been used with some success. In this approach, the desired sleep time is achieved by advancing the sleep time by 3 hours every day; however, patients often revert back to the original advanced sleep phase. This type of treatment may not be an option as it requires some degree of flexibility in the patient’s daily schedule to achieve the late sleep time and can be difficult to maintain (Moldofsky et al., 1986).

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FREE-RUNNING TYPE (NONENTRAINED TYPE) Clinical presentation and diagnosis Individuals with free-running type typically have a variable sleep period, with sleep onset and wake times successively delayed by 1–2 hours each day. This pattern is analogous to that seen during free running when all external time cues (Zeitgebers) are absent. Sleep duration and waking function may be normal when individuals allow their sleep–wake to free-run in time with their circadian pacemaker (Shibui et al., 1998). However, for many people social and work obligations make sleeping on this schedule difficult, so that when an individual forces sleep into the wrong circadian phase a variety of sleep complaints may be present depending on where the sleep is in relation to the circadian rhythm of sleep propensity (Shibui et al., 1998). Complaints may include difficulty falling or staying asleep, and/or excessive sleepiness that can be associated with impairment of social, occupational, or other areas of daily functioning. Diagnosis of free-running type is based on a detailed clinical history, and the altered sleep pattern as described above should be present for at least 2 months (Table 58.3). Other medical, mental, or sleep disorders that may better explain the disturbed sleep pattern should be ruled out (American Psychiatric Association, 2000; American Academy of Sleep Medicine, 2005). Depressive symptoms, personality and mood disorders are often comorbid conditions and should be considered in the evaluation. A sleep–wake diary or actigraphy monitoring for several weeks should be used in diagnosis of this disorder (see Figure 58.1C). Sleep diaries and activity monitoring may demonstrate a progressive shift in the timing of sleep and wake times, and the lack of stable entrainment of the sleep–wake cycle to the 24-hour physical environment. One study of sleep and rhythms in 59 blind individuals found that the best indicator of a circadian rhythm disorder was daytime napping (Lockley et al., 1999). Careful examination of Table 58.3 Diagnostic criteria: free-running type I.

II.

III.

A complaint of insomnia or excessive sleepiness related to desynchronization between the 24-hour light–dark cycle and the endogenous circadian rhythm of sleep–wake. Sleep log or activity monitoring (with a sleep log) for at least 7 days that typically demonstrates a delay in the sleep–wake period of about 1 hour each day. The sleep disturbance should not be better explained by another current sleep, medical, neurological, mental, substance or medication use disorder.

the sleep–wake cycle may also reveal two distinct sleep–wake cycle periods, which can be separated by phase jumps (Wollman and Lavie, 1986; Uchiyama et al., 1996; Hayakawa et al., 2005). In addition, serial measurements of circadian marker rhythms such as DLMO or nadir of the core body temperature rhythm may be used to confirm the diagnosis as they may also demonstrate a free-running circadian rhythm (Klein et al., 1993). It is important to distinguish between individuals with free-running type and those with DSPT. Some individuals with DSPT may exhibit a successive delay of their sleep–wake period for several days that may be confused with free-running circadian rhythm disorder (Regestein and Monk, 1995). In a recent report of 57 individuals with free-running type, 26% of those studied were reported to have been previously misdiagnosed with DSPT (Hayakawa et al., 2005). Furthermore, the use of chronotherapy for individuals with DSPT has been reported to induce free-running type in some instances (Oren and Wehr, 1992; McArthur et al., 1996).

Prevalence Free-running type is reported primarily in totally blind individuals (Sack et al., 1992). Reports indicate that approximately 50% of blind people in the USA have free-running circadian rhythms (Sack et al., 1992) and that about 70% report complaints of chronic sleep disruption (Mills et al., 1978; Martens et al., 1990). Although free-running type is most common in the blind, there have recently been a number of reported cases in sighted individuals (Weber et al., 1980; McArthur et al., 1996; Boivin et al., 2003; Hayakawa et al., 2005).

Pathophysiology In blind individuals, free-running type is most likely due to either the absence or reduced entraining effects of light. In some cases, totally blind individuals with no conscious light perception exhibit normal light-induced suppression of melatonin and do not report difficulties with sleep (Czeisler et al., 1995). In some individuals the melatonin rhythm may be altered (McArthur et al., 1996; Nakamura et al., 1997; Palm et al., 1997). Other nonphotic synchronizing agents such as social activity are often insufficient to entrain some individuals, particularly those with coexistent learning difficulties (Palm et al., 1991). Less is known of the cause in sighted individuals. Several theories have been suggested, including a reduced sensitivity to light, a longer than normal circadian period (Uchiyama et al., 2002), and an increased incidence of psychiatric disorders such as depression

CIRCADIAN RHYTHM SLEEP DISORDERS or personality disorder that may alter or remove social cues (McArthur et al., 1996). A recent report of a large number of sighted individuals with free-running type showed that the incidence of psychiatric complaints was 28% (Hayakawa et al., 2005). Although in a case report a misdiagnosis of psychiatric disorders was made in an individual with free-running type, upon treatment with melatonin the psychiatric diagnosis was no longer present (Dagan and Ayalon, 2005). Similar to reports in blind individuals, there is a case report of a child with learning impairment and low melatonin levels who responded well to melatonin treatment (Akaboshi et al., 2000). There are also reports of an internal desychronization between sleep and melatonin in five patients with this disorder (Uchiyama et al., 2002). Free-running type may also be due to genetic alterations, and has been linked to an alteration in the CKIepsilon (CKIe) gene, similar to that seen in DSPT (Takano et al., 2004).

Treatment In both blind and sighted individuals, melatonin is most often used to treat free-running type (Palm et al., 1991; Sack et al., 1991; Tzischinsky et al., 1992; Lapierre and Dumont, 1995; McArthur et al., 1996; Palm et al., 1997). Melatonin treatment begins when the individual’s free-running sleep period is at a conventional or desired time. Various doses of melatonin have been used, but several studies have shown that 0.5 mg is enough to entrain rhythms (Hack et al., 2003) and to maintain entrainment of the sleep–wake cycle in most blind individuals (Sack et al., 2000; Lewy et al., 2001). Melatonin is typically administered near the time of the expected DLMO (approximately 9 pm) when sleep is at a conventional phase (i.e., 11 pm) (Tzischinsky et al., 1992; McArthur et al., 1996; Mukai et al., 2000). Bright light may be a treatment option for sighted individuals (Hoban et al., 1989) or for blind people with circadian light perception (Skene et al., 1999). Combination treatments using vitamin B12 and benzodiazepines have also shown some success (Kamgar-Parsi et al., 1983; Okawa et al., 1990; Yamadera et al., 1996b).

IRREGULAR SLEEP^WAKE TYPE Clinical presentation and diagnosis Irregular sleep–wake type is characterized by a lack of a clear circadian rhythm of sleep–wake (Table 58.4). Typically, there are several sleep episodes (at least three) of varying length throughout the day, and napping may be prevalent. Total sleep time may be normal for age. Complaints of insomnia and excessive sleepiness are present, depending on the time of day. Sleep

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Table 58.4 Diagnostic criteria: irregular sleep–wake type I. II.

III. IV.

A chronic complaint of insomnia and/or excessive sleepiness. Sleep log or activity monitoring (with a sleep log) for at least 7 days demonstrates several sleep episodes (minimum of three) in a 24-hour period. The total amount of sleep per 24-hour period is normal for age. The sleep disturbance should not be better explained by another current sleep, medical, neurological, mental, substance or medication use disorder.

diary and actigraphy monitoring for at least 7 days show a clear lack of circadian organization of the sleep–wake cycle with multiple irregular sleep bouts during a 24-hour period (American Psychiatric Association, 2000; American Academy of Sleep Medicine, 2005). When making a diagnosis it is important to consider poor sleep hygiene and a voluntary irregular sleep schedule, usually seen in shiftwork and travel across time zones (jetlag).

Prevalence The prevalence of irregular sleep–wake type is not known, but the condition is thought to be rare in the general population (Yamadera et al., 1996a). However, it has been shown to be associated with neurological disorders such as dementia, in children with learning impairment, and following brain injury (Witting et al., 1990; Hoogendijk et al., 1996; Pillar et al., 2000).

Pathophysiology Irregular sleep–wake type is believed to be the result of disrupted circadian regulation and/or reduced exposure to environmental signals. This disorder has been seen in association with neurological disorders such as dementia and in children with learning impairment (Witting et al., 1990; Hoogendijk et al., 1996). Institutionalized elderly often have a reduction in exposure to external synchronizing agents such a light and activity, and this may be a predisposing or precipitating factor in the development of circadian rhythm sleep disorders (van Someren et al., 1996; Pollak and Stokes, 1997).

Treatment The primary aim of treatment for irregular sleep–wake type is to consolidate the sleep–wake cycle. The most effective treatments to date involve increasing exposure to synchronizing agents such as bright light (Van Someren et al., 1999; Ancoli-Israel et al., 2002;

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Ancoli-Israel et al., 2003) and structured social activities (Okawa et al., 1991). Administration of 3 mg melatonin in the evening to children with learning impairment has been successful in increasing the nighttime sleep period (Pillar et al., 2000). Combination therapy with bright light, chronotherapy, vitamin B12, and hypnotics was reported to be successful in almost half of the patients studied (Yamadera et al., 1996b). Treatment of this disorder can be difficult due to the prevalence of the disorder in patient populations with dementia and retardation.

SHIFTWORK TYPE (SHIFTWORK DISORDER)

Prevalence It is estimated that up to 20% of the workforce in industrialized countries is employed in some form of shiftwork (Presser, 1999). Sleep disturbance and circadian misalignment are normal responses to shiftwork (Knauth et al., 1980; Knauth and Rutenfranz, 1981; Akerstedt, 1995). However, not all shiftworkers have the circadian rhythm sleep disorder, shiftwork type (Akerstedt and Torsvall, 1981). The prevalence of shiftwork type is estimated to be approximately 1% in the general population and up to 10% in night and rotating shiftworkers, according to a study conducted in the USA (Drake et al., 2004).

Clinical presentation and diagnosis

Pathophysiology

The circadian rhythm sleep disorder, shiftwork type, is characterized by complaints of insomnia and excessive sleepiness that are temporarily associated with a work schedule that occurs during the usual sleep period (Table 58.5). These symptoms should be associated with the shiftwork schedule over a period of at least 1 month. Sleep log or activity monitoring for a minimum of 7 days should demonstrate a disturbed circadian and sleep time misalignment (American Academy of Sleep Medicine, 2005). The sleep log and activity monitoring can also be useful in determining the degree of sleep curtailment. A work history or log is also useful to determine the relationship between the sleep and work schedule. In combination, the history, sleep and work logs can be useful in differentiating between the influences of the work schedule and other psychosocial factors on sleep time. The sleep disturbance and excessive sleepiness should not be better explained by another sleep disorder such as sleep apnea, medical, neurological or mental disorder, or medication use or substance abuse (American Academy of Sleep Medicine, 2005).

The circadian rhythm sleep disorder, shiftwork type results when the major sleep episode occurs during the normal wake period. As a result of sleeping in opposition to the circadian alerting process, sleep is usually curtailed by 1–4 hours daily (Knauth et al., 1980; Knauth and Rutenfranz, 1981; Akerstedt, 1995). The subsequent sleep loss and wakefulness during a period of low circadian alertness leads to excessive sleepiness during work. There are variations in the ability to cope with shiftwork (Akerstedt and Torsvall, 1981) and not all shiftworkers have the circadian rhythm sleep disorder, shiftwork type. Several factors that may influence the ability to cope with shiftwork have been identified, including age (Harma et al., 1994), domestic responsibilities (Folkard et al., 1978), commute times, diurnal preference, and other sleep disorders. A myriad of shiftwork schedules are used in today’s 24/7 society, but work at night and work starting in the early morning (before 6 am) are the most common cause of sleep complaints (Akerstedt, 1995). Patients may complain of problems initiating sleep as they are attempting to sleep at a time of low circadian sleep propensity. Symptoms of shiftwork type may persist for several days after the last nightshift or on days off, even when sleep is at conventional times. This continued difficulty is due to a partial adjustment of the circadian system to the altered schedule over a series of consecutive work periods. The adaptation of the circadian system to the work schedule will depend on the number of consecutive nightshifts and the speed and direction of shift rotation.

Table 58.5 Diagnostic criteria: shiftwork type I.

II. III.

IV.

A complaint of insomnia or excessive daytime sleepiness associated with a recurring work schedule that occurs during the usual sleep time. The symptoms are associated with the work schedule over the course of at least 1 month. Sleep log or activity monitoring (with a sleep log) for at least 7 days demonstrates a misalignment between the endogenous circadian rhythm and the sleep–wake cycle. The sleep disturbance should not be better explained by another current sleep, medical, neurological, mental, substance or medication use disorder.

Treatment Treatment for the circadian rhythm sleep disorder, shiftwork type is aimed at reducing the key symptoms of insomnia and excessive sleepiness, either by

CIRCADIAN RHYTHM SLEEP DISORDERS realigning the internal circadian clock with the altered sleep schedule or by directly treating the symptoms with hypnotics or stimulants. Treatment plans to shift the internal circadian clock should include good sleep hygiene, bright light exposure during the work period, and avoiding light on the way home from work in the morning by wearing dark sunglasses and/or appropriately timed melatonin administration. Treatments to combat directly the complaints of excessive sleepiness include naps (Bonnefond et al., 2001) and stimulants such as caffeine (Walsh et al., 1995) and modafinil (Walsh et al., 2004), which was approved in 2004 by the US Food and Drug Administration (FDA) for treatment of shiftwork type. Insomnia complaints can be treated by short-term use of sleeping medications (Walsh et al., 1995). Both continuous (Dawson and Campbell, 1991; for a review see Burgess et al., 2002) and intermittent (Baehr et al., 1999; Boivin and James, 2002; Crowley et al., 2003) bright light exposure have been used successfully to increase phase adjustment in shiftworkers (Eastman et al., 1995). In addition to phase-shifting effects, bright light has acute alerting effects that have been shown to improve cognitive performance (for a review see Campbell et al., 1995). Bright light administered prior to the temperature minimum will phase-delay circadian rhythms. Bright light exposure can be administered either at the beginning of the shift for 3–6 hours during the nightshift or intermittently in 20-minute blocks each hour (Boivin and James, 2002; Crowley et al., 2003). It is useful to move the light exposure progressively later each night as the circadian system delays, to ensure that light is administered in the phase-delay portion of the phase–response curve to light. It is also important to avoid light exposure on the way home from work in the phase-advance portion of the phase response to light by wearing dark sunglasses. Several studies have reported adaptation to nightwork with early morning light avoidance alone (Eastman et al., 1994; Boivin and James, 2002; Crowley et al., 2003). Recent studies have shown that melatonin administered at bedtime does not provide a significant increase in the phase delay beyond what is produced by light avoidance in the morning, bright light during the nightshift and/or sleep in a dark room (Crowley et al., 2003). However, reports indicate improvements in daytime sleep durations (Dawson et al., 1995; Sharkey et al., 2001) and limited increases in nocturnal alertness following melatonin administration prior to daytime sleep periods (for a review see Burgess et al., 2002). Treatment of shiftwork type by realigning the internal circadian clock may be useful only for shift schedules with multiple nightshifts. Schedules that are fast rotating or highly variable do not provide enough

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opportunity for the relatively slow-moving circadian clock to adapt. Therefore, other treatments such as hypnotics, napping, and stimulants (Akerstedt and Ficca, 1997) may be used to reduce complaints of insomnia and excessive sleepiness. The effectiveness of any treatment is influenced by a variety of factors including sleeping environment (quiet and dark), social or familial demands, and patient motivation. Due to the variety of shift schedules and individual differences in response to shiftwork, effective treatment may involve a period of trial and error, and consultation with the physician.

JETLAG TYPE (JETLAG DISORDER) Clinical presentation and diagnosis The circadian rhythm sleep disorder, jetlag type is a transitory disorder resulting from a temporary misalignment between the circadian clock and the external environment, due to rapid travel across at least two time zones. Symptoms range from difficulty sleeping, excessive daytime sleepiness, general malaise, impaired daytime function, and gastrointestinal upset (Boulos et al., 1995). The sleep disturbance should not be better explained by another current sleep, medical, neurological, or mental disorder, or from medication use or substance abuse (Table 58.6). If symptoms persist for longer than 2 weeks, this may indicate the development of psychophysiological insomnia (American Academy of Sleep Medicine, 2005).

Prevalence and pathophysiology Jetlag can affect all age groups; however, not all travelers crossing time zones suffer from jetlag. There are several factors that may influence the severity and duration of jetlag symptoms, including the direction of travel (east or west), number of time zones crossed, and individual differences such as age. Eastward travel generally results in difficulty falling asleep, and westward travel in difficulties maintaining sleep (Boulos et al., 1995). Table 58.6 Diagnostic criteria: jetlag type I.

II.

III.

A complaint of insomnia or excessive daytime sleepiness associated with jet travel across at least two time zones. Associated impairment in daytime function, general malaise, or somatic symptoms such as gastrointestinal disturbance occurring within 1–2 days after travel. The sleep disturbance should not be better explained by another current sleep, medical, neurological, mental, substance or medication use disorder.

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The symptoms of jetlag result from the combination of the misalignment between the internal circadian system and local clock time and the resulting sleep loss (American Academy of Sleep Medicine, 2005). Several factors can predispose or precipitate symptoms of jetlag, including stress, sleep deprivation, and excessive caffeine or alcohol use. Older individuals also tend to be at a greater risk of developing jetlag symptoms due to a reduced tolerance to the circadian misalignment associated with jet travel (Moline et al., 1992).

Treatment Treatment for jetlag is most successful when the aim is to speed up the realignment of circadian rhythms with the new time zone. To reduce the impact of jetlag it is important to get enough sleep, avoid excessive use of caffeine and alcohol, and to get light exposure or avoid light exposure at the appropriate times (Daan et al., 1984; Waterhouse et al., 1997). Light exposure, either natural or artificial, is an effective way to re-entrain to the destination time. When traveling east, the circadian clock typically needs to be phase-advanced and thus individuals should avoid morning light at the new destination (by staying indoors or wearing dark sunglasses) and should try and get as much light as possible in the afternoon. When traveling west, the circadian clock typically needs to phase-delay, so individuals should try to avoid light in the early morning and get as much light as possible in the early evening. It is possible to reduce the duration of jetlag symptoms upon arrival at the new destination by shifting the circadian clock using light prior to travel. For more details of how to achieve this, sample anti-jetlag plans and instructions for developing individual anti-jetlag plans are available on online at the Physicians’ Information and Education Resource website: http://pier.acponline.org. Exogenous melatonin can also be used to shift circadian rhythms, and has been shown to reduce subjective symptoms of jetlag in several studies (Herxheimer and Petrie, 2003; Herxheimer and Waterhouse, 2003). In order to achieve a phase advance, melatonin should be taken approximately 5–7 hours prior to normal bedtime (home time). However, it has been reported that melatonin taken at bedtime at the new destination is effective in reducing symptoms of jetlag (Herxheimer and Petrie, 2003). Jetlag symptoms include daytime sleepiness and difficulty sleeping, and thus stimulants such as caffeine and hypnotic medications can be useful in alleviating symptoms. Slow-release caffeine improved daytime alertness and melatonin improved sleep following an eastward flight (Beaumont et al., 2004). The hypnotic

zolpidem, given for three consecutive nights starting with the first night sleep at the new destination, has been shown to improve sleep in some travelers (Jamieson et al., 2001).

CIRCADIAN RHYTHM SLEEP DISORDER DUE TO MEDICAL CONDITION A number of medical and neurological disorders have been associated with circadian rhythm disturbances, including dementia, movement disorders, blindness, and hepatic encephalopathy (Cordoba et al., 1998; American Academy of Sleep Medicine, 2005). The symptoms depend on the underlying neurological or medical disorder, but can range from alterations in sleep phase to irregular sleep–wake patterns. These alterations in the circadian rhythm of sleep can lead to complaints of excessive daytime sleepiness and difficulty initiating or maintaining sleep (Table 58.7). The demographics are specific to the underlying medical or neurological disorder. Diagnosis of this disorder can be difficult, because a clear causal relationship cannot be established. Instead, circadian rhythm disturbances are often comorbid with the medical or neurological disorder. Furthermore, environmental and behavioral factors can also magnify the circadian disturbance. For example, in patients with Alzheimer’s disease, irregular sleep–wake rhythm or alterations in circadian phase have been proposed to be secondary to neuronal loss within the SCN (Swaab et al., 1985; Harper et al., 2004). However, there is also evidence that diminished exposure to circadian synchronizing agents such as light and activity also plays an important role in the development of circadian rhythm sleep disorders (Ancoli-Israel et al., 1997; Alessi and Schnelle, 2000). Table 58.7 Diagnostic criteria: circadian rhythm sleep disorder due to medical condition I.

II. III.

IV.

A complaint of insomnia or excessive daytime sleepiness related to changes of the circadian system or a desynchronization between the endogenous circadian system and exogenous factors that influence the timing and duration of sleep. An underlying medical or neurological disorder is the predominant cause of the circadian rhythm disorder. Sleep log or activity monitoring (with a sleep log) for at least 7 days demonstrates disturbed or low amplitude of the circadian rhythm of sleep–wake. The sleep disturbance should not be better explained by another current sleep, mental, substance or medication use disorder.

CIRCADIAN RHYTHM SLEEP DISORDERS

SUMMARY Circadian rhythm sleep disorders are characterized by a persistent or recurrent pattern of sleep disturbance due to alterations of the circadian system or a misalignment between the internal circadian timing system and the external environment. The timing of sleep has an abnormal temporal distribution within the day. As a result of this sleep disturbance, patients complain of insomnia and excessive daytime sleepiness, which results in an associated disruption of social and/or occupational functioning. Diagnosis and management of these disorders is aided by detailed characterization of circadian rhythms including sleep logs, wrist activity monitoring, and DLMO. Although an alteration in the circadian timing system is believed to underlie many of the circadian rhythm sleep disorders, behavioral and social factors can play an important role in perpetuating and exacerbating these disorders. Treatment strategies are limited for circadian rhythm sleep disorders, but include interventions such as sleep hygiene, maintaining stable sleep–wake times, exposure to either natural or artificial light at the correct time of day and avoidance of light at the wrong time of day, and appropriately timed melatonin administration. It should be noted that the use of melatonin has not been approved by the FDA, and adverse vascular and endocrine effects need to be taken into account. With our increasing knowledge of the circadian and sleep systems it will be an important challenge to apply this information to clinical practice in the treatment of sleep disorders and emerging areas such as chronopharmacology.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 59

Fatal familial insomnia and the role of the thalamus in sleep regulation PASQUALE MONTAGNA * Department of Neurological Sciences, University of Bologna Medical School, Bologna, Italy

THE PRION DISEASES Human prion diseases, also defined as transmissible spongiform encephalopathies, are rare fatal neurodegenerative diseases that include several clinical forms known as “kuru”, Creutzfeldt–Jakob disease (CJD), Gerstmann–Straussler–Sheinker syndrome (GSS), the so-called “new variant” CJD, and familial and sporadic fatal insomnia (FFI and SFI). Prion diseases may also occur in animals, such as in sheep (“scrapie”), deer (deer wasting disease), mink (mink encephalopathy), and bovines (the so-called “mad cow disease” or bovine spongiform encephalopathy) (Collinge, 2001). Prion diseases may be sporadic, genetic, and infectious, and are characterized by the accumulation of a pathogenic variant of the prion protein, which induces degenerative changes in the central (and sometimes the peripheral) nervous system according to still unclear pathogenic mechanisms. The conversion of the naturally occurring prion protein (so-called cellular prion protein, or PrPC) into a protease-resistant isoform (so-called PrPRes or PrPSc, Sc meaning scrapie), which then accumulates in the brain, is considered a pathogenic step common to all of the prion diseases (Prusiner, 1987). The cellular prion protein is codified by the PRNP gene located on the short arm of chromosome 20. Its translated product is a 253-amino-acid structure that undergoes post-translational modifications at the amino- and carboxy-terminals, and glycosylation at two sites (Asn181 and Asn197). This glycoprotein weighs 33–35 kDa, is associated with the cellular membrane where it is attached to the outer cell surface with a glycosylphosphatidylinositol anchor, binds copper at an octapeptide repeat, and is expressed ubiquitously throughout

the central nervous system, particularly in the hippocampal formations. Expression patterns of PrPc in the brain comprise expression in both neurons and glial cells (astrocytes and oligodendrocytes), a rostrocaudal gradient, and association with g-aminobutyric acid (GABA)ergic neurons containing calcium binding proteins (Moleres and Velayos, 2005). The principal neuropathological features of the prion diseases, varying in the different clinical forms, are neuronal loss, spongiform changes, and gliosis, associated with the deposition of variable amounts of PrPSc (Prusiner, 1987; DeArmond et al., 1998; Collins et al., 2004). Extracellular amyloid plaques are found in about 15% of brains with prion disease (Roberts and Clinton, 1992). According to the “prion only” pathogenic hypothesis (Prusiner, 1987), the key step in prion pathogenesis is represented by the conformational conversion of the normal PrPC isoform into an abnormally misfolded protein PrPSc, which has an increased b-sheet (from 3% to 43%) and reduced a-helical (from 42% to 30%) content, reduced solubility, and is resistant to the action of proteases such as proteinase-K. This altered PrPSc isoform(s) is thought to be responsible for transmission of prion diseases to both humans and animals, but the presence of the naturally occurring PrPC is necessary for establishment of the disease (Brandner et al., 1996). PrPSc has been indeed postulated to interact with the host’s PrPC, inducing the transformation of its a-helices into a b-sheet conformation and thus provoking the transformation of PrPC into PrPSc (Pan et al., 1993; Ma and Lindquist, 2002). The subsequent steps along the pathogenic cascade are, however, still incompletely understood, and the very function of PrPC remains unclear at present. The accumulation and amyloid-like aggregation of

*Correspondence to: Pasquale Montagna, M.D., Professor of Neurology, Department of Neurological Sciences, University of Bologna Medical School, Via U. Foscolo 7, 40123 Bologna, Italy. E-mail: [email protected]

982 P. MONTAGNA PrPSc, possibly associated with the loss of the naturally disease. It has been reported worldwide, and its clinical occurring PrPC, has been shown to lead to mitochonand pathological features remain comparable in popudrial dysfunction induced by oxidative stress (Choi lations with different genetic backgrounds (Nagayama et al., 1998) and to disturbances in intracellular calcium et al., 1996; Almer et al., 1999; Harder et al., 1999; (Florio et al., 1998). Such metabolic alterations, misTabernero et al., 2000). FFI is fortunately a rare disfolding of the abnormal PrP isoforms in the endoplasease, having been reported in about 27 kindreds up mic reticulum, or their impaired clearance by the to now. ubiquitin–proteasome complex would then activate cell The disease usually runs clinically defined phases. death pathways along the apoptotic cascade (apoptosis The initial phase usually starts with subtle changes in is known to occur in prion diseases; Dorandeu et al., sleep, vegetative functions, and personality, so subtle 1998), and subsequent neurodegeneration. as to be often neglected by the patient and physician These pathogenic problems notwithstanding, the or to be trivialized into manifestations of stress or “(prion) protein only” hypothesis has represented a overwork. Patients complain that sleep is no longer remarkable reversal of the “nucleic acid only” parasatisfying or refreshing, that they have increasing diffidigm for infectious diseases, as prions are thought to culties in falling and remaining asleep, and can no lonbe devoid of nucleic acid and infectivity in prion disger nap in the afternoon. They feel fatigued and may eases resides within the prion protein itself. The argulook somnolent in the daytime, yet are unable to fall ment that this “prion protein only” mechanism could asleep and maintain sleep. From the outset, autonomic not account for the variable features of the clinical dissymptoms are often associated with these sleep eases and infectivity experiments collapsed when it was abnormalities, characterized by slightly increased body shown that infectious prions come in different strains temperature, especially in the evening, tachycardia and according to the conformational species of a particular irregular rapid breathing, and impotence in males. prion encoded by the sequence of the PrP gene of the Blood pressure also increases, and there is perspirainfected animal. Thus, the “prion protein only” hypothtion, salivation, and tearing. Patients are reported by esis is also able to account for the variety of the pathrelatives as apathetic or uninvolved, but intellectual ological and clinical features found in the different functioning generally remains unaffected. prion diseases, which had previously been thought The sleep and autonomic alterations increase proimpossible to explain without the help of information gressively, until peculiar behavioral abnormalities from nucleic acids. appear, consisting of dream enactment suddenly arising out of wakefulness, especially when the patients FAMILIAL FATAL INSOMNIA are left unstimulated. During such “oneiric stupors”, patients lapse into a state of unresponsiveness and Clinical features perform complex gestures that, upon awakening and FFI was first identified in 1986 in an Italian family as according to the patient’s report, appear to be well an autosomally dominant transmitted disease characcorrelated to the content of a dream (Figure 59.1). terized by peculiar alterations in sleep and autonomic These “oneiric stupors” increase progressively in frefunctions, and in which neuropathological examination quency and duration, while recall of the dream condisclosed prominent thalamic and inferior olivary tent becomes progressively more difficult; at this changes (Lugaresi et al., 1986). FFI is a disease with point hypertension and other autonomic changes are onset usually in mid life: mean age at onset is 51 years, usually well developed. but the onset may range from 36 to 62 years. FFI The middle phases see the onset of motor affects both sexes equally, leading to death within a impairment, in the form of spontaneous and stimumean disease course of 18 months (range 8–72 months) lus-evoked myoclonus, pyramidal system involvement, (Lugaresi et al., 1986; Montagna et al., 1998). Two difdysmetria and ataxia, and dysarthria with dysphagia. ferent disease courses are described, and attributed to In the final phases of the disease, patients become the effects of the 129 PRNP codon polymorphism, progressively bedridden and finally end up in a state which seems to modulate not only the disease duration of akinetic mutism, with stupor and coma preceding but also the clinical features (see below); patients may death. Death, however, may supervene suddenly in have a short (less than 11 months; mean 9.1 months) or every phase of the disease, even when motor abnormala prolonged (more than 11 months, mean 30.8 months) ities are absent, and especially in patients whose disdisease duration. ease has a short course. FFI was recognized as a genetically transmitted These symptoms and signs are those most freprion disease in 1992 (Medori et al., 1992a, b) and quently observed and typical of FFI, and resemble represents the third most frequent genetic prion those historically reported in the so-called thalamic

FATAL FAMILIAL INSOMNIA AND THE ROLE OF THE THALAMUS IN SLEEP REGULATION 983

Fig. 59.1. Sequential frames recorded in a patient with familial fatal insomnia, showing complex semi-purposeful movements during an oneiric stupor episode.

dementia (Petersen et al., 1992). They are by no means universal, however, and FFI kindreds display a degree of clinical variation, often related to the length of the disease. Patients with a short disease course manifest more marked sleep and autonomic abnormalities, whereas those with slower disease have more evident motor abnormalities (sometimes present even at the onset of the disease) and may suffer convulsive seizures. In some kindreds, moreover, overlap of clinical features has been reported, with siblings manifesting a full spectrum of phenotypes from typical CJD to FFI, to cerebellar ataxia without insomnia (McLean et al., 1997; Zerr et al., 1998b; Rossi et al., 1998; Taniwaki et al., 2000). Phenotypic heterogeneity has even been reported for half-brothers with the FFI mutation (Johnson et al., 1998). Although a genetic etiology (the 129 PRNP codon polymorphism) for the different duration of the disease has been postulated, there must

surely be other still unknown reasons, both genetic and nongenetic, for the observed clinical variability.

Clinical laboratory findings Electroencephalographic (EEG) and polysomnographic recordings performed at various times during the clinical course of the disease in FFI show several remarkable changes in sleep macro- and micro-structure and in the organization of the circadian rhythms. A characteristic feature is the early disappearance of sleep spindles and K-complexes, which is readily evident upon spectral EEG analysis with loss of power in the sigma band (Sforza et al., 1995). The loss of sleep spindles is particularly evident in patients with a short disease course, but is eventually brought about in the course of FFI. Loss of spindles is permanent and spindles cannot be evoked even by the administration of

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Fig. 59.2. Sleep histogram recorded in a patient with familial fatal insomnia at an early stage of the disease, showing the lack of deep phases 3–4 NREM sleep and a reduction in REM sleep, associated with frequent arousals and loss of the normal cycling of sleep. At this stage of the disease, the sleep spindles were still recognizable and there were no dissociated polysomnographic features. Black bar denotes dark period.

barbiturates or benzodiazepines, drugs that usually provoke spindling on the EEG (Tinuper et al., 1989). Likewise, barbiturates and benzodiazepines cannot induce slow-wave sleep (SWS). In fact, the next striking abnormality consists of the progressive loss of SWS, which characterizes deep nonrapid eye movement (NREM) sleep stages (Sforza et al., 1995) (Figure 59.2). Thus, EEG is characterized in the early–middle stages of FFI, by a pattern of alternation between an alpha activity of wakefulness mixed with theta trains associated with a waking behavior and normal response to external stimuli, and a desynchronized EEG activity with rapid eye movements (REMs), an often incomplete loss of antigravitary muscle tone, irregular muscle jerks, and autonomic fluctuations with tachycardia, tachypnea, and irregular breathing. Behavior during the latter periods is peculiar, characterized by unresponsiveness to presented external stimuli and by the subsequent report of a dreaming mentation, which the patient is at first able to report upon awakening and which can be often observed to correspond closely to the quasi-purposeful gestures and jerks enacted during the state. As patients can be woken up easily, at least in the initial stages, these states were termed “oneiric stupors” (Tinuper et al., 1989). Thus, florid stages of the disease are characterized mainly by two states of vigilance, alternating throughout the 24 hours. The cyclic structure of sleep is consequently lost, and short periods of REM sleep and SWS can often be seen to arise directly from a state of wakefulness, associated with absent or minimal antigravitary muscle atonia or with a decrease of body core temperature in the case of REM sleep, or a buildup of EEG delta activity in the case of SWS periods (Figure 59.3). Eventually, in some patients, both SWS and REM sleep may completely disappear. This pattern is especially evident in patients with a short disease course, whereas those with longer disease may

conserve some deep sleep and cyclic alternation of the sleep stages for some time. Later stages of the disease develop a monomorphic, low, unreactive EEG activity, with tracings becoming flat in the periods before death. During such activity, the patient is akinetic and unresponsive, and animated by the presence of isolated segmental or diffuse, spontaneous and evoked myoclonic jerks. Remarkably, the periodic spike discharges that characterize the EEG in prion diseases are nearly always absent in patients with a short disease course, and may be present in the more prolonged disease courses just a few days or weeks before death. Autonomic tests disclose alterations concomitant with the sleep changes, consisting of sympathetic activation (increased heart rate and blood pressure, increased breathing rate, increased body core temperature) both at rest and upon stimulations such as the Valsalva maneuver, isometric handgrip, or the tilt test. Parasympathetic functions remain unaffected (Cortelli et al., 1991). Autonomic features can be seen to have a state-dependent modulation, sympathetic activity decreasing whenever short periods of SWS appear on the EEG. They are attended by increased plasma levels of catecholamines, such as norepinephrine and epinephrine, and are associated with endocrine changes with hypercortisolemia in the presence of normal or even low levels of adrenocorticotropic hormone (Portaluppi et al., 1994a; Montagna et al., 1995). Abnormal plasma levels of catecholamines and sympathetic activation are associated with loss of their circadian rhythmicity (Avoni et al., 1991) with, in particular, disruption of somatotropin secretion (Portaluppi et al., 1995). The nocturnal rise in melatonin is lost with disease progression (Portaluppi et al., 1994b). Actigraphic recordings in a patient with FFI with a short disease course also demonstrated the loss of any circadian rhythmicity in motor activity, showing persistently 80% increased motor activity. In this patient,

FATAL FAMILIAL INSOMNIA AND THE ROLE OF THE THALAMUS IN SLEEP REGULATION 985 SubW “NRem” “Rem” 14.48

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Fig. 59.3. (A) Sleep histogram and (B) excerpts of related polysomnographic (PSG) recordings in a patient with familial fatal insomnia at an advanced stage, showing lack of slow-wave sleep and brief, often clustered, episodes of REM sleep (on the histogram). Black bar denotes dark period. PSG excerpts demonstrate the dissociated features of the “subwakefulness” state (SubW) (mixed alpha–theta EEG activity, irregular jerky and more tonic muscle activity), the “NRem” light sleep (mixed alpha–delta EEG activity, irregular muscular jerks, irregular antigravitary muscle tone, eye movements, and irregular breathing and heart rates; absent sleep figures such as sleep spindles and K-complexes), and “Rem” sleep (lack of complete antigravitary atonia, limb muscle irregular jerks interspersed with more tonic activity). ECG, electrocardiogram; EOG, electro-oculogram; resp., respirogram; SaO2, oxygen saturation; TA, thoracoabdominal; R, right; L, left.

recordings in an isolated respiratory chamber demonstrated a 60% increase in metabolic consumption, indicating a very high catabolic rate (Plazzi et al., 1997). Dissociation between conserved rest–activity and absent hormonal circadian rhythms (melatonin and cortisol) is also possible in FFI (Dauvilliers et al., 2004). Routine examination of the cerebrospinal fluid (CSF) is unremarkable in FFI, and levels of hypocretin-1 are essentially normal (Martinez-Rodriguez et al., 2003; Dauvilliers et al., 2004). Increased levels of the 14-3-3 protein in the CSF, a hallmark of sporadic CJD and other prion diseases, is not particularly helpful in the diagnosis, being found in only 50% of FFI cases (Zerr et al., 1998a). Neuropsychological studies in affected individuals show alterations in vigilance, attention, working memory, and temporal orientation (Gallassi et al., 1992, 1996). Frontal executive functions are those prevalently affected. Patients perform quite well on global intelligence tests until and unless vigilance levels are markedly disrupted. Therefore, because of the important vigilance abnormalities, which should, in principle, be absent in true dementias, FFI represents a progressive

confusional–oneiric state rather than a true dementing illness (Gallassi et al., 1996). Nonaffected carriers of the FFI PRNP mutation, followed sequentially with a battery of neuropsychological tests in order to disclose any initial intellectual change, did not demonstrate any significant abnormality in the tests or any mental impairment prior to the clinical onset of disease as defined by the symptoms and signs of insomnia (Cortelli et al., 2006).

Neuroimaging findings Brain metabolism in FFI was assessed by means of [18F] fluorodeoxyglucose positron emission tomography (18F-FDG-PET) in affected patients at different times in their clinical course (Perani et al., 1993; Cortelli et al., 1997). In stages of the disease when patients display severe polysomnographic alterations with oneiric stupors and insomnia, [18F]-FDG-PET demonstrates severe hypometabolism of the thalamus bilaterally, often associated with some hypometabolism of the gyrus cinguli. This thalamic hypometabolism may also be accompanied in later stages by hypometabolism of

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the basal ganglia, especially the caudate, cerebellum, and cortex, especially frontotemporal areas. When motor disability becomes prominent, hypometabolism is always more widespread and affects, besides the thalami and the basal ganglia, all cortical regions except the occipital lobe, which is peculiarly preserved in FFI. Cortical hypometabolism outside the frontal limbic areas is more evident in patients with a prolonged disease course. From a metabolic point of view, therefore, FFI is a predominantly thalamolimbic hypometabolic state; this characteristic metabolic “signature” of FFI has been found even in patients displaying atypical clinical symptoms (Bar et al., 2002), and is thus a helpful sign in the differential diagnosis. Thalamic hypometabolism may also be a marker in preclinical carriers of the FFI mutation, as a study of presymptomatic carriers of the 178 PRNP codon mutation followed longitudinally with 18F-FDG-PET confirmed that the first alteration in brain metabolism to be found and detectable 13 months prior to disease onset (as defined by symptoms and signs of insomnia) was thalamic hypometabolism (Cortelli et al., 2006); remarkably, in these patients limbic areas and the basal ganglia became hypometabolic too, but only after the clinical onset of the disease, whereas the neocortical regions never became significantly hypometabolic, even 10 months after disease onset (Cortelli et al., 2006) (Figure 59.4). A distinct temporal pattern of spreading brain metabolic changes is thus present in FFI, whereby the thalamus becomes hypometabolic even before symptom onset, and is in turn followed by the limbic areas and basal ganglia, whereas neocortical regions become hypometabolic only late in the disease course, if at all. Single-photon emission computed tomography with 2-b-carbomethoxy-3-b-(4-iodophenyl)-tropane in two

Neuropathological aspects Neuropathological examination demonstrates severe changes in the thalamus in FFI. These consist of marked (up to 80%) loss of neurons, especially in the anterior ventral and the mediodorsal nuclei, associated with reactive astrogliosis (Lugaresi et al., 1986; Manetto et al., 1992). The changes are much less evident, and sometimes absent, in the other thalamic nuclei, the pulvinar excepted. Spongiform changes, the hallmark of prion diseases, are not usually found in the thalamus, but are encountered in the neuropil and the cerebral cortex, especially in layers II–IV, particularly in patients with a prolonged course. Indeed, gliosis and some spongiosis of the entorhinal cortex are the only changes found in the cerebral cortex of patients dying with a short disease course, whereas gliosis and spongiosis become more prominent and affect all lobes in patients who die after a prolonged course. Other less consistent changes are gliosis and loss of neurons (Purkinje and granule cells) in the cerebellum, and occasionally in the basal ganglia and the nucleus basalis of Meynert. Only gliosis, but no neuronal loss, is found in the hypothalamus and the periaqueductal gray. The other consistent change characteristic of the disease is marked loss of neurons in the inferior olivary nuclei, to a degree comparable to that in the thalamus, which thus makes FFI a preferential thalamic–olivary atrophy on neuropathological grounds. Although

13 months before clinical onset

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patients with FFI disclosed abnormal availability of the serotonin transporter in the thalamus–hypothalamic region (reduced by 57–73%), which was thought to be secondary to the peculiar sleep abnormalities in FFI (Kloppel et al., 2002).

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Fig. 59.4. [ F]fluorodeoxyglucose positron emission tomography in a control subject (A) and a patient with familial fatal insomnia (B & C), showing thalamic hypometabolism (arrows in B) 13 months prior to disease onset as defined by the symptoms of insomnia. In addition to the thalamus, limbic areas and basal ganglia show hypometabolism but only after the clinical onset of the disease (arrows in C), whereas neocortical areas remain normometabolic even after disease onset. (From Cortelli et al., 2006, with kind permission. #Oxford University Press.) 18

FATAL FAMILIAL INSOMNIA AND THE ROLE atrophy of the anterior ventral and mediodorsal thalamic nuclei together with the inferior olives is found in all cases of FFI, the changes in the basal ganglia and especially those in the cerebral cortex depend upon the length of the disease, being more evident the more prolonged the duration. A noteworthy consideration is that FFI displays neuropathological changes distinct from those seen in the more common forms of prion disease, especially sporadic CJD. Specific features of FFI are the selective atrophy of the mediodorsal nucleus, and the loss of parvalbumin-positive GABAergic interneurons in the thalamus (Macchi et al., 1997; Guentchev et al., 1999; Masullo and Macchi, 2001). Serotonergic systems also seem particularly vulnerable in FFI, as shown by immunohistochemical studies of median raphe nuclei in FFI brains (Wanschitz et al., 2000) and by studies of serotonin metabolites in the CSF (Cortelli et al., 2001). As befits a prion disease, the brain in FFI accumulates the typical protease-resistant PrPSc deposits (Parchi et al., 1995). Peculiar to FFI brains is that these deposits of PrPSc are scant, the amount being only 10–20% of that observed in sporadic CJD. Remarkably, the amount of PrPSc in the thalamus is particularly small, while deposits are found especially in the cortex and in patients with a more prolonged disease course. Indeed, with disease progression, deposits in the cerebral cortex (and basal ganglia) increase, whereas those in the thalamus and the brainstem remain uncorrelated to disease duration, showing a kind of ceiling effect. Deposits of PrPSc are more widespread than the histopathological changes of neuronal loss and astrogliosis, and there is no relationship between neuronal loss and PrPSc deposits. This suggests that the thalamic, especially the mediodorsal, nuclei, where the dissociation (severe neuronal loss in the face of scarce PrPSc) is particularly evident, have a specific vulnerability in FFI (Parchi et al., 1995).

Molecular neurobiology FFI is transmitted as an autosomal dominant disease due to a mutation in the PRNP gene, whereby a GAC!AAC transition results in a D178N substitution at codon 178 of the gene (Medori et al., 1992a, b). The same missense mutation is, however, found in some pedigrees of CJD that have clinical and neuropathological features different from those in FFI, namely a lack of sleep changes and a preferential involvement of the cerebral cortex rather than the thalamus (Goldfarb et al., 1991). However, a detailed genetic analysis of these FFI and CJD pedigrees, both harboring the 178 codon mutation (178CJD), showed that all FFI kindreds are characterized by the presence

OF THE THALAMUS IN SLEEP REGULATION 987 of a 129 codon polymorphism coding for the amino acid methionine on the mutated allele, whereas the 178CJD kindreds all express valine (Goldfarb et al., 1992). Thus two distinct phenotypes, FFI and 178CJD, are linked to the same mutation but to a different intragenic polymorphism: the 178 PRNP codon mutation determines disease, but the histopathological and clinical features are dictated by the 129 codon polymorphism present on the mutated allele (Petersen et al., 1994). The modifying effects of the 129 codon polymorphism were further confirmed in a FFI kindred harboring another intragenic polymorphism, a 24-base pair PRNP deletion (Bosque et al., 1992), and in a general review of the phenotypic spectrum of prion diseases (Kova`cs et al., 2002). The 129 PRNP codon polymorphism is known also to exert modifying influences on the clinical characteristics of other prion diseases, in particular on the susceptibility to iatrogenic and “new variant” CJD, and on age of disease onset (Puoti et al., 2000; Collinge, 2001). In Caucasians, the 129 codon of the PRNP gene specifies either methionine or valine, with 34–49% of subjects being met/met homozygotes, 42–56% met/val heterozygotes, and the remainder val/val. How the 129 codon exerts these modifying effects is still unknown; the 129 valine genotype has been linked to increased PrPRes production, and 129 heterozygosity to increased amyloid plaque aggregation (Hauw et al., 2000). Monari et al. (1994) demonstrated that the genetic differences between FFI and 178CJD were also reflected in the type of PrPSc being accumulated in the brain: whereas FFI brains accumulated a 19-kDa PrPSc, 178CJD brain deposits were of a 21-kDa PrPSc. These different isoforms of PrPSc were also characterized by different glycosylation patterns; PrP isoforms can be un-, mono- and di-glycosylated, and the unglycosylated form is particularly scant in FFI. The different molecular weight of the two PrPSc, the FFI and 178CJD PrPSc, is explained by a different site of cleavage by proteinase-K, probably due to a different conformation of the two protein isoforms. The 21-kDa PrPSc was defined as type 1 and the 19-kDa isoform as type 2 PrPSc; this was the first demonstration of different types of PrPSc with distinct biochemical and pathogenic properties (the prion “strains”). That the clinicopathological features of FFI and other prion diseases were indeed pathogenically related to the particular type of PrPSc isoform (“prion strain”) accumulated was demonstrated conclusively by experimental transmission studies performed in transgenic animals. Prion diseases are indeed infective and can be transmitted to experimental animals, as clearly shown by Collinge et al. (1995) and Tateishi et al. (1995). Remarkably, when extracts from FFI brains

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were inoculated into transgenic mice (MHu2M) expressing a chimeric human–mouse PrP gene, mice developed a prion disease characterized by prominent thalamic pathology and the accumulation of a prion strain (PrPSc) similar in weight to that found in the donor patient brain, a 19-kDa type 2 PrPSc (Telling et al., 1996). In contrast, when brain extracts inoculated into the same transgenic mice came from patients with sporadic CJD or harboring an E200K codon PRNP mutation, the mice developed a prevalent cortical pathology and accumulated a type 1 PrPSc. This demonstrated that the conformation of the PrPSc acts as a template for the formation of nascent PrPSc molecules, and confirmed that prion strain diversity (and consequently their ability to induce different clinicopathological features) is encrypted in the particular conformation of any specific PrP isoform, with no participation from the donor DNA. These results were instrumental in confirming the “prion protein only” theory of prion pathogenicity. Transmission experiments with extracts from SFI (see below) brains gave further support to this theory (Mastrianni et al., 1999). It is currently thought that PrPC, for some unknown reason and when mutated, undergoes a conformational change that makes it into a proteinase-K- resistant isoform that acts as a template to convert nascent PrP molecules into PrPSc ones (Prusiner, 1987). How this leads to loss of neurons and reactive astrogliosis in specific brain structures cannot, however, yet be explained satisfactorily. The D178N PRNP mutation results in abnormal intracellular transport of the protein (Petersen et al., 1996) and there is evidence for neuronal apoptosis in FFI brains (Dorandeu et al., 1998), but the intermediate pathogenic steps remain unclear. In particular, the specific vulnerability of the thalamolimbic structures remains unexplained. The mechanisms behind the effects of the 129 codon polymorphism are also puzzling. It was hypothesized that, because the 178 and 129 residues are close in the tertiary structure of the protein, different interactions between valine and methionine residues resulted in a different protein conformation (or isoform) (Parchi et al., 1998). More recently, using molecular dynamics, Shamsir and Dalby (2005) examined the effects of both the codon 178 mutation and 129 codon polymorphism on protein dynamics and conformations. They found that methionine variants had higher stability than valine variants, and that elongation of b-sheets and new b-sheet formation occurred more readily in valine variants. The conversion propensity for the D178N variant has also been shown to depend strongly upon the M/V polymorphism at codon 129, at least in vitro (Apetri et al., 2005). These studies provide a molecular rationale for the observed strain specificity of FFI and 178CJD.

Another hypothesis held forth was a role for the 129 codon polymorphism in modifying the interaction of the PrP with a receptor or protein present in thalamolimbic structures (Lugaresi et al., 1998). The picture is further complicated by the finding that even the 129 codon polymorphism on the nonmutated allele may exert an influence on the clinical phenotype; indeed, patients with a short disease course (less than 11 months) were found to be predominantly met/met homozygotes at the 129 PRNP codon, whereas a more prolonged disease was a feature in met/val heterozygote patients (Montagna et al., 1998). How this may happen remains unclear, especially when considering that the nonmutated allele does not contribute to PrPSc generation in FFI (Chen et al., 1997). Moreover, considerable variation in phenotypic expression has been reported even within 129 met/met homozygotes (Zarranz et al., 2005), suggesting that other genetic/ environmental factors are at work in modifying the clinical expression of the 178 codon mutation.

SPORADIC FATAL INSOMNIA In 1999, the first cases were reported of sporadic patients displaying the clinical and neuropathological features typical of FFI in the absence of a family history and of the specific D178N mutation that typifies the disease, or indeed of any other PRNP mutation (Mastrianni et al., 1999; Parchi et al., 1999). Such cases were termed sporadic fatal insomnia (SFI), and it was shown that type of PrPSc deposited in the brain (type 2) and amount and pattern of deposition (with a preferential deposition in the thalamus) were the same as those observed in FFI. Another characteristic of SFI is represented by the fact that all observed cases have been met/met homozygotes at codon 129 of PRNP. That the sleep abnormalities typical of FFI also characterize SFI was shown in a study by Scaravilli et al. (2000), who performed polysomnography in a patient with SFI. Remarkably, SFI could be transmitted to the experimental animal much in the same way as FFI (Mastrianni et al., 1999), and transmission experiments showed that both type of PrPSc and histopathological lesion profile were the same as FFI. This was considered further proof that the conformation of the protein itself codifies for its pathogenic properties.

FFI and SFI as model diseases for sleep regulation: the role of the thalamus Correlation of the clinical features of FFI with brain in vivo metabolic and post-mortem neuropathological findings implicate the thalamus in the genesis of the peculiar abnormalities observed in FFI, specifically the wake–sleep alterations and autonomic changes.

FATAL FAMILIAL INSOMNIA AND THE ROLE Prominent abnormalities of the wake–sleep cycle, in particular the loss of sleep spindling and a marked reduction of SWS, and autonomic hyperactivity can be observed at stages of the disease when the only significant abnormalities in brain FDG-PET consist of hypometabolism of the thalami and the cingular cortex. Therefore it was contended that disruption in the thalamolimbic circuits represents the fundamental pathogenic mechanism underlying the sleep and autonomic alterations of FFI (Tinuper et al., 1989; Sforza et al., 1995; Lugaresi et al., 1998). The mediodorsal and the anterior ventral thalamic nuclei represent the fulcrum of the pathological changes in FFI. Both of these nuclei have connections with forebrain limbic areas, and represent intermediate stations in the circuitry that connects the cortex with the subcortical hypothalamic and brainstem regions devoted to sleep and wake regulation. In FFI, the lesions in the thalamus would relieve some of these hypothalamic and brainstem structures of cortical control. Activation of these subcortical hypothalamic and brainstem regions would in turn lead to autonomic and motor hyperactivity, and inability to produce deep sleep. That sleep spindles and K-complexes disappear early in the course of FFI is indeed consistent with their thalamic origin in the reticular nucleus (Steriade, 2003). Even though pathology in the reticular nucleus is difficult to ascertain in FFI, it should be noted that the reticular nucleus sends efferents to the mediodorsal nucleus (Velayos et al., 1998), and moreover that lesions of the reticular nucleus itself have been shown to reduce the amount of EEG delta oscillations and to result in death of the experimental animal (Marini et al., 2000). On the other hand, FFI as a model disease vindicates the early studies of Hess (1944), which implicated the thalamus in the pathogenetic mechanisms of sleep. Hess found that electrical stimulation of the medial thalamus induced sleep in the cat, and accordingly hypothesized that the medial thalamus exerts a trophotropic influence, in the sense of favoring those bodily functions devoted to energy restoration (whereas the lateral thalamus exerts ergotropic functions, i.e., aimed at energy expenditure). Hess’s findings, confirmed by Parmeggiani (1964), were later disputed by Naquet et al. (1965), so that the thalamus was not considered to be involved in the regulation of sleep any more, and even disappeared from some textbooks of sleep physiology. However, evidence for a role for the thalamus in deep sleep generation was also provided by Villablanca et al. (1972a, b), who demonstrated that thalamectomized cats (so-called “athalamic” cats) had severely reduced REM and NREM sleep; remarkably, these cats

OF THE THALAMUS IN SLEEP REGULATION 989 had permanently absent sleep spindles that could not be evoked by thiopental administration, in a way reminiscent of patients with FFI (Tinuper et al., 1989). Marked reductions in REM and NREM sleep in the face of preserved sleep spindles were also observed in cats with intact thalamus but ablated cortex and striatum (so-called “diencephalic” cats). These studies bear, importantly, on the issue of FFI and sleep regulation, as FFI is characterized pathologically by atrophy and hypometabolism of the thalamus plus the limbic cortex, and accordingly it is to be expected that these combined lesions be attended by even more prominent abnormalities and loss of SWS. Intriguingly, and similar to the findings in FFI, both “diencephalic” and “athalamic” cats, although unable to sleep, still continued to display drowsiness. Ibotenic lesions in the mediodorsal thalamic nucleus reduced the amount of SWS in the cat, whereas comparable lesions in the anterior thalamic nucleus remained ineffective (Marini et al., 1988, 1989). The evidence from experimental animal studies is also supplemented by clinical reports: bilateral stereotactic lesions of the thalamus in a parkinsonian patient were followed by persistent insomnia (Bricolo, 1967), and patients with bilateral paramedian lesions of the thalamus (because of vascular insult or calcifications) display loss of sleep spindles and deep sleep, and also abnormal autonomic functions in many ways resembling FFI (Guilleminault et al., 1993; Bassetti et al., 1996; Montagna et al., 2002). These patients pass most of the daytime in a state of “subwakefulness” (or presleep behavior), akin to stage 1 NREM sleep, reminiscent of FFI and of the “athalamic” and “diencephalic” cats of Villablanca. Finally, a role for the thalamus in sleep, particularly in SWS generation, was provided by neuroimaging studies in humans, whereby synchronized sleep was attended by thalamic hypometabolism (Andersson et al., 1998) and SWS by lower metabolic rate in the thalamus and limbic and paralimbic areas (Braun et al., 1997). Cerebral blood flow covaries negatively with EEG delta activities, particularly in the thalamus, the orbitofrontal and cingular cortex, and the brainstem reticular formation (Hofle et al., 1997). It is indeed remarkable that the pattern of neural deactivation during physiological deep sleep in humans resembles the PET studies in FFI. Medial thalamic structures also represent centers of integration of autonomic activities. A role for the dorsomedial nucleus in the regulation of autonomic activities was demonstrated by studies with bicuculline injections, which caused hypertension and tachycardia through mechanisms implying the removal of GABAergic tonic inhibition (Stotz-Potter and Benarroch, 1998).

990 P. MONTAGNA This whole body of observations demonstrates that away” and referring to sleep loss of organic origin, the thalamus is a neural region important for the generand excitata referring to the motor and autonomic actiation not only of sleep spindles, which signal the transivation) was coined for patients who display prominent tion from light to deep sleep (the sleep “proper”), but of sleep alterations such as loss of SWS and oneiric behaSWS itself. The thalamus acts in concert with the foreviors, associated with hyperactivity in sympathetic brain, especially limbic systems. Indeed, the mediodorfunctions and with motor overactivity not respecting sal nucleus is integrated within pathways coming from circadian rhythmicity (Lugaresi and Provini, 2001). the hypothalamus and basal forebrain, with direct Based on the clinicopathological and brain metabolic GABAergic interconnections (Gritti et al., 1998). The correlations already found in FFI, agrypnia excitata thalamic lesions in FFI probably introduce a diaschisis was considered a dysfunction within the thalamolimbic between the forebrain cortical regions and the hypothalcircuits, and proposed as a useful concept in clinical amus and the brainstem areas governing sleep and autoneurology (Montagna and Lugaresi, 2002). nomic functions (Lugaresi et al., 1998), resulting in a The concept of agrypnia excitata may help in everyfunctional imbalance with loss of SWS and autonomic day practice to define patients and try to localize hyperactivity (Hess’s ergotropic activation). If we the anatomical correlates of their clinical features. conceive of sleep as a kind of instinctive behavior Moreover, it allows intriguing considerations on the (Moruzzi, 1969), the medial thalamus and mesial limbic physiopathology of sleep that bear not only on the concortex may be conceptualized as repositories of neural ceptualization of the wake–sleep states, but also on the representations of motivational drives, including the current scoring methods of sleep. FFI has been thus need for sleep (Sewards and Sewards, 2003). construed as a model disease for sleep physiopaA question mark pertains, however, to the role thology, akin to Von Economo’s clinicopathological played by atrophy of the inferior olives in the sympstudies of encephalitis lethargica which allowed him tomatology of FFI. It has been hypothesized that to appreciate the role of the hypothalamus in sleep tremor and myoclonus are clinical features possibly regulation. A remarkable feature of agrypnia excitata related to the olivary atrophy and attending serotoneris the fact that patients display a normal occurrence gic abnormalities (the inferior olives receive a substanof drowsiness in the face of severely abnormal and tial serotonergic innervation) (Welsh et al., 2002). sometimes completely absent SWS and REM sleep Remarkably, however, the inferior olives project to stages. Variously defined as “subwakefulness”, the cerebellum, and cerebellectomy (or lesions of the “pseudo-hypersomnia”, or “presleep behavior” in superior cerebellar peduncle) in cats alters the wake– patients affected with paramedian thalamic lesions sleep cycle by specifically producing a significant and attributed to “de-arousal” (Guilleminault et al., increase in drowsiness episodes, and a shortening of 1993; Bassetti et al., 1996), these periods of drowsiness wake and SWS, with lengthening of paradoxical sleep resemble polygraphically stage 1–2 NREM sleep and (Cunchillos and De Andres, 1982), features reminiscent may represent the predominant state during daytime. of FFI. Therefore, a possible role for the inferior oliIn agrypnia excitata it is possible to have normal vary atrophy (through the intermediation of the cerewake and light sleep stages (stage 1 NREM sleep), bellum?) in the pathogenesis of the sleep disturbances but sleep spindles (i.e., NREM sleep stage 2 and deeper of FFI, specifically the increased subwakefulness state, sleep) and SWS cannot be generated. This calls for a cannot be discounted. different conceptualization of NREM sleep, and for a scoring system different from that currently in use (Rechtschaffen and Kales, 1968). FFI and the concept of “agrypnia excitata” NREM sleep is currently considered a monotonic FFI and SFI do not represent the only diseases characprocess, in which synchronization of EEG sleep waves terized by loss of sleep, and autonomic and motor occurs progressively from stage 1 and 2 (light sleep) overactivation. Similar clinical features and polysomdown to deeper sleep stages characterized by delta nographic findings have been reported in other clinical EEG. Sleep spindles herald the transition from light conditions unrelated to prion pathologies, such as to deep sleep stages. Such a view is controversial, delirium tremens, a syndrome of withdrawal from however, as not all authors accept that light sleep chronic alcohol and benzodiazepine or meprobamate be put together with SWS into a single physiological chronic intoxication (Plazzi et al., 2002b), and Morprocess. For instance, when behavioral monitoring van’s chorea, which can be considered an autoimmune (response to auditory bursts) was applied to the definilimbic encephalitis associated with peripheral neurotion of the sleep stages and compared with EEG scormyotonia (Liguori et al., 2001). Accordingly, the term ing, only in EEG stages 3, 4, and REM sleep could a “agrypnia excitata” (agrypnia meaning “chasing sleep significant distinction with wakefulness be achieved

FATAL FAMILIAL INSOMNIA AND THE ROLE (Dement and Kleitman, 1957; Ogilvie et al., 1989). This led Ogilvie et al. (1989) to separate a “sleep-onset period” corresponding to light sleep, and during which cognitive response is still possible. The findings in FFI and agrypnia excitata concur with the view that light sleep phases up to the development of the sleep spindles should be separated from SWS, and that they should be conceptualized as a distinct vigilance state, whose relationship with relaxed vigilance and drowsiness should be reappraised (Montagna and Lugaresi, 2002). These light sleep phases are, moreover, identified cognitively by peculiar mental processes (mental imageries, absence of rational thought, spatial and temporal illusions) that led Critchley to recognize the specificity of, and to propose, the term “predormitum” for this particular state (Critchley, 1955). Moreover, the “predormitum” is the time for the occurrence of specific physiological (slow eye movements, hypnic jerks) and pathological (propriospinal myoclonus at the wake–sleep transition; Montagna et al., 1997) motor events, which also argue for the specificity of this vigilance state. Thus, following the concept of sleep as a kind of instinctive behavior (Moruzzi, 1969), the appetitive phase corresponding to “presleep behavior” or drowsiness/light sleep stage 1 NREM sleep is followed under appropriate conditions by the consummatory phase, corresponding to the SWS/REM sleep cycles. The basic mechanisms and functions underlying the generation of these two different states of “sleep” must ultimately be different. As drowsiness is still possible with severe thalamic lesions, the mechanisms for generation of drowsiness or sleep onset must reside elsewhere. There is evidence that a dissociation of rest versus true sleep can be effected in the experimental animal (Villablanca, 1966), and rest behavior but not true sleep is found in chronic medullary and midpontine cats (Siegel et al., 1986). Based on lesion experiments, Villablanca (Villablanca, 1966; Villablanca et al., 2001) concluded that sleep and wakefulness are controlled by dual independent mechanisms, with “brain sleep (i.e., true sleep, SWS) and wakefulness” originating in the rostral brain, and “body sleep (i.e., rest, drowsiness) and wakefulness” originating in caudal brainstem structures. These considerations are also consistent with a phylogenic view of sleep as a process emerging from the rest–wake rhythmicity displayed by lower (poikilothermic) animals that cycle between rest and activity, whereas true sleep (both SWS and REM sleep) is found only in homeotherms, in agreement with the “presleep theory” of the ontogenetic development of sleep, whereby both REM sleep and SWS emerge from a common “dissociated” state in neonates (Frank and Heller, 1997).

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In accordance with these views, and with the clinical and laboratory findings derived from agrypnia excitata, Lugaresi et al. (2004) proposed that drowsiness/ light stage 1 NREM sleep represents an independent vigilance state with autonomous mechanisms and functions, on a par with wakefulness, whereas deep (slow wave) sleep and REM sleep are comparable to the “rest” state of the poikilothermic animals. They also suggested a caudorostral neural organization of these three sleep stages: “rest”/drowsiness being organized at a caudal brainstem (reticular?) level, REM sleep at a pontine level, and SWS at a more rostral, thalamolimbic level.

Prions and sleep The function(s) of the prion protein remains still unknown. Its relatively well preserved structure throughout evolution seems to indicate an essential role in cell biology. Prions have neuroprotective properties (Chiarini et al., 2002) and have been implicated in cellular adhesion and cell signaling (Martins and Brentani, 2002). As prions bind copper and they are taken up actively into caveolae, acting as a sink for copper, they could have a role in copper metabolism (Brown and Sassoon, 2002), which would translate into a protective action from oxidative stress. The abundant expression of PrPC in the hippocampus has been taken to indicate an essential role of prions in memory formation (Tompa and Friedrich, 1998). However, nitrergic mechanisms may play a role in the pathophysiology of the prion diseases (Velayos and Alfageme, 1999) and the presence of the cellular PrP isoform in a subset of GABAergic neurons containing calcium binding proteins suggests that PrPC plays a role in the metabolism of calcium (Moleres and Velayos, 2005). Gleaned from the abnormal findings in FFI, a role proposed for the prion protein was sleep regulation (Tobler et al., 1997). Mice devoid of PrP (knockout mice, 129/SV “null”) display an alteration in both circadian activity rhythms and patterns (Tobler et al., 1996). Moreover, when these null mice are studied for sleep abnormalities, they display sleep fragmentation with increased numbers of waking episodes and abnormal (faster but lesser) buildup of slow-wave activity at the wake to NREM sleep transitions. These mice also express a larger and more prolonged increase in slowwave activity when recovering from sleep deprivation (Tobler et al., 1997). On the basis of these findings, a role for the prion protein in promoting sleep continuity (Tobler et al., 1997) and more generally in sleep regulation (Huber et al., 1999) was proposed. In later studies, however, a conclusion was reached that differences between

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the null and control mice could be better explained by a different need for recovery after sleep deprivation expressed by the occipital brain areas; indeed the larger increase of slow-wave activity after sleep deprivation was restricted to the occipital regions, and these differences appeared after the waking–NREM sleep transitions, making it unlikely that PrP is involved in the mechanisms enabling the transition to sleep (Huber et al., 2002). Thus, there is only equivocal experimental evidence for a role of the prion protein in sleep regulation. The clinical evidence, although forthcoming, remains also circumstantial. Several lines of evidence indicate that animals infected with prions exhibit sleep abnormalities, often in the early stages of the disease. Early disturbances of consciousness were noted in squirrel monkeys infected with CJD agents (Cathala et al., 1981). After scrapie inoculation, rats displayed spindle-shaped bursts of diphasic spikes during quiet wakefulness, and changes in the sleep–wakefulness cycle, characterized by decreased active wakefulness, increased quiet wakefulness, and diminished SWS. These EEG disturbances clearly preceded the onset of the clinical signs (Bassant et al., 1984). Twenty months after intracerebral inoculation of a CJD agent, cats developed unusual sleep, especially REM sleep, abnormalities (Gourmelon et al., 1987). Two strains of transmissible mink encephalopathy (TME) are known, called hyper (HY) and drowsy (DY). After passage into hamsters, although HY hamsters manifest hyperesthesia and cerebellar ataxia, lethargy and drowsiness are found in DY hamsters (Bessen and Marsh, 1992). These different clinical features in mink encephalopathy are related to different scrapie strains with distinct PrP properties (Bessen and Marsh, 1994), in a way reminiscent of the distinctive features of FFI versus 178CJD, and confirm that strain diversity encoded in different structural properties of the prion protein specifies the clinical differences. Also, monitoring of circadian activity revealed early abnormalities, most pronounced during the nocturnal active phase in mice with bovine spongiform encephalopathy and scrapie (Dell’Omo et al., 2002). Similar findings are seen in some human prion encephalopathies. Generally, the changes in sleep organization occur with the beginning of the clinical phase (Court and Bert, 1995) and precocious loss of sleep was documented by serial polysomnography in a few patients with sporadic CJD (Vitrey et al., 1971; Terzano et al., 1995). These findings are not, however, universal in the human prion encephalopathies: studies performed in GSS have demonstrated a completely normal structure of sleep and circadian organization (Pierangeli et al., 2004), casting doubt on the proposal

that the prion protein itself is responsible for the abnormal sleep–wake regulation observed in FFI. These negative findings are more in agreement with the pathological location of changes in the thalamolimbic areas as responsible for the sleep–wake abnormalities, and this contention is also supported by those cases of human prion encephalopthies different from FFI in which prominent abnormalities of the sleep–wake and other circadian rhythms were observed, as in many of these cases pathology included relevant changes in thalamic regions (Chapman et al., 1996; Taratuto et al., 2002). Polysomnographic studies performed in presymptomatic carriers of the FFI PRNP mutation also support such an explicatory hypothesis, as no significant differences were found in the absolute and relative power of the alpha, sigma, theta and delta EEG bands in presymptomatic FFI carriers, and sleep macrostructure was comparable to that in noncarriers (Ferrillo et al., 2001). Moreover, in a follow-up polysomnographic and PET study, loss of the sigma band (corresponding to spindle activity) on spectral EEG analysis was found to be associated with thalamic hypometabolism 13 months before the onset of the clinical symptoms of FFI (Cortelli et al., 2006), suggesting that the earliest sleep abnormalities in FFI, i.e., loss of sleep spindles, occur concomitantly with the metabolic changes in the thalamus. The role of the 129 codon polymorphism in FFI was instead underlined by a study of spectral EEG characteristics comparing 129 met/val against 129 met/met carriers: spindle frequency band power and delta/spindle activity ratio were found correlated with 129 PRNP codon polymorphism, which was especially abnormal in the met/met homozygotes (Plazzi et al., 2002a). A role, however, for the codon 129 PRNP polymorphism for insomnia complaints in the general population was not confirmed in a genetic association study (Pedrazzoli et al., 2002).

CONCLUSIONS FFI has offered important insights into the pathophysiology of the prion diseases, and at the same time has been proposed as a model disease for a role of the thalamus and thalamolimbic circuits in the regulation of sleep and of the autonomic nervous system. Comparison of the clinical and pathological features between FFI and 178CJD allowed the first recognition of a novel mechanism for genetic heterogeneity, related to the influence of an intragenic (codon 129) polymorphism; moreover, FFI has been instrumental in the recognition of the existence of different prion strains (e.g., type 1 (21 kDa) and type 2 (19 kDa) PrPSc) and, following the transmission experiments, has helped to confirm the “protein only” theory of prion infectivity, whereby

FATAL FAMILIAL INSOMNIA AND THE ROLE OF THE THALAMUS IN SLEEP REGULATION 993 the phenotypic characteristics of the disease are enciphered in the protein conformational structure and are independent of any DNA transmitted by the donor of the inoculum. This is an important new paradigm in the biological sciences. In the study of sleep and the thalamus, clinicopathological correlations in FFI implicated the anterior and medial thalamus and their limbic connections in the generation of SWS. As a consequence, the concept of agrypnia excitata was proposed as a useful concept in clinical neurology and with relevant consequences for sleep physiology. The existence of normal light sleep vis á vis with loss or even absence of SWS argues for intrinsically different basic mechanisms underlying these two types of sleep, and moreover suggests that they are organized in different brain regions and subserve different functions. Accordingly, it has been proposed that light sleep/drowsiness represents an autonomous state of being, on a par with wake, deep, and REM sleep, and that a reappraisal of the concept of NREM sleep and its scoring methods is necessary.

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Portaluppi F, Cortelli P, Avoni P et al. (1995). Dissociated 24-hour patterns of somatotropin and prolactin in fatal familial insomnia. Neuroendocrinology 61: 731–737. Prusiner SB (1987). Prions and neurodegenerative diseases. N Engl J Med 317: 1571–1581. Puoti G, Rossi G, Giaccone G et al. (2000). Polymorphism at codon 129 of PRNP affects the phenotypic expression of Creutzfeldt–Jakob disease linked to E200K mutation. Ann Neurol 48: 269–270. Rechtschaffen A, Kales A (1968). A Manual of Standardized Terminology, Techniques and Scoring Techniques for Sleep Stages of Human Subjects. Brain Research Institute, Los Angeles. Roberts GW, Clinton J (1992). Prion disease: the spectrum of pathology and diagnostic considerations. In: SB Prusiner, J Collinge, J Powell et al. (Eds.), Prion Diseases of Humans and Animals. Ellis Horwood, New York, pp. 215–240. Rossi G, Macchi G, Porro M et al. (1998). Fatal familial insomnia: genetic, neuropathologic, and biochemical study of a patient from a new Italian kindred. Neurology 50: 688–692. Scaravilli F, Cordery RJ, Kretzschmar H et al. (2000). Sporadic fatal insomnia: a case study. Ann Neurol 48: 665–668. Sewards TV, Sewards MA (2003). Representations of motivational drives in mesial cortex, medial thalamus, hypothalamus and midbrain. Brain Res Bull 61: 25–49. Sforza E, Montagna P, Tinuper P et al. (1995). Sleep–wake cycle abnormalities in fatal familial insomnia: evidence of the role of the thalamus in sleep regulation. Electroencephalogr Clin Neurophysiol 94: 398–405. Shamsir MS, Dalby AR (2005). One gene, two diseases and three conformations: molecular dynamics simulations of mutants of human prion protein at room temperature and elevated temperatures. Proteins 59: 275–290. Siegel JM, Tomaszewski KS, Nienhuis R (1986). Behavioral states in the chronic medullary and midpontine cat. Electroencephalogr Clin Neurophysiol 63: 274–288. Steriade M (2003). The corticothalamic system in sleep. Front Biosci 8: 878–899. Stotz-Potter E, Benarroch E (1998). Removal of GABAergic inhibition in the mediodorsal nucleus of the rat thalamus leads to increases in heart rate and blood pressure. Neurosci Lett 247: 127–130. Tabernero C, Polo JM, Sevillano MD et al. (2000). Fatal familial insomnia: clinical, neuropathological, and genetic description of a Spanish family. J Neurol Neurosurg Psychiatry 68: 774–777. Taniwaki Y, Hara H, Doh-Ura K et al. (2000). Familial Creutzfeldt–Jakob disease with D178N-129M mutation of PRNP presenting as cerebellar ataxia without insomnia. J Neurol Neurosurg Psychiatry 68: 388. Taratuto AL, Piccardo P, Reich EG et al. (2002). Insomnia associated with thalamic involvement in E200K Creutzfeldt–Jakob disease. Neurology 58: 362–367. Tateishi J, Brown P, Kitamoto T et al. (1995). First experimental transmission of fatal familial insomnia. Nature 376: 434–435. Telling GC, Parchi P, DeArmond SJ et al. (1996). Evidence for the conformation of the pathologic isoform of the

prion protein enciphering and propagating prion diversity. Science 274: 2079–2082. Terzano MG, Parrino L, Pietrini V et al. (1995). Precocious loss of physiological sleep in a case of Creutzfeldt Jakob disease: a serial polygraphic study. Sleep 18: 849–858. Tinuper P, Montagna P, Medori R et al. (1989). The thalamus participates in the regulation of the sleep–waking cycle: a clinico-pathological study in fatal familial thalamic degeneration. Electroencephalogr Clin Neurophysiol 73: 117–123. Tobler I, Gaus SE, Deboer T et al. (1996). Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 380: 639–642. Tobler I, Deboer T, Fischer M (1997). Sleep and sleep regulation in normal and prion protein-deficient mice. J Neurosci 17: 1869–1879. Tompa P, Friedrich P (1998). Prion proteins as memory molecules: an hypothesis. Neuroscience 86: 1037–1043. Velayos JL, Alfageme F (1999). Forebrain and brainstem perivascular neurons projecting to the thalamus (an anatomic explanation of the pathophysiology of fatal familial insomnia). Eur J Anat 3: 87–92. Velayos JL, Oliva M, Alfageme F (1998). Afferent projections to the mediodorsal and anterior thalamic nuclei in the cat: anatomical–clinical correlations. Brain Pathol 8: 549–552. Villablanca J (1966). Behavioural and polygraphic study of ‘sleep’ and ‘wakefulness’ in chronic decerebrate cats. Electroencephalogr Clin Neurophysiol 219: 562–577. Villablanca J, Salinas-Zeballos ME (1972a). Sleep– wakefulness EEG and behavioral studies of chronic cats without the thalamus: the ‘athalamic’ cat. Arch Ital Biol 110: 383–411. Villablanca J, Marcus R (1972b). Sleep–wakefulness EEG and behavioral studies of chronic cats without neocortex and striatum: the ‘diencephalic’ cat. Arch Ital Biol 110: 348–382. Villablanca J, De Andre`s I, Olmstead CE (2001). Sleep– waking states develop independently in the isolated forebrain and brain stem following early postnatal midbrain transection in cats. Neuroscience 106: 717–731. Vitrey M, Huguet P, Samson-Dollfus D (1971). Two sleep records obtained during the course of Jakob Creutzfeldt disease. Electroencephalogr Clin Neurophysiol 30: 253–254. Wanschitz J, Kloppel S, Jarius C et al. (2000). Alteration of the serotonergic nervous system in fatal familial insomnia. Ann Neurol 48: 788–791. Welsh JP, Placantonakis DG, Warsetsky SI et al. (2002). The serotonin hypothesis of myoclonus from the perspective of neuronal rhythmicity. Adv Neurol 89: 307–329. Zarranz JJ, Digon A, Atares B et al. (2005). Phenotypic variability in familial prion diseases due to the D178N mutation. J Neurol Neurosurg Psychiatry 76: 1491–1496. Zerr I, Bodemer M, Gefeller O et al. (1998a). Detection of 14–3–3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt–Jakob disease. Ann Neurol 43: 32–40. Zerr I, Giese A, Windl O et al. (1998b). Phenotypic variability in fatal familial insomnia (D178N-129M) genotype. Neurology 51: 1398–1405.

Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 60

Sleep disorders in Parkinson’s disease 1

ALEKSANDAR VIDENOVIC 1 * AND CYNTHIA L. COMELLA 2 Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

2

Department of Neurological Sciences, Section of Movement Disorders, Rush University Medical Center, Chicago, IL, USA

INTRODUCTION Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects approximately 300 per 100,000 population (Strickland and Bertoni, 2004). The clinical features include bradykinesia, rest tremor, muscle rigidity, and postural instability without atypical signs, such as early prominent dementia, early autonomic dysfunction, supranuclear gaze palsy, or cerebellar signs (Suchowersky et al., 2006). Idiopathic parkinsonism typically begins on one side of the body, progressing to involve both sides but remaining asymmetrical. PD motor signs are typically very responsive to levodopa (Pahwa et al., 2006). The characteristic pathological finding in PD is degeneration of pigmented neurons in the substantia nigra with formation of Lewy bodies (Cardoso et al., 2005). Additional brain areas are also affected, including the locus coeruleus, dorsal motor nucleus of the vagus, and the pedunculopontine nucleus (Jellinger, 2003). Degeneration of these nondopaminergic brainstem regions may begin prior to degeneration of the substantia nigra (Braak et al., 2003a) and accounts for many of the nonmotor features seen in PD, including many of the sleep disorders commonly associated with PD. Sleep disturbances and excessive daytime sleepiness (EDS) affect 60–80% of patients with PD during the course of their disease (Lees et al., 1988; Factor et al., 1990; Brotini and Gigli, 2004; Dhawan et al., 2006). This chapter reviews the disorders of daytime alertness and nocturnal sleep in idiopathic parkinsonism.

DISORDERS OF DAYTIME ALERTNESS Epidemiology EDS is common in PD (Hobson et al., 2002; Arnulf, 2005), affecting up to 50% of patients with PD. EDS

has been shown to be more common in PD than in age-matched nonparkinsonian healthy controls, or those with a chronic disease (diabetes) (Tandberg et al., 1999). EDS has been variably associated with male sex, duration of PD, and severity of the disease (Ondo et al., 2001; Pal et al., 2001). Prospective longitudinal studies of EDS are limited, with one study of 142 patients with PD showing that EDS increases in frequency at a rate of 6% per year (Gjerstad et al., 2002). There also may be differences in EDS frequency based on ethnicity, although few studies have assessed this systematically (Barbar et al., 2000; Furumoto, 2004). For example, in the Honolulu–Asia Aging Study, which included 3845 elderly Japanese–American men, the frequency of EDS in PD was 8.9%, and did not differ significantly from that in nonparkinsonian controls (Barbar et al., 2000). Another study found an increase in EDS in Japanese patients with PD, but with a lower prevalence than in Caucasians (Furumoto, 2004). These observations suggest that there may be ethnic differences in prevalence, or, alternatively, that factors relevant to a particular group, such as dosing of dopaminergic medications, may play a role. The frequency of unexpected sudden onset of sleep or “sleep attacks” in PD became a major safety concern following reports of associated motor vehicle accidents (Frucht et al., 1999). “Sleep attacks” manifest as overwhelming sleepiness that occurs without warning or with a prodrome that is sufficiently short or overpowering to prevent the patient from taking appropriate protective measures (Frucht et al., 1999). The initial report of sleep attacks stimulated brisk discussions and investigations into the existence and frequency of this phenomenon in PD (Frucht et al., 2000; Olanow et al., 2000). The rapid transition from

*Correspondence to: Aleksandar Videnovic, M.D., Northwestern University, Feinberg School of Medicine, Department of Neurology, 710 North Lake Shore Drive, Suite 1106, Chicago, Illinois 60611, USA. Tel: 312-503-1819, Fax: 312-908-5073, E-mail: [email protected]

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wakefulness to sleep in PD has been shown during electrophysiological monitoring in case reports (Ulivelli et al., 2002; Pacchetti et al., 2003). Patients with sleep attacks do not have shorter sleep latencies on the Multiple Sleep Latency Test (MSLT) than those without (Roth et al., 2003; Moller et al., 2005), and do not have greater nighttime sleep disruption (Roth et al., 2003). True sleep attacks occurring without a prodrome of drowsiness, however, appear to be rare, affecting 0.7–4% of patients with PD (Hobson et al., 2002; Paus et al., 2003; Korner et al., 2004). Although some studies have found a higher frequency of sleep attacks, with reports as high as 32% in PD (Montastruc et al., 2001; Ondo et al., 2001; Tan et al., 2002), these studies did not separate out patients with ambient drowsiness. Sleep attacks have been found to be associated with dopaminergic agents (Chaudhuri et al., 2002a). Treatment with levodopa alone appears to have the lowest risk for sleep attacks, followed by dopamine agonist (DA) monotherapy. Combination treatment with levodopa and DA therapy has the highest frequency of sleep attacks (Paus et al., 2003). The addition of entacapone to levodopa has also been described as triggering sleep attacks (Bares et al., 2003; Santens, 2003).

Etiology and pathophysiology EDS in PD may be primary to the disease itself, secondary to nocturnal sleep deprivation from coexistent sleep disorders, or to the use of daytime medications, in particular DAs. It is clear from pathological studies that the neurodegenerative process in PD originates in brainstem areas outside the substantia nigra (Braak et al., 2003a; Jellinger, 2003), and may even begin outside the central nervous system (Braak et al., 2003b). Hence, it is likely that there are subtle nonmotor features, such as EDS, that may precede the onset of motor symptoms. In the Honolulu–Asia Aging Study, there was more than a threefold increase in the risk of developing PD in elderly men with EDS that could not be accounted for by any other factor (odds ratio 2.8, 95% confidence interval 1.1 to 6.4; p ¼ 0.014) (Abbott et al., 2005), suggesting that EDS may be an early manifestation of extranigral involvement. Clinical evidence supporting EDS as an intrinsic part of PD comes from studies demonstrating that nighttime sleep is not reduced in patients with PD with EDS (Rye et al., 2000; Arnulf et al., 2005). Some studies observed an association between EDS and more advanced disease with longer duration (Tandberg et al., 1999; Gjerstad et al., 2002; Hobson et al., 2002; O’Suilleabhain and Dewey, 2002; Kumar et al., 2003). Other studies failed to find these associations (Arnulf et al., 2002; Brodsky et al., 2003; Braga-Neto et al., 2004).

In narcolepsy, the loss of the hypothalamic wakepromoting substance, hypocretin (orexin), underlies the development of sleepiness. In PD, although lumbar spinal fluid hypocretin levels do not differ from those in controls (Overeem et al., 2002), ventricular cerebrospinal fluid (CSF) hypocretin levels are significantly reduced (Drouot et al., 2003), suggesting that the loss of the wake-promoting effects of this hypothalamic system may be involved. These initial observations are further strengthened by the work of Fronczek and colleagues (2007), who found reduced post-mortem hypocretin brain tissue and CSF concentrations, as well as reduced number of hypocretin neurons in patients with PD relative to controls. Genetic associations of sleepiness in PD with catechol-O-methyltransferase genotypes (Frauscher et al., 2004) and (909T/C) preprohypocretin polymorphisms (Rissling et al., 2005) suggest a link between the dopaminergic systems and hypocretin systems for sleep–wake regulation. These genetic associations, however, have not been consistent (Rissling et al., 2006). Factors associated consistently with an increased frequency of EDS are the use and dosage of dopaminergic agents. Treatment with dopaminergic medications, including dopamine precursor levodopa and the direct DAs, pergolide, cabergoline, ropinirole, and pramipexole, has been observed to cause sleepiness (Schapira, 2000; Happe and Berger, 2001; Pal et al., 2001; Sanjiv et al., 2001; Tan, 2003; Razmy et al., 2004; Stevens et al., 2004; Arnulf, 2005; Plowman et al., 2005; Romigi et al., 2005). A comparison of daytime sleepiness among 50 treated, 25 untreated patients with PD, and age-matched healthy controls identified dopaminergic agents to be the principal factor associated with EDS (Fabbrini et al., 2002). Approximately half of the untreated patients who went on to receive dopaminergic medications developed EDS within 1 year (Fabbrini et al., 2003). Both subjective and objective measures of sleepiness increased following a treatment with dopaminergic medications (Kaynak et al., 2005). It is not clear whether a specific dopaminergic medication, or class of medications, is more likely to be causative. Although direct DAs are thought to be the major culprits, one of the first efficacy studies of chronic levodopa treatment showed that somnolence was a limiting side-effect in 13.7% of patients (Lesser et al., 1979). Decreased mean sleep latency during the MSLT was documented in patients after L-dopa intake compared with placebo (Garcia-Borreguero et al., 2003). Clinical trials comparing levodopa with pramipexole or ropinirole to assess for effects on the development of motor fluctuations showed that somnolence was an adverse effect regardless of drug treatment.

SLEEP DISORDERS IN PARKINSON’S DISEASE During the initial treatment and drug titration, sleepiness was more frequent with DA. However, when patients were on stable doses, there was no difference between agonist therapy and levodopa (Rascol et al., 2000; Holloway et al., 2004). These studies, however, did not evaluate patients specifically for EDS. Crosssectional studies have been fairly consistent in finding that dopaminergic drugs are the major contributor to EDS (Ondo et al., 2001; Paus et al., 2003; Stevens et al., 2004). Although some have suggested that the direct DAs cause sleepiness as a class effect (Schlesinger and Ravin, 2003), in most studies the major predictive factor for EDS was not the specific type of dopaminergic agent, but rather the total dose or burden of dopaminergic therapy, including both levodopa and direct DAs (Hobson et al., 2002; Razmy et al., 2004; Stevens et al., 2004). A study of 80 patients with PD currently taking DAs who were assessed using subjective ratings of sleepiness, and quantitative measures including overnight polysomnography, the MSLT, and the Maintenance of Wakefulness Test (MWT), showed that approximately 19% had objective pathological sleepiness. The main risk factor associated with EDS was high levodopa equivalents. Subjective assessments of daytime sleepiness measured using the Epworth Sleepiness Scale (ESS) did not correlate with sleepiness measured on the quantitative tests. One interesting observation from this study was that patients taking the highest doses of dopaminergic therapy, who were at the highest risk for EDS, did not accurately report the presence or severity of their daytime somnolence (Razmy et al., 2004). In some patients, medicationinduced somnolence may wane with chronic use (Happe and Berger, 2001). In addition to the roles of the disease process and medications, it has been postulated that nocturnal sleep deprivation may contribute to EDS. This has not been evaluated systematically. Most studies that use polysomnography include patients with PD referred to a sleep laboratory, often with subjective complaints of EDS. The only large study to evaluate sleep architecture in a general sample of patients with PD did not specifically correlate polysomnographic measures of nocturnal sleep with daytime sleepiness (Diederich et al., 2005b). Sleep disorders such as sleep apnea, periodic limb movements during sleep (PLMD), and sleep fragmentation are frequent in PD, and may contribute to daytime sleepiness (Apps et al., 1985; Fitzpatrick, 1995; Arnulf et al., 2002; Young et al., 2002; Poewe and Hogl, 2004; Diederich et al., 2005a), as is found in nonparkinsonian elderly (Coleman et al., 1982; Rosenthal et al., 1984; Seneviratne and Puvanendran, 2004). The presence of snoring, suggesting sleep apnea, is strongly associated with daytime sleepiness

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(Hogl et al., 2003b; Braga-Neto et al., 2004). However, restless legs syndrome (RLS) has not been associated with increased daytime sleepiness (Ondo et al., 2002). It is likely that nocturnal sleep deprivation due to sleep disorders confers a susceptibility to EDS that may be enhanced or triggered by use of dopaminergic medications (Comella, 2003).

Evaluation An evaluation of EDS includes an interview for EDS and a neurological examination. Specific inquiry into daytime sleepiness often brings out symptoms that the patient may not recognize as associated with the disease, or erroneously associates with the motor symptoms. Additional history from the patient’s caregiver may provide more accurate evidence of the presence and severity of EDS (Razmy et al., 2004). EDS in PD has been assessed with a variety of methodologies, some general and others developed particularly for use in PD. Several subjective measures have been used (Santamaria, 2004). ESS, consisting of items assessing the tendency to doze in eight different situations (Johns, 1991, 1992), has been the most widely used, but has not been validated in the PD population. In patients with PD, as many as 4% who report ESS scores higher than 15 do not report somnolence (Brodsky et al., 2003; Razmy et al., 2004). The Parkinson’s Disease Sleep Scale (PDSS) (Chaudhuri et al., 2002b; Chaudhuri and MartinezMartin, 2004) assesses both nighttime sleep and daytime sleepiness (Figure 60.1). Although this scale has not yet been fully validated or extensively used in PD, it may be a practical clinical screening instrument (Abe et al., 2005). The Scales for Outcomes in PDSleep Scale (SCOPA-S) is another recently developed scale consisting of 11 items to assess sleep disturbances in PD that is undergoing further psychometric testing (Marinus et al., 2003) (Figure 60.2). Objective measures of daytime sleepiness used to evaluate patients with PD include the MSLT and the MWT. These two methods provide quantitative measures of physiological sleepiness and the ability to maintain wakefulness respectively (Stevens et al., 2004). Actigraphy is a useful indicator for diurnal activity levels, although it has not been assessed adequately in PD as a measure of sleep–wake cycles (Van Someren, 1997; Comella et al., 2005).

Treatment The treatment of EDS in PD has not been evaluated systematically, although treatment strategies have been recommended (Kumar et al., 2002; Comella, 2003; Thorpy and Adler, 2005). If a primary sleep disorder

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Fig. 60.1. The Parkinson’s Disease Sleep Scale. Patients are asked to mark their responses according to severity by placing a cross on the 10-cm line. The millimeter scale printed on a transparency (not shown) is then applied on the 10-cm lines to measure the response in decimal figures, 10 representing the best and 0 the worst score. (Adapted from Chaudhuri et al., 2002b. #BMJ Publishing Group.)

is suspected because of nocturnal activity or snoring, the patient should be referred to a sleep laboratory for monitoring. Readjustment of dopaminergic agents, with dose reduction, replacement of one DA for another, or discontinuation of direct DA therapy may improve EDS. Improvement in sleep hygiene during the day with regular sleep/wake schedules, short naps, and regular exercise may also be beneficial. If EDS does not respond to these measures, the use of wake-promoting medications can be considered (Rye, 2006). Wake-promoting agents including bupropion, methylphenidate, amphetamines, and modafinil have been used for the treatment of EDS in narcolepsy (Silber, 2001; Chakravorty and Rye, 2003; Rye, 2006). Amphetamines have addictive properties, can cause disruption of nocturnal sleep with adverse cardiovascular effects, and therefore are rarely used for the treatment of somnolence in patients with PD. Modafinil is a novel wake-promoting agent whose mechanism of action is not fully understood. Modafinil has been evaluated in open-label and controlled trials for

Fig. 60.2. The Scales for Outcomes in Parkinson’s diseaseSleep Scale (SCOPA-S) consists of two parts: the NS subscale addresses nighttime sleep problems with a maximum score 15, and the DS subscale addresses daytime sleepiness with a maximum score of 18 (higher scores correlate with more severe sleep problems). An additional question evaluates overall sleep quality on a seven-point scale (not included in the overall NS score). (Adapted from Marinus et al., 2003. #Associated Professional Sleep Societies.)

the treatment of EDS associated with PD. Modest improvement in ESS scores and global rating scores of sleepiness was reported in patients with PD treated with modafinil at doses 100–200 mg per day (Hogl et al., 2002; Adler et al., 2003). A third controlled trial, however, did not show any benefit from modafinil (Ondo et al., 2005). A small open-label study showed that modafinil may reduce sleep attacks, and therefore allow for titration of dopaminergic agents in patients with PD with sleepiness (Nieves and Lang, 2002). Modafinil does not affect the motor symptoms of PD; side-effects are rare and include insomnia, constipation, dizziness, diarrhea, raised blood pressure, and hot flashes.

DISORDERS OF NOCTURNAL SLEEP Nighttime sleep disturbances are common in PD, affecting up to 90% of patients (Lees et al., 1988; Factor et al., 1990; Tandberg et al., 1998). Sleep disturbances are more prevalent among patients with PD compared with healthy controls. In a study of 239 patients with PD, 60% reported sleep problems, compared with 45% of patients with diabetes and 33% of healthy controls (Tandberg et al., 1998). The most common sleep disorders in PD include sleep fragmentation secondary to recurrent PD symptoms, rapid eye movement (REM)

SLEEP DISORDERS IN PARKINSON’S DISEASE sleep behavior disorder (RBD), sleep apnea, and RLS/ PLMD (Comella, 2003).

Sleep fragmentation Sleep fragmentation is the most common sleep disturbance in PD (Factor et al., 1990). It has numerous causes, including nocturia (Lees et al., 1988; Suchowersky et al., 1995; Kumar et al., 2002; Kuno et al., 2004), pain (Goetz et al., 1987), depression, chronic health problems, and medication use (benzodiazepines) (Barbar et al., 2000). Other primary sleep disorders may also contribute to nocturnal sleep fragmentation in PD. Although the sleep maintenance insomnia in PD may vary in individual patients over time, its frequency overall remains high (Gjerstad et al., 2007). The recurrence of PD symptoms during the night is a frequent cause of sleep fragmentation. Although the motor symptoms of PD may be lessened during sleep, electrophysiological studies have shown a recurrence of tremor in the later stages of sleep (April, 1966; Stern et al., 1968; Askenasy and Yahr, 1990), increased muscle activity (Askenasy and Yahr, 1985; Askenasy, 1993), bradykinesia manifested by difficulty turning over in bed (Stack and Ashburn, 2006), akathisia (Linazasoro et al., 1993), painful dystonia and dyskinesias (van Hilten et al., 1993, 1994). Treatment with levodopa may improve these nighttime symptoms (Bergonzi et al., 1975; Askenasy and Yahr, 1985; Juncos et al., 1987; Lees, 1987; Jansen and Meerwaldtt, 1990; Sage and Mark, 1991; Van den Kerchove et al., 1993). Similar improvements have been observed with apomorphine and cabergoline (Priano et al., 2003; Romigi et al., 2006). Although antiparkinson medications may improve nocturnal sleep due to alleviation of PD symptoms, they may also cause sleep disruption and alter sleep architecture (Kales et al., 1971; Brunner et al., 2002; Hogl et al., 2003a; Comella et al., 2005). Levodopa has been shown, at least acutely, to alter REM sleep (Kales et al., 1971; Lavie et al., 1980) and give rise to vivid dreams (Nausieda et al., 1982). The direct DAs may increase nocturnal activity, as assessed using polysomnography or actigraphy (van Hilten et al., 1994; Hogl et al., 2003a; Comella et al., 2005). Vivid dreaming, nightmares, and hallucinations are causes of frequent awakenings in a subset of patients with PD (Grandas and Iranzo, 2004). It has been postulated that dopaminergic induced sleep fragmentation is an early stage of later developing dopaminergic-related hallucinations (Moskovitz et al., 1978; Nausieda et al., 1982, 1984). Although this may be the case in susceptible patients, sleep disruption has not been found to be the primary cause of hallucinations in longitudinal studies (Pappert et al., 1999; Goetz et al., 2005).

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REM sleep behavior disorder (RBD) and REM sleep without atonia (RWA) RBD was initially described in 1986 (Schenck et al., 1986). The salient features of RBD include loss of muscle atonia during REM sleep, and the occurrence of dream enactment behaviors (Schenck et al., 1988, 1989). REM sleep without atonia (RWA) is manifested as abnormal muscle activation during REM sleep without overt behavior (Schenck and Mahowald, 2002). It has been speculated that RBD may be an indicator of presymptomatic PD (Postuma et al., 2006). A followup evaluation of the patients with RBD showed that as many as 38% subsequently developed a parkinsonian disorder (Schenck et al., 1996). About half of patients with RBD and coexistent neurodegenerative disorder report the onset of RBD prior to the initial clinical manifestations of their neurodegenerative disorder (Olson et al., 2000).

EPIDEMIOLOGY RBD and RWA have been observed in as many as 50% of patients with idiopathic parkinsonism (Comella et al., 1993, 1998; Gagnon et al., 2002; Scaglione et al., 2005). The variability in the frequency of RBD can be attributed in part to differences in the selection and referral patterns of patients with PD, and the differing methods of ascertainment, some studies using clinical criteria and others polysomnography. RBD and RWA are more frequent in patients with parkinsonian disorders, including multiple systems atrophy and dementia with Lewy bodies (Plazzi et al., 1997; Boeve et al., 2001, 2003b; Vetrugno et al., 2004; Iranzo et al., 2005; Boeve and Saper, 2006), than in idiopathic parkinsonism. In PD, RBD has been reported to be more common in men than in women, and occurs at a more advanced age and stage of the disease (Scaglione et al., 2005). RBD may also be associated with longer duration and higher daily doses of dopaminergic medications (Ozekmekci et al., 2005).

CLINICAL

FEATURES

The clinical features of RBD in PD range from nocturnal vocalizations to complex, vigorous behaviors (Schenck and Mahowald, 1991; Comella et al., 1998). RBD may be sufficiently violent to cause injuries to patients and/or caregivers, including ecchymosis, lacerations, fractures, and dislocations (Comella et al., 1998; Olson et al., 2000). Episodes of RBD happen after the first hours of sleep, when REM periods begins, and become more frequent in the early hours of the morning, coinciding with more prolonged REM periods. RBD tends to fluctuate in frequency and severity, often

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occurring sporadically (Pacchetti et al., 2005). The use of antidepressants with serotonergic activity may exacerbate symptoms (Onofrj et al., 2003; Winkelman and James, 2004). Over 50% of patients with PD and RBD have hallucinations or delusions (Pacchetti et al., 2005). One longitudinal study of patients with PD followed for the onset of RBD and hallucinations over an 8-year period showed that the occurrence of RBD increased over time, affecting 6% of patients at baseline and 34% after 8 years. This study further showed that RBD and hallucinations were related (Onofrj et al., 2002). Patients with PD and RBD may have mild cognitive deficits on frontal lobe testing (Sinforiani et al., 2005). In those without cognitive impairment, EEG spectral analysis has shown slowing in frontal, parietal, and occipital areas (Gagnon et al., 2004). Clinical criteria alone are only about 33% sensitive in making the diagnosis of RBD. Polysomnography may be needed to determine the presence of RBD (Eisensehr et al., 2001). Furthermore, other disorders, such as sleep apnea, may mimic the clinical history of RBD (Iranzo et al., 2005). Polysomnographic findings of RBD in PD include excessive chin muscle tone, limb jerking, and dream enactment during REM sleep.

PATHOPHYSIOLOGY RBD may predate motor symptoms of parkinsonism by many years (Schenck et al., 1996; Olson et al., 2000; Boeve et al., 2003b), and has been hypothesized to be an early marker for Lewy body disorders that precedes the onset of motor symptoms (Boeve et al., 2006). Other early markers for PD have included reduction in olfaction, visual abnormalities, constipation, and cardiac sympathetic denervation (Langston, 2006). Patients with primary RBD have recently been shown to have similar olfactory dysfunction and visual impairments, as well as subtle motor abnormalities, not sufficient to diagnose parkinsonism, but suggesting that in some patients RBD may be a harbinger of PD (Stiasny-Kolster et al., 2005; Postuma et al., 2006). Taken together, these observations suggest that the degenerative process in PD may begin outside the substantia nigra. These clinical observations are supported by pathological evidence indicating that degeneration begins in the extranigral brainstem areas and the olfactory bulb, prior to the onset in the substantia nigra (Hishikawa et al., 2003; Jellinger, 2003). Additional evidence supporting this hypothesis comes from neuroimaging studies in primary RBD (Albin et al., 2000; Eisensehr et al., 2000, 2003; Hilker et al., 2003). One

study assessing striatal presynaptic dopamine transporters using IPT-SPECT (N-(3-iodopropene-2-yl)-2betacarbometoxy-3beta-(4-chlorophenyl) tropane singlephoton emission computed tomography) showed that both patients with subclinical and those with clinically manifest RBD showed progressive reductions in dopamine transporters, placing them between normal controls and clinically manifested PD (Eisensehr et al., 2003). The anatomical areas involved in RBD include the pedunculopontine nucleus (PPN), locus coeruleus and subcoeruleus complex, gigantocellular reticular nucleus, and dorsal raphe (Gagnon et al., 2006). These areas are also affected in PD. PPN was shown to have marked depletion of cholinergic neurons with Lewy body formation (Hirsch et al., 1987). It is clear that RBD is not specific for PD. It is more frequent in other parkinsonian disorders, including multiple system atrophy and dementia with Lewy bodies, and is more likely to present at an earlier stage in these disorders (Boeve et al., 2001; Iranzo et al., 2005). Recently, it has also become evident that RBD may not be specific for the synuclein pathology, with observations of the disorder in nonsynuclein disorders, such as progressive supranuclear palsy and spinocerebellar ataxia (Friedman et al., 2003; Arnulf et al., 2005).

TREATMENT

OF

RBD

IN

PD

There are no controlled trials of pharmacotherapy in RBD. Small doses of clonazepam (0.25 mg as initial dose) have been found to reduce or eliminate the symptoms (Schenck et al., 1987; Olson et al., 2000; Ozekmekci et al., 2005; Schenck and Mahowald, 2005). Donepezil was reported to improve RBD in three patients (Ringman and Simmons, 2000). Melatonin has been observed to be effective at doses ranging from 3 to 12 mg in 14 patients with parkinsonism (Kunz and Bes, 1997, 1999; Takeuchi et al., 2001; Boeve et al., 2003a, 2004). Pramipexole has been beneficial in five patients (Fantini et al., 2003).

RBD, EDS,

AND HALLUCINATIONS IN

PD

Approximately 40% of patients with PD have dopaminergic medication-induced hallucinations. A clinically based study showed that severe cognitive impairment, duration of PD, and daytime sleepiness were independent predictors of visual hallucinations (Fenelon et al., 2000). A cross-sectional study showed that 82% of patients with PD and medication-induced hallucinations had a sleep disturbance (Pappert et al., 1999). A longitudinal study further reported that severe sleep disturbance was associated with the development of hallucinations (de Maindreville et al., 2005). One hypothesis suggests that hallucinations in PD arise

SLEEP DISORDERS IN PARKINSON’S DISEASE from REM sleep disruption with the intrusion of dream imagery into waking hours (Comella et al., 1993; Arnulf et al., 2000; Manni and Mazzarello, 2001; Manni et al., 2002). Support for this hypothesis was provided by studies using polysomnography and the MSLT that demonstrated an increased occurrence of nighttime RBD and abnormal REM sleep during daytime napping (Arnulf et al., 2000; Rye et al., 2000). Daytime hallucinations were often coincident with daytime REM intrusions (Arnulf et al., 2000). The simultaneous occurrence of RBD and REMrelated hallucinations suggests that in some patients, dysregulation of REM sleep may be the primary factor in the pathogenesis of dopaminergic medication-induced hallucinations. The presence of coexistent hallucinations and RBD is associated with a more pronounced cognitive impairment affecting short- and long-term memory, logical abilities, and frontal cognitive processing in patients with PD (Sinforiani et al., 2006). The presence of abnormal motor behaviors with characteristic polysomnographic recordings may help to differentiate between RBD and REM-related hallucinations. The occurrence of REM sleep during the MSLT is a characteristic polysomnographic finding in narcolepsy (Chakravorty and Rye, 2003). A narcolepsy-like phenotype has been described in 39% of sleepy patients with PD (Arnulf et al., 2002; Rye, 2003, 2006), and ventricular CSF hypocretin levels are reduced (Drouot et al., 2003). In contrast to narcolepsy, cataplexy has not been described in PD, and a recent study suggested that there is little overlap between these disorders (Baumann et al., 2005).

Sleep-disordered breathing Irregular respirations with worsening respiratory patterns during sleep and central hypoventilation were first observed in postencephalitic parkinsonism (Strieder et al., 1967). In idiopathic parkinsonism, increased respiratory rates while awake and during REM sleep were observed in 12 patients, without evidence of hypoventilation or sleep apnea (Apps et al., 1985). Subsequently, sleep apnea has been inconsistently associated with PD. In early, untreated PD, the occurrence of sleep apnea did not differ from that in normal age-matched controls (Ferini-Strambi et al., 1992; Wetter et al., 2000), and 31% of patients with PD assessed by polysomnography were shown to have sleep apnea (Ferini-Strambi et al., 1992). In 54 sleepy patients with more advanced PD who were referred to a sleep laboratory, 20% had moderate to severe sleep apnea (Arnulf et al., 2002). Other studies, although demonstrating sleep disruption, did not find

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increased respiratory abnormalities when comparing advanced with mild PD (Young et al., 2002). These discrepancies may be related to different methodologies, inclusion criteria, patient selection, differing medication regimens, and specific definitions of sleep-disordered breathing. Although it is not clear whether obstructive sleep apnea is more common in PD than in age-matched controls, it is of interest that most studies reporting sleep apnea note that the body mass index of patients with PD who have obstructive sleep apnea/hypopnea syndrome (OSAHS) is not increased (Efthimiou et al., 1987; Arnulf et al., 2002; Maria et al., 2003; Diederich et al., 2005a), in contrast to the general population in which an increased body mass index is a strong predictor for obstructive sleep apnea (Schafer et al., 2002). In most PD series, the apnea index is mild to moderate, although one study indicated that moderate to severe sleep apnea was present in 20% of patients (Arnulf et al., 2002). Snoring was found in up to 73% of patients with PD (Maria et al., 2003). In early PD, nocturnal respiratory parameters did not differ from those in normal controls (Wetter et al., 2000). The frequency of sleep apnea may increase with increasing PD duration and severity (Maria et al., 2003), although this association has not been found in other studies (Young et al., 2002). Sleep-disordered breathing may be less prevalent in idiopathic parkinsonism than in other parkinsonian disorders, such as multiple system atrophy (Wetter et al., 2000). The pathophysiology of OSAHS in PD is not fully understood. It has been hypothesized that OSAHS in PD may be linked to the brainstem areas involved in PD, or to the respiratory muscle involvement that can improve following administration of levodopa (Nakano et al., 1972; Hovestadt et al., 1989; Fitzpatrick, 1995; Herer et al., 2001; Yoshida et al., 2003). Polysomnography is required to evaluate the presence and severity of sleep apnea, and should be obtained in patients with PD with EDS and/or a history suggestive of sleep apnea (Arnulf, 2005; Rye, 2006). Although continuous positive airway pressure is a widely accepted and effective treatment for OSAHS, it has not been evaluated systematically in idiopathic parkinsonism.

RLS and PLMD in PD RLS is common disorder affecting approximately 7% of the population. It increases with aging. Several studies have addressed the prevalence of RLS in the PD population; documented rates are between 8% and 20% (Table 60.1). RLS has a marked response to levodopa. SPECT revealed subtle evidence of decreased

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A. VIDENOVIC AND C.L. COMELLA

Table 60.1 Prevalence of restless legs syndrome in Parkinson’s disease No. of subjects

Prevalence (%)

Reference

IRLSSG criteria

PD

Controls

PD

Controls

Comments

Nomura et al., 2006

þ

165

131

12

2.3

Braga-Neto et al., 2004 Krishnan et al., 2003

 þ

86 126

none 128

49.9 7.9

n/a 0.8

Kumar et al., 2002 Ondo et al., 2002 Tan et al., 2002

 þ þ

149 303 125

115 none none

14.1 20.8 0

1 n/a n/a

PSQI score higher in patients with PD/RLS versus patients with PD without RLS and controls Higher prevalence than in Caucasians RLS investigated with a single question Depression more prevalent in patients with PD/RLS Lower ferritin levels in patients with PD/RLS RLS investigated with a single question Lower ferritin levels in patients with PD/RLS RLS prevalence in PD similar to that in general population

IRLSSG, International Restless Legs Syndrome Study Group; PD, Parkinson’s disease; PSQI, Pittsburg Sleep Quality Index; RLS, restless legs syndrome.

basal ganglia dopamine activity in patients with RLS (Poewe and Hogl, 2004). Despite the responsiveness to dopaminergic agents, alterations of dopamine activity, and the suggestion of increased frequency of RLS in PD, these two entities are distinct. The increased frequency of RLS in PD is likely to arise from confounds such as an associated iron deficiency (Ondo et al., 2002). Although patients with RLS have depleted iron stores in dopaminergic areas without dopaminergic cell depletion (Connor et al., 2003), patients with PD have an increased iron content in the basal ganglia (Graham et al., 2000). Patients with PD and RLS have more pronounced nocturnal sleep dysfunction relative to those without RLS (Nomura et al., 2006). The relationship between RLS/PLMD and EDS in PD has not been studied extensively. Available data show that patients with PD with daytime somnolence do not have more frequent RLS or PLMD (Arnulf et al., 2002; Ondo et al., 2002; Braga-Neto et al., 2004). When RLS and PD coexist, the pharmacological approaches include direct DAs (ropinirole, pramipexole, pergolide), anticonvulsant medications (gabapentin), opioids, and clonazepam. Levodopa is not used to treat RLS because of the frequent occurrence of augmentation (the occurrence of RLS symptoms earlier during the day with increased severity and more body areas affected) (Guilleminault et al., 1993; Allen and Earley, 1996). DAs are considered first-line therapy in moderate to severe PD. Although these medications have been evaluated as a treatment of PD motor

symptoms, they have not been assessed adequately as a treatment for PD/RLS. Alternatively, gabapentin, benzodiazepines, and opioids may be used for the treatment of RLS and PLMD in PD.

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patients with Parkinson’s disease and multiple system atrophy. Sleep 23: 361–367. Winkelman JW, James L (2004). Serotonergic antidepressants are associated with REM sleep without atonia. Sleep 27: 317–321. Yoshida T, Kono I, Yoshikawa K et al. (2003). Improvement of sleep hypopnea by antiparkinsonian drugs in a patient with Parkinson’s disease: a polysomnographic study. Intern Med 42: 1135–1138. Young A, Home M, Churchward T et al. (2002). Comparison of sleep disturbance in mild versus severe Parkinson’s disease. Sleep 25: 573–577.

Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 61

Sleep disorders in neurodegenerative diseases other than Parkinson’s disease 1

2

R. ROBERT AUGER 1 * AND BRADLEY F. BOEVE 2 Mayo Center for Sleep Medicine, Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA

Mayo Center for Sleep Medicine, Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA

INTRODUCTION The relationship between neurodegenerative diseases and sleep disorders is increasingly being recognized, as is the profound effect of impaired sleep on health in general. We begin this chapter by discussing normal age-related changes in sleep/wakefulness processes, attempting where possible to correlate these changes with clinical sleep disturbances. It is our hope that such a background will enhance understanding of the sleeprelated findings of neurodegenerative diseases, and/or generate further hypotheses. The bulk of the literature addressing this topic involves patients with Alzheimer’s disease (AD), and the focus is therefore necessarily weighted in this direction. It should be noted, however, that a substantial number of patients with typical clinical features of AD are not confirmed to have this condition when examined post mortem, and prove instead to have other dementing illnesses such as dementia with Lewy bodies (DLB). This is an important caveat, considering the fact that some sleep disorders, such as rapid eye movement (REM)-sleep behavior disorder (RBD), are closely associated with specific neurodegenerative illnesses, and thus their presence may be of diagnostic and pathophysiological significance. The review of neurodegenerative diseases commences with a discussion of circadian dysrhythmias in dementia, followed by a review of RBD, and the significance of its presence in the setting of dementia. The phenomenon of nocturnal agitation will be examined subsequently, followed by a discussion of the role of medications in the exacerbation of insomnia, with a particular emphasis on cholinesterase inhibitors. An exploration

of primary sleep disorders in association with neurodegenerative diseases will ensue, with a particular focus on sleep-disordered breathing and restless legs syndrome (RLS). We will proceed with a comprehensive literature review regarding multiple system atrophy and progressive supranuclear palsy, followed by a review of investigations of other neurodegenerative diseases for which comparatively fewer data are available. We conclude with evidence-based recommendations regarding the symptomatic treatment of insomnia.

CHANGES IN SLEEP WITH NORMAL AGING Overview Sleep-related symptoms are common in elderly patients. A study by the National Institute on Aging comprising over 9000 community-dwelling individuals (aged 65 years and over) reported that more than 50% of the cohort described having at least one of five sleep complaints occurring on a chronic basis. These included difficulty initiating or maintaining sleep, early awakening, requiring a nap during the day, or feeling poorly rested (Foley et al., 1995). An increased prevalence of medical and psychiatric illnesses is felt to be primarily responsible for this age-related increase in sleep disturbances, as demonstrated by the relatively low prevalence of insomnia in healthy individuals from this study (Foley et al., 1995) and other studies (Vitiello et al., 2002). Longitudinal studies similarly demonstrate a low incidence of insomnia in those without a depressed mood or impaired physical health (Foley et al., 1999).

*Correspondence to: R. Robert Auger, M.D., Mayo Center for Sleep Medicine, Gonda 17W. 200 First Street, SW. Rochester, MN 55905, USA. Tel: 507-266-7456, Fax: 507-266-7772, E-mail: [email protected]

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The cumulative data therefore suggest that sleep disturbance is not a result of the aging process per se, and that underlying etiologies should be actively sought in those with complaints related to sleep. In a prospective study of a large number of communitydwelling elderly residents, insomnia was the strongest predictor of both mortality and nursing home placement in the male cohort (Pollak et al., 1990), and in a large observational study a subjective complaint of daytime sleepiness predicted increased mortality (Newman et al., 2000). Well established associations with sleep disturbances include painful medical conditions, pulmonary disease, congestive heart failure, gastrointestinal disorders, incontinence, and menopause (Sleep Research Society, 2005). In addition, 60–90% of patients with major depression report insomnia (Weissman et al., 1996; McCall et al., 2000; Ohayon et al., 2000), and up to 44% report hypersomnia (Novick et al., 2005). Although their relative contribution to sleep disturbance is uncertain with the available data, the prevalence of primary sleep disorders also increases with age, some of which appear to be particularly pronounced in those with neurodegenerative diseases. However, poor health does not explain all of the sleep complaints of older adults. Both objective and subjective measures of sleep quality may still decline in older adults who remain healthy, and approximately 27% describe at least one chronic sleep complaint (Morin and Gramling, 1989; Foley et al., 1995; Ohayon et al., 2004). Following is a summary of the phenomena that may contribute to age-related changes in sleep in otherwise healthy individuals.

Changes in sleep architecture with normal aging Objective sleep parameters change with age, and include a decrease in sleep efficiency (time asleep divided by time in bed), decreased percentage of REM and slow-wave sleep (SWS), and a related increase in the remaining nonrapid eye movement (NREM) stages of sleep (Van Cauter et al., 2000). Apart from continued deterioration of sleep efficiency, however, there are no significant changes in these measurements after the age of 60 years (Ohayon et al., 2004), and it is therefore unlikely that these ontogenetic findings contribute predominantly to increased sleep-related complaints with progressive age.

et al., 1998; Carrier et al., 1999; Yoon et al., 2003). Numerous physiological studies also report age-related advances of circadian rhythms (Czeisler et al., 1992; Duffy et al., 1998, 2002; Carrier et al., 1999; Yoon et al., 2003), but results have been conflicting overall (Monk et al., 1995; Youngstedt et al., 2001). Campbell and Dawson (1992) investigated whether objective sleep disturbances were associated with phase advances, by exposing seven healthy young adults to morning bright light, while holding the time of sleep constant. The subjects exhibited deleterious changes in sleep architecture, as well as increased wakefulness after sleep onset (WASO), but overall sleep efficiency remained high. A separate study confirmed a greater tendency for a “morningness” circadian preference with advanced age, and demonstrated that this tendency was a significant mediator of numerous age-related changes in sleep (Carrier et al., 1997). It can therefore be concluded that advances in the phase of sleep contribute partially to the sleep fragmentation described in the elderly. However, as this change in entrained circadian phase has not been shown to be accompanied by a change in circadian period with healthy aging (Czeisler et al., 1999), alterations in phase relationships (discussed further below) may be particularly implicated.

Changes in phase relationships A variety of studies have used rigorous circadian protocols to assess the temporal relationship between circadian phase and wake time (i.e., phase relationship), which has also generated conflicting results (Czeisler et al., 1992; Duffy et al., 1998, 2002; Carrier et al., 1999; Yoon et al., 2003). Nevertheless, there are data that suggest that altered phase relationships may play a role in the sleep disturbances of elderly individuals. In one study (Duffy et al., 1998), subjective complaints of maintaining sleep occurred more frequently in elderly subjects when sleep was attempted at abnormal circadian phases. As suggested by these authors, such early awakenings may also have a secondary role in maintaining phase advances via inadvertent exposure to the phase advance portion of the light phase– response curve. A separate group found that the degree of desynchronization between the urinary 6-sulfatoxymelatonin (6-SMT) acrophase and the timing of the sleep period correlated directly with both total sleep time and WASO, as measured by polysomnography (Youngstedt et al., 1998a).

Advances in circadian phase Age-related changes in the timing of sleep have been described frequently. Older people generally retire earlier at night and awaken earlier in the morning than younger individuals (Czeisler et al., 1992; Duffy

Changes in melatonin excretion and circadian rhythmicity Age-related reductions in circadian rhythm amplitudes have been described in a variety of endocrine and

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES neuroendocrine substances, as reviewed by Touitou and Van Cauter & colleagues, and described by others (Iguichi et al., 1982; Sack et al., 1986; Young et al., 1988; Waldhauser et al., 1988; Bojkowski and Arendt, 1990; Skene et al., 1990a; Touitou, 1995; Van Cauter et al., 1998; Kennaway et al., 1999; Ferrari et al., 2000), but on an inconsistent basis (Kennaway et al., 1999; Zeitzer et al., 1999; Fourtillan et al., 2001). In view of the large intersubject variation in melatonin production (Arendt, 1995), longitudinal studies will ultimately be required to resolve the question of whether its concentration declines with age. Of major importance from a practical standpoint, studies addressing clinical correlations are scarce, and similarly conflicting. One study of healthy elderly individuals demonstrated an association between core body temperature amplitude and decreased sleep efficiency, in the setting of an abrupt advance in the sleep–wake cycle (Carrier et al., 1996). Another study of otherwise healthy, relatively medication-free, elderly adults complaining of depression or insomnia failed to show a correlation between any parameter of 24-hour melatonin excretion rhythms (as measured by 6-sulfatoxymelatonin, the urinary metabolite of melatonin (6-SMT)) and various actigraphically and polygraphically determined sleep measurements (Youngstedt et al., 1998a).

Changes in the circadian photic input pathway DYSFUNCTION

OF LIGHT TRANSMISSION

The photic input pathway mediating circadian regulation by light is distinct from the visual system, and is comprised of the retina–retinohypothalamic tract– suprachiasmatic nuclei (SCN)–pineal axis (reviewed in Brainard et al., 2001). The circadian rhythmicity of melatonin secretion is regulated via this pathway, and its output is inhibited by light. Circadian dysfunction can occur if there is an aberration in the reception of the light stimulus itself, or at any point within the aforementioned pathway. Measurable abnormalities in melatonin secretion can therefore serve as a proxy for upstream disturbances within the axis. As environmental light is the major source of entrainment of the human circadian system, dysfunction in reception of this stimulus is a potential explanation for age-related declines in melatonin production and abnormalities in rhythm, although this remains unproven. Cataracts and maculopathy are more common in the elderly (Meisami et al., 2002), and with aging there is a progressive decline in the capacity of the lens to transmit short wavelength light (Lutze and Bresnick, 1991), as well as a reduction in short-wavelength responsive cone (S-cone) sensitivity (Suzuki

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et al., 1998). Interestingly, a separate population of photoreceptors in retinal ganglion cells has been identified, distinct from rods and cones, with particular sensitivity to short-wavelength light, resulting in potent suppression of melatonin (Brainard et al., 2001; Thapan et al., 2001). Melanopsin is thought to be the visual pigment within these structures that is responsible for transducing photic information via the retinohypothalamic tract (Hattar et al., 2002). Semo et al. (2003) described an approximately 40% reduction in the number of melanopsin-positive retinal ganglion cells in aged mice compared to their younger counterparts, and an agerelated reduction in short-wavelength sensitivity has recently been demonstrated in a case–control study of elderly women (Herljevic et al., 2005). Nevertheless, two studies of healthy elderly humans have demonstrated maintained responsiveness of the circadian pacemaker to light of varying intensities (3500 lux or above), as assessed by both core body temperature and serum melatonin levels (Klerman et al., 2001; Benloucif et al., 2005). Moreover, evening bright light exposure has been demonstrated to be an effective treatment for elderly individuals with sleep maintenance insomnia (Campbell et al., 1993).

SUPRACHIASMATIC

NUCLEI

Research involving the SCN logically complements studies involving melatonin, as this is the master circadian pacemaker in mammals, and regulates the circadian rhythmicity of multiple physiologic variables (Moore and Eichler, 1972; Stephan and Zucker, 1972). Global neurodegeneration of the SCN with aging has been demonstrated (Swaab et al., 1985), in addition to a loss of circadian and seasonal variation in the number of vasopressin-expressing neurons in elderly versus younger individuals (Hofman and Swaab, 1994, 1995). One group demonstrated a reduced sensitivity in aged hamsters to the photic induction of the phosphoprotein Fos in the SCN, which corresponded to a decrease in the phase-shifting effects of light on the circadian rhythm of locomotor activity (Zhang et al., 1996). Using a smaller number of subjects, the same group demonstrated a small, wavelength-dependent decrease in light transmittance through the ocular lens of older hamsters, but no significant differences with respect to retinal innervation of the SCN (Zhang et al., 1998). Taken together, these findings suggest that neither senile changes in lens transmittance nor age-related changes in the retinohypothalamic tract can account entirely for changes in light sensitivity in these aged hamsters, suggesting either a process intrinsic to the SCN itself, or a decline in photoreceptor

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sensitivity. In an intriguing complementary human study involving healthy older subjects, investigators compared the phase-delaying effects of experimentally manipulated moderate-intensity light (using core body temperature and melatonin assays) with those of younger subjects from a prior experiment, and found that the older group exhibited decreased sensitivity in their phase responses, despite an overall preserved reaction to the stimulus itself (Duffy et al., 2007).

CHANGES

IN THE PINEAL GLAND

Studies investigating the production site of melatonin have also been conflicting. One showed a loss of rhythmicity in melatonin concentration in the post-mortem pineal glands of aged human subjects compared with a younger cohort, as demonstrated by a lack of significant day–night concentration differences with measurements in the former group (Skene et al., 1990b). A separate post-mortem study of pineal tissue demonstrated a significant difference in this variable only among a limited range of younger age groups, however, and also noted a significant effect of time of death and length of photoperiod, highlighting the complexity of such assessments (Luboshitzky et al., 1998). Calcium content in the pineal gland (thought to reflect the degree of inactive pinealocytes) increases with age in rats (Humbert and Pevet, 1991), and uncalcified pineal gland volumes in a group of 26 humans were positively associated with melatonin excretion (Kunz et al., 1999). Thus, progressive hypoactivity of the pineal gland is a potential explanation for a decline in melatonin production. However, as mentioned above, the clinical relevance of decreased production is debatable, and the very existence of the phenomenon is the subject of some controversy. Moreover, the pineal gland findings themselves are conflicting, as a separate case report found significant pineal calcification in the setting of organ hyperactivity (Puig-Domingo et al., 1992).

ENVIRONMENTAL

LIGHT EXPOSURE

Although overall responsiveness to light appears to remain intact in elderly humans (Klerman et al., 2001; Benloucif et al., 2005), the intensity of the stimulus may be reduced, both in community-dwelling and institutionalized individuals. In a case–control study of a relatively small number of nondemented elderly nursing home residents suffering from insomnia, subjects showed diminished nocturnal melatonin secretion versus controls, which correlated with comparatively lower levels of environmental light (Mishima et al., 2001). Total light exposure was also significantly lower compared with that in a separate age-matched control group without insomnia complaints. Midday exposure to bright light of 4 hours’

duration for 4 weeks (comparable to that received by controls at baseline) restored melatonin levels to those of controls, and significantly decreased nocturnal wake time, as assessed by actigraphy. As significant phase shifts were not observed, the physiological mechanism influencing this change is not clear (Mishima et al., 2001). There is also evidence to suggest that community-dwelling elderly people are exposed to reduced illumination levels in their daily lives. A study by Campbell et al. (1988) showed that healthy elderly controls received approximately 69% of the duration of bright light received by healthy young subjects, although this difference was not significant owing to large intragroup variability.

Nonphotic circadian inputs to the SCN Activity-induced phase shifts are accomplished via a pathway separate from the retinohypothalamic tract, namely through the intergeniculate leaflet and the geniculohypothalamic tract. The effects of aging on this pathway have been studied in hamsters, but have produced conflicting results. One such study demonstrated partial or total unresponsiveness to the phaseshifting effects of activity in old hamsters (Van Reeth et al., 1992), whereas another study found that this effect was preserved (Duncan and Deveraux, 2000). In a case–control study involving a small number of young and elderly human subjects, mean phase shifts with exercise (as assessed by the dim-light melatonin onset) were comparable in both groups, although there was greater variability in response in the elderly group, underlining the need for larger sample sizes for further clarification (Baehr et al., 2003).

Behavioral factors Voluntary behavior may also influence circadian rhythms and other sleep parameters. In one study (Yoon et al., 2003), older subjects who took evening naps showed earlier sleep-offset times and a more advanced acrophase of the 6-SMT rhythm than older subjects who abstained from evening naps. Correlations were also demonstrated between advanced rhythms and earlier patterns of illumination exposure, however, making it difficult to extricate the relative influence of earlymorning light exposure and/or evening naps on the advancement of circadian rhythms. Supporting the role of the latter variable, Buxton et al. (2000) utilized a constant routine protocol to demonstrate the independent effect of the timing of sleep/darkness on circadian phase in a group of healthy young men. Finally, variations in physical activity also appear to have a bearing on objective sleep indices and cognitive functioning. Naylor et al. (2000) demonstrated an increased percentage of SWS and improvement in memory-requiring tasks in

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES

Summary Further study of the age-related changes concerning sleep structure, circadian physiology (including anatomical correlates), and mitigating environmental and behavioral factors may enhance the understanding of the sleep disturbances associated with normal aging, Alzheimer’s disease, and other neurodegenerative diseases, and generate future hypotheses. Clinical correlations associated with these changes are generally scarce and less than definitive, but there appear to be potential contributions from circadian phase advances, changes in phase relationships, decreased environmental light exposure, in addition to behavioral factors such as evening napping, early-morning exposure to the advanced phase portion of the light response curve, and a decrement in physical activity. (See Chapter 41: Normal and abnormal sleep in the elderly.)

SLEEP DISTURBANCES IN DEMENTING ILLNESSES Overview By 2030, the population of Americans aged 65 years and older is expected to double from approximately 36 million to 71.5 million, and by 2050 will grow to nearly 87 million (National Center for Health Statistics, 2005) (Figure 61.1). The incidence of dementing illnesses increases with the aging process (Figure 61.2),

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and the prevalence of AD in the USA is expected to increase as much as fourfold over the next approximately 50 years (Brookmeyer et al., 1998) (Figure 61.3). The care of these patients is associated with considerable economic burden. During 2002, approximately 7 million Americans aged 65 years and over needed long-term care, a number that is expected to grow to 12 million by the year 2020 (America’s Health Insurance Plans, 2002). The current annual financial impact of AD in the USA is estimated to be $100 billion (Fillit, 2000). Apart from the economic costs, institutionalization of the elderly can be emotionally catastrophic for patients and caregivers alike. 50.00 Incidence Rate (% per year)

healthy residents of a retirement facility after 2 weeks of structured physical and social activities, compared with that in controls who did not receive the intervention.

10.00 5.00 1.00 0.50 Baltimore East Boston Framingham Rochester

0.10 0.05 60 60

70

80 Age (years)

90

Fig. 61.2. Age-specific incidence rates of Alzheimer’s disease on a log scale from four US studies: Framingham, East Boston, Rochester, and Baltimore. (Redrawn with permission from Brookmeyer et al., 1998. #American Public Health Association.)

100

Number of People (millions)

90 80 70 60 50 40

65 and over

30 20 10

85 and over

0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050 Calendar Year Projected

Fig. 61.1. Number of people in the USA aged 65 years and over and aged 85 years and over, in selected years 1900–2000 and projected years 2010–2050. Data refer to resident population. Source: US Census Bureau, Decennial Census and Projections.

U.S. Prevalence of Alzheimer’s Disease (millions)

1016

R.R. AUGER AND B.F. BOEVE 14.0 12.0 10.0 8.0 6.0 4.0 2.0 0 2000

2010

2020 2030 Calendar Year

2040

Fig. 61.3. Projections of Alzheimer’s disease prevalence in the United States: 1997–2047. Estimates and ranges (dashed lines) are based on the mean, minimum, and maximum agespecific incidence rates given in Brookmeyer et al. (1998). (Adapted with permission from Brookmeyer et al., 1998. #American Public Health Association.)

In cross-sectional studies involving clinic or community-based populations of patients with AD, persistent sleep disturbances were found to affect approximately 25–40% (Carpenter et al., 1995; McCurry et al., 1999; Moran et al., 2005). The origins of this problem are at least in part related to innate changes associated with disease progression. One study demonstrated a progressive reduction in the percentage of SWS, and an increased mean number of nighttime awakenings with progressive severity of AD, with significant differences versus controls even in those of mild disease (Vitiello et al., 1990). As sleep/wake variables are highly predictive of the variance in cognitive and functional status within populations of patients with AD (Moe et al., 1995), correction of underlying sleep disturbances may represent an opportunity to improve these parameters. The burden of sleep disturbance is shared by caregivers, as evidenced by the fact that it is a major factor influencing the decision to institutionalize the afflicted patient, ahead of incontinence in one survey report (Pollak and Perlick, 1991). A study of communitydwelling caregivers of spouses with moderate to severe AD demonstrated poorer subjective sleep quality, reduced total sleep time (as assessed by polysomnography), and greater functional impairment compared with noncaregiving controls (McKibbin et al., 2005). Identification and treatment of underlying sleep disturbances therefore provides an additional opportunity to reduce caregiver burden and, potentially, to decrease the rate of institutionalization and associated costs. AD is the most common form of irreversible dementia, present in approximately 60–80% of cases (Boeve and Silber, 2005). DLB occurs in approximately 15–25% of those with irreversible dementia, and is therefore considered the second most common etiology. The frontotemporal dementias, encompassing

Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal lobar degeneration with ubiquitin-positive inclusions, and dementia lacking distinctive histology, account for approximately 10–15% of cases (Boeve and Silber, 2005). The prevalence of vascular dementia is debated, with recent studies suggesting pure vascular dementia probably accounts for less than 20% of cases (Boeve and Silber, 2005). Creutzfeldt–Jakob disease, fatal familial insomnia, and Gerstmann–Straussler–Scheinker syndrome are rare causes of dementia, and comprise the primary human prion disorders (Table 61.1). As mentioned above, most of the literature on sleep disturbances in dementia involves patients with a clinical diagnosis of AD. As some of these patients will prove not to have AD when examined post mortem, much of the literature on this topic has likely included cases with non-AD disorders, and thus the reported findings may not be specific for AD. Furthermore, sleep-related issues may be quite different from one disorder to another, as illustrated by the association between DLB and RBD.

Circadian dysrhythmias, insomnia, and dementia (pertaining primarily to AD) Although the precise incidence and prevalence of circadian dysrhythmias in the demented population are not known, they have been described by several groups, as assessed by polysomnography (Prinz et al., 1982; Vitiello and Prinz, 1989) and actigraphy (AncoliIsrael et al., 1997). An irregular sleep–wake rhythm (American Academy of Sleep Medicine, 2005) appears to be the most prominent circadian sleep disorder in

Table 61.1 Principal causes of irreversible dementia

Type of dementia Alzheimer’s disease Dementia with Lewy bodies Frontotemporal dementias Pick’s disease Corticobasal degeneration Progressive supranuclear palsy Dementia lacking distinctive histopathology Vascular dementia Human prion disorders Creutzfeldt–Jakob disease Fatal familial insomnia Gerstmann–Straussler–Scheinker syndrome

Proportion of cases 60–80% 15–25% 10–15%

20% Rare

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES 1017 this population, and one polysomnographic study spe(residents of the same facility) replicated the findings cifically described this phenomenon in the severely of this group (Satlin et al., 1995; Volicer et al., 2001), demented (50% of whom had a neuropathological and demonstrated significant differences with respect diagnosis of AD), despite a similar amount of total to both patients with FTD and controls, suggesting a sleep time within a 24-hour period, as compared to neurobiological basis for the divergent circadian findage-matched controls (Prinz et al., 1982). Ancoli-Israel ings (Harper et al., 2001). As these investigations did et al. (1989) evaluated a large number of institutionanot perform assessments of the sleep–wake cycle comlized elderly with actigraphic monitoring and found parable to those mentioned above (Pat-Horenczyk et al., that they averaged no more than 40 minutes of sleep 1998; Bliwise et al., 1992), however, the data are not necper hour, and 50% awakened at least 2–3 times per essarily conflicting. It is equally plausible that the phase hour, a phenomenon not differentiated by age, amburelationship between the sleep period and core body lation status, presence of sleep-disordered breathing, temperature is altered, so that sleep onset remains or administration of sedative/hypnotics. Further eviadvanced despite a delay in core body temperature. dence that this disturbance is innate to the neurodegenSuch alterations in phase relationships have been erative process is highlighted in a study by Vitiello and reported for normal elderly patients (Duffy et al., Prinz (1989), which showed that the percentage of day1998, 2002; Yoon et al., 2003), and have been correlated time sleep increased incrementally with severity of AD with sleep disturbances in select instances (Duffy et al., in community-dwelling patients. 1998; Youngstedt et al., 1998a). The occurrence of other circadian rhythm sleep disorders, such as the advanced and delayed sleep phase Changes in melatonin excretion and rhythmicity types (ASPD and DSPD) (American Academy of Sleep Medicine, 2005), also needs to be considered in this Data concerning melatonin parameters in demented population, as their treatments require specific interpatients are less numerous than those regarding the ventions. The prevalence of both conditions is elderly in general, are similarly conflicting in nature, unknown in this population, although ASPD is thought and frequently without clinical correlates. In a case– to occur at a prevalence of 1% in middle-aged adults control study of 10 AD inpatients with disturbed and increase with age (Ando et al., 1995; American sleep/wake rhythms, subjects exhibited reduced serum Academy of Sleep Medicine, 2005). The prevalence melatonin amplitudes compared with age-matched conof DSPD has been estimated at 0.7% in adults (Ando trols, which correlated directly with actigraphically et al., 1995). A more thorough review of these condirecorded nocturnal wakefulness (Mishima et al., tions can be found in Chapter 58. 1999). This finding was not replicated, however, in a separate study of community-dwelling patients with INTRINSIC CORRELATES predominantly mild AD (utilizing 6-SMT), despite the fact that sleep efficiency was significantly decreased Changes in circadian phase (Luboshitzky et al., 2001). Another group specifically Akin to the findings reported for normal aging, one measured melatonin concentrations during the nocturstudy of demented patients showed an advance of nal acrophase in 27 severely demented patients (59% sleep onset (as measured by actigraphy) with proclinical AD), and compared them with levels in healthy gressive severity of dementia (type unspecified) (Patelderly and young subjects (Dori et al., 1994). Similar to Horenczyk et al., 1998). A more homogeneous study other studies involving nondemented elderly patients of community-dwelling patients with AD, utilizing sleep (Iguichi et al., 1982; Waldhauser et al., 1988; Ferrari diaries filled out by caregivers, also demonstrated earet al., 2000), significant differences in amplitude were lier bedtimes versus those in controls (Bliwise et al., demonstrated when comparing elderly to young 1992). As neither study employed physiological assesspatients, but not when comparing demented and nonments, however, the correlation between these findings demented patients of the same age (Dori et al., 1994). and objective circadian measurements is uncertain. Disturbances in the circadian rhythm of melatonin Two case–control studies that utilized core body temsecretion have also been assessed. In one study of perature as a circadian marker actually demonstrated 13 hospitalized demented patients (85% clinical AD) phase delays in demented AD patients of moderate with a history of sleep/wake disturbances, 31% demonor greater severity (Satlin et al., 1995; Volicer et al., strated an arrhythmic pattern of serum melatonin con2001), in addition to increased percentage of nocturnal centration versus approximately 6% of patients activity (measured via piezoelectric monitoring). Morewithout dementia, and 9% of age-matched healthy conover, a separate study in patients with neuropathologitrols (Uchida et al., 1996). Clinical correlations were cally defined AD and frontotemporal dementia (FTD) lacking, however, as only five patients manifested

1018 R.R. AUGER AND B.F. BOEVE sleep/wake disturbances at the time of the study, et al., 1995; Pat-Horenczyk et al., 1998; Harper et al., including four demented patients (50% of those with 2001; Volicer et al., 2001), and correlations have been arrhythmic findings) and one patient (11%) with predemonstrated with subjective and objective sleep disturserved rhythms (Uchida et al., 1996). bances in non-demented elderly individuals (Duffy More convincingly, however, a large study of et al., 1998; Youngstedt et al., 1998a). patients with a neuropathological diagnosis of AD Homogeneity of study populations is important, as demonstrated significant differences in post-mortem Mishima et al. (1997) demonstrated intact body tempercerebrospinal fluid (CSF) melatonin levels compared ature rhythms in hospitalized patients with AD, in conwith age-matched controls (Liu et al., 1999). When trast to rhythms that were disorganized and of low separating the AD patients by apolipoprotein E epsilon amplitude in patients with vascular dementia, despite 4 allele (ApoE4) status, those that were homozygous the fact that the rest–activity rhythm was disturbed in demonstrated significantly lower levels than those that both groups. The authors therefore suggest that the were heterozygous (Liu et al., 1999). A more recent rest activity and temperature rhythms may have a difstudy demonstrated an association between polymorferent pathological basis, but their claims were not bolphic variation at monoamine oxidase A (an enzyme stered by neuropathological confirmation of dementia involved in melatonin synthesis, via degradation of diagnoses. serotonin) and sleep disturbance among an AD cohort (Craig et al., 2006). The cumulative data therefore sugOther circadian assessments gest that decreased CSF melatonin is inherent to the Other reported disruptions of AD patients’ physiology neurodegenerative process, although no relationship include reversal or dampening of diurnal variability in heart has been demonstrated between melatonin levels and rate (Reynolds et al., 1995) and blood pressure (Otsuka the onset, duration, or severity of dementia (Liu et al., 1990), although not necessarily in early-stage disease et al., 1999). Finally, based on the limited data avail(Cugini et al., 1999). One group demonstrated a disable, the pineal gland is unlikely to be responsible for ruption of neuroendocrine circadian parameters in decreased melatonin concentrations, as it has not demented elderly patients (of multiple types) compared demonstrated any of the neuropathological hallmarks with age-matched healthy controls, including a negative of AD (Pardo et al., 1990). correlation with severity of dementia, nocturnal growth hormone secretion, and plasma cortisol measurements, Core body temperature parameters suggesting that these changes were related to increased damage to the central nervous system (Magri et al., The physiological assessment of core body temperature 1997). Finally, indicating the breadth to which hypotha(considered one of the best markers of underlying cirlamic function may be impacted by AD, Young and cadian rhythms) has produced a myriad of findings in Greenwood (2001) reported an association with a shift patients with AD. Okawa et al. (1991) noted disorgato higher relative caloric intake at morning meals in nized body temperature rhythms in 59% of highly those with severe AD, consistent with a phase advance demented (79% multi-infarct dementia, remainder with respect to this variable. AD) nursing home patients versus 12% in controls. Amplitude findings have been less convincing, and Changes in the circadian photic input pathway have been reported not to differ between patients with AD (of varying degrees of severity) and age-matched Dysfunction of light transmission. As described controls (Prinz et al., 1984, 1992; Satlin et al., 1995), above, the photic input pathway mediating circadian even when sleep disturbances were objectively demonregulation by light is distinct from the visual system, strated (Prinz et al., 1992; Satlin et al., 1995). and circadian abnormalities can therefore be construed Nevertheless, in a subgroup of patients with desynas emanating from a decrement in the stimulus itself, chronized core body temperature and locomotor activor from any point of stimulus reception within the ity rhythms, temperature amplitudes were significantly aforementioned circadian axis. It is controversial as blunted, and sleep disturbances were more profound to whether the visual system is affected in patients (Satlin et al., 1995), suggesting that the finding may be with AD, but a decrease in intensity of the light stimusignificant in the setting of altered phase relationships. lus is a plausible contributing factor for circadian dysThe role of such alterations in the sleep disturbances rhythmias in this population. of dementia warrants further investigation, in that preOne large prospective study showed an increased viously mentioned studies have suggested possible aberincident risk of clinically diagnosed AD in those with rations between core body temperature circadian phase advanced age-related maculopathy, but this risk was and the sleep/wake cycle (Bliwise et al., 1992; Satlin of uncertain significance when adjusted for tobacco

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES use and the presence of atherosclerosis (Klaver et al., 1999). Two separate electrophysiological studies noted decreased retinal potentials in electroretinograms targeted to ganglion cells in patients diagnosed with clinical AD, as compared to their age-matched counterparts (Katz et al., 1989; Trick et al., 1989). Even more convincing data have been demonstrated in studies of patients with a neuropathological diagnosis of AD (Hinton et al., 1986; Blanks et al., 1989, 1996a, b). A case–control study demonstrated axonal degeneration in the optic nerve of 80% of patients (Hinton et al., 1986), and the same group demonstrated degeneration of retinal ganglion cells in 75% (Hinton et al., 1986), for an overall 36% reduction in neuroretinal loss as compared to age-matched controls (Blanks et al., 1996a, b). Pathological changes in the retina and optic nerve were clearly distinguishable from those in age-matched controls (Hinton et al., 1986) and consistent with a neurodegenerative process (Blanks et al., 1996a, b). Nevertheless, specimens lacked the typical histopathological features seen in the brains of patients with AD (Hinton et al., 1986; Blanks et al., 1989). Despite these promising results, there are also a number of studies indicating that visual deficits in AD do not stem from neuroretinal dysfunction. In vivo assessments by scanning laser polarimetry of patients with clinical diagnoses of mild to moderate AD demonstrated no differences in retinal nerve fiber layer thickness as compared to controls (Kergoat et al., 2001). More definitively, in contrast to the observed degenerative changes mentioned above, one study noted a comparable reduction in density of retinal ganglion cells in neuropathologically diagnosed patients with AD compared with age-matched controls (Curcio Drucker, 1993), and a separate study reported that myelinated axon number in the optic nerve of post-mortem AD patients were unaffected versus controls (Davies et al., 1995). Suprachiasmatic nuclei. As alluded to above, investigations involving the SCN complement studies assessing circadian parameters, as it is the master circadian pacemaker in mammals, and regulates the circadian rhythmicity of melatonin and other physiological variables. Interestingly, one group demonstrated an approximately 60% decrease in the total SCN cell number in patients with AD (Swaab et al., 1985), in addition to a 68% reduction in gene expression of vasopressin (one of the major neuropeptides in the SCN) (Liu et al., 2000) as compared to age-matched controls.

1019

Detailed post-mortem examination suggested decreased cell counts were particularly localized to the SCN, and did not impact adjacent hypothalamic nuclei, such as the supraoptic and paraventricular nuclei (Goudsmit et al., 1990). Investigation of the specific nature of the pathological damage of the structure revealed neurofibrillary tangle formation (Stopa et al., 1999), providing further evidence that damage to this region is part of the neuropathological process of AD. Curiously, however, neuritic plaques, another characteristic neuropathological feature of AD, were not seen (Stopa et al., 1999). In the clinical arena, a study of hospitalized patients with severe AD and a lack of ophthalmological disorders did not demonstrate the expected melatonin suppression to bright light, whereas both agematched nondemented hospitalized patients and healthy community-dwelling individuals demonstrated preservation of this response (Ohashi et al., 1999). Although these results support a disruption of either afferent or efferent connections emanating from the SCN in the AD group, melatonin parameters were not predictive of sleep disturbances (Ohashi et al., 1999). Environmental light exposure. Decreased environmental illumination exposure has been demonstrated in institutionalized patients with varying severities of dementia (type unspecified) (Ancoli-Israel et al., 1991a, 1997; Shochat et al., 2000). In one nursing home sample, the median daytime light exposure was 52 lux*, and a median of only 10.5 minutes were spent over 1000 lux (Shochat et al., 2000). A separate study demonstrated inappropriately raised daytime melatonin levels in hospitalized elderly patients both with and without dementia, as compared to healthy age-matched community-dwelling subjects, a discrepancy attributed to the low level of light exposure in the hospitalized group (Ohashi et al., 1999). Perhaps less intuitively, however, a study of community-dwelling patients with AD showed that they were exposed to light intensities exceeding 2000 lux significantly less than age-matched controls, suggesting that this phenomenon may be due to more than externally imposed variables (Campbell et al., 1988). With regard to clinical correlations, one large study demonstrated an inverse relationship between daytime light exposure and sleep disturbances in the demented elderly, regardless of the severity of dementia (type unspecified), suggesting that increased 24-hour light exposure can result in sleep improvement (Shochat et al., 2000).

*Note: the lux is the unit of illuminance in the International System. 1 lux is equal to the illumination of a single surface 1 m away from a single candle. The illuminance of direct sunlight is 100,000 lux, but normal daylight, which is filtered through a cloudy sky, is between 5000 and 10,000 lux.

1020

R.R. AUGER AND B.F. BOEVE Unfortunately, no significant differences in actigraphyBEHAVIORAL FACTORS derived sleep measures were demonstrated, although Poor sleep hygiene practices, including decreased physsubjective sleep quality ratings (per caregiver) improved ical activity and excessive sleeping during daytime modestly, and the medication was well tolerated, even at hours, have been described in nursing home populahigh doses (10 mg). Moreover, one patient with a spetions. A study by Schnelle et al. (1998) assessed a large cific circadian rhythm sleep disorder demonstrated a number of residents in eight different nursing homes robust response, suggesting that this medication may during daytime hours, and observed that they were in be useful in selected circumstances for this population bed during 36% of observations, and asleep nearly (Singer et al., 2003). Finally, in vitro experiments have 25% of the time. As opposed to nocturnal disturreported antioxidant and neuroprotective properties of bances, such daytime behaviors may be unrecognized melatonin (as reviewed in Pappolla et al., 2000), which or of little concern to caregivers, and may exacerbate has led to interest in its potential role as a preventative complaints during nighttime hours (Bliwise et al., and therapeutic agent in AD. 1990; McCurry et al., 1999). A separate study correThe substance is not regulated by the US Food and lated subjective daytime sleepiness among patients Drug Administration (FDA), and is available as a nutriwith AD to impaired functional status (independent tional supplement. Verification of purity of the product of level of cognitive impairment), and highlighted the is therefore difficult. With regard to safety concerns, a need to assess systematically whether improvement of comprehensive review by the National Academy of daytime alertness could ameliorate functional disability Sciences stated that, given available data, short-term (Lee et al, 2007). use of melatonin in total daily doses of 10 mg or less Environmental noise related to activities in the in healthy adults appears to be safe, but that caution workplace has also been shown to have deleterious should be heeded when administering to children or to effects on the sleep of institutionalized patients women of reproductive age (Committee on the Frame(Schnelle et al., 1998). Further highlighting the contribuwork for Evaluating the Safety of Dietary Supplements, tion of extrinsic variables and sleep disturbance, one 2005). Adverse effects have been reported at higher study showed that the average duration of nighttime doses, however, and even at lower doses in those with sleep episodes in incontinent nursing home residents preexisting central nervous system, cardiovascular, gaswas 20 minutes, and the average longest duration trointestinal, or dermatological conditions (Committee of sleep episode was 84 minutes, for an overall poor on the Framework for Evaluating the Safety of Dietary sleep efficiency of 66% (Schnelle et al., 1993). This Supplements, 2005). Ramelteon, a melatonin receptor disruption was attributed in part to caregiver reposiagonist hypnotic that is FDA-approved for indefinite tioning, highlighting the importance of equating sleep use, may be an option if concerns arise regarding quality with other medical cares. over-the-counter melatonin, but its use has not been studied specifically in the demented population. SPECIFIC TREATMENTS Melatonin

Light therapy

Reflecting the numerous studies previously discussed, the use of melatonin for sleep disturbances has been explored in both healthy and demented elderly patients. In a systematic review of six small randomized controlled trials (RCTs) investigating its use (0.5–6 mg) for insomnia in relatively healthy older people, positive effects on objective sleep quality were noted in all but one study (Olde Rikkert and Rigaud, 2001). These improvements were evidenced predominantly as decreased sleep latency (as measured by actigraphy or polysomnography), particularly in patients with chronic benzodiazepine use. As the studies did not demonstrate improvements of subjective sleep quality, however, their clinical relevance is debatable. A large, multicenter, placebo-controlled trial investigated the use of melatonin as a treatment for sleep disturbances in the AD population (Singer et al., 2003).

Many studies have examined the effects of bright light therapy on specific sleep parameters, but in general the results have been equivocal, due to confounding variables such as small numbers of subjects, heterogeneous dementia populations, exclusive use of subjective ratings, different timing, duration, mode, and intensity of light exposure, and uncontrolled research designs (reviewed in Ancoli-Israel et al., 2002). In the largest controlled trial to date of institutionalized patients with AD, both evening and morning bright light (2500 lux, 2 hours’ duration for each condition), administered for a period of 10 days, were superior to the sham treatment with regard to actigraphically determined sleep consolidation, with improvements of about 35% (Ancoli-Israel et al., 2003) (Figure 61.4). As nocturnal sleep disturbance is one of the more burdensome caregiver complaints, this treatment may

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES

Max Sleep B out (Min)

150 130

Treatment

110 90 70 50 Baseline

Days 1-5

Morning Bright Evening Bright

Days 6-10

Follow-up

Morning Dim Red

Fig. 61.4. Treatment of circadian dysrhythmias: phototherapy with bright or dim red light. (Redrawn with permission from Ancoli-Israel et al., 2003. #Taylor and Francis.)

have substantial impact. These results were not replicated, however, in a more recent RCT (also utilizing actigraphic measurements) of institutionalized patients with AD who received morning or afternoon bright light of similar intensity (2500 lux, 1 hour duration for each condition), 5 days of the week, for 10 weeks (Dowling et al., 2005). These discrepant results are admittedly difficult to compare, however, due to truncated treatment duration, both on a daily and weekly basis, in the latter (Dowling et al., 2005) as compared to the former (Ancoli-Israel et al., 2003) study. It is noteworthy that both studies showed overall minimal impact on measured circadian rhythms (regardless of the timing of treatment), suggesting that the response to light at different circadian phases is altered in AD, perhaps due to deterioration in the SCN (Ancoli-Israel et al., 2003; Dowling et al., 2005). This finding may be important in and of itself, as altered phase relationships are thought to play a role in the sleep disturbances of elderly individuals (Duffy et al., 1998; Youngstedt et al., 1998a). Nevertheless, subjects receiving evening light in the earlier study (Ancoli-Israel et al., 2003) demonstrated strengthening of the circadian activity rhythm, and subjects in either treatment group of the more recent study (Dowling et al., 2005) demonstrated relative stability of the rest–activity acrophase as compared to the control group, who exhibited a mean phase delay as the study ensued. Moreover, a study of severely demented inpatients (the majority with a clinical diagnosis of AD) found that an increase in daytime environmental illumination increased stability of the rest–activity rhythm in visually intact patients, as measured by actigraphy (Van Someren et al., 1997), and objective improvements in sleep (also actigraphically determined) were seen in nondemented elderly nursing

1021

home residents with increased exposure to daytime light, as described above (Mishima et al., 2001). A recent study of demented inpatients (type unspecified) investigated the use of bright ambient light (not requiring patients to remain stationary), and demonstrated beneficial (and similar) effects in actigraphically measured nighttime sleep in those receiving either “all day” light or morning light, as compared to those receiving evening light or placebo (Sloane et al., 2007). Based on these cumulative data, it appears that increased 24-hour light exposure, regardless of timing, is most likely to result in beneficial effects on sleep and circadian rhythms. Clearly, the optimal intensity, duration, and timing of exposure to light is yet to be established, but the treatment appears to have potential for sleep disruption in those with AD. Moreover, it is possible that benefits from treatment accrue over the long term, as bright light therapy has been shown to prevent the age-related loss of vasopressin-expressing neurons in the SCN of rats (Lucassen et al., 1995), the gene expression of which is markedly reduced in patients with AD (Liu et al., 2000). Finally, given that shortwavelength light has recently been found to be more effective than longer wavelengths at suppressing melatonin, future treatments may be further refined (Brainard et al., 2001; Thapan et al., 2001).

Dementia with Lewy bodies and REM sleep behavior disorder OVERVIEW RBD is an important consideration in the differential diagnosis of elderly patients with sleep disturbances, as it can result in significant injury, is readily treatable, and its presence may assist in the diagnosis of specific neurodegenerative diseases. Although normal REM sleep is characterized by skeletal muscle atonia, RBD is characterized by a lack of atonia during REM sleep, with resultant injurious or disruptive behavior, often as a result of dream enactment. The condition is diagnosed definitively with polysomnography, and requires the appearance of sustained or intermittent elevation of submental electromyographic (EMG) tone and/or excessive phasic submental or limb EMG activity, combined with either video documentation or a frank history of movements during REM sleep (American Academy of Sleep Medicine, 2005). Self-injury from RBD has been reported in 32–79% of patients, ranging from minor ecchymoses to subdural hematomas (Schenck et al., 1993; Olson et al., 2000). Assaults on the bed partner occur in approximately two-thirds of cases and result in injuries in 16% (Olson et al., 2000). Differentiating RBD from other causes of nocturnal agitation can usually be

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R.R. AUGER AND B.F. BOEVE

accomplished by taking a careful history. RBD is shortlived and tends to occur during the second half of the night (when REM sleep typically occurs), and involves vigorous limb movements and vocalizations. Dream content is frequently recalled, mirrors observed behaviors, and predominantly involves a defensive scenario against attack (Olson et al., 2000). The condition most often affects men (approximately 87%), commences in the sixth or seventh decade (Schenck et al., 1993; Olson et al., 2000), and is associated with neurological disorders in 48–75% (Schenck et al., 1993; Sforza et al., 1997; Olson et al., 2000). A large body of clinical and autopsy data suggests that this condition is more frequently found in Parkinson’s disease (PD), DLB, and multiple system atrophy (MSA) (Schenck et al., 1993, 1997b; Uchiyama et al., 1995; Sforza et al., 1997; Arnulf et al., 2000; Olson et al., 2000; Turner et al., 2000; Boeve et al., 2001, 2003b, 2007). All of these disorders are characterized by abnormal deposition of a-synuclein in the cytoplasm of neurons or glial cells, and are referred to collectively as the “synucleinopathies”. (For purposes of clarification, classification of other neurodegenerative diseases based on histopathological features is provided in Table 61.2.)

COGNITION

AND

RBD

The significance of RBD in association with dementia has been explored in several studies. One group investigated the clinical characteristics of 37 such patients with and without parkinsonism, and described impairment in visual perceptual organizational skills, constructional praxis, and verbal fluency, all characteristics of DLB, rather than AD (Boeve et al., 1998). Thirty-four (92%)

Table 61.2 Neurodegenerative diseases Type of disorder

Conditions

Synucleinopathies

Parkinson’s disease (PD) Dementia with Lewy bodies (DLB) Multiple system atrophy (MSA) Alzheimer’s disease (AD) Pick’s disease Corticobasalganglionic degeneration (CBGD) Progressive supranuclear palsy (PSP) Huntington’s disease (HD) Spinocerebellar atrophy (SCA) Fatal familial insomnia (FFI) Creutzfeldt–Jakob disease (CJD)

Tauopathies

Polyglutamine diseases Prionopathies

of these patients met formal criteria for clinically possible or probable DLB (McKeith et al., 1996). In addition, three patients were autopsied, and all had limbic Lewy bodies (with or without additional neocortical Lewy bodies) (Boeve et al., 1998). A subsequent study compared the psychometric tests of 31 patients with dementia and RBD to 31 controls with autopsy-proven AD (Ferman et al., 1999). The RBD group showed significantly worse performance in measures of attention, visual perceptual organization, and letter fluency, whereas the AD group had significantly worse performance on confrontation naming and verbal memory, a pattern of cognitive differences similar to that reported between DLB and AD. Most recently, neuropsychometric features were explored in patients with dementia and RBD, but without accompanying parkinsonism or visual hallucinations (Ferman et al., 2002). Neurocognitive data from this group were compared with the profiles of patients with clinically probable DLB and neuropathologically diagnosed AD. The neurocognitive profile between the probable DLB and dementia with RBD groups did not differ and, when compared with the AD group, both groups had worse visual perceptual organization and sequencing, and better confrontation naming and verbal memory. In addition, of the 14 patients (56%) with dementia with RBD for whom follow-up information was available, 9 (64%) developed visual hallucinations and/or parkinsonism 1–6 years after the initial evaluation. The cumulative data therefore imply that, whether or not parkinsonism or visual hallucinations are present, the presentation of dementia accompanied by RBD is suggestive of an underlying diagnosis of DLB, and it is now officially regarded as such (McKeith et al., 2005). Despite this strong clinical affiliation, however, the precise sensitivity and specificity of the concomitant presence of these two disorders has not yet been determined. However, to date, more than 97% of all patients with RBD plus dementia who have undergone postmortem examination have demonstrated Lewy body pathology (Schenck et al., 1997b; Turner et al., 2000; Boeve et al., 2001, 2003b; Boeve and Saper, 2006), and there have been no pathologically confirmed cases of RBD in pure AD, Pick’s disease, FTD, or vascular dementia (Boeve et al., 1998, 2001, 2003b). If future analyses support the RBD–synucleinopathy association, the presence of this sleep disorder could have significant pathophysiological implications, as early detection of evolving neurodegenerative diseases may be possible.

IDIOPATHIC RBD When not accompanied by a neurological disease, RBD is deemed idiopathic. In some instances, however, this condition may be the presenting symptom of an evolving

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES disease, and precede other neurological manifestations by many years. Studies by Schenck et al. (1996, 2003) demonstrated that 65% of 26 patients with idiopathic RBD developed a parkinsonian disorder or dementia within a mean of 13 years of onset of symptoms. There are additional data that support the presence of synuclein pathology in idiopathic cases. In a retrospective study, RBD was recalled as the first manifestation of 52% of patients with RBD and PD, 60% with dementia and RBD, and 36% with RBD and MSA (Olson et al., 2000). The median time from onset of RBD to onset of other symptoms of the neurological disorder was 3–4 years. Recent literature shows that, even in the absence of a discretely associated neurological disorder, patients with RBD frequently exhibit subclinical abnormalities on testing of color vision, olfactory function, cognition, motor function, and autonomic function, with a pattern typically seen in patients with synucleinopathies (Ferini-Strambi et al., 1996, 2004; Fantini et al., 2002, 2003b, 2005, 2006; Stiasny-Kolster et al., 2005; Postuma et al., 2006). Intriguing neuroimaging studies supplement these findings. Mazza et al. (2006), utilizing single-photon emission computed tomography, demonstrated cerebral perfusion abnormalities in eight elderly subjects with idiopathic RBD compared with nine controls, with an anatomical metabolic profile consistent with that of patients with PD. A study investigating 17 cognitively normal adults with dream-enactment behavior showed a reduced cerebral metabolic rate for glucose in regions preferentially affected in patients with DLB (Caselli et al., 2006). This has led some to suggest that the term “cryptogenic” be used in lieu of the term “idiopathic” (Mahowald, 2006) but, until recently (Teman et al., 2009), available studies have not included younger cohorts. Iatrogenic factors have been attributed to select cases of RBD or REM sleep without atonia (RSWA), the presumed substrate for RBD. Case reports regarding its association with antidepressants date nearly 30 years (Guilleminault et al., 1976; Bental et al., 1979; Schenck et al., 1992; Niiyama et al., 1993; Schutte and Doghramji, 1996), also reviewed by Winkelman and James (2004). Perhaps more convincingly, a case–control retrospective study by Winkelman and James (2004) showed that subjects receiving serotonergic antidepressants have an increased frequency of RSWA. RBD has also been associated with the use and withdrawal of other medications and substances (Gross et al., 1966; Greenberg and Pearlman, 1967; Tachibana et al., 1975; Hishikawa et al., 1981; Stolz and Aldrich, 1991; Silber, 1996; Iranzo and Santamaria, 1999; Plazzi et al., 2002; Vorona and Ware, 2002), and in

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association with other sleep disorders (Schenck and Mahowald, 1992; Schenck et al., 1997a). There is controversy regarding the relationship between RBD and psychiatric disturbances (Hurwitz et al., 1998), but several studies have shown potential relationships between severe stress or posttraumatic stress disorder (Hefez et al., 1987; Schenck et al., 1988; Sugita et al., 1991; Ross et al., 1994; Husain et al., 2001) and RBD.

PATHOGENESIS The pathogenesis of RBD is not clear. Pontomedullary pathways are involved in the suppression of muscle activity in REM sleep, and interruption of these pathways in cats results in abnormal REM motor behavior (Hendricks et al., 1982). It has therefore been postulated that lower brainstem pathology may result in RBD. Some authors have also suggested that RBD is part of the wide spectrum of dopamine deficiency disorders. Functional neuroimaging studies have shown decreased nigrostriatal dopaminergic projections in association with idiopathic RBD (Albin et al., 2000; Eisensehr et al., 2000), but it is uncertain whether this finding has direct relevance on the pathophysiology of RBD, or whether patients simply exhibited a subclinical state of PD. It is not known why the a-synucleinopathies appear to be associated with RBD, and the association remains a subject of debate, as will be discussed further below. It is possible that the anatomical site of the pathology is most important. Pathogenetic findings are further discussed in the section of MSA, and in greater detail elsewhere in this book (see Chapter 53).

TREATMENT Although few studies have directly investigated treatments for the sleep disturbances of patients with DLB, there are multiple options available for the treatment of RBD. Despite the absence of controlled studies, current data support clonazepam (0.25–1.5 mg) as first-line treatment for this condition (Schenck and Mahowald, 1990; Schenck et al., 1993; Olson et al., 2000). If clonazepam is contraindicated or ineffective, melatonin (3–12 mg) may be considered, either alone or in conjunction with clonazepam (Kunz and Bes, 1999; Takeuchi et al., 2001; Boeve et al., 2003a). An independent role for ramelteon, a melatonin receptor agonist, has not been investigated. Other agents with anecdotal benefit include donepezil (Ringman and Simmons, 2000), carbamazepine (Bamford, 1993), triazolam (Olson et al., 2000), clozapine (Olson et al., 2000), and quetiapine (Boeve et al., 2002). Two case series suggest that pramipexole may also be effective (Fantini et al., 2003a; Schmidt et al., 2006). Nonpharmacological measures

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are always indicated, and consist primarily of protecting the bedroom environment.

Hallucinations and nocturnal agitation OVERVIEW Even in the absence of RBD, hallucinations and nocturnal agitation are commonly associated with sleep disturbances in the demented population, and are frequently subsumed under the term “sundowning”. The wide-ranging prevalence estimates of this phenomenon (2–25%) in institutionalized patients with AD reflects the dependency of this nonspecific term on the particular behavior of investigation, the assessment instrument used, and the duration of observation (Cohen-Mansfield, 1989; Martin et al., 2000). As mentioned above, underlying medical illnesses need to be considered in all patients presenting with sleep disturbances, a point that warrants particular emphasis in the case of nocturnal agitation, which may be indicative of an underlying delirium. An important prospective study noted that new-onset delirium in geriatric patients was associated with poor nutritional status, use of physical restraints, insertion of a bladder catheter, addition of four or more medications, and other events, such as fecal impaction or acute infection (Inouye and Charpentier, 1996). Some also believe that nocturnal agitation can result from an innate chronobiological disturbance (Lebert et al., 1996; Volicer et al., 2001). As alluded to previously, one study (Volicer et al., 2001) correlated the magnitude of core body temperature delay in patients with AD to the propensity for behavioral symptoms to occur in the afternoon or early evening (i.e., “sundowning”), providing a potential physiological correlate to such behaviors. As dementia progresses, the differentiation between dream mentation, visuoperceptual dysfunction, and reality can become blurred, which can also contribute to nocturnal agitation. This appears frequently to be contributory in DLB and PD with dementia (Boeve et al., 2002). As recent data suggest that hallucinations in PD without dementia may represent REM sleep intrusions (Arnulf et al., 2000), it is possible that a similar process contributes to hallucinations in those with DLB and PD with dementia, which are thought to possess the same disease substrate.

PHARMACOLOGICAL

TREATMENTS

There are frequently instances where nocturnal agitation is associated with the underlying neurodegenerative disease itself, and not with a specific sleep disorder, medical disorder, or other secondary factor. Three atypical neuroleptics, olanzapine, risperidone,

and quetiapine, have demonstrated efficacy in the treatment of psychosis and behavioral disturbances in elderly patients, the former two of which underwent large RCTs (Katz et al., 1999; Street et al., 2000; Fujikawa et al., 2004). Two of these studies (Street et al., 2000; Fujikawa et al., 2004) specifically studied patients with AD, and the other investigated a demented population consisting primarily of patients with AD (73%) (Katz et al., 1999). Although there are few data to guide selection among these agents, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE-AD) study did not find significant differences in efficacy or tolerability among the three agents, although time to discontinuation due to lack of efficacy was greater for olanzapine and risperidone than for quetiapine (Schneider et al., 2006). As somnolence is a prominent side-effect of these agents (Katz et al., 1999; McManus et al., 1999; Street et al., 2000), they see much off-label use as sedative hypnotics in those with sleep-related behavioral disturbances. However, given the recent “black box” warning placed on their labels, in addition to demonstration of generally modest efficacy (Schneider et al., 2006), the pros and cons of their use should be considered on a case by case basis. The drugs are not technically approved for treating dementia-related disturbances, and an analysis of 17 controlled trials involving these patients revealed a risk of death approximately 1.7 times that seen in placebo-treated patients, mostly due to cardiovascular or infectious causes (Stone, 2005). Given their demonstrated efficacy, and potential for improved quality of life for patients and their caregivers, these risks need to be balanced against the inherent risk of agitation. Numerous other agents have been investigated for the general treatment of agitation in demented patients of various etiologies, but no studies have addressed nocturnal agitation specifically. Three RCTs demonstrated positive findings with carbamazepine (Tariot et al., 1998) and citalopram (Pollock et al., 2002), and negative findings with divalproex sodium (Tariot et al., 2005). A separate RCT involving patients with moderate to severe AD receiving stable doses of donepezil showed a decrease in agitation in those receiving concomitant memantine (an N-methyl-D-aspartate receptor antagonist) (Tariot et al., 2004). As these studies often employ comparisons of point differences on quantitative scales, clinical meaningfulness is often debatable. Two case reports describe a beneficial effect of donepezil on the cognitive disturbances of patients with DLB (Kaufer et al., 1998), and anecdotal benefit is described in a large number of case series and reports involving demented patients of varying etiologies, including trazodone (Houlihan et al., 1994) and selegiline (Schneider et al., 1991). Beta-blockers have

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES 1025 also been described as effective in a variety of case et al., 2003; Dowling et al., 2005), suggesting that the reports and one small RCT, all involving patients diagresponse to light at different circadian phases is altered nosed with AD (reviewed in Weiler and Goodman, in AD, perhaps due to deterioration in the SCN. 1987). Two case reports also describe efficacy for zolAlessi et al. (1999) described decreased agitation in pidem (10–15 mg) in nocturnal wandering associated 47% of demented inpatients after implementing a variwith AD (Shelton and Hocking, 1997). ety of sleep hygiene principles, including increased daytime physical activity, and a decrease in nocturnal noise from attending staff. Finally, although not studied sysNONPHARMACOLOGICAL TREATMENTS tematically, behavioral treatments and potential anteceAs mentioned above, an inverse relationship between dents for agitation have been reviewed by Carlson daytime light exposure and sleep disturbances in the et al. (1995), who recommend reducing external stimulademented elderly has been described (Shochat et al., tion, gentle redirection of the patient when agitated, 2000), and an increase in daytime environmental illumiand appropriate modification of caregiver behavior to nation has been shown to increase the stability of the address misperception of actions and affects. rest–activity rhythm (Van Someren et al., 1997). In addition, timed bright light has been shown to improve sleep Medication-induced insomnia in consolidation (Ancoli-Israel et al., 2003) and stabilize demented patients rest–activity rhythms (Ancoli-Israel et al., 2003; Dowling Medication use can also contribute to poor sleep in the et al., 2005), but with conflicting results. elderly population. Central nervous system stimulants, At least two studies involving small numbers of beta-blockers, bronchodilators, calcium channel blockpatients have specifically evaluated the effect of light ers, corticosteroids, decongestants, antidepressants, on agitated behaviors. In an open trial, Satlin et al. antihistamines, and thyroid hormones are all known (1992) investigated the effects of evening bright light to contribute to insomnia. In addition, sedating drugs treatment (1500–2000 lux, 2 hours duration) for 7 days may lead to excessive daytime sleepiness, which may on AD inpatients with afternoon/nocturnal agitation, in turn contribute to insomnia (Sleep Research Society, and described improvement of sleep consolidation (as 2005). In the case of dementing illnesses, the medicaassessed by nurses’ behavioral observations), and tions used to treat these conditions can themselves increased stability of the locomotor activity rhythm result in deleterious sleep effects. Donepezil (up to (as assessed by actigraphy), with a trend toward 10 mg) has been associated with incident insomnia in advancing the acrophase. Although individual agitation up to 18% in two large RCTs investigating its efficacy ratings (including documentation of use of restraints, in patients with AD (Rogers et al., 1998; Burns et al., medications, and clinical ratings) did not change signi1999). In addition, several case reports have described ficantly during the assessment, composite scores vivid dreaming and nightmares in association with this designed to assess the severity of sundowning medication (Ross and Shua-Haim, 1998; Yorston and improved significantly, and sundowning severity was Gray, 2000), possibly related to its propensity to increase in turn related to the degree of instability of the rest/ REM density (Schredl et al., 2006). Clinical experience activity rhythm. A more recent RCT by Lyketsos suggests that morning instead of nighttime dosing of et al. (1999) assessed the effects of treatment of instidonepezil can ameliorate these nocturnal effects. tutionalized demented patients (majority with a clinical With regard to other cholinesterase inhibitors, diagnosis of AD) with morning bright light (10,000 lux, galantamine has been the most rigorously studied with 1-hour duration) for 4 weeks, and demonstrated an regard to sleep-related outcomes (in patients with AD), approximately 2-hour increase in caregiver-assessed and did not demonstrate deleterious effects compared total nocturnal sleep time, but no differences in ratings to placebo, at a dose of 24 mg daily (Markowitz of behavioral disturbances, a discrepancy perhaps paret al., 2003). A pilot RCT comparing actigraphically tially due to the fact that the investigators excluded and subjectively determined sleep effects of galantapatients who met independent criteria for sleep–wake mine and donepezil in community-dwelling patients cycle disturbances, as defined by the Diagnostic and with AD and in their caregivers demonstrated no cliniStatistical Manual of Mental Disorders (American cally significant evidence of sleep fragmentation, and Psychiatric Association, 2000). Guidance regarding trends toward beneficial effects of galantamine were the nature and timing of light therapy in the treatment described (Ancoli-Israel et al., 2005a). of agitation is difficult to ascertain, as studies have not Rivastigmine (up to 12 mg) demonstrated no worsshown shifts in circadian rhythms that are predictable ening of sleep in patients with DLB per subjective with the knowledge of the light phase–response curve assessment on the neuropsychiatric inventory in one in normal individuals (Satlin et al., 1992; Ancoli-Israel

R.R. AUGER AND B.F. BOEVE

study, but demonstrated objective disturbances of sleep, in the form of decreased sleep efficiency and total sleep time (at a dose of 1 mg), in a separate study of young healthy subjects (Holsboer-Trachsler et al., 1993; McKeith et al., 2000). Perhaps most importantly, however, in a study that evaluated the efficacy of rivastigmine in patients with AD after 2 years of treatment, the incidence of insomnia was not markedly different between the active treatment and placebo groups at the three assessment points, and there was actually a higher rate of insomnia in the placebo group at the 2-year assessment (Grossberg et al., 2004). Case reports of nightmares do not exist for these latter two medications, but our clinical experience clearly shows that nightmares as well as insomnia can occur with galantamine and rivastigmine. In young healthy subjects, both agents increased REM density. In the rivastigmine group, the magnitude of this phenomenon was related directly to increasing dose (maximum dosage 2 mg), but in the galantamine group the effect was observed at 10 mg, and negatively correlated with increased dose (Holsboer-Trachsler et al., 1993; Riemann et al., 1994). Therefore, there is no convincing evidence that cholinesterase inhibitors will promote better sleep in dementing illnesses; there is some evidence that donepezil can impair sleep; and further evidence that sleep is not markedly impaired by rivastigmine or galantamine. In those with worsened sleep of any kind with nighttime dosing of any of these agents, morning dosing of donepezil can be tried, as can administration of the second daily dose of galantamine and rivastigmine to early evening.

Obstructive sleep apnea in dementing illnesses (pertaining primarily to Alzheimer’s disease) There are conflicting data as to whether obstructive sleep apnea (OSA) is more common in patients with AD (Reynolds et al., 1985b; Bliwise et al., 1989). A large genetic study demonstrated an association between the ApoE4 allele and OSA, strongest in those under the age of 65 years (Gottlieb et al., 2004), although the potential mechanism underlying this finding is unclear. As there is a marked increase in intracranial pressure and changes in cerebral perfusion during apneic events (Siebler et al., 1990; Hayakawa et al., 1996), one would expect that OSA would more likely be associated with vascular dementia, if indeed there is a relationship. As OSA is common in the elderly population, however, reaching a prevalence of approximately 20% by the age of 65 years (Young et al., 2002), it is frequently comorbid with dementing illnesses (Figure 61.5).

0.3 0.25 SDB Prevalence

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0.2 0.15 0.1 0.05 0 35

45

55 65 Age in Years

75

85

Fig. 61.5. Prevalence of obstructive sleep apnea (OSA) by age. SDB, sleep-disordered breathing. (Redrawn with permission from Young et al., 2002. #American Thoracic Society.)

Indeed, one study showed that the severity of dementia (type unspecified) correlated with the severity of OSA (Ancoli-Israel et al., 1991b), suggesting cumulative deleterious effects on cognition. The effects of sleepdisordered breathing on cognition are further highlighted by several reports of patients initially diagnosed with delirium or dementia, who were later found to have OSA, with cognitive symptoms responsive to nasal continuous positive airway pressure (CPAP) therapy (Scheltens et al., 1991; Lee, 1998; Munoz et al., 1998). Many studies involving nondemented patients have demonstrated that untreated OSA results in dose-dependent neuropsychological deficits, excessive daytime sleepiness, diminished mood, and decrements in quality of life (Cartwright and Knight, 1987; Bedard et al., 1991; Redline et al., 1997). Deleterious effects may be due either to chronic intermittent hypoxia or to sleep deprivation and subsequent daytime sleepiness (Bedard et al., 1991; Roehrs et al., 1995). Dampening of general intellectual performance, as assessed by global scales, as well as more specific deficits of executive function, appear most directly related to the degree of nocturnal hypoxemia, whereas attention and memory deficits seem to be related to daytime sleepiness (Bedard et al., 1991). One group analyzed those with at least moderate severity OSA (mean respiratory disturbance index 41.0  4.5, range 14.2–75.0) for frontal lobe dysfunction and demonstrated significant decrements in the ability to initiate new mental processes and to inhibit automatic ones, in conjunction with a tendency to demonstrate perseverative errors. Patients were also affected by deficits of visual and verbal learning abilities, and had reduced memory spans. Intermittent hypoxemia (versus typical anoxic cerebral damage), in conjunction with daytime sleepiness, was considered to be responsible for the uniqueness of this profile, as compared to those with typical frontal lobe damage (Naegele et al., 1995).

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES 1027 Treatment of severe OSA with CPAP for 6 months OTHER SLEEP DISORDERS LIKELY improved most deficits in one study, and restored the TO BE COMORBID WITH deficits attributable to impaired daytime vigilance to NEURODEGENERATIVE DISEASES those of normal controls (Bedard et al., 1993). Some Restless legs syndrome/periodic limb specific executive deficits, previously attributed to the movements of sleep degree of nocturnal hypoxemia, were found to persist, however, suggesting the possibility of irreversible RLS is characterized by unpleasant urges to move the anoxic brain damage to selected regions (Bedard limbs, precipitated by rest, temporarily relieved by et al., 1993). In patients with the most severe OSA activity, and worse or exclusively present during evenfrom another series (Naegele et al., 1995), treatment ing hours (American Academy of Sleep Medicine, with CPAP for 4–6 months normalized all previously 2005). Although the data are less than definitive, there described impairments, with the exception of shortis some suggestion that RLS may be more common term memory-related tests (Naegele et al., 1998). As in specific neurodegenerative illnesses, including PD objective measures were not obtained in this popula(Menza and Rosen, 1995), MSA (Iranzo et al., 2000), tion, it remains unclear as to whether the remaining spinocerebellar ataxia 3 (SCA-3) (Schols et al., 1998; deficits could be attributed to residual sleepiness. Iranzo et al., 2003), and Huntington’s disease (HD) Equally important on a clinical level, treatment of (Evers and Stogbauer, 2003). Regardless of the veracity OSA with CPAP has been shown to restore decrements of these associations, it is a very prevalent condition, in quality of life to levels comparable to that in the norseen in approximately 10% of those over the age of 65 mal population (Jenkinson et al., 1997), and also demonyeas (Rothdach et al., 2000), and therefore also likely strated improved symptoms of depression in two RCTs to be comorbid with AD and other dementing illnesses. (Engleman et al., 1994, 1997). All of the above highlight As it is a purely clinical diagnosis, challenges are the importance of detecting OSA at an early stage of imposed by those with limited historical abilities, but it severity, and emphasize its characterization as a largely should be considered in the differential diagnosis in anyreversible cause of cognitive impairment. one with sleep disturbances and/or nocturnal wandering. Although, overall, published results are lacking in Bed partners can often provide sufficient historical the demented population, preliminary results from a details that raise suspicion for RLS. RCT utilizing CPAP therapy demonstrated improveAt least 80% of patients with RLS exhibit periodic ments in cognitive parameters in patients with mild to limb movements of sleep (PLMS) (defined as a periodic moderate AD and concomitant OSA (mean apnealimb movement index (PLMI) >5/hour) (Montplaisir hypopnea index (AHI) 27.1) after a period of 3 weeks et al., 1997a), but the specificity of this finding is low. (Ancoli-Israel et al., 2006). In particular, Wisconsin The prevalence of PLMS increases significantly with Card Sorting Test scores, a measure of mental flexibilage, with estimates of 45% in older adults compared ity, were improved, suggesting that treatment with this with 5–6% in younger adults (Sleep Research Society, modality may offer additional improvement beyond 2005). Moreover, there is considerable debate in the that achieved by cholinesterase inhibitors. Subjective literature as to the clinical significance of this finding. sleepiness, as measured by the Epworth Sleepiness Twenty-two elderly individuals with a mean PLMI of Scale (Johns, 1991), also improved, and compliance 34.5/hour demonstrated no correlation between the with CPAP did not differ between the AD and control index and subjective insomnia, number of arousals, groups (Chong et al., 2006). Interestingly, preliminary subjective or objective total sleep time, or other polyresults from one group showed improvement of OSA somnographic parameters (Youngstedt et al., 1998b). in patients with mild–moderate AD from donepezil Similarly, no correlation was found between complaints alone, with a conjectural role of cholinergic stimulation of insomnia or subjective and objective sleepiness (Moraes et al., 2008). It remains to be seen whether (assessed by a multiple sleep latency test, MSLT) and these results are generalizable to the severely demented the PLMS arousal index in 67 patients with a variety population. of sleep disorders (Mendelson, 1996). A more homogeFinally, of potential relevance to the burdened careneous group of 34 patients with PLMS and daytime givers of demented patients, data from the nondemensleepiness (but without other sleep disorders) similarly ted population describe significant improvement in demonstrated no correlation between the PLMI and spouse sleep parameters with initiation of CPAP in either the mean MSLT sleep latency or polysomnogram the affected partner (Beninati et al., 1999), in addition sleep efficiency, and the eventual diagnosis was that of to quality-of-life improvement (Parish et al., 2003). idiopathic hypersomnia (Nicolas et al., 1998). Finally, Comparable data do not yet exist for the demented with a large sample size, Ancoli-Israel et al. (1991c) population. demonstrated modest correlations with PLMS and

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general dissatisfaction with sleep, but no correlations were found with reports of daytime sleepiness. Various studies have shown a high prevalence of PLMS in samples of patients with a wide range of sleep disorders, including narcolepsy, RLS, OSA, RBD, and PD (reviewed by Montplaisir et al., 2000). They are therefore common in the elderly and in patients with a wide range of different sleep symptoms and disorders, and may simply represent epiphenomena of frequently dubious clinical significance. The somewhat controversial diagnosis of periodic limb movement disorder is ascribed to a patient when PLMS are thought to result in sleep disturbance, but, as noted above, is it clearly a diagnosis of exclusion (American Academy of Sleep Medicine, 2005). Although frequently a primary phenomenon, secondary causes of RLS or PLMS should always be considered. RLS is associated with iron deficiency, and ferritin levels of 50 mg/l or less are correlated with increased disease severity (Sun et al., 1998). If low stores are identified, sources of blood loss should be pursued vigorously. Other secondary causes include chronic renal failure (Winkelman et al., 1996, 2002; Collado-Seidel et al., 1998) and peripheral neuropathy (Iannaccone et al., 1995; Polydefkis et al., 2000). Less well established iatrogenic causes of RLS or PLMS include treatment with neuroleptics (Horiguchi et al., 1999; Kraus et al., 1999) and lithium (Heiman and Christie, 1986; Terao et al., 1991). A recent large retrospective study confirmed an association with PLMS and the use of selective serotonin reuptake inhibitors or venlafaxine (but not bupropion) (Yang et al., 2005), but another study failed to demonstrate such a correlation with antidepressants and RLS (Brown et al., 2005). Pharmacotherapy consists primarily of the dopaminergic agents (Silber et al., 2004), and two agents, ropinirole and pramipexole, have recently been approved by the FDA for this purpose. These agents should be used with caution in those with psychosis, and are also associated with insomnia. In one series, 68% of treated PD patients complained of insomnia, and an increased prevalence was correlated with the duration of levodopa therapy (Nausieda et al., 1982). Paradoxically, the dopaminergic agents are also rarely associated with hypersomnia, due to an unknown mechanism (Frucht et al., 1999; Montastruc et al., 2001; Hobson et al., 2002). Finally, 8–40% of treated PD patients experience visual hallucinations, and approximately one-fourth of treated patients report the possibly related phenomenon of altered dream experiences (van Hilten et al., 1993; Arnulf et al., 2000; Kulisevsky and Roldan, 2004). Recent reports have also implicated these agents in compulsive sexual and gambling behaviors (Dodd et al., 2005; Klos et al., 2005; Tippmann-Peikert et al., 2007).

Alternative treatments for RLS include gabapentin, opiates, and benzodiazepines (Silber et al., 2004). RLS and PLMS are covered in further detail elsewhere in the text (see Chapter 56).

Primary disorders of hypersomnolence The incidence and prevalence of hypersomnia in the various neurodegenerative conditions are not known, but a primary hypersomnia has been suggested most frequently in patients with advanced Parkinson’s disease (see Chapter 60) (Tandberg et al., 1999; Rye et al., 2000; Overeem et al., 2002; Drouot et al., 2003). Preliminary results from a study of drug-free patients with mild to moderate AD without nocturnal sleep disorders demonstrated significantly reduced mean sleep latencies on MSLT compared with controls, despite similar amounts of total sleep time between the groups (Bonanni et al., 2005). Modafinil stimulant therapy has been shown to improve subjective sleepiness in patients with PD, but objective improvements were not demonstrated (as assessed by the maintenance of wakefulness test) (Hogl et al., 2002; Adler et al., 2003). Treatments for hypersomnolence in other populations afflicted with neurodegenerative disorders have not been investigated directly, but low-dose methylphenidate (5 mg or less) has been reported to improve subjective sleepiness and apathy in elderly patients in a nursing home (Gurian and Rosowsky, 1990).

Central sleep apnea Central sleep apnea (CSA) is known to occur in patients with primary cardiac and central nervous system dysfunction. The frequency of CSA in the neurodegenerative diseases is not known, but is thought to be much less common than OSA (Boeve et al., 2002). In CSA related to cardiac dysfunction, maximization of function is the first line of treatment. CPAP, bi-level positive airway pressure, adaptive servoventilation, supplemental oxygen, benzodiazepines, or a combination of the above can provide symptomatic improvement in some cases. Therapeutic trials may require an additional night of polysomnography to determine which single or combination therapy provides maximal benefit. This topic is reviewed in further detail elsewhere in the text (see Chapter 27).

MULTIPLE SYSTEM ATROPHY Overview MSA is a neurodegenerative disease characterized by combinations of parkinsonism, dysautonomia, cerebellar dysfunction, and features of pyramidal tract

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES 1029 dysfunction. The designation encompasses Shy–Drager restriction of abduction of the cords or complete syndrome, striatonigral degeneration, and sporadic oliimmobility (Kavey et al., 1989; Sadaoka et al., 1996; vopontocerebellar atrophy, with the terms often used Silber Levine, 2000). Occasionally, only one cord is interchangeably. As its neuropathological characterisinvolved initially, with later progression to both (Wiltics include a-synuclein oligodendroglial inclusions in liams et al., 1979). Despite its utility, laryngoscopy the basal ganglia, brainstem, cerebellum, and spinal lacks sensitivity, as a normal examination in the awake cord, it is also classified as a synucleinopathy, as state does not guarantee that nocturnal stridor is described above (see also Table 61.2). The condition carabsent (Kavey et al., 1989; Sadaoka et al., 1996; Silber ries a poor prognosis, with a mean survival time (from and Levine, 2000). Polysomnography with synchroonset of symptoms) of 8.5 years (Bower et al., 1997). nized audiovisual monitoring is therefore essential in Sleep complaints are extremely common in MSA, the evaluation, and accompanying esophageal pressure with 70% of patients complaining of nocturnal disturmonitoring has been shown to assess upper airway narbances (Ghorayeb et al., 2002). Objective findings rowing most definitively (Sadaoka et al., 1996). buttress these complaints in the form of reduced total sleep time and low sleep efficiency (Plazzi et al., 1997; Pathogenesis Iranzo et al., 2000; Wetter et al., 2000; Vetrugno et al., 2004; Ghorayeb et al., 2005c). Sleep architecture changes, The pathogenesis of the symptom is controversial, and in the form of a reduced percentage of SWS, and an both peripheral and central factors may play a role. accompanying increase in the remaining NREM stages Abduction of the cords is caused by contraction of the of sleep, have been described in one case–control study posterior cricoarytenoid (PCA) muscles, which are inner(Vetrugno et al., 2004), but such changes were not vated by branches of the recurrent laryngeal nerves, observed in a separate study investigating drug-free whose nuclei are found in the nucleus ambiguous to patients (Wetter et al., 2000). RBD and sleep-related the medulla. Studies involving patients with MSA with breathing disorders have a definitive presence in MSA, stridor have yielded contradictory results. Definite and will therefore be the main focus of discussion. neurogenic atrophy of the PCA muscles was found in two of three cases in one series (Bannister et al., 1981), neither of two in a second study (DeReuck and Van Sleep-related breathing disorders Landegem, 1987), and in all six in a third (Hayashi STRIDOR et al., 1997). EMG studies, using concentric needle electrodes, found no evidence of denervation changes in the Overview and assessment PCA muscles (Merlo et al., 2002). In comparison to conThe most characteristic respiratory sleep disorder in trols, the recurrent laryngeal nerve was reported as norMSA is nocturnal stridor. Reports of the frequency mal in one case (DeReuck and Van Landegem, 1987), of this phenomenon range widely from 13% to 42 % revealed axonal loss in one of two cases (Bannister (Wenning et al., 1994; Plazzi et al., 1997; Wenning et al., 1981), and showed reduced myelinated fiber count et al., 1997; Ghorayeb et al., 2002; Yamaguchi et al., in six cases (Hayashi et al., 1997). 2003; Vetrugno et al., 2004), the smaller estimate from An early report described loss of neurons in the a review of 203 pathologically proven cases (Wenning caudal two thirds of nucleus ambiguus (Lapresle and et al., 1997). One study suggested that stridor occurs Annabi, 1979), but the structure was reported as normore frequently in the cerebellar type (MSA-C) than in mal in two other cases (Bannister et al., 1981). In a the parkinsonian type (MSA-P) (Vetrugno et al., 2004), more systematic study of MSA patients, Ikeda et al. but the opposite has also been reported (Ghorayeb (2003) replicated the finding of neuronal loss in this et al., 2005c). The symptom may occur at any stage structure, and also demonstrated accompanying loss of the disease and may occasionally be the presenting of vagal axons with denervation of laryngeal abductor feature (Martinovits et al., 1988). muscles in three patients with stridor, as compared A careful sleep history is crucial, as the patient’s to three patients without stridor and controls. Benarsleeping partner may describe a strained, high-pitched, roch et al. (2003) similarly demonstrated neuronal loss harsh, inspiratory sound, and will often be able to in the ventrolateral portion of the nucleus ambiguus distinguish it from previously noted snoring (Ghorayeb in all five patients with MSA compared with controls, et al., 2002). Relying on the clinical distinction alone, but did not find significant differences between the however, can be difficult for physicians and lay two patients with stridor and the three without, persons alike, and have potentially disastrous consesuggesting that this finding in itself is unlikely to be quences (Kavey et al., 1989). Laryngoscopic assessthe sole pathophysiological correlate of laryngeal ment is indicated in suspected cases, and may show stridor.

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Paradoxical activity and dystonia of vocal cord adductors have also been implicated in this symptom. Surface (Isozaki et al., 1994) and wire (Plazzi et al., 1996; Isono et al., 2001; Merlo et al., 2002) electrode recordings during sleep have shown paradoxical activity in the adductor thyroarytenoid (TA) (Isozaki et al., 1994; Plazzi et al., 1996; Isono et al., 2001) and cricothyroid (Plazzi et al., 1996) muscles during stridorous inspiration, in addition to abnormal tonic activity (Plazzi et al., 1996; Merlo et al., 2002). The cumulative data therefore suggest that there is a heterogeneous nature to laryngeal stridor in MSA, and studies with a large number of patients will be necessary to clarify the various contributions from central and peripheral sources. Treatment Because stridor is considered to be a poor prognostic feature and is associated with sudden death during sleep (Guilleminault et al., 1977; Kavey et al., 1989; Munschauer et al., 1990; Hughes et al., 1998; Silber and Levine, 2000), timely initiation of treatment is important. In a study of 30 patients with MSA, those with stridor had a significantly shorter survival duration from the time of evaluation, with 9 of 11 (82%) dying a mean of 1.8 years after sleep studies had been performed (Silber and Levine, 2000). In comparison, 6 of 19 patients (32%) without stridor died, a mean of 2.4 years after presentation (Figure 61.6). Invasive options Tracheostomy has traditionally been considered to be the optimal therapy for laryngeal stridor (Williams et al., 1979; Kavey et al., 1989; Munschauer et al., 1990) and, in the study mentioned above (Silber and Levine, 2000), the procedure had been performed in both survivors. Securing consent to perform tracheostomy is made difficult by the fact that patients, unaware themselves of stridor, are unconvinced of its 1.0

Surviving

0.8 0.6 0.4

No stridor

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Stridor

0.0 2

4

6

8

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Fig. 61.6. Kaplan–Meier survival curves from disease onset in patients with and without stridor. (Redrawn from Silber and Levine, 2000. #John Wiley & Sons.)

necessity, and fear it will result in decreasing quality of life. In addition, the procedure has not proven to be entirely life-saving, as evidenced by the fact that two of four patients in the study of Silber and Levine (2000) died 1 year after presentation. As respiratory failure was present in both of these patients and in 3 of 6 nonstridorous patients who died, central neurogenic hypoventilation likely also contributes to mortality in this patient group. Experience with other invasive options is limited. In one subject with MSA with stridor, bilateral vocal cord abductor paralysis and related sleep apnea were managed successfully by unilateral vocal cord lateralization (Kenyon et al., 1984). In another subject, unilateral arytenopexy and vocal cord pinning were not effective (Kneisley and Rederich, 1990). A single study of unilateral injection of botulinum toxin into the TA muscle reported improvement of stridor in 3 of 4 patients at 1 month postinoculation, confirmed by both laryngoscopy and reduction in tonic EMG activity (Merlo et al., 2002). Nasal CPAP Nasal CPAP represents a relatively noninvasive treatment option in selected patients. A prospective study of 13 MSA patients with stridor (2 with diurnal stridor) utilized CPAP (titrated to eliminate stridor, apneic events, and oxyhemoglobin desaturation) and followed patients for a mean of 21 months (Iranzo et al., 2004). Although untreated stridor was associated with poor survival, median survival time was not significantly different for the nonstridorous group and the stridorous group treated with CPAP. The mechanism underlying efficacy of this therapy is thought to be due to the attenuation of adductor muscle activity during inspiration, with positive airway pressure functioning as a mechanical splint for the laryngeal wall (Isono et al., 2001). This treatment is not applicable to all patients with stridor, however, and compliance must be ensured. In the study by Iranzo et al. (2004), the two patients with diurnal stridor receiving CPAP eventually required tracheostomy due to the development of respiratory failure. In another study, all five patients treated with CPAP died a mean of 2.4 years after the sleep evaluation (Silber and Levine, 2000), perhaps partially accounted for by the fact that this group contained one patient with diurnal stridor, one with persistent stridor despite CPAP use, and one with poor CPAP compliance. Although Iranzo et al. (2004) reported excellent subjective compliance with CPAP in their study, Ghorayeb et al. (2005b) found compliance to be poor, possibly

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES owing to their inclusion of severely disabled patients. Of 12 MSA patients with stridor with or without sleep apnea (including 3 with isolated stridor), only 5 (42%) demonstrated long-term compliance (12 months or more) during a mean follow-up period of nearly 25 months. Only 1 (20%) of those with long-term compliance had isolated stridor (Ghorayeb et al., 2005b). Severity of motor impairment at the initiation of treatment (i.e., less severe disease) was the only factor that differed significantly between compliant and noncompliant patients. Age, disease duration, AHI, and the presence of sleep complaints did not differ significantly between compliant and noncompliant groups. The cumulative data therefore suggest that CPAP therapy is optimal for those with isolated nocturnal stridor, with or without accompanying sleep apnea, at relatively early stages of the disease. Serial assessments should occur to ensure compliance and to ascertain whether stridor has recurred. Polysomnography should be repeated if necessary to ensure that CPAP is titrated properly, and tracheostomy should be kept in mind continually, particularly if patient characteristics differ markedly from those mentioned above.

OTHER

CAUSES OF SLEEP-DISORDERED BREATHING

Overview Regardless of whether stridor is present, one should also be mindful of the presence of other sleep-disordered breathing events in patients with MSA. A variety of conditions have been described, including OSA and CSA, periodic breathing both during sleep and awake in the erect position, Cheyne–Stokes’ breathing, apneustic breathing, cluster breathing, and irregular breathing (Lockwood, 1976; Chokroverty et al., 1978; Williams et al., 1979; McNicholas et al., 1983; Chokroverty et al., 1984; Munschauer et al., 1990; Plazzi et al., 1997; Tachibana et al., 1997; Silber and Levine, 2000; Vetrugno et al., 2004). The precise incidence and frequency of these events is largely unknown, but OSA was found in 7 (37%) of 19 consecutive patients with MSA (Vetrugno et al., 2004). The independent influence of these phenomena on mortality in these patients is also uncertain, but alveolar hypoventilation, resulting in hypercapnic respiratory failure during sleep and sometimes wakefulness, may be the cause of death in some patients, as alluded to above (Williams et al., 1979). Occasional patients with MSA may present initially with predominant respiratory insufficiency, and relatively limited motor and autonomic problems (Glass et al., 2006). Although clinical and other assessments might assist one in screening for these conditions, polysomnography is essential for accurate characterization, and can inform treatment.

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Pathogenesis Defects in respiratory regulation are thought in part to involve the metabolic control system, as evidenced by cases of markedly impaired ventilatory responses to hypoxia (McNicholas et al., 1983; Tsuda et al., 2002) and hypercapnia (McNicholas et al., 1983; Chester et al., 1988). As this is unlikely to account for irregular respiratory rhythms, however, pathological involvement of the neuronal circuitry in the pons and medulla is presumed to underlie these abnormalities. Support for this contention was demonstrated by intact behavioral respiratory control (which originates in supramedullary structures) in patients with impaired chemosensitivity (McNicholas et al., 1983). In addition, autopsy studies of the brainstem of patients with MSA and respiratory disturbances have shown gliosis and neuronal loss in the medulla, pons, and midbrain (Lockwood, 1976; Chokroverty et al., 1978; Munschauer et al., 1990). More detailed pathological studies by Benarroch and colleagues, using case–control methodologies, demonstrated depletion of both serotonergic (Benarroch et al., 2004) and cholinergic (Benarroch et al., 2001) neurons in the medullae of patients with MSA, which represent potential pathophysiological correlates for the numerous autonomic and respiratory disturbances seen in these patients. A separate case–control study of 13 patients with MSA, utilizing functional brain imaging, demonstrated a significant correlation between the severity of OSA and thalamic cholinergic deficits, in turn related to degeneration of brainstem cholinergic neurons originating from the pedunculopontine and laterodorsal tegmental nuclei (Gilman et al., 2003). Statistical significance was not maintained when the results were age adjusted, however. Treatment Treatments for OSA, CSA, and other respiratory dysrhythmias are not specific for MSA, and are covered elsewhere in this text (see Chapters 25–27).

Nocturnal motor disturbances REM

SLEEP BEHAVIOR DISORDER

Clinical and demographic features As alluded to above, the association between MSA and RBD has been described in numerous cases (Coccagna et al., 1985; Schenck et al., 1986; Schenck and Mahowald, 1990; Wright et al., 1990; Tison et al., 1995; Plazzi et al., 1997; Sforza et al., 1997; Tachibana et al., 1997; Olson et al., 2000; Silber and Levine, 2000), and three cases have been confirmed by autopsy (Boeve et al., 2003b).

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Although the precise incidence and prevalence of RBD in MSA is not known, it appears to be present in most patients. In a series of 21 consecutive cases not referred specifically for sleep symptoms, RSWA was found in 20 of 21 (95%) and abnormal motor behavior was recorded in 19 (90%) (Tachibana et al., 1997). Of 39 consecutive patients with MSA, 6 referred for sleep symptoms, relatives reported nocturnal vocalizations or motor behavior in 27 (69%), and 35 (90%) were determined to have RBD after polysomnography (Plazzi et al., 1997). In a more recent series, RBD was found in 100% of 19 consecutive patients (Vetrugno et al., 2004). In contrast to the male predilection described for the other two synucleinopathies (PD and DLB), RBD in association with MSA appears to occur equally in male and female patients (Plazzi et al., 1997; Olson et al., 2000). As in other cases of idiopathic RBD, symptoms may be the initial manifestation of MSA, and precede other neurological findings by nearly two decades (Plazzi et al., 1997; Olson et al., 2000). The presence of RBD has been used to predict the presence of MSA in patients presenting with autonomic failure (Plazzi et al., 1998). Pathogenesis Certain findings specific to MSA are relevant to the high frequency of RBD in these patients. Cholinergic inputs from the pontine perilocus coeruleus (peri-LC) neurons innervate nuclei of the reticular formation of the medulla, which in turn trigger events of REM sleep, including muscle atonia. As loss of pontine cholinergic neurons in MSA has been described (Benarroch, 2003; Gilman et al., 2003), this may contribute to the development of RBD in patients with MSA. Although there is also loss of monoaminergic neurons in the LC and the rostral raphe in MSA, one study suggested a striking preservation of the latter group of “REM off” serotonergic neurons (Benarroch et al., 2002), perhaps further influencing REM sleep regulation. Such a sparing was not demonstrated in a subsequent study with a similar number of patients, however, highlighting the need for further clarification (Benarroch et al., 2004). Finally, based on the recent identification of sites for the REM-on and REM-off flip-flop switch in the rat (Lu et al., 2006), in which lesions to the sublaterodorsal nucleus resulted in RSWA, one could hypothesize that this nucleus undergoes degeneration in MSA – this remains to be seen. Treatment Management of RBD in MSA is similar to that in other neurodegenerative disorders, with an important caveat.

Clonazepam should be used with caution in patients with autonomic respiratory instability, untreated stridor, or gait disturbances due to ataxia or parkinsonism.

Restless legs syndrome/periodic limb movements of sleep Motor dyscontrol in NREM sleep also may be common in MSA, with PLMS reported in 24 (83%) of 29 patients in one study, with a mean PLMI of 103/hour (Silber and Levine, 2000). However, a separate study investigating drug-free patients failed to identify a difference in the PLMI as compared to controls (Wetter et al., 2000). Finally, in a prospective study of 20 patients, RLS was reported in 15%, but it is uncertain what criteria were used to generate this diagnosis (Iranzo et al., 2000).

Primary hypersomnia Subjective sleepiness was reported in half of patients with MSA and in 30% of subjects with PD in one study (Ghorayeb et al., 2002). Patients with MSA with this complaint had greater disease severity (as assessed by standardized scales) than those without, and it therefore remains unclear as to whether this is due to an intrinsic disorder of sleepiness with increasing severity, as in PD (Tandberg et al., 1999; Rye et al., 2000; Overeem et al., 2002; Drouot et al., 2003), or to other factors (Ghorayeb et al., 2002). In support of the former explanation, a recent neuropathological study described marked loss of hypocretin neurons in MSA (but to a lesser degree than reported in narcolepsy), which, given their widespread projections to sleep and autonomic regulatory areas, could conceivably contribute to both hypersomnolence and autonomic dysfunction in afflicted patients (Benarroch et al., 2007).

PROGRESSIVE SUPRANUCLEAR PALSY Overview Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by an akinetic parkinsonian syndrome, a lack of responsiveness to levodopa, early gait instability, supranuclear vertical gaze palsies, pseudobulbar palsy, and a frontal lobe-type dementia. Typical histological findings include gliosis and neuronal loss with neurofibrillary tangles in multiple subcortical nuclei, with relative preservation of the cortex and hippocampus. The tau-positive neurofibrillary tangles, tufted astrocytes, neuronal threads, and coiled bodies in oligodendroglia have led investigators to classify PSP as a tauopathy (see Table 61.2). Sleep disturbances appear to be quite common. A questionnaire study of 437 patients with a clinical

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES diagnosis of PSP revealed that 50% reported a change in sleep patterns or difficulty sleeping, more than 3 years’ postdiagnosis (Santacruz et al., 1998). Indeed, sleep fragmentation has been correlated with dementia and severity of illness (Aldrich et al., 1989). Objective findings support these complaints. A polysomnographic study of six patients with PSP versus age- and sex-matched controls demonstrated decreased total sleep time, decreased sleep efficiency, increased WASO, and an increased percentage of stage 1 sleep. The percentage of REM sleep was also decreased, with decreased REM period duration (Montplaisir et al., 1997b). Other polysomnographic findings include reports of reductions in sleep spindle density (Montplaisir et al., 1997b). Specific sleep disorders associated with PSP are not well established, although a recent study suggested an association with RBD (Arnulf et al., 2005).

REM sleep behavior disorder RBD was found in 13% of PSP subjects in one study (Arnulf et al., 2005). Importantly, when associated with PSP, RBD tends to present concomitantly or after the onset of PSP features, in contrast to RBD often preceding the motor and cognitive features of the synucleinopathies. The management of RBD in PSP is similar to that reported for PD, DLB, and MSA.

Other sleep disorders Despite the extensive brainstem pathology seen in patients with PSP, sleep-disordered breathing does not appear to be common. In a prospective case–control oximetry study of 11 patients with a mean disease duration of 4.0 years, infrequent decreases of 4% or more in oxyhemoglobin saturation were noted in 3 patients, but all were at a frequency of less than 5/hour (De Bruin et al., 1996). In a separate series, Aldrich et al. (1989) noted that 2 of 10 patients had sleepdisordered breathing, 1 predominantly central and 1 predominantly obstructive. Studies with limited numbers of patients suggest other potentially fruitful areas of investigation. Raised PLMIs were reported in 2 of 10 patients in one study, ultimately of indeterminate clinical significance (Aldrich et al., 1989). Abnormal mean sleep latencies (less than 8 minutes) were demonstrated in 27% of a series of 15 patients with PSP with comparable arousal indices and longer total sleep times than those with normal mean sleep latencies (Arnulf et al., 2005). None of the sleepy subjects demonstrated two or more sleep-onset REM periods when assessed by MSLT, suggesting a different mechanism for hypersomnia compared with that in those with PD (Rye et al., 2000; Arnulf et al., 2005).

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Pathogenesis The overarching pathophysiology of sleep disturbances in patients with PSP may be due to the extensive brainstem pathology, although this apparently does not manifest with an increased frequency of sleep-disordered breathing. The profound sleep maintenance insomnia seen in these patients has been hypothesized to be due to immobility, but appears to be more severe than that seen in patients with similar neurodegenerative illnesses, such as PD (Aldrich et al., 1989).

OTHER NEURODEGENERATIVE DISEASES ASSOCIATED WITH SLEEP DISTURBANCES Corticobasal degeneration Corticobasal degeneration (CBD) is a neurodegenerative disorder characterized by progressive asymmetrical rigidity, apraxia, and other findings reflecting cortical and basal ganglia dysfunction (Boeve, 2000). The pathological hallmarks are gliosis and large achromatic neurons distributed asymmetrically in frontal or parietal cortical areas, as well as tau-positive astrocytic plaques, neuronal threads, and oligodendroglial coiled bodies. Sleep-related issues remain anecdotal at this juncture, and involve nocturnal motor disturbances. RSWA, but not frank RBD, has been reported (Kimura et al., 1997; Wetter et al., 2002), and in one case was accompanied by PLMS, with equal distribution during REM and NREM sleep (Wetter et al., 2002). Evidence from other series of patients with probable CBD suggests that RBD is very uncommon (Boeve et al., 2001). There is an interesting case report of unilateral PLMS, with simultaneous findings of positron emission tomography-confirmed hypometabolism in the contralateral frontoparietal, basal ganglia, and thalamic areas, perhaps providing a window onto the mechanism of this phenomenon (Iriarte et al., 2001).

Spinocerebellar ataxia 3/Machado–Joseph disease SCA-3, otherwise known as Machado–Joseph disease, is caused by a polyglutamine expansion on chromosome 14q21, and a wide spectrum of clinical manifestations have been observed (Margolis, 2002). With regard to sleep disturbance, one study demonstrated significantly decreased total sleep time, sleep efficiency, and REM sleep percentage in patients with SCA-3 as compared to healthy controls (Iranzo et al., 2003). A variety of other specific sleep disorders has also been reported. RLS has been described in 45–56% of those with SCA-3 (Schols et al., 1998; Iranzo et al., 2003), utilizing

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International Restless Legs Syndrome Study Group criteria. This is an intriguing finding, as chromosome 14q has been implicated in RLS in selected populations (Bonati et al., 2003; Levchenko et al., 2004). Nevertheless, a case–control study of a large number of French Canadian patients with idiopathic RLS revealed no intergroup differences with respect to SCA-3 trinucleotide repeats, and no expansions in the pathological or intermediate range were observed in any subject (Desautels et al., 2003). Sleep-disordered breathing has also been described. In a case series of 5 patients with SCA-3, 3 (60%) met the criteria for CSA, one of whom exhibited Cheyne–Stokes’ respiration (Kitamura et al., 1989). The overall incidence of this finding was lower (16%) in a series of 19 patients, however (Isozaki et al., 2002). Vocal cord abduction restriction was described in 3 of 9 patients (33%) in one laryngoscopic study, only 1 of whom was symptomatic. This phenomenon has been proposed to be related to neuronopathy of the nucleus ambiguus (Iranzo et al., 2003), which is supported by the findings of Isozaki et al. (2002), who showed neurogenic atrophy of the intrinsic laryngeal muscles in patients with SCA-3 and vocal cord abduction palsy. Patients with SCA-3 may also have RBD or RSWA (Fukutake et al., 2002; Iranzo et al., 2003; Syed et al., 2003), again verifying that these conditions are not entirely specific to the synucleinopathies. One group suggested that RBD may be secondary to brainstem dysfunction inherent to the condition (Iranzo et al., 2003). Other unusual parasomnias have been reported. One group described a NREM parasomnia characterized by complex aperiodic motor movements (Ghorayeb et al., 2005a). Only neuroleptics were temporarily effective, despite multiple medication trials. Another report described prolonged sleepwalking and violent motor behavior arising from NREM sleep, followed by prolonged confusion and disorientation (Kushida et al., 1995). This patient also proved to be a therapeutic challenge, but ultimately improved with a combination of temazepam and carbidopa–levodopa. Finally, sparse reports exist regarding sleep disturbances in other spinocerebellar ataxias, including RLS/PLMS in spinocerebellar ataxia type 6 (Boesch et al., 2006b), and PLMS, RSWA, and other REM sleep abnormalities in spinocerebellar ataxia type 2 (Boesch et al., 2006a; Tuin et al., 2006).

Huntington’s disease HD is caused by a polyglutamine expansion on chromosome 4p16, and has an autosomal dominant mode of inheritance. It is characterized by dementia and chorea

with onset between 25 and 45 years of age, and has a relentless disease progression. Sleep disturbances were reported in 20% of patients in one series (Myers et al., 1985), and over 60% reported impaired sleep as an important contributor to overall disease morbidity (Taylor and Bramble, 1997). Insomnia appears to be the most common complaint, and parallels disease progression (Hansotia et al., 1985; Wiegand et al., 1991). Approximately 50% of surveyed patients reported persistence of choreoathetoid movements into sleep (Taylor and Bramble, 1997), and dyskinetic movements have been documented objectively following shifts to lighter sleep stages, during stage 1 sleep, and, rarely, during other stages of sleep (Fish et al., 1991a). Objective findings have been demonstrated in both medicated and drug-free patients in the form of prolonged sleep latency, and reduced sleep efficiency and SWS (Wiegand et al., 1991). Increased sleep spindle density in comparison with controls has been reported by two groups (Emser et al., 1988; Wiegand et al., 1991), a finding interestingly reported in other basal ganglia disorders, but not without controversy (Wein and Golubev, 1979; Jankel et al., 1983; Fish et al., 1990). More specific sleep complaints are mainly anecdotal in nature. One report documented a family with comorbidity of HD and idiopathic RLS, but it is uncertain what criteria were used to diagnose the latter condition (Evers and Stogbauer, 2003). A case–control study, using actigraphically derived measures, demonstrated disrupted night–day activity patterns in patients with HD versus controls (Morton et al., 2005). This finding was mirrored in an animal model, with eventual complete disorganization of the rest–activity cycle with disease progression, accompanied by a marked disruption in the expression of circadian clock genes, pointing to pathological involvement of the SCN. A precise mechanism for this finding has yet to be identified, however (Morton et al., 2005). Finally, although no specific association with sleep-disordered breathing and HD has been established, a case report described good tolerance of CPAP in a patient with both conditions, in the instance that such a treatment was necessary (Banno et al., 2005).

Dystonia Dystonia is characterized by sustained or twisting postures often mixed with jerky or oscillatory movements. It may be primary or secondary to a variety of causes. Case–control studies of sleep in dystonia have been few, with small numbers of patients on medication or with prior neurosurgery (Askenasy, 1981; Jankel et al., 1983). In four patients with severe dystonia musculorum deformans, increased sleep latency and decreased sleep

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES efficiency was described, in addition to a decreased percentage of REM sleep (Jankel et al., 1983). The severity of sleep fragmentation is directly proportional to the severity of the motor disturbance (Wein and Golubev, 1979). Involuntary movements are most frequent during wakefulness, but may persist during sleep at a reduced frequency and amplitude, and are maximally reduced during SWS (Askenasy, 1981). A more detailed sleep study of patients with this and other movement disorders showed persistence of dyskinetic movements following shifts to lighter sleep stages and during stage 1 sleep, but very rarely during other stages of sleep (Fish et al., 1991a). This same group (Fish et al., 1991b) reported preserved REM atonia in primary and secondary dystonia, demonstrating the maintenance of brainstem inhibitory mechanisms in these conditions, despite decreased inhibitory mechanisms of dystonia. One particular type of predominantly juvenile dystonia (called hereditary progressive dystonia with marked diurnal fluctuation, dopa-responsive dystonia, or Segawa variant) often shows distinct circadian variability, with dystonic symptoms worsening as wakefulness ensues, and improving markedly subsequent to sleep (reviewed by Segawa, 2000). Two case–control studies reported a large number of high-amplitude spindles in dystonia (Wein and Golubev, 1979; Jankel et al., 1983), but a study by Fish et al. (1991b) failed to demonstrate significant differences in the number, amplitude, or duration of sleep spindles, and suggested that the finding was nonspecific in the latter two studies, and perhaps influenced by previous neurosurgery or concomitant benzodiazepine administration.

Fatal familial insomnia Fatal familial insomnia (FFI) is a rare autosomal dominant prion disease. It is associated with a mutation at codon 178 of the prion protein gene, causing substitution of asparagine for aspartic acid. As this mutation has been described in some familial Creutzfeldt–Jakob disease kindreds, the differing phenotypes are thought to be accounted for by the modifying effect of a polymorphism characterized by methionine at codon 129, although this is the subject of some controversy (Collins et al., 2004). Its onset is generally in the fifth decade, and it is rapidly progressive, with an illness duration with a mean of approximately 15 months (Collins et al., 2001, 2004). Insomnia develops in the setting of other neurological problems, including cerebellar ataxia and autonomic dysfunction (Collins et al., 2001). Polysomnography reveals severe disruption of the sleep–wake cycle, markedly

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reduced SWS and REM sleep, reduced sleep efficiency, and limb jerks without periodicity (Lugaresi et al., 1986; Scaravilli et al., 2000). Some degree of RSWA has also been reported (Scaravilli et al., 2000). Neuropathological examination of the brain reveals severe neuronal loss in the anterior ventral and dorsomedial thalamic nuclei (Lugaresi et al., 1986; Manetto et al., 1992). As the condition appears to have incomplete penetrance (Collins et al., 2001), it should be considered in any patient with a prominent sleep–wake disturbance associated with other motor or autonomic findings, regardless of family history. Sporadic cases of FFI and no identifiable mutation in the prion protein have also been reported (Parchi et al., 1999; Scaravilli et al., 2000). Management is symptomatic as no curative treatment exists. FFI is covered in greater detail elsewhere in this text (see Chapter 59).

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is characterized by a combination of upper and lower motor neuron signs resulting from progressive degeneration of neurons of bulbar nuclei, ventral horn cells of the spinal cord, and cortical upper motor neurons. Sensory functions and continence are preserved. ALS can be associated with profound sleep disturbances secondary to sleepdisordered breathing and associated factors (Bhatt et al., 2005), and in one study 25% of patients reported symptoms of insomnia (Hetta and Jansson, 1997). In a case series using objective measures, mean sleep efficiency was 70%, with a mean total sleep time of approximately 5 hours (Ferguson et al., 1995). In a prospective study of 21 patients with ALS (Gay et al., 1991), severe nocturnal oxygen desaturation was most strongly correlated to dysfunction of the respiratory muscles, although obstructive sleep-disordered breathing was common as well. Symptomatic respiratory muscle weakness is usually noted late in the course of the disease, but sleep-disordered breathing has been reported at an early stage (Kimura et al., 1999; Barthlen and Lange, 2000; Takekawa et al., 2001). Treatment of sleep-disordered breathing is accomplished with CPAP, noninvasive positivepressure ventilation, or invasive ventilation via tracheostomy. ALS is covered in greater detail elsewhere in this text (see Chapter 64).

SYMPTOMATIC TREATMENT OF INSOMNIA Nonpharmacological In the absence of a specific entity that can be attributed to sleep complaints, symptomatic treatment is

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necessary. Nonpharmacological options are important to consider in the management of insomnia, either alone or in combination with medications. Implementation of sleep hygiene principles is relatively simple, and can result in significant benefits. One pilot RCT of incontinent nursing home patients (mean mini mental state examination score 13.3; Folstein et al., 1975) applied a variety of such principles and demonstrated that daytime physical activity, in combination with strategies to reduce nocturnal environmental disturbances, improved sleep efficiency (as measured by actigraphy), and decreased agitation in 47% of subjects (versus 7% of controls) (Alessi et al., 1999). The expanded version of this study demonstrated more modest beneficial effects on nighttime sleep, however, perhaps due in part to insignificant reductions in nighttime noise and light levels in the intervention group (Alessi et al., 2005). Negative results from a larger controlled study, also investigating the effect of mixed modality interventions on institutionalized patients, suggest that future interventions should address reduction of nighttime noise more aggressively (Ouslander et al., 2006). Possibly in additional support of the influence of this variable on successful outcomes, another group, also utilizing a RCT design, studied community-dwelling patients with AD, and examined the effects of caregiver-implemented sleep hygiene principles on sleep and other parameters, in conjunction with increased daytime light exposure (administered via a lightbox) (McCurry et al., 2005). Patients participating in the active treatment group showed a significant reduction in nighttime awakenings, as assessed by actigraphy, in addition to significantly decreased WASO, and improved depression scores. Results were maintained at 6 months’ follow-up, and additional decreases in duration of nighttime awakenings emerged (McCurry et al., 2005). Two RCTs involving elderly nondemented patients indicated that subjective sleep quality (assessed by the Pittsburgh Sleep Quality Index) improved with structured exercise programs (King et al., 1997; Singh et al., 1997), including in those with depressive disorders (Singh et al., 1997). A large RCT of community-dwelling patients with AD demonstrated that those exposed to a standardized combined exercise and caregiverimplemented behavioral plan showed superior physical functioning and depression scores than those receiving routine medical care, which was maintained at 2 years of follow-up (Teri et al., 2003). As sleep was not assessed in any manner, it is uncertain whether these benefits also result in an improvement of sleep quality, as described in nondemented elderly patients. It is nevertheless useful to know that such a program can be implemented in the moderate to severely impaired patients with AD who comprised the study population.

More creative interventions have also been tested. A large prospective study of elderly general medical patients with sleep complaints showed that a protocol consisting of a massage, a warm drink, and relaxation tapes resulted in a progressive increase in subjective sleep quality that was directly correlated to greater adherence with each of the three parts of the protocol (McDowell et al., 1998). The interventions were also associated with decreased administration of hypnotics by 23%. A RCT comparing behavioral and pharmacological therapies for late-life primary insomnia in nondemented individuals (mean age 65 years) over a period of 8 weeks showed comparable treatment effects for all active treatment groups versus placebo (including a combined pharmacological and behavioral treatment group). However, at long-term follow-up at 12 and 24 months after discontinuation of the active treatment, only the group that had received solely behavioral treatments exhibited a durable response (Morin et al., 1999). Such treatments would clearly be impractical in the severely demented, and their applicability to milder forms of dementia has yet to be determined.

Pharmacological Sedative hypnotics are sometimes required in the elderly population, due to failure or impracticality of nonpharmacological treatments. Practitioners are frequently reluctant prescribers, however, owing to reports linking their use with exacerbation of sleep-disordered breathing and cognitive impairment (Reynolds et al., 1985a), in addition to increasing the risk of falls (Tinetti et al., 1988; Wang et al., 2001). The latter concern must be balanced against the results of recent studies suggesting that sleep complaints are better predictors of falls in community-dwelling and institutionalized adults than medications, and that medications may simply be a proxy for the underlying sleep disturbance (Koski et al., 1998; Brassington et al., 2000; Avidan et al., 2005). Bolstering this theory, untreated insomnia predicted more falls than in those who reported insomnia despite use of hypnotics, and subjects who took hypnotics but had no insomnia complaints had no significantly greater risk for falls (Avidan et al., 2005). Although multiple hypnotics have demonstrated short-term efficacy (see Chapter 46), there are few long-term data (with the exception of eszopiclone), and only selected studies have specifically addressed the elderly population. An unblinded open-label trial of zolpidem (10 mg), taken for a period of 3 months by 80 medically stable individuals aged over 70 (mean 78.6 years), was generally well tolerated, with persistent subjective efficacy (Cotroneo et al., 2004). Eszopiclone (1–2 mg) has shown favorable safety and

SLEEP DISORDERS IN NEURODEGENERATIVE DISEASES efficacy in a large RCT of medically stable elderly individuals with primary insomnia (mean age 72.3 years), for a period of up to 2 weeks (Scharf et al., 2005). A similar short-term study investigating the use of zaleplon (5–10 mg) in elderly individuals with primary insomnia (mean age 72.5 years) was extended to a single-blind open-label phase, with favorable results up to 12 months (Ancoli-Israel et al., 2005b). Unfortunately, few studies exist to guide the clinician in the symptomatic treatment of insomnia in those with neurodegenerative diseases. A small pilot study of low-dose (0.125 mg) triazolam in community-dwelling patients with AD and sleep disturbances did not reveal any group effect on sleep parameters (as measured by actigraphy), although there was marked interindividual variability (McCarten et al., 1995). The drug was well tolerated, and had no effect on a computerized assessment of short-term memory (McCarten et al., 1995). In a study involving approximately 60 elderly patients with dementia (type unspecified), zolpidem (10–20 mg) significantly improved total sleep time compared with placebo over a 3-week interval, as assessed by nurses’ responses to a questionnaire. The medication was well tolerated at lower doses, and rebound insomnia did not emerge after discontinuation in either active treatment group (Shaw et al., 1992). Finally, rather curiously, one case report described markedly improved sleep consolidation in a patient with AD who was administered methylphenidate, 20 mg, in divided doses during daytime hours (Kittur and Hauser, 1999).

CONCLUSION Understanding the changes associated with sleep in the normal aging process may provide insights into the mechanisms leading to the sleep disturbances that are seen in association with neurodegenerative diseases. Pathological disturbances may in some instances represent an exaggeration of normal age-related changes, as exemplified by discriminative objective findings in sleep architecture and consolidation when comparing individuals with AD of even mild severity to controls. Sleep disorders are particularly well described in the AD population, but as most of the literature involves those with clinical diagnoses, it is possible that certain findings are associated with this condition inappropriately, but equally plausible that other findings are nonspecific, and attributable to those with different types of dementing illness. The association between DLB and RBD highlights the importance of the former scenario. Future studies involving well defined homogeneous populations with dementia are therefore highly desirable.

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The research involving sleep and neurodegenerative diseases is exciting for a variety of reasons. Apart from the scientific knowledge to be gained from further understanding, recognition and treatment of coexisting sleep disorders has the potential to reduce considerably patient and caregiver burden, and to reduce the financial costs to society. All of these points are of major relevance when considering the rapid aging of our population, and the concomitant increased incidence of dementing and other neurological illnesses.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 62

Sleep and stroke 1

CLAUDIO L. BASSETTI 1 * AND DIRK M. HERMANN 2 Department of Neurology, University Hospital Zurich, Zurich, Switzerland 2

Department of Neurology, University Hospital Essen, Essen, Germany

INTRODUCTION Understanding sleep disturbances is important in the management of stroke, for several reasons. First, poststroke sleep–wake disorders (SWDs) and sleepdisordered breathing (SDB) are frequent. This is due to the fact that: (a) brain damage per se can impair sleep–wake and breathing control; (b) the consequences of stroke (immobilization, pain, hypoxia, depression, etc.) may also impair these functions; and (c) similar risk factors are associated with stroke and SDB. Second, SWDs and SDB have a negative impact on stroke evolution and outcome. Recurrent hypoxias and hemodynamic instability have a negative impact on stroke evolution, recurrence, and mortality. In addition, sleep fragmentation/disturbances impair daytime wakefulness, cognitive functions, and mood, which in turn unfavorably influence rehabilitation outcome and quality of life. Third, SWDs and SDB – once recognized – can often be treated. This chapter gives an overview of our present understanding of the clinical characteristics, pathophysiology, and management of SWDs and SDB following stroke.

SLEEP^WAKE DISORDERS AND STROKE Sleep and wakefulness are functional states of the brain that are controlled by structures in the preoptic area of the hypothalamus thalamus, brainstem, and posterior hypothalamus. In view of the involvement of such a large number of structures throughout the brain in sleep–wake regulation, it is not surprising that stroke (focal ischemia or hemorrhage) may lead to increased sleep needs (hypersomnia), inability to sleep (insomnia), sleep architectural changes, and abnormal sleep behaviors (parasomnias).

Frequency and clinical characteristics of sleep–wake disorders after stroke HYPERSOMNIA, EXCESSIVE APATHY, FATIGUE

DAYTIME SLEEPINESS,

The clinical spectrum of poststroke arousal disorders is broad and includes hypersomnia, excessive daytime sleepiness (EDS), fatigue, and other disturbances. Hypersomnia is defined as an abnormal sleep propensity with increased sleep needs in 24 hours. Excessive daytime sleepiness is defined as an abnormal urge to sleep during wakefulness. Patients fight off sleep and may fall asleep during inappropriate time (involuntary naps, “sleep attacks”). The score on the Epworth Sleepiness Scale (ESS) is typically above 10 (Johns, 1994). In some patients, hypersomnia coexists or evolves progressively to severe apathy with lack of spontaneity and initiative, slowness, poverty of movement, and/or catalepsy, a condition for which the term akinetic mutism was coined (Cairns et al., 1941). Akinetic mutism and its less severe form, usually referred to as apathy/abulia, may persist despite normalization of vigilance or even after the appearance of insomnia. A peculiar form of apathy with lack of autoactivation (when patients are left alone they tend to doze off, close their eyes, and sleep) but preserved heteroactivation has been called “pure psychic akinesia” and athymormia (Laplane et al., 1984). Fatigue corresponds to physical exhaustion, lack of energy, and physical tiredness. The Fatigue Severity Scale (FSS) score in these patients is typically above 3 (Valko et al., 2008). Conversely, the ESS score is often normal in these patients, who may also complain of insomnia (Johns, 1994).

*Correspondence to: Professor C.L. Bassetti, Director, Neurocenter (EOC) of Southern Switzerland, Via Tesserete 46, CH-6903 Lugano, Switzerland. Tel: 41 91 811 6658, Fax: þ41 91 811 6915, E-mail: [email protected]

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On clinical grounds, hypersomnia, EDS, apathy/abulia, and fatigue may be sometimes difficult to separate and can in fact coexist in a given patient (Bassetti and Valko, 2006; P.O. Valko et al., unpublished observations). In addition to an increased sleep propensity, patients often exhibit disturbances in circadian distribution of sleep and wakefulness, control of sleep–wake transition, regulation of tonic and phasic attention, eating, sexual behavior, and mood. Poststroke hypersomnia had already been observed as a complication of thalamic and mesencephalic stroke in the 19th and early 20th century (Claude and Loyez, 1912; Freund, 1913). Most reports of poststroke hypersomnia were with brainstem and thalamic strokes. In a recent systematic study of 285 consecutive patients, we found that at 2118 months after stroke, fatigue (46% of patients with a FSS score 3), EDS (28% of patients with an ESS score 10), and hypersomnia (27% with sleep needs 10 hours/ day) were common, often observed in association with extrathalamic topographies of stroke (P.O. Valko et al., unpublished observations). Hypersomnia is pronounced in the first weeks to months after stroke, whereas fatigue often persists, even beyond the first year (Hermann et al., 2008; Valko et al., 2008). The most dramatic form of poststroke hypersomnia is observed after bilateral (less commonly, unilateral) paramedian thalamic and thalamomesencephalic strokes (Figure 62.1). Patients typically present initially with sudden onset of coma. After awakening, patients have severe hypersomnia and sleep-like behavior for up to 20 hours per day (Figure 62.2). Patients present, in addition, a vertical gaze palsy, other neurological deficits (oculomotor palsy, gait ataxia), neurocognitive (amnesia, inattention, dementia) and psychiatric deficits (delirium, disinhibition, childish behavior, etc.) (Freund, 1913; Chiray et al., 1923; Schuster, 1937; Fac¸on et al., 1958; Castaigne and Escourolle, 1967; Castaigne et al., 1981; Bassetti et al., 1996b; Hermann et al., 2008). Hypersomnia improves usually within months. Patients with bilateral strokes may, however, report an increase in sleep needs per day of several hours for years (Hermann et al., 2008). Apathy (see below) and amnesia/attention deficits usually dominate the long-term course. Less dramatic forms of poststroke hypersomnia can be observed after striatal, upper pontine, medial pontomedullary, and even cortical strokes (with and without mass effect) (Bassetti, 2005; Bassetti and Valko, 2006; P.O. Valko et al., unpublished observations). A presleep behavior with normal or altered body posturing and breathing patterns can be observed after subcortical and thalamic stroke. Patients constantly complain of an increased sleep urge, yawn, stretch, curl up, and close their eyes but are unable to fall

asleep completely (Catsman-Berrevoets and Harskamp, 1988). Hypersomnia with hyperphagia (Kleine–Levin-like syndrome) has been reported after multiple cerebral strokes (Drake, 1987). In some patients, episodes of hypersomnia, mutism, and akinesia alternate with episodes of insomnia, psychomotor agitation, or confusional state (Fac¸on et al., 1958; Fisher, 1983). Sometimes, the transition from wakefulness to sleep, and vice versa, is impaired and patients may present a dream–reality confusion (oneiric state). Hypersomnia with cataplexy, hypnagogic hallucinations, and sleep paralysis has been described in patients with symptomatic narcolepsy in whom the posterior hypothalamus was injured following cerebral hypoxia due to cardiac arrest (Rivera et al., 1986) or diencephalic stroke after surgical removal of a craniopharyngioma (Scammell et al., 2001).

INSOMNIA Insomnia is defined by difficulty initiating or maintaining sleep, early awakenings, insufficient sleep quality, and corresponding poor daytime functioning. In most cases insomnia after stroke is due to the complications of stroke and not due to brain damage per se (see below). In fact, only a few cases of “neurogenic” poststroke insomnia (agrypnia) have been reported in the literature. A patient with a pontomesencephalic stroke and almost complete insomnia for more than 2 months was described by van Bogaert (1926). Girard et al. (1962) reported a patient with locked-in syndrome due to bilateral basal pontine stroke with extension to the pontine tegmentum who experienced nearly complete, polysomnographically proven, insomnia for as long as 6 months. Poststroke insomnia was also observed after bilateral and unilateral paramedian and lateral thalamic strokes, and after unilateral upper tegmental pontine strokes (Garrel et al., 1966; Autret et al., 2001; Bassetti, 2005). We recently observed a patient with severe insomnia lasting for weeks after a unilateral, lateral thalamic hemorrhage (Figure 62.3). In a systematic study of 277 consecutive patients, insomnia was found in the first months after stroke in 57% of patients. In 18% of patients, insomnia appeared for the first time (de novo) after brain damage (Leppa¨vuori et al., 2002). This suggests that insomnia is not at all a rare phenomenon after stroke, and that it may not be restricted to selected stroke topographies.

PARASOMNIAS Strokes in the pontine tegmentum may result in rapid eye movement (REM)-sleep behavior disorder, in which patients act out their dreams with an increased

SLEEP AND STROKE muscular phasic activity and a loss of physiological atonia during REM sleep (Culebras and Moore, 1989; Kimura et al., 2000). Patients with tegmental pontine or mesencephalic strokes may experience Lhermitte’s peduncular hallucinosis, characterized by complex, often colorful, dream-like visual hallucinations, particularly in the evenings and at sleep onset (Lhermitte, 1922; van Bogaert, 1927). Unimodal (visual, acoustic) and multimodal dreamlike hallucinations have been reported by patients with striatal, thalamic (Figure 62.4), and brainstem lesions

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(Cascino and Adams, 1986; Martin et al., 1992; Fukutake and Hattori, 1998). Release phenomena and seizures after thalamic and cortical stroke can lead to increased dreaming, recurrent nightmares, or a syndrome of dream–reality confusion (Boller et al., 1975). A transient or persistent decrease/cessation of dreaming and dream recall (Charcot–Wildbrand syndrome; Charcot, 1883) can occur in patients with deep frontal, occipital, and thalamic stroke (Gru¨nstein, 1924; Solms, 1997; Bischof and Bassetti, 2004). Hobson (2002) recently gave a first-person account of his own

Fig. 62.1. Hypersomnia after bilateral paramedian thalamic stroke. A 65-year-old man with initial coma, followed by severe hypersomnia (A), vertical gaze palsy (B), amnesia, and disturbed time perception (Zeitgefu¨hl). Brain magnetic resonance imaging shows a bilateral paramedian thalamic stroke (C, D). Polysomnography performed after 12 days demonstrates a drastic reduction of sleep spindles (E) and loss of the spindle peak (12–14-Hz activity) on spectral analysis. (Continued)

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Fig. 62.1—cont’d (F), compared with the normal control (G). A severe central apnea (apnea–hypopnea index 54/hour) was observed in the acute phase (in the absence of any signs of cardiac dysfunction) but not on follow-up a few months later. Actigraphy performed within the first month after stroke shows time “asleep” (rest or sleep) during 61% of the recording time (2 weeks) (H). One year after stroke, the patient still reported increased sleep needs (15 hours per day), apathy (athymormia), and attentional/memory deficits. Modafinil at a dose of 200 mg per day improved the hypersomnia.

24 20 Sleep/24 hours

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F2,28 = 8.418; p < 0.01

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Fig. 62.2. Hypersomnia after paramedian thalamic stroke. Evolution of subjectively estimated sleep need/day over the first year after unilateral and bilateral paramedian stroke. *p<0.01 bilateral versus left and right unilateral stroke. (Reproduced with permission from Hermann et al., 2008. #Lippincott Williams & Wilkins.)

insomnia and loss of dreaming following lateral medullary stroke. A unilateral restless legs syndrome with periodic limb movements in sleep was described after (contralateral) left thalamic stroke (Unrath and Kassubek, 2006). We have observed a new-onset severe insomnia accompanied by involuntary, jerky, and tremor-like movements of the left leg and arm appearing periodically at sleep onset and during light nonrapid eye movement (NREM) sleep contralateral to a (rightsided) lacunar stroke in the ventral pons (Figure 62.5) (unpublished observations).

CIRCADIAN

DISTURBANCES

Particularly in patients with striatal, thalamic, mesencephalic, and pontine stroke, insomnia may be accompanied by an inversion of sleep–wake cycle with agitation during the night and hypersomnia during the day.

SLEEP EEG (ARCHITECTURE)

CHANGES

Recent experimental data suggest the existence of a relationship between sleep EEG synchronization and cognitive functions in the healthy as well as damaged brain (Uhlhass and Singer, 2006). The study of sleep

SLEEP AND STROKE

Fig. 62.3. Insomnia after unilateral thalamic stroke (hemorrhage). A 72-year-old woman with severe, new-onset insomnia persisting for several weeks after unilateral hypertensive hemorrhage in the lateral thalamus.

electroencephalography (EEG) changes may therefore offer the unique opportunity of testing, and documenting, the functional integrity of a neuronal system that is relevant not only for nighttime (sleep EEG generation) but also for daytime (cognitive) functions. Like the wake EEG, the sleep EEG also undergoes reorganization after acute brain damage. Data on this subject are scarce. Supratentorial strokes A reduction in total sleep time and sleep efficiency can follow acute supratentorial stroke. A reduction of sleep spindles (spindling) can be seen after ipsilateral or

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bilateral paramedian thalamic stroke (Bassetti et al., 1996b, Hermann et al., 2008) or after unilateral hemispheric stroke (Greenberg, 1966; Hachinski et al., 1979, 1990; Gottselig et al., 2002; Rossetti et al., 2005). In unilateral paramedian thalamic stroke sleep spindles may be also normal (Bassetti et al., 1996b; Santamaria et al., 2000; Hermann et al., 2008). Changes in slow-wave sleep may occur with (Figure 62.6; see also Fig. 62.1) and without changes in sleep spindles (Bassetti and Aldrich, 2001; Mu¨ller et al., 2002; Hermann et al., 2008). Usually, a reduction of slow-wave sleep and slow-wave activity (on spectral analysis) is observed. Rarely, an increase of slow-wave EEG activity can be observed during sleep, often in association with an increased slow-wave activity during wakefulness (Yokohama et al., 1996; Mu¨ller et al., 2002). Bastuji et al. (1994) reported an increase in slowwave and REM sleep in a patient with hypersomnia recorded 8 months after a bilateral thalamomesencephalic stroke. A transient reduction in REM sleep often occurs in the first few days after supratentorial stroke (Hachinski et al., 1979; Giubilei et al., 1992; Bassetti and Aldrich, 2001). REM sleep reduction may persist for months after hemispheric strokes (Figure 62.7). Cortical blindness has also been associated with a reduction in REM sleep (Appenzeller and Fischer, 1968). Sawtooth waves may be decreased bilaterally after large hemispheric lesions, or may be preserved in the presence of a strongly reduced sleep spindle activity (Bassetti and Aldrich, 2001). In severe hypersomnia following paramedian thalamic strokes, prolonged polysomnographic recordings can demonstrate an almost continuous state of light

Fig. 62.4. Dream-like hallucinations after left paramedian thalamic stroke (A, B). A 62-year-old woman with initial confusional state, abulia, anomia, and moderate–severe amnesia, in the absence of major sleep–wake disturbances. In the first few days after hospital admission she reported recurrent episodes of visual and acoustic hallucinations in the form of human figures (mostly relatives), seen on the right side of the visual field, experienced as dreaming. Seven months after the stroke she had persistent memory problems and almost daily episodes of psychic hallucinations (“sensed presence”) as well as a disturbed time perception (Zeitgefu¨hl). (Reproduced with permission from Bassetti, 2005. #Thieme.)

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Fig. 62.5. Insomnia and left-sided periodic limb movements after right paramedian pontine stroke. A 60-year-old patient with unilateral lacunar stroke in the right paramedian pons (A, B) who developed severe insomnia with involuntary, jerky, and tremor-like movements of the left leg and arm appearing periodically at sleep onset and during sleep – periodic limb movements (LM) (C).

healthy subject

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Fig. 62.6. Decreased slow-wave sleep after bilateral paramedian thalamic stroke (A). A 69-year-old patient with severe hypersomnia, amnesia, and vertical gaze palsy. Two weeks after stroke, polysomnography demonstrates a profound decrease in slow-wave activity (SWA) (B).

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Fig. 62.7. REM sleep reduction after hemispheric stroke in five patients with first supratentorial stroke (meanSD age 5012 years, meanSD stroke volume 3024 ml) and significant reduction (P < 0.001) in amounts of REM sleep during the acute phase (first week after stroke, 3820 min) and chronic phase (mean interval 15 months after stroke, 449 min) compared with hospitalized controls.

NREM stage 1 sleep (subwakefulness, presleep state), reflecting an inability to make the transition from wakefulness to sleep or to produce full wakefulness (Guilleminault et al., 1993; Bassetti et al., 1996b; Hermann et al., 2008). In patients with paramedian thalamic stroke, recovery from hypersomnia may occur despite the persistence of significant NREM sleep changes (Bassetti et al., 1996b; Hermann et al., 2008). Typically, some reduction of sleep spindles persists, however, over time. Infratentorial strokes Bilateral paramedian infarctions of the pontine tegmentum or large bilateral infarctions in the ventrotegmental pons can lead to a reduction in NREM and, especially, REM sleep (Cummings and Greenberg, 1977; Tamura et al., 1983; Autret et al., 1988; Landau et al., 2005), and may also be found in the absence of subjective sleep complaints. Lesions leading to reduced REM sleep have been reported in some cases to be unilateral (Landau et al., 2005). Physiological EEG sleep features such as sleep spindles, Kcomplexes, and vertex waves may be lost completely (Markand and Dyken, 1976; Autret et al., 1988). In one patient an alteration of the sleep EEG (runs of 2–3-Hz “pointed waves”) was found only during REM sleep ipsilaterally to a pontine tegmental stroke (Kushida et al., 1991). Patients usually present clinically with crossed or bilateral sensorimotor deficits, oculomotor disturbances, and, at least initially, disturbances of consciousness. In rare instances the only focal finding in a patient with severe sleep EEG changes may be horizontal gaze palsy (Vallderiola et al., 1993). Isolated REM sleep loss can persist for years without cognitive or behavioral consequences (Obrador et al., 1975). An increase in sleep time (as well as light NREM sleep EEG) was reported in a patient with hypersomnia

and unilateral hemorrhage in the tegmentum of the pons (Arpa et al., 1995). An increase of REM sleep was described in a patient with akinetic mutism following a bilateral, ventrotegmental pontine stroke (Popoviciu et al., 1980).

Pathophysiology of sleep–wake disorders after stroke In patients with stroke, SWDs are often of multifactorial origin. In addition to brain damage per se, environmental factors including noise, light, and intensive medical monitoring may contribute to the development of SWDs. Furthermore, stroke-related comorbidities or complications such as cardiac failure, sleep apnea, seizures, infections, fever, and drugs may aggravate sleep fragmentation and result in sleep disturbances. Finally, anxiety, depression, and psychological stress (difficulties in coping with stroke in general) frequently accompany and complicate stroke, and may further contribute to SWDs. The importance of these factors is well illustrated by the high occurrence rate of SWDs even among patients in the intensive care unit (ICU) without brain damage (Broughton and Baron, 1978; Krachmann et al., 1995).

HYPERSOMNIA, EXCESSIVE APATHY, FATIGUE

DAYTIME SLEEPINESS,

The majority of poststroke hypersomnias are due to decreased arousal because of lesions involving the different arousal systems (originally named the ascending reticular activating system, ARAS). This “passive” hypersomnia may be accompanied by focal, multifocal, or diffuse cortical hypometabolism, as examined by positron emission tomography (Levasseur et al., 1992). The most severe and persisting forms of dearousal are seen in patients with bilateral lesions of the thalamus, subthalamic area, tegmental midbrain, and upper pons, where fibers of the ascending arousal

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systems are bundled and can be severely injured even by a single small lesion. Mental arousal seems to be affected more severely by medial lesions, whereas motor arousal is impaired more strongly by lateral lesions (Castaigne and Escourolle, 1967; Passouant et al., 1967). In cortical and deep hemispheric lesions (for example in caudate strokes) sparing the thalamus, de-arousal is usually mild or transient, probably because of the widespread distribution of arousal projections at this level. In large hemispheric strokes, de-arousal results from disruption of the ARAS in the upper brainstem secondary to vertical (transtentorial) or horizontal displacement of the brain due to brain edema (Ropper, 1989). The occurrence of sleep–wake disturbances following cortical or striatal strokes without mass effect (Vock et al., 2002) supports the assumption of the role of these structures in maintenance of arousal and more generally in sleep–wake regulation. In paramedian thalamic infarcts, hypersomnia results from the interruption of the arousal systems, as well as from the disruption of sleep spindle generators in the thalamus (Bassetti et al., 1996b; Hermann et al., 2008). As a consequence, patients may be “suspended” in NREM sleep stage I, incapable of producing full wakefulness and “true” sleep. Hypersomnia with increased sleep per 24 hours (“active hypersomnia”) has very rarely been documented by polysomnography in patients with thalamic, hypothalamic, mesencephalic, or pontine stroke (Rivera et al., 1986; Arpa et al., 1995; Scammell et al., 2001). In a 51-year-old man, narcolepsy-like symptoms (excessive daytime sleepiness, hallucinations, sleep paralysis, and cataplexy) appeared following cerebral hypoxia due to cardiac arrest (Rivera et al., 1986). A narcolepsylike syndrome developed after bilateral diencephalic stroke in a 23-year-old man following surgical removal of a craniopharyngioma (Scammell et al., 2001). In this latter patient, cerebrospinal fluid (CSF) hypocretin-1 (orexin A) levels were low, indicating a symptomatic form of narcolepsy. In two of our patients with hypersomnia following thalamic and pontine stroke, normal CSF hypocretin-1 levels were found (unpublished observations). Hypersomnia with increased REM sleep can be induced in the cat by a small bilateral lesion of the ventrolateral periaqueductal gray matter at the level of the trochlear nucleus (Petitjean et al., 1975; Sastre et al., 1996). This alteration is mediated by g-aminobutyric acid type A (GABAA) receptors, and stimulation of these receptors by muscimol leads to a pronounced increase in REM sleep for 50–100% of the recording time. In human patients, similarly high proportions of REM sleep have not been described.

Several forms of fatigue may develop following stroke in connection with SWDs (hypersomnia, excessive daytime sleepiness, and insomnia), mood and emotional changes, neurological deficits, and neuropsychological–cognitive sequelae. Psychological stress with inadequate coping with stroke consequences in general plays a role, as suggested by the absence of a clear correlation between poststroke fatigue and stroke size or site (P.O. Valko et al., unpublished observations), and a high frequency of fatigue following myocardial infarction (without brain damage) (Leegard, 1983). However, fatigue is often associated also with hypersomnia and EDS and poor stroke outcome, suggesting a neurogenic component, at least in a subgroup of patients with poststroke fatigue (P.O. Valko et al., unpublished observations).

INSOMNIA Mild to moderate insomnia is a frequent, usually nonspecific, and multifactorial complication of acute stroke. Most cases of insomnia after stroke are due to complications of stroke and not to brain damage per se. Recurrent arousals, sleep discontinuity, and sleep deprivation may result from pre-existing disorders (e.g., heart failure, pulmonary disease), SDB, medications, infections, fever, inactivity, environmental disturbances (e.g., on an ICU), stress, and depression. In a recent study, the use of psychotropic agents, anxiety, dementia, pre-existing insomnia, and stroke severity (as estimated by the Barthel Index) were found to be risk factors for poststroke insomnia (Leppa¨vuori et al., 2002). Insomnia may rarely be related to brain damage (see above), a situation for which the term agrypnia has been suggested (Hobson, 2002). Lesions in the dorsal/ tegmental brainstem areas, the paramedian and lateral thalamus (see Figure 62.3), and subcortical areas were observed in association with poststroke and posttraumatic insomnia (van Bogaert, 1926; Ron et al., 1980; Johns, 1994). The observation in some of these patients of rapid transitions from insomnia to hypersomnia emphasizes the dual role of brain areas such as the thalamus, basal forebrain, and brainstem in sleep– wake regulation.

SLEEP–WAKE DISORDERS EVOLUTION/OUTCOME

AFTER STROKE AND STROKE

The presence of sleep architectural disturbances after stroke are associated with neuropsychiatric (depression, anxiety) and neurocognitive disturbances, and have a negative impact on rehabilitation, daily functioning, and quality of life (Wyller et al., 1998;

SLEEP AND STROKE Leppa¨vuori et al., 2002). In addition, based on observations made in normal subjects (including those after sleep deprivation), SWDs are expected to be directly implicated in poststroke attentional, neurocognitive, and mood changes (Horne, 1993). Only a few studies, however, have addressed this subject (Ron et al., 1980; Bassetti et al., 1996b; Hermann et al., 2008). In 11 consecutive patients with first-ever supratentorial stroke, Siccoli et al. (2008a) reported a significant correlation between sleep EEG and cognitive changes in both the acute and subacute phase of stroke (Figure 62.8). Finally, the presence of SWD and sleep architecture changes may be of prognostic value (Vock et al., 2002; Hermann et al., 2008). For example, poor sleep efficiency, decreased spindles, K-complexes, and slow-wave sleep predict poor outcome after hemispheric stroke (Hachinski et al., 1979; Bassetti and Aldrich, 2001). In paramedian thalamic stroke, on the other hand, we could not find such a relationship (Hermann et al., 2008).

Circadian factors influencing stroke onset Circadian factors influence the temporal pattern of onset of ischemic and hemorrhagic stroke (Chaturvedi et al., 1999; Passero et al., 2000). Cerebrovascular events, similar to myocardial infarcts and sudden death, appear most frequently in the morning hours (i.e., between 6 am and noon), and particularly within the first hour after awakening. A meta-analysis of 31 publications including 11,816 patients found a 49% increase in all types of stroke (ischemic, hemorrhagic, transient ischemic attack (TIA)) at that time of the day, compared with other times (Elliott, 1998).

Diagnosis and treatment of sleep–wake disorders after stroke The recognition of poststroke SWD depends upon a high degree of suspicion. Most SWDs, and particularly insomnia and hypersomnia, are usually well recognizable on clinical grounds. Not uncommonly, the presence/severity of SWD is first fully realized when patients leave the hospital and get back to their prestroke life conditions. The correlation of poststroke SWD and sleep EEG is not very good, particularly when brain damage includes thalamocortical structures that are involved in wake and EEG generation (Vock et al., 2002). In patients with poststroke hypersomnia, for example, sleep EEG may reveal either a reduction or, less commonly, an increase of NREM and/or REM sleep. Particularly in supratentorial strokes, the Multiple Sleep Latency Test may be inadequate for assessment of poststroke SWD (Bassetti et al., 1996b). Actigraphy, conversely, may be helpful to estimate changes in sleep–wake rhythms and sleep/rest needs following stroke (see Figure 62.1), although a differentiation between sleep and severe apathy cannot be made (Bassetti and Valko, 2006; Hermann et al., 2008).

HYPERSOMNIA

100.0 90.0 Sleep efficiency (%)

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Although intracerebral and subarachnoid hemorrhages rarely occur during the night hours, 20–40% of all ischemic strokes present at night (i.e., during sleep) (Elliott, 1998; Bassetti and Aldrich, 1999a). Strokes at night have been shown to be associated with more severe deficits and obesity (see also below; JimenezConde et al., 2007).

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Fig. 62.8. Cognitive functions and sleep EEG after hemispheric stroke. Correlation between sleep efficiency and nonverbal fluency in 15 patients tested within the first 8 days after a nonlacunar hemispheric stroke (Pearson’s correlation coefficient r ¼ 0.749, p ¼ 0.002). (Modified from Siccoli et al., 2008a.)

Treatment of poststroke hypersomnia is often ineffective (Hermann and Bassetti, 2003; Bassetti and Valko, 2006). In individual patients some improvement has been seen in thalamic and mesencephalic stroke with amphetamines, modafinil, methylphenidate, and levodopa/dopa agonists (see Figure 62.1). Improvement of apathy and presleep behavior in patients with paramedian thalamic stroke has been reported with 20–40 mg bromocriptine (Catsman-Berrevoets and Harskamp, 1988). A clearcut improvement in alertness with 200 mg modafinil was observed in a patient with bilateral mesodiencephalic paramedian infarction (Autret et al., 2001). Treatment of an associated depression with stimulating antidepressants may also improve poststroke hypersomnia. A favorable influence on early poststroke rehabilitation was reported after both methylphenidate (5–30 mg/day, 3-week trial) and levodopa (100 mg/day, 3-week trial) treatment, an effect that may, at least in part, be related to improved alertness in these patients (Grade et al., 1998; Scheidtmann

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et al., 2001). It is unclear which treatments are beneficial in poststroke fatigue. Amantadine, stimulating antidepressants, stimulations, and stress management education may be considered (de Groot et al., 2003).

INSOMNIA Treatment of poststroke insomnia should include placement of patients in private rooms at night, protection from nocturnal noise and light, increased mobilization with exposure to light during the day, and, when unavoidable, temporary use of hypnotics that are relatively free of cognitive side-effects, such as zolpidem and benzodiazepines (Hermann and Bassetti, 2003; Bassetti, 2005). It should be kept in mind that benzodiazepines may enhance not only sedation and neuropsychological deficits in stroke patients but also lead to the re-emergence of other neurological symptoms (Lazar et al., 2002). Treatment of an associated depression with sedative antidepressants may also improve poststroke insomnia. In a study of 51 stroke patients, mianserin 60 mg/day led to a better improvement of insomnia than placebo, even in patients without associated depression (Paloma¨ki et al., 2003). Antidepressants may be preferable for long-term management of poststroke insomnia.

SLEEP-DISORDERED BREATHING AND STROKE Frequency and clinical characteristics of sleep-disordered breathing after stroke Approximately 50–70% of stroke patients have SDB, as defined by an apnea–hypopnea index (AHI) 10/ hour (Bassetti et al., 1996a, 2006; Dyken et al, 1996;

Bassetti and Aldrich, 1999b; Parra et al., 2000; Wessendorf et al., 2000a; Hui et al., 2002; Turkington et al., 2002; Selic et al., 2005; Siccoli et al., 2008b). Patients with recurrent stroke have a higher likelihood of SDB than first-ever stroke victims (Dziewas et al., 2005). In most studies no significant differences were found in the frequency of SDB according to topography, subtype (ischemic versus hemorrhagic), and presumed etiology of stroke. A few studies have suggested a link between poststroke SDB and macroangiopathy (Bassetti et al., 2006), microangiopathy/leukoencephalopathy (Harbison et al., 2003), or stroke due to patent foramen ovale (Ozdemir et al., 2008). The frequency of SDB was found in two studies to be similar in patients with TIA and those with ischemic stroke (Bassetti et al., 1996a; Parra et al., 2000). In a third study, a similarly high frequency of SDB in 86 patients with TIA (AHI 15/hour in 50%) was reported, but no significant differences in frequency or severity of SDB were noted in comparison with 86 controls matched for age (meanSD age 6610 years) and sex (McArdle et al., 2003). The most common form of SDB in stroke patients is obstructive sleep apnea (OSA) (Figure 62.9). Occasionally, patients may have both OSA and central sleep apnea (CSA)/Cheyne–Stokes breathing (CSB), with predominance of the first in REM sleep and of CSA/ CSB in light NREM sleep (Bassetti et al., 1996a, 1997; Parra et al., 2000). CSB is characterized by cyclic fluctuations in breathing drive, hyperpneas alternating with apneas or hypopneas in a gradual waxing-and-waning fashion (American Academy of Sleep Medicine, 2005). In the

Fig. 62.9. Obstructive sleep apnea (OSA) in acute ischemic stroke in a 61-year-old man with right paramedian pontine infarction (A); National Institutes of Health stroke score 11. A sleep study 1 week after stroke demonstrates severe OSA (apnea– hypopnea index 75/hour) (B). (MRI-image courtesy of Professor A. Valavanis, Division of Neuroradiology, University Hospital, Zurich, Switzerland.)

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Fig. 62.10. Cheyne–Stokes-like breathing (CSB) in acute ischemic stroke in a 63-year-old man with mild left anterior choroidal artery infarction (A); National Institutes of Health stroke score 8. Patient had a history of hypertension, no heart failure (ejection fraction on echocardiography 55%), no decreased level of consciousness, normal 24-Holter electrocardiogram. A sleep study 3 days after stroke demonstrated severe CSB (apnea–hypopnea index (AHI) 53/hour) (B). One week later there was a spontaneous improvement of CSB (AHI 16/hour).

first few days after stroke, central sleep apnea and/or CSB may also be very frequent, and present in up to 30–40% of patients (Figure 62.10) (Parra et al., 2000; Iranzo et al., 2002; Hermann et al., 2007; Siccoli et al., 2008b). The presence of bilateral strokes, heart failure, pulmonary disease, and profound disturbances of consciousness, traditionally described in stroke patients with CSB, is not always necessary (Bassetti et al., 1997; Hermann et al., 2007; Siccoli et al., 2008b). In addition, in the subacute phase of stroke, the presence of SDB has been linked to a reduced cardiac ejection fraction (Nopmaneejumruslers et al., 2005). SDB improves from the acute to the subacute phase of stroke, but about 50% of patients still exhibit an AHI 10/hour 3 months after the event (Parra et al., 2000; Harbison et al., 2002; Hui et al., 2002; Bassetti et al., 2006). In the first three studies published, the

AHI improvement was from 22 to 17 per hour after the first 3 months (Parra et al., 2000), from 30 to 24 per hour after 6 weeks (Harbison et al., 2002), and from 32 to 16 per hour after 6 months (Bassetti et al., 2006). Central events appear to improve more than obstructive events (Parra et al., 2000). One study suggested a better improvement of SDB in hemorrhagic strokes compared with ischemic strokes (Szucs et al., 2002). Restitution of neurological deficits (e.g., of motor paresis, central respiratory drive), improvement of chest/lung function (e.g., recovery from pneumonias), and disappearance of acute cardiac complications (i.e., heart failure, arrhythmia), as well as a decrease in time spent in supine bed position, may play a role. Central hypoventilation, failure of automatic breathing (Ondine’s curse), and other neurogenic

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breathing disturbances are less common and usually associated with brainstem and spinal cord strokes (Bassetti et al., 1997). SDB can present with a variety of symptoms and signs that are sometimes attributed to the underlying brain damage. Nighttime symptoms of SDB include difficulty falling asleep (sleep onset insomnia; see below), respiratory noises (snoring, stridor), irregular or periodic respiration (including apneas), agitated sleep with increased motor activity and frequent awakenings, sudden awakenings with or without choking sensations, shortness of breath, palpitations and fear (“panic attacks”), orthopnea, and increased sweating. In patients with severe hypoventilation, arousal responses can be suppressed by increasing sleep debt and may lead – in conjunction with cardiac rhythm abnormalities – to sleep-related death. Daytime symptoms of SDB are headaches, fatigue, and EDS, cognitive and mental deficits with concentration and memory difficulties, irritability, and depression. Some patients may exhibit breathing irregularities during wakefulness, including dyspnea, apneas, inspiratory breath-holding (apneustic breathing; see below), irregular breathing, rapid shallow breathing (hyperpnea and central hyperventilation; see below), or hiccups. Importantly, daytime fatigue and sleepiness are not always present in patients with SDB (Bassetti et al., 2006). Because of an overlap in the neurogenic mechanisms controlling sleep, breathing, and other somatic and autonomic functions, disorders of breathing in stroke patients are often associated with a variety of other abnormalities. For example, patients with Wallenberg’s syndrome may develop a combination of hiccups (Currier et al., 1961), irregular breathing, OSA (Askenasy and Goldhammer, 1988), central hypoventilation (Hunziker et al., 1964), Ondine’s curse (Bogousslavsky et al., 1990), insomnia, sweating (Rousseaux et al., 1996), and cardiovascular abnormalities with sudden death during the acute course (Caplan et al., 1986).

Pathophysiological links between sleep-disordered breathing and stroke DISORDERED

BREATHING DURING WAKEFULNESS

AFTER STROKE

Considering the complex anatomy and physiology of breathing control, brain damage is expected to impair respiration during wakefulness in different ways according to type, extension, and topography of the lesion. The mechanisms involved in stroke patients with disordered breathing can be differentiated based on topography: (1) involvement of afferent inputs to the

medullary respiratory neurons (e.g., posterior spinal cord stroke) (Lahuerta et al., 1992) – this may lead to a reduction or cessation of airflow of obstructive or nonobstructive type (and central obstructive hypopneas and apneas); (2) direct dysfunction of medullary respiratory neurons (e.g., medullary stroke) – this can manifest with central apneas, irregular breathing (Biot’s or ataxic breathing), and failure of automatic breathing (Ondine’s curse) during both wakefulness and sleep; (3) involvement of the efferent respiratory control at the level of respiratory neurons (e.g., anterior medullary or spinal stroke) (Howard et al., 1998) may be accompanied by central or obstructive hypopneas and apneas; and (4) dysfunction of supramedullary breathing control mechanisms can present with a variety of forms of disordered breathing. Cortical, corticobulbar, and corticospinal lesions may affect volitional breathing partially (respiratory apraxia) or completely (failure of voluntary breathing) (Munschauer et al., 1991). The lesion may be as high as in the frontal cortex and as low as at the cervicomedullary junction (Newsom-Davis, 1974). These patients cannot hold their breath or voluntarily change their respiratory rate. Bilateral lesions in the ventrotegmental pons were reported to cause inspiratory breath-holding (apneustic breathing) (Plum and Alvord, 1964) or metronomically regular and rapid breathing (central neurogenic hyperventilation) (Plum and Swanson, 1959). In patients with pontomedullary lesions, complex abnormalities of voluntary and automatic breathing can be observed. These patients may exhibit irregular breathing (cluster breathing), central apneas, hiccups, and stridor during wakefulness and sleep.

SLEEP-DISORDERED

BREATHING AS A CONSEQUENCE

OF STROKE

Poststroke SDB is a complex pathophysiological phenomenon of usually multifactorial origin. In addition to brain damage per se, pre-existing respiratory, metabolic (e.g., increased body mass index) and cardiovascular (e.g., heart failure) conditions together with indirect complications of brain damage (e.g., aspiration, immobility, respiratory infection, pain, sleep fragmentation due to pain and other factors, autonomic changes) favor the appearance of SDB. The supine position is favored by stroke patients and may also be implicated (Brown et al., 2008). Poststroke obstructive sleep apnea The appearance de novo or the worsening of a preexisting OSA may be favored by a disturbed coordination of upper airway, intercostal, and diaphragmatic

SLEEP AND muscles due to brainstem or hemispheric lesions. The presence of dysphagia, for example, was found in some (but not all) studies to predict the presence of OSA in stroke patients (Bassetti et al., 1996a, Turkington et al., 2002; Martinez-Garcia et al., 2006). Body mass index and neck circumference (Turkington et al., 2002) as well as diabetes and nocturnal onset of stroke (Bassetti et al., 2006) were also linked with the presence of (obstructive) SDB. Strokes at night have been shown, on the other hand, to be associated with a greater clinical severity and obesity, suggesting a potential link with SDB (JimenezConde et al., 2007). A reduced ventilatory sensitivity to inhaled carbon dioxide may also contribute to OSA in patients with rostrolateral medullary lesions (Morrell et al., 1999). Of note, the presence of prestroke leukoencephalopathy predicts a more severe poststroke OSA (Harbison et al., 2003). Poststroke central sleep apnea/Cheyne–Stokes breathing Poststroke CSB was first reported in patients with bilateral supratentorial or infratentorial (mostly pontine) strokes associated with disturbed consciousness and/or heart failure (Brown and Plum, 1961; Lee et al., 1974; Lanfranchi et al., 2003; Nopmaneejumruslers et al., 2005). More recently, CSB presenting only during sleep has also been reported in patients with unilateral stroke and preserved consciousness in the absence of clinically overt heart failure (Nachtmann et al., 1995; Bassetti et al., 1997; Hermann et al., 2007; Siccoli et al., 2008b). In stroke patients with CSA/CSB, nocturnal transcutaneous partial pressure of carbon dioxide is lower and the prevalence of a reduced left ventricular ejection fraction (LVEF) is higher than in stroke patients without CSA (Nopmaneejumruslers et al., 2005). However, patients with CSA and reduced LVEF do not necessarily exhibit evidence of clinical heart failure (Bassetti et al., 1997; Nopmaneejumruslers et al., 2005; Siccoli et al., 2008b). In addition to a subtle cardiac dysfunction, it is possible that also the topography of stroke (involving the brain control of respiration and/or autonomic functions, for example in the thalamus (see Figure 62.1), cingulum, or insula) may play an important role in the pathophysiology of poststroke CSB (Bassetti et al., 1997; Hermann et al., 2007; Siccoli et al., 2008b). Finally, CSA/CSB and OSA may potentiate one another (Bassetti A Aldrich, 1999b) and in some cases result from similar predispositions. This may explain the high prevalence of both central and obstructive breathing abnormalities in stroke patients.

STROKE

SLEEP-DISORDERED

1063 BREATHING AS A RISK FACTOR

FOR STROKE

That SDB may predispose to stroke was suggested recently by four longitudinal studies. By stratifying 1022 patients admitted to a sleep laboratory into two groups with an AHI 5 or <5 per hour that were followed for up to 6 years, Yaggi et al. (2005) found that OSA was associated with an increased risk for stroke and death (hazard ratio 2.24, 95% confidence interval (CI) 1.3 to 3.86). Even after adjusting the patients for established risk factors, such as arterial hypertension, diabetes mellitus, atrial fibrillation, hyperlipidemia, and smoking status, SDB was still remaining a statistically significant risk factor (hazard ratio 1.97, 95% CI 1.12 to 3.48). Increased severity of SDB was associated with higher stroke and death risk, patients with AHI >36/hour being associated with a hazard ratio of 3.30 (95% CI 1.74 to 6.26). A similar approach was used by Marin et al. (2005), who recruited 1387 men with OSA syndrome and snoring from a sleep clinic and compared them with 377 simple snorers and a population-based sample of 264 healthy men, matched for age and body mass index. After a mean follow-up period of 10.1 years, the authors showed that patients with untreated severe OSA (AHI >30/hour) had a significantly higher incidence of fatal and nonfatal cardiovascular events (e.g., stroke, myocardial infarcts, coronary artery bypass surgery, percutaneous transluminal coronary angiography) than patients with mild–moderate OSA (AHI >5 and 30 per hour), patients with OSA of any severity treated with continuous positive airway pressure (CPAP), simple snorers, and healthy participants. Multivariable analysis, adjusting for potential confounders (hypertension, diabetes, cardiovascular disease, lipid disorders, smoking status), showed that untreated severe OSA increased the risk of fatal and nonfatal cardiovascular events compared with that in healthy participants. The major limitation of the latter two studies is that vascular risk was examined in patients with SDB admitted to sleep laboratories and compared with that in patients suffering from other sleep disorders or healthy controls. Thus, the risk profile of these patients may not represent that of the general population. Two population-based studies tried to overcome this limitation. In a cross-sectional analysis analysing 1475 subjects, Arzt et al. (2005) showed that patients with an AHI 20/hour in the general population have an increased risk of stroke (odds ratio 4.33, 95% CI 1.32 to 15.24) compared with those without SDB (AHI <5/ hour) after adjustment for known risk factors. In a subsequent longitudinal study, the authors evaluated the risk of suffering a first-ever stroke over the next

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4 years. In the unadjusted population, persons with SDB (AHI 20/hour) had an increased stroke risk. After adjustment for age, sex, and body mass index, this association was no longer significant (odds ratio 3.08, 95% CI 0.74 to 12.81). Recruiting an elderly population of 394 noninstitutionalized stroke-free subjects (aged over 70 years), Munoz et al. (2006) showed after a follow-up of 6 years that persons with severe SDB (AHI >30/hour) had an increased risk of developing a stroke (hazard ratio 2.52, 95% CI 1.04 to 6.01), even when the data were adjusted for sex, which was found to be associated with stroke. A strong limitation of this latter investigation was that as many as 2528 persons had to be screened in order to include fewer than 400 participants, owing to the fact that many subjects did not meet inclusion criteria or were unwilling to participate. This raised some doubt about whether this cohort was representative of the general population (Lavie and Lavie, 2007). SDB, arterial hypertension, and atherogenesis Nocturnal apneas are associated with recurrent hypoxemias and hypercapnias, arousals from sleep, intrathoracic pressure changes, and sympathetic activation (Shamsuzzaman et al., 2003). Particularly obstructive apneas induce cerebral blood flow changes during and after apnea episodes (Ba˚lfors and Franklin, 1994; Hajak et al., 1996; Diomedi et al., 1998; Netzer et al., 1998; Leslie et al., 1999). Furthermore, inflammatory responses are induced in the vasculature of patients with SDB who have an increase in, for example, interleukin-6 and -18 (Minoguchi et al., 2005), C-reactive protein (Shamsuzzaman et al., 2003), and fibrinogen (Wessendorf et al., 2000b). The injured vessel also releases trophic factors, such as vascular endothelial growth factor (Lavie et al., 2002; Schulz et al., 2002), that promote the vascularization and growth of developing atherosclerotic plaques. Observations from the Wisconsin Sleep Cohort have shown that an AHI >15/hour is independently associated with a threefold increased risk of developing arterial hypertension within a 4-year period (Peppard et al., 2000). Compared with subjects without SDB with matched age and comorbid risk factors, patients with SDB also exhibit a more pronounced atheromatosis, reflected by an increased intima–media thickness (IMT) of the common carotid artery, as revealed by duplex sonography (Silvestrini et al., 2002). The degree of IMT thickening increases with the severity of the sleep-related breathing disturbance (Altin et al., 2005; Minoguchi et al., 2005; Wattanakit et al., 2007). Remarkably, IMT changes in patients with SDB

correlate well with inflammatory responses in their blood (Minoguchi et al., 2005). SDB, coronary disease, and heart failure SDB promotes atherogenesis not only in carotid and peripheral arteries, but also in the coronaries, resulting in ischemic electrocardiographic changes, ischemic heart disease, and left ventricular failure (Shamsuzzaman et al., 2003). In patients with heart disease, SDB predisposes to cardiac rhythm abnormalities. As many as 82% of cardioconverted SDB patients without CPAP exhibited recurrence of rhythm abnormalities, compared with only 42% in CPAP-treated patients with SDB (Kanagala et al., 2003). Atrial fibrillation is a well known trigger of cerebral thromboembolism. This, together with paradoxical embolisms during long apneas due to right-to-left shunts in patients with patent foramen ovale (Beelke et al., 2002), may provide an explanation for cardioembolic events in patients with SDB (Ozdemir et al., 2008). This is further supported by the observation of an increased risk of stroke in patients with coronary artery diseases and sleep apnea (Valham et al., 2008). SDB and white matter injury That cardiac dysfunctions may indeed contribute to stroke risk is suggested by a longitudinal magnetic resonance imaging study by Robbins et al. (2005). Patients showing progression in the severity of brain white matter disease were significantly more likely in that follow-up study to have a Cheyne–Stokes-like respiration pattern and also showed an increased number of central, but not obstructive, apneas. In a further subanalysis, the same group showed that the AHI in their patients did not correlate with the severity of brainstem white matter injury (Ding et al., 2004). As CSB and CSA are often associated with clinically overt or subclinical heart failure (see above), the high incidence of white matter lesions in patients with CSB points towards a cardioembolic origin of brain infarcts in this patient population. Although one smaller cross-sectional study did not confirm a link between SDB and subcortical white matter damage (Davies et al., 2001), and another study found a relationship between obstructive apneas and silent brain infarcts (Minoguchi et al., 2007), these data suggest that not only OSA but also CSB may confer an increased cerebral embolic risk. SDB, metabolic syndrome, and type II diabetes In view of the fact that SDB is associated with arterial hypertension, atherosclerosis, and obesity, it was suggested that the metabolic syndrome may be the common denominator of most, if not all, of the

SLEEP AND STROKE pathologies discussed above. Indeed, recent cross-sectional studies have shown that patients with OSA have a higher prevalence of insulin resistance, dyslipidemia, and dyscholesterolemia, even when adjusted for known confounders such as age, smoking status, and body mass index (Coughlin et al., 2004; Reichmuth et al., 2005; Kono et al., 2007; Parish et al., 2007; Peled et al., 2007). Other studies have not confirmed that finding (Sanders and Givelber, 2003; Sharma et al., 2007). One prospective longitudinal study addressed the relationship between SDB and type II diabetes (Reichmuth et al., 2005), and revealed a nonsignificant trend for patients with OSA (AHI 15/hour) to develop type II diabetes more frequently over a 4-year interval than patients without OSA (AHI <5/hour) adjusted for age, sex, and body habitus (odds ratio 1.62, 95% CI 0.67 to 3.65). Of note, two studies of independent populations found diabetes to be an independent risk factor for SDB in stroke patients (Bassetti et al., 2006). Effects of SDB treatment (CPAP) on vascular morbidity If SDB plays a clinically significant role as a risk factor in vascular diseases, its reversal via CPAP treatment should prevent the pathophysiological sequelae attributed to the breathing abnormalities. Indeed, previous studies have shown favorable effects of CPAP on arterial hypertension (Faccenda et al., 2001; Pepperell et al., 2002; Coughlin et al., 2007). Pepperell et al. (2002) reported that therapeutic CPAP reduced mean arterial blood pressure (MAP) by 2.5 mmHg, whereas subtherapeutic CPAP levels increased blood pressure by 0.8 mmHg. This effect is clinically relevant, as a 3.3-mmHg reduction in MAP would be expected to be associated with a stroke risk reduction of approximately 20%. Interestingly, CPAP reduced both systolic and diastolic blood pressure during sleep and wakefulness, indicating a sustained improvement of vascular function. Treatment with CPAP may also favorably influence surrogate markers of vascular disease. Two different studies were able to demonstrate that CPAP treatment leads to a progressive decrease of both factor VII clotting activity and fibrinogen levels (Chin et al., 1996, 1998). The decrease in exogenous clotting activity was associated with a decrease in systolic as well as diastolic blood pressure (Chin et al., 1998). Bokinsky et al. (1995) reported that CPAP improved platelet activation and aggregation immediately – in the first night after initiation of treatment. Evidence that CPAP improves dyslipidemia and insulin resistance in obese patients with SDB is so far lacking. In one study

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evaluating CPAP effects over 6 weeks, no changes in the metabolic profile were found (Coughlin et al., 2007).

Sleep-disordered breathing after stroke and stroke evolution/outcome SHORT-TERM

OUTCOME

The severity of SDB, expressed as AHI, in the first night after hospital admission predicts early neurological worsening and a less favorable short-term outcome (Iranzo et al, 2002; Selic et al., 2005; Siccoli et al., 2008b). Patients with moderate to severe sleep apnea (AHI > 30/hour) exhibit higher daytime and nighttime blood pressure values compared with patients without sleep apnea (AHI <10/hour) (Figure 62.11) (Selic et al., 2005). The raised daytime and nighttime blood pressure levels may contribute, together with recurrent hypoxias, to the less favorable outcome, which was found to be independent of other cardiovascular risk factors, such as body mass index, arterial hypertension, smoking, diabetes, or hyperlipidemia (Iranzo et al., 2002). The presence of SDB has been shown in several studies to predict a longer acute hospitalization (Kaneko et al., 2003; Selic et al., 2005; Siccoli et al., 2008b).

LONG-TERM

OUTCOME

Long-term functional outcome is negatively affected by SDB. In a study of 120 patients, the presence of SDB predicted a worse Barthel index and higher mortality at 6 months (Turkington et al., 2004). In patients admitted to a stroke rehabilitation unit, oxygen desaturation and OSA were significantly and independently related to functional impairment and length of hospitalization (Good et al., 1996; Kaneko et al., 2003). Long-term survival is also negatively affected by SDB. In a case–control study involving 400 stroke patients, a history of snoring increased the mortality rate from stroke at 6 months (Spriggs et al., 1992). In patients with first-ever stroke or TIA, SDB predicts an increased mortality in the following 2–10 years (Dyken et al., 1996; Parra et al., 2004; Bassetti et al., 2006; Sahlin et al., 2008). This effect appears to be more pronounced for OSA than for CSA (Sahlin et al., 2008). Severe sleep apnea was found to be associated also with recurrent stroke (Dziewas et al., 2005).

Diagnosis and treatment SDB is best diagnosed by respiratory polygraphy that monitors nasal airflow and thoracic and abdominal respiratory movements, in addition to oximetry (capillary oxygen saturation). Conventional polysomnography offers additional information (e.g., on the

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C.L. BASSETTI AND D.M. HERMANN 200 180

*

*

*

*

160 140

*

mmHg

120

*

* *

100 80 60 40 20 0 AHI<10

AHI<10-30 SBP night 1 SBP day 2

SBP night 2 DBP night 1

AHI>30 DBP day 2 DBP night 2

Fig. 62.11. Blood pressure in the acute phase of stroke in patients with and without sleep-disordered breathing. Mean systolic (SBP) and diastolic (DBP) blood pressure values during night 1, day 2, and night 2 in patients without sleep apnea (apnea– hypopnea index (AHI) <10/hour), with mild sleep apnea (AHI 10–30/hour), and with moderate–severe sleep apnea (AHI >30/hour). Values are meansd. *P<0.05 versus patients without sleep apnea (AHI <10/hour). (Reproduced with permission from Selic et al., 2005. #Lippincott Williams & Wilkins.)

specific type of breathing disturbance, sleep architecture, motor activity, etc.), but is more expensive and less commonly available in acute settings, and should therefore be reserved for complex situations. Based on nasal airflow, respiratory movements, and oxygen desaturation recordings, various forms of SDB can be defined, including OSA, CSA, and CSB. The AHI and the number and severity of desaturations are indicators of the severity of SDB. Using a cost–effectiveness model, Brown et al. (2005) found that screening for SDB in stroke patients was cost-effective as long as the treatment of stroke patients with OSA by CPAP improved patient utilities by more than 0.2 for a willingness-to-pay of $50,000 per quality-adjusted life year (QALY), and by 0.1 for a willingness-to-pay of $100,000 per QALY. Treatment of SDB in stroke patients represents a clinical, technical, and logistical challenge (Hermann and Bassetti, 2003). Treatment strategies should always include prevention and early treatment of secondary complications (e.g., aspiration, respiratory infections, pain) and a cautious use or avoidance of alcohol and sedative–hypnotic drugs, which may all affect breathing control negatively during sleep (Hermann and Bassetti, 2003). Patient positioning in the acute phase may influence oxygen saturation as well (Rowat et al., 2001; Turkington et al., 2002; Brown et al., 2008). Weight loss

and use of lateral sleeping position can also improve SDB. CPAP is the treatment of choice for OSA. Automatic systems can be used for simultaneous detection of upper airway obstructions and treatment, which is made possible by automatic titration of CPAP (Disler et al., 2002; Bassetti et al., 2006). Compliance with CPAP has been reported to be as high as 70% in the rehabilitation setting (Wessendorf et al., 2001). Other groups working in the acute stroke setting have reported lower percentages (Hui et al., 2002; Martinez-Garcia et al., 2005, Bassetti et al., 2006; Hsu et al., 2006). In a randomized trial of stroke patients with severe SDB (AHI 30/hour), usage of CPAP was very low with a mean of 1.4 hours per night (Hsu et al., 2006). In our experience, only about 50% of stroke patients with SDB can be treated in the acute phase, and only about half of these patients will stay on CPAP in the long run (Bassetti et al., 2006). Compliance is certainly influenced by the spontaneous improvement of SDB after the acute phase (see above) and by the absence in most patients with stroke and SDB of daytime sleepiness (Barbe´ et al., 2001). In addition, compliance can be expected to be a problem in stroke patients with severe facial/bulbar palsy (difficulties related to mask discomfort), severe motor deficits (difficulties in handling the CPAP device/mask), dementia, delirium, aphasia, anosognosia, and bulbar palsy.

SLEEP AND STROKE In patients with central apneas and CSB, improvement can be achieved with oxygen (Nachtmann et al., 1995). A novel method of ventilatory support called adaptive servoventilation may be considered in the latter patients. In a recent study it was shown that such treatment prevented central apneas in stroke patients with heart failure more efficiently than CPAP or oxygen (Teschler et al., 2001). Tracheostomy and mechanical ventilation may become necessary in patients with central hypoventilation. A few outcome studies have also appeared in patients with stroke and SDB. Wessendorf et al. (2001) reported an improvement in subjective wellbeing and nighttime blood pressure values in a group of 41 and 16 patients, respectively, with stroke and SDB, who were treated with CPAP over 10 days. Sandberg et al. (2001) reported that treatment of SDB is associated with improved ratings for depression in poststroke patients, as revealed by the Montgomery– Asberg Depression Rating Scale. No improvement was found on neurological recovery as assessed by the Barthel Index. Martinez-Garcia et al. (2005) studied 51 patients with stroke and an AHI 20/hour. After 18 months, 29% of the patients were still on CPAP. This group had a significantly lower incidence of new vascular events.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 63

Sleep and headache TERESA PAIVA * Institute of Molecular Medicine, Medical Faculty of Lisbon, Lisbon, Portugal

INTRODUCTION Headache and sleep disturbances are commonly reported problems in neurological practice and both have important individual and socioeconomic impacts. Their mutual relationships have been known for many years, but the full understanding of the underlying mechanisms involved is still unclear. Basically, it is known that a headache may cause a sleep disturbance, a sleep disturbance may be the cause of a headache, and both sleep and headache may be the consequence of another underlying condition (Paiva et al., 1995). From clinical practice data it is clear that such a relation is complex, because a headache can be the result of both too much and too little sleep, and can be both cured by sleep and induced by it. This complexity must be considered in any scientific and clinical approach in order to achieve a deeper and clearer insight. The recent publication of revised versions of the International Classification of Headache Disorders (ICHD-II) (Olesen, 2005) and International Classification of Sleep Disorders (ICSD-2) (American Academy of Sleep Medicine, 2005) implies an updated review with some new concepts. In the ICHD-II, some sleep entities are individualized, namely headache related to sleep apnea and hypnic headache, whereas in the ICSD-2 sleep-related headaches are referred to other classifications in Appendix A. The first section of this chapter describes clinical aspects of sleep–headache relations: sleep and headache prevalence; clinical evaluation (parameters used to characterize the mutual influences); sleep disturbances coursing with headaches; headaches coursing with sleep disturbances; sleep disturbances and headache as comorbid symptoms; and when to suspect a sleep disturbance in the evolution of a chronic headache, and vice versa. The second section deals with

functional links between sleep and headache, addressing the physiological, anatomic, chronobiological, and genetic aspects as well as neurotransmitters and neuromodulators.

CLINICAL ASPECTS OF SLEEP^ HEADACHE RELATIONS Sleep and headache prevalence Headache patients more often report daytime symptoms (fatigue, tiredness, or sleepiness) and sleep problems (insomnia) (Paiva et al., 1995; Jennum and Jensen, 2002). In a specialized headache clinic, 17% of the patients had awakening or nocturnal headache, and 53% of them (9% of the total headache population) had a sleep disorder (Paiva et al., 1997). A recent population study showed that poor sleep and anxiety have an important impact on the lives of headache sufferers. Those with moderate sleep problems had experienced significantly more headaches in the previous 3 months than controls (percentage occurrence 76% versus 24%; odds ratio 4.8), and the picture was still more impressive for severe sleep problems (percentage 87% versus 13% respectively; odds ratio 13.0) (Boardman et al., 2005). The prevalence of chronic morning headache (CMH) is 7.6%, as determined in a European study including a total of 1890 subjects from the UK, Germany, Italy, Portugal, and Spain. CMH is more common in females and in subjects between 45 and 64 years of age. The most significant associated factors are anxiety, depressive disorders, insomnia, dyssomnia, and circadian rhythm disorder (Ohayon, 2004). The picture is similar in young subjects: in the USA, a national survey including 6072 adolescents showed a clear relation between insomnia and headache

*Correspondence to: Teresa Paiva, M.D., Ph.D., Centro do Sono, CENC, Rua Conde das Antas, 5, 1700 Lisboa, Portugal. Tel: 351213715450, Fax: 351213715459, E-mail: [email protected]

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in less than 10% (Rhee, 2000). A Hong Kong crosssectional questionnaire survey of 3355 secondary school students (response rate 98%), attempting to investigate common illnesses, found a similar prevalence for headache and insomnia: headache/dizziness (23.6%) and chronic anxiety/insomnia (20.1%) (Lau et al., 2000).

Clinical evaluation Headache evaluation should include at least a brief sleep history (Rains and Poceta, 2005), and this should also be applied to sleep patients who also need a headache evaluation. As well as conventional questions, the sleep history should specifically address symptoms of sleep onset (sleep latency, limb discomfort or restlessness, anxiety); nocturnal symptoms (snoring, nocturia, dreaming, abnormal behaviors), morning symptoms (dry mouth, headache, body pain, fatigue), and diurnal symptoms (sleepiness, performance difficulties, fatigue, depression, pain). Headache history should consider type, location, frequency, time of occurrence,

severity, triggers, associated and premonitory symptoms, relieving and aggravating factors, and family history of headache. Several other clinical parameters must also be considered in order to evaluate sleep–headache relations: (1) sleep as a trigger for headaches; (2) headaches related to the duration of sleep or changes in the sleep schedule; (3) sleep stage-related headaches; (4) association with a specific sleep pattern; (5) sleep as a headache reliever; (6) headaches and dreams; and (7) headaches affecting sleep. A summary is shown in Table 63.1.

SLEEP-TRIGGERED

HEADACHES

Headaches are classified as sleep related when 75% of the episodes occur during sleep or upon awakening. Several of the currently known headache entities sometimes fulfil these requirements: migraine, cluster headache (CH), chronic paroxysmal hemicrania (CPH), hypnic headache, exploding head syndrome, and nocturnal hypertension headache.

Table 63.1 Clinical evaluation of sleep and headaches Sleep history Sleep onset (sleep latency, limb restlessness, anxiety) Nocturnal symptoms (snoring, nicturia, dreaming, abnormal behaviors) Morning symptoms (dry mouth, headache, body pain, fatigue) Diurnal symptoms (sleepiness, performance difficulties, fatigue, depression, pain) Headache Type and location Frequency Time of occurrence (time of the day, relation to sleep and to awakening) Severity Associated and premonitory symptoms Triggers Relieving and aggravating factors Familiar cases Sleep–headache interactions Sleep as a trigger for headaches Migraine, CH, CPH, hypnic headache, exploding head syndrome Headaches related to the duration of sleep Migraine: excess, lack, scheduling of sleep or changes in sleep schedule Tension headache: lack of sleep Sleep phase-related headaches Most headaches occur in REM and NREM sleep, with higher probability for REM Exploding head syndrome and turtle headache in sleep–wake transitions Association with a specific sleep pattern Migraine: signs of lower cortical activation Tension headache: decreased sleep efficiency Sleep as a headache reliever Migraine Headaches and dreams Dreams culminating in a migraine Greater anger and apprehension Headaches affecting sleep CH, CPH, and hypnic headache may induce insomnia and awakenings CH, cluster headache; CPH, chronic paroxysmal hemicrania; NREM, nonrapid eye movement; REM, rapid eye movement.

SLEEP AND HEADACHE

SLEEP

DURATION AND SLEEP SCHEDULE

Normal subjects, when sleep deprived, may experience a dull or pressing bilateral headache in the forehead (Blau, 1990). Migraine attacks can be precipitated by excessive sleep or lack of sleep (Sahota and Dexter, 1990). A recent population study evaluating the prevalence of migraine and tension headache in Japan, by means of structured questionnaires in adult residents of Daisen (n ¼ 5758; 4795 responders, 83.3% response rate) showed that “lack of sleep” triggered 51.6% of cases of migraine with aura, 44.1% of migraine without aura, 32.0% of episodic tension headache, and 36.6% of chronic tension headache; the “excess sleep” trigger was significantly less common, being 3.3%, 8.9%, 5.6%, and 1.4% respectively (Takeshima et al., 2004). Migraineurs sleeping for fewer than 6 hours had more severe headaches and more sleep-related headaches (Kelman and Rains, 2005). Lack of sleep is also a cause for tension headaches (Drake et al., 1990). Transient modification in sleep schedule (weekends, trips, etc.) by sleeping too little, too much, or by changing routines can precipitate headaches (Spierings et al., 2001), particularly migraine (Olesen, 2005). A short nap may also precipitate an attack (Blau, 1982). Furthermore, it is known that both migraine (Fox and Davies, 1998) and cluster headache (Russel, 1981; Manzoni et al., 1983) have a circadian distribution of the attacks (Peres, 2005).

SLEEP

STAGE AND SLEEP-STATE LEVEL

The fact that headaches may be related to the sleep stage implies that they will occur during specific moments of the night. For instance, an event related to slow-wave sleep will usually occur during the first 60 minutes of sleep; the first rapid eye movement (REM) period has a latency around 90 minutes; REM-related events tend to occur during the last hours of sleep; and those with no special sleep-stage relations will have no specific temporal profile. Events related to wake–sleep or sleep–wake transitions appear at sleep onset, upon morning awakening, or during awakening from sleep. It has been stated that certain headache entities occur in relation to specific sleep stages (Sahota and Dexter, 1990), but the available data provide conflicting results. Migraine occurrence after diurnal or nocturnal sleep seems to be related to excessive percentages of stages 3 and 4 nonrapid eye movement (NREM) sleep, but also to REM sleep (Dexter, 1979). CH is often triggered by REM sleep (Dexter and Riley, 1975; Kudrow et al., 1984) and by NREM sleep (Pfaffenrath et al., 1986). Some researchers have proposed hypoxia, and not the sleep stage per se, as the

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main trigger for CH attacks (Kudrow et al., 1984; Kudrow, 1994; Nobre et al., 2003). CPH has been considered a REM-locked headache (Kayed et al., 1973), but polysomnographic studies have shown that the trigger is not the sleep state but a sustained increase in blood pressure (Concili et al., 1994). Hypnic headache occurrence across the night may vary, but for the majority of patients (60% of 71 cases) the pain started 3 hours after falling asleep (Evers and Goadsby, 2003). A few patients have been recorded by polysomnography during attacks; some had REMrelated and others NREM-related headaches (Arjona et al., 2000; Evers and Goadsby, 2003). In nocturnal headache hypertension syndrome, pain can appear in the morning hours. In exploding headache syndrome, attacks occur during the transition from wakefulness to sleep, and in the turtle syndrome pain appears after morning awakening when the patient pulls the sheet over their head (Evers and Goadsby, 2003).

SLEEP

PATTERN

A total of 164 children with migraine evaluated by questionnaire had longer sleep latency and poorer sleep quality than 893 controls (Bruni et al., 1997). In an actigraphic study in children with migraine, the only difference observed was decreased nocturnal motor activity on the day before the crisis (Bruni et al., 2004). Adult migraineurs recorded in nonheadache periods had normal sleep patterns and muscular (EMG) activity in spite of a clear increase in REM sleep duration and latency (Drake et al., 1990). Adult migraineurs showed, the day before the crisis, a decreased number of arousals, lower REM density and alpha power, suggesting a decrease in cortical activation (Goder et al., 2001). In line with these findings, a decreased EEG complexity was observed in the first two NREM cycles in patients with spontaneous nocturnal attacks (Strenge et al., 2001). Patients with tension-type headaches also have persistently poor sleep with reduced sleep efficiency and slow-wave sleep, as observed in a polysomnographic study of 10 patients (Drake et al., 1990).

SLEEP-RELIEVED

RELIEVER)

HEADACHES (SLEEP AS A HEADACHE

A migraine attack is often ended by a short nap or by nocturnal sleep (Blau, 1982), particularly in children (Barlow, 1994). In 1283 migraineurs, 85% chose to sleep or rest because of headache and 75% were needed to do so in order to relieve the pain (Kelman and Rains, 2005). This was also true for confusional migraine (Ehyai and Fenichei, 1978; Parrino et al., 1986).

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T. PAIVA

DREAMS

AND HEADACHES

There are possible relationships between unpleasant dreams and migraine. In a study of 37 patients, the dream contents before a nocturnal migraine involved mostly anger, misfortune, apprehension, and aggressive interactions (Heather-Greener et al., 1996). In some patients, dreams with terrifying content may terminate in a migraine, but only on certain occasions (Levitan, 1984).

EFFECT

OF HEADACHES ON SLEEP

Insomnia and sleep disruption may occur in patients with CH and CPH due to fear of nocturnal attacks (Kayed et al., 1973; Kudrow et al., 1984; Paiva et al., 1995). In chronic daily headaches, sleep disruption is considered to have a psychogenic origin because the pain starts after awakening (Sahota and Dexter, 1990). Hypnic headaches also induce nocturnal awakenings (Raskin, 1988; Newman et al., 1990).

Sleep disturbances associated with headaches INSOMNIA Insomnia is defined as a repeated difficulty in sleep initiation, duration, consolidation, or quality that occurs despite an adequate time and opportunity for sleep (American Academy of Sleep Medicine, 2005). The relation between insomnia and headache is probably very complex. Insomnia is a common complaint; like most headaches, it is more frequent in women. Headache and insomnia have a variety of causes and both can be defined as a “complaint” or as a “clinical entity”, inducing frequent equivocal estimates. The problem of comorbidity arises from several studies, in the sense that both may reflect another clinical problem, such as depression. In a study of 50 insomniacs, 24 subjects (48%) also complained of headache, but only 10% had headache upon awakening. Most headaches that did not occur upon awakening fulfilled the criteria of migraine without aura (37.5%) or episodic tension-type headache (50%) (Alberti et al., 2005).

SLEEP

APNEA AND SNORING

Obstructive sleep apnea syndrome (OSAS) is characterized by repetitive episodes of total or partial cessation of breathing (American Academy of Sleep Medicine, 2005). Patients snore and are often obese with a large neck and/or craniofacial abnormalities (micrognathia and retrognathia, and bird-like face); they also have excessive daytime sleepiness, nocturia, dry mouth upon waking, or hypertension.

According to the ICHD-II (Olesen, 2005), the headache in sleep apnea is classified in the group with homeostasis disturbance (item 10.1.3). The diagnostic criteria imply the existence of recurrent headaches, present upon awakening, with apnea confirmed by polysomnography, and clinical improvement with effective treatment of the apnea. Furthermore, at least one of the fulfilling criteria should be present: a frequency greater than 15 days per month; pressing quality without nausea; no photophobia or phonophobia; resolution within 30 minutes. To determine the prevalence of this association, two strategies have been used: evaluation of headache in a population of patients with OSAS, and evaluation of OSAS in a headache population. In the past two decades, many authors have followed the first strategy (Boutros, 1989; Aldrich and Chauncey, 1990; Jennum et al., 1994; Poceta and Dalessio, 1995; Ulfberg et al., 1996; Greenough et al., 2002; Neau et al., 2002; Goder et al., 2003; Sand et al., 2003; Idiman et al., 2004). Patients with OSAS often complain of headache, which is reduced with continuous positive airway pressure (CPAP) treatment (Wright and White, 2000). Headache frequency in OSAS ranges from 32.9% to 58.5%; it is mainly a morning tension-type headache, mainly frontal, frontotemporal, or temporal (38.9%) in location, tightening or pressing (78.9%), and mild to moderate (84.2%) (Alberti et al., 2005). However, when evaluating in a headache clinic the prevalence of OSAS in 903 patients was no different from that expected from data in the general population (Jensen et al., 2004). OSAS severity and headache is another contradictory aspect: the relationship found in some studies (Alberti et al., 2005) was not confirmed in others (Greenough et al., 2002; Neau et al., 2002). A significant association between headache and depression in OSAS was found in a controlled study (Neau et al., 2002). Self-reported snoring has also been associated with morning and daytime headache, but the relation is considered weaker than with sleep apnea (Jennum et al., 1994; Ulfberg et al., 1996; Neau et al., 2002). However, habitual snoring was more frequent in patients with chronic daily headaches (24%) than in controls (14%) (Scher et al., 2003). The relations between sleep apnea and headache are more pronounced in the elderly (Barthlen, 2002). There is controversy concerning the underlying mechanisms. Headache has been attributed to intracranial pressure variations, lower oxygen saturations, and hypercapnia during apnea (Jennum and Borgesen, 1989; Doyle and Tami, 1991; Alberti et al., 2005). However, none of these features was detected in other controlled studies (Neau et al., 2002). In intracranial disorders associated with sleep apnea, some studies have measured intracranial pressure (ICP).

SLEEP AND HEADACHE Most of them found increased B waves of ICP, mostly during REM sleep, and in some studies headaches remitted with CPAP treatment (Hanigan and Zallek, 2004). Obstructive sleep apnea was considered to be the cause of increasing headaches in two shunted patients with low-pressure ventriculoperitoneal shunts. Neurophysiological evaluation in these patients during REM sleep showed multiple Lundberg A waves in ICP in association with obstructive sleep apneas; in one patient, headaches during nocturnal awakenings were associated with a sudden increase in ICP (Hanigan and Zallek, 2004).

NARCOLEPSY Narcolepsy is characterized by irresistible daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis (American Academy of Sleep Medicine, 2005). The association between narcolepsy and migraine (Dahmen et al., 1999) is controversial. In a population of 100 narcoleptics, Dahmen et al. (2003) found a migraine prevalence of 44% in women and 28.3% in men. The German Migraine and Headache Society Study Group (2003), however, had different results: in an evaluation of 96 narcoleptics, a similar prevalence of migraine was observed in patients (21.9%) and controls (19.8%).

RESTLESS

LEGS SYNDROMES AND PERIODIC LIMB

MOVEMENTS IN SLEEP

Restless legs syndrome (RLS) is characterized by a strong and nearly irresistible urge to move the legs. The sensations are worse at rest and more frequent in the evening and during the night; they are relieved by moving or walking (American Academy of Sleep Medicine, 2005). Periodic limb movements in sleep (PLMS) may or may not be associated with restless

1077

legs syndrome, and manifest as repetitive and stereotyped movements that occur during sleep (American Academy of Sleep Medicine, 2005). The prevalence of both RLS and PLMS increases with age. Complaints of morning or daytime headaches are three to five times more frequent in patients with RLS (Ulfberg et al., 2001). Fifty patients with severe headaches who qualified for treatment with dopamine receptor blocking agents had a prevalence of RLS of 34%; this group had a higher risk of developing akathisia as a treatment side-effect (Young et al., 2003). In children, PLMS and RLS show a significant association with morning headaches (Chervin and Hedger, 2001). Nobre et al. (2003) found no significant increase in the prevalence of PLMS in patients with CH. There is a case report of excessive PLMS in a patient with hypnic headaches (Kocasoy Orhan et al., 2004).

OTHER

SLEEP DISORDERS

Hypersomnia and nocturnal bruxism are associated with increased occurrence of a tension-like headache. In bruxism, this may eventually be related to sleep fragmentation and increased muscular activity during sleep. Sleep disorders associated with headache are summarized in Table 63.2.

Headaches associated with sleep disturbances Headache disorders related to sleep complaints are primary headaches such as migraine, tension-type headache, cluster headache, and hypnic headache. Other rare entities, not included in the ICHD-II (Olesen, 2005), may occur exclusively in relation to sleep: exploding head syndrome and the turtle headache (Evers and Goadsby, 2003) (Table 63.3).

Table 63.2 Sleep disturbances that may be present with headaches Sleep disturbance

Headache

Headache type

Comorbidity

Insomnia

48% (Alberti et al, 2005)

Depression

OSAS

Sleep apnea headache (32–58.5%) (American Academy of Sleep Medicine, 2005) Migraine(??) ?

Daytime headache, morning headache, migraine, tension-type headache Morning headache

Narcolepsy Restless legs, PLMS

Morning headache, daytime headache

OSAS, obstructive sleep apnea syndrome; PLMS, periodic limb movements in sleep.

Depression(?)

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T. PAIVA

Table 63.3 Headaches relations with sleep and sleep disturbances Headache

Sleep disturbance

Trigger

Reliever

Sleep stage

Circadian influences

Migraine Tension headache CH CPH Hypnic headache Exploding head syndrome

Insomnia Insomnia OSAS, PLMS ? Insomnia Insomnia

Yes, often Sometimes Yes Yes Yes Yes

Yes, often Variable No No No No

REM/NREM No REM/NREM REM REM/NREM Wake–sleep transition

Yes No Yes Yes Yes No

CH, cluster headache; CPH, chronic paroxysmal hemicrania; NREM, nonrapid eye movement; OSAS, obstructive sleep apnea syndrome; PLMS, periodic limb movements in sleep; REM, rapid eye movement.

MIGRAINE Migraine with and without aura is characterized by paroxysmal episodes of pain, lasting from 4 to 72 hours, associated with some of the following symptoms: nausea, vomiting, photophobia, and phonophobia. When associated with aura, migraine is preceded by neurological symptoms, mostly visual, that subside when the pain starts; for a detailed description, see ICHD-II (Olesen, 2005). Relations between migraine and sleep have been established in several studies, in both children (Bruni et al., 1997; Aaltonen et al., 2000; Miller et al., 2003; Bruni et al., 2004) and adults (Kelman and Rains 2005). Patients with chronic migraine reported shorter sleep duration than those with episodic migraine; they were also more likely to have trouble falling and staying asleep, to have a headache triggered by sleep, and to choose sleep as a headache reliever (Kelman and Rains, 2005). The most common migraine triggers are emotional stress, hypoglycemia, lack or excess of sleep (weekend migraine), sensorial stimulation (loud noise, bright light, strong odor, heat, or cold), or physical stimulation (physical exercise) (Rasmussen, 1993). Rest and sleep usually bring pain relief (Blau, 1982). Headaches and migraine with aura may be related to extended sleep duration: subjects experienced headache (but not migraine) with extended sleep night (Moss et al., 1987). Changes in the quality of sleep may arise up to 2 days before a migraine attack (Spierings et al., 2001). A circadian distribution of attacks has been studied. In 3582 attacks in 1689 adult migraineurs, crisis occurred mainly in the early morning (Fox and Davies, 1998). Overuse of medication may worsen the sleep pattern and the headache of migraineurs. Withdrawal of the misused medications can alleviate the associated sleep disturbance, and reduce headache frequency and

intensity (Hering-Hanit et al., 2000). Sleep problems evaluated by the Nottingham Health Profile provided one of the highest scores affecting negatively the quality of life of patients with migraine (Passchier et al., 1996). Several authors have described a strong association between somnambulism and migraine (Barabas et al., 1983; Dexter, 1986; Giraud et al., 1986; Pradalier et al., 1987; Paiva et al., 1994).

TENSION-TYPE

HEADACHE

In tension-type headache the pain is usually bilateral, and is felt as pressure or tightening with a duration ranging from 30 minutes to several days, fluctuating in intensity but not associated with nausea and vomiting. Tension-type headache can be subdivided into episodic (less than 15 days of headaches per month) and chronic (more than 15 days of headache per month) types (see ICHD-II; Olesen, 2005). Here, too, sleep problems evaluated by the Nottingham Health Profile provided one of the highest scores negatively affecting quality of life (Passchier et al., 1996). In 245 patients with chronic tension-type headache, sleep was impaired in one-third for more than 10 days per month (Holroyd et al., 2000). Sleep disturbances were confirmed by polysomnographic studies in 10 individuals with tension-type headache and in 10 mixed (migraine plus tension) headache sufferers. Patients with tension headache had reduced sleep duration and efficiency, frequent awakenings, increased nocturnal movements, and a marked reduction in slow-wave sleep. Those with mixed headaches had reduced sleep and slow-wave sleep, increased awakenings, and reduced REM sleep and REM latency (Drake et al., 1990). In order to identify possible physiological mechanisms, temporalis EMG activity was measured during sleep and wake in patients with tension-type headache and controls, but no significant differences were found

SLEEP AND HEADACHE during sleep (Clark et al., 1997). Tension-type headache is often described in patients with insomnia, hypersomnia, and circadian disturbances.

CLUSTER

HEADACHE

CH is characterized by episodes of intense lateralized pain over and around the eye, lasting for 15–180 minutes, with a daily frequency of episodes ranging from 1 to 8, and accompanied by homolateral symptoms (tearing, rhinorrhea, myosis, and ptosis) and agitation or restlessness. The cluster of pain has a duration of weeks or months, and repeats with long intervals of one or more years (see ICHD-II; Olesen, 2005). The clockwise onset of attacks suggests a circadian influence. The temporal profiles of pain in CH have been investigated. Of a total of 77 attacks in 22 patients, 75% began between 9 pm and 10 am, with two overnight peaks at 9–11 pm and 4–7 am (Russel, 1981). These data have been confirmed in other series (Manzoni et al., 1983). There was no difference in the severity of diurnal and nocturnal attacks (Russel, 1981). Patients with CH have a higher prevalence of sleep apnea (Kudrow et al., 1984; Chervin et al., 2000; Nath and Chervin, 2000), which varies from 58.3% (Nobre et al., 2003) to 80.6% (Graff-Radford and Newman, 2004). They have an 8.4-fold increased risk of sleep apnea compared with controls. This risk increases to 24.38 if the body mass index is above 25 kg/m2 and the patient is male and aged 50 years or more (Nobre et al., 2003). CPAP treatment of sleep apnea in patients with CH reduces the severity (Nath and Chervin, 2000). Sleep-disordered breathing probably does not cause CH, but may worsen CH attacks. Transient situational insomnia has been described in association with CH, normalizing when the cluster period subsides (Sahota and Dexter, 1993). Nobre et al. (2003) found no significant increase in the prevalence of periodic limb movements, although the prevalence rate was relatively high: 37.5% in patients with CH and 28% in controls. According to Kudrow et al. (1984), patients with CH have a higher prevalence of prior parasomnias, mostly enuresis and sleepwalking, but also night terrors, tooth grinding, and sleep talking. Sleep studies have suggested that clusters may be provoked by the transition phase from REM to NREM sleep and/or are related to hypoxemia (Kudrow et al., 1984; Chervin et al., 2000; Nobre et al., 2003; Weintraub, 2003). However, associations with other sleep stages and states have been observed; only 20% were REM sleep related (Pfaffenrath et al., 1986). Headache attacks are related to REM sleep in episodic CH, although this relationship is unclear in chronic CH; most chronic CH evolves from episodic

1079

CH (Pfaffenrath et al., 1986). The circadian influence is presumed to be due to the fact that serum levels of melatonin are low during clusters and melatonin is useful in CH treatment (Costa et al., 1998; Peres, 2005).

HYPNIC

HEADACHE

First described by Raskin (1988), hypnic headache is now included in the ICHD-II. Pain occurs exclusively during sleep and induces awakening. One of the following features must exist: more than 15 episodes per month, duration after awakening longer than 15 minutes, and complaints beginning after 50 years of age; there are no associated autonomic symptoms and no intracranial pathology (see ICHD-II; Olesen, 2005). The pain is usually dull, moderate, and bilateral. In the majority of reported cases, pain starts between 120 to 180 minutes after sleep onset; pain may sometimes worsen in the supine position, improving in the upright position (Evers and Goadsby, 2003). Headache attacks occur predominantly during nocturnal sleep but may also occur during daytime naps. Some authors describe an association between headache episodes and slow-wave sleep (Arjona et al., 2000) or REM sleep, or with nocturnal desaturations (Dodick, 2000; Evers and Goadsby, 2003; Pinessi et al., 2003); others found no special association with any of these features (Manni et al., 2004). Sleep efficiency is reduced due to pain-induced awakenings, but other sleep parameters are usually normal (Evers and Goadsby, 2003). A circadian disturbance has been described (Peres, 2005). Treatment includes lithium and caffeine at bedtime (Olesen, 2005).

OTHER

HEADACHE ENTITIES

There are some rare disorders not included in the ICHD-II that are related exclusively to sleep. Exploding head syndrome occurs mostly at sleep onset. It is not a pain but an explosive noise in the head that prevents sleep onset; it also appears after the age of 50 years, and there is an occasional description of its appearance in all sleep stages (Evers and Goadsby, 2003). Turtle headache occurs in the morning after the final awakening when the subject pulls the covers over their head, retracting beneath the sheet (Evers and Goadsby, 2003).

Sleep disturbances and headache as comorbid symptoms Headaches and sleep disturbances may have a common cause, either “intrinsic” or “extrinsic”.

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HEADACHES AND SLEEP DISTURBANCES A COMMON “INTRINSIC” CAUSE

T. PAIVA HAVE

Psychological and psychiatric disturbances (mostly depression) are a frequent cause of both headache and insomnia (Sahota and Dexter, 1990; Marazziti et al., 1995; Paiva et al., 1995; Pine et al., 1996; Maizels and Burchette, 2004); this is true for migraine (Breslau and Davis, 1993; Merinkangas and Angst, 1993; Swartz et al., 2000) and for tension headache (Puca et al., 1999). Depression per se has a negative impact upon sleep as it induces insomnia, reduction of slow-wave sleep, and, in some cases, REM sleep abnormalities. These situations may cause a vicious cycle, which is difficult to handle clinically: depression induces headache and insomnia, which, when chronically maintained, reinforce depressive symptoms maintaining the disturbed cycle. In a recent publication from a headache clinic, 289 patients were evaluated; psychiatric association showed a clear influence in somatic symptoms. The most common comorbid symptoms were fatigue (73% of cases), insomnia (60%), and indigestion (55%); the association of these three symptoms was present in 33% of all patients. This comorbidity was more evident in those suffering from chronic migraine (Maizels and Burchette, 2004). Nocturnal seizures may induce nocturnal or morning headache in children and adults (Kohrman and Carney, 2000). Another possible cause is fibromyalgia syndrome (FMS) (Wolf et al., 1990). This is a common and longlasting condition with widespread musculoskeletal pain and tender points at specific anatomical sites. Headaches (tension-type or migraine), insomnia, nonrestorative sleep, and restless legs are common (Jennum et al., 1993; Clauw, 1995; Paiva et al., 1995). Patients also have fatigue, orthostatic hypotension, tachycardia, effort intolerance, cognitive psychological disturbances, paresthesias, irritable bowel syndrome, and bladder dyskinesia. Alpha–delta sleep is very common but not pathognomonic of FMS (Moldofsky et al., 1988; Branco et al., 1994); it is a specific sleep electroencephalographic pattern. The association between headache and sleep disturbances is weaker in the chronic fatigue syndrome (Bell et al., 1994; Komaroff et al., 1996). It is characterized by chronic fatigue, impairment of cognitive functions, poor sleep, headache, recurrent sore throat, muscle aches, arthralgias, and postexertional malaise (Jennum et al., 1993). In one study, 61 patients with myofascial pain also reported important sleep complaints, with an average Pittsburgh Sleep Quality Index (PSQI) score of 11.1  4.5 (the PSQI cutoff point is 5). The most

affected dimension of poor sleep was sleep duration. These patients also presented higher levels of psychological distress (Vasquez-Delgado et al., 2004). Headache and sleep problems are often associated with other medical diseases. Patients with nocturnal hypoxemia and hypercapnia, as in chronic obstructive lung disease (George, 2000) and neuromuscular disease (Barthlen, 1997), often complain of insomnia, daytime sleepiness, and headaches.

HEADACHE A COMMON

AND SLEEP DISTURBANCES HAVE

“EXTRINSIC”

CAUSE

Snorers’ spouses or companions have a higher prevalence of insomnia, morning headaches, daytime sleepiness, and fatigue (Ulfberg et al., 2000). Chronic substance abuse, particularly of ergot derivatives and/ or analgesics, is a frequent cause of daily chronic headaches; these patients also have insomnia. In some patients, discontinuation of the abused substance was sufficient to treat headaches and insomnia; in others, insomnia and headaches fluctuated independently (Paiva et al., 1995). A large set of external causes, involving either medications (antiepileptics, beta-blockers, and nitroglycerine), toxic agents, or infectious organisms, may induce headache as well as sleep disturbances. However, in these situations both symptoms appear among a broader spectrum of disturbance and, more likely, represent a nonspecific response of the central nervous system to external aggression. Benzodiazepine withdrawal syndrome includes insomnia, headache, irritability, anxiety, hand tremor, sweating, concentration difficulties, nausea, weight loss, palpitations, and muscular pain (Potursson, 1994). Caffeine withdrawal includes headaches, decreased wakefulness and motor activity, but has no evident effects on nocturnal sleep (Hufer and Buttig, 1994). Caffeine withdrawal headache is, however, relatively rare: around 0.4% in epidemiological studies (Sjaastad and Bakketeig, 2004). Psychoactive substance use is also associated with headaches, sleep disorders, and psychiatric disturbances (Ardila and Bateman, 1995). Exposure to organic solvents may induce headache, sleepiness, vertigo, concentration difficulties, and mood swings (Indulski et al., 1996). Infectious diseases, such as pertussis in adults, are often associated with sleep disturbances (52%) and headaches (14%) (Postels-Multani et al., 1995). In infection with human immunodeficiency virus, the 12 common symptoms are fatigue, fever, imbalance, paresthesias, memory loss, cough, nausea, diarrhea, sadness, skin problems, headache, and sleep disturbances (Whalen et al., 1994).

SLEEP AND HEADACHE Posttraumatic stress following acts of violence includes excitability, distrust, avoidance, concentration difficulties, fatigue, headaches, nightmares, and insomnia (De Mol, 1994). The main symptoms of acute mountain sickness are headache, nausea, loss of appetite, fatigue, dizziness, and sleep disturbances. Highaltitude headache (Silber et al., 2003) is considered in the ICHD-II – in item 10.1.1, which is headache with a homeostasis disturbance (Olesen, 2005). The influence of altitude upon sleep is also recognized: periodic breathing, frequent awakenings, suffocation, and lighter sleep stages and arousals on resolution of apnea (Weil, 2005). Both headache and sleep disturbance share the same treatment recommendations: progressive adjustment to altitude and acetazolamide. Mobile phone radiation is another possible extrinsic cause of headache and sleep disturbance (Al-Khlaiwi and Meo, 2004).

When to suspect a sleep disturbance in the evolution of a chronic headache, and vice versa Identification of sleep disorders in patients with chronic headache is worthwhile as treatment of sleep disorders in these patients may improve their headaches.

MORNING

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Table 63.4 Morning headaches Alerting symptoms

Possible entity

Polysomnography

Snoring, sleepiness, obesity, large neck, bird-like face, other typical symptoms of apnea Nonrestorative sleep, more tired in the morning, jerks, RLS, unexplained depression Urge to move legs at sleep onset

OSAS

Always required

PLMS

Always required

RLS

Persistent pain and fatigue, nonrestorative sleep Inability to initiate and maintain sleep, nonrestorative sleep

FMS

Clinical evaluation is sufficient; PSG required to evaluate PLMS PSG required eventually

Insomnia

Clinical evaluation is sufficient; PSG required to evaluate organic causes

HEADACHES

Morning and nocturnal headache may be a warning symptom of a sleep disturbance. In headache clinics, 12–41.7% of patients with severe morning and nocturnal headaches had sleep apnea (Neau et al., 2002) and 53% had headaches associated with a sleep disorder (Paiva et al., 1997). The subgroup of patients with sleep disorders had a high prevalence of daytime sleepiness, nocturnal sleep disturbance, suffocation, sleepwalking, sleep paralysis, and work-related problems due to sleepiness (in 80% of cases), a predominance of men, and several patients had a late-onset or late-worsening headache (Paiva et al., 1995, 1997). Of 432 subjects in a sleep laboratory, patients with obstructive sleep apnea and other sleep disorders had a higher headache frequency, mostly morning headaches, compared with healthy subjects (Goder et al., 2003). Occurrence of headaches was associated with a decrease in total sleep time, sleep efficiency, and amount of REM sleep, and an increase in wake time during the preceding night. Morning headaches are more frequent in RLS and PLMS (Ulfberg et al., 2001). In a polysomnographic study of headache sufferers with morning headaches, FMS was suspected whenever the alpha–delta sleep pattern was found by polysomnography (Paiva et al., 1995).

FMS, fibromyalgia syndrome; OSAS, obstructive sleep apnea syndrome; PGS, polysomnography; PLMS, periodic limb movements in sleep; RLS, restless legs syndrome.

In summary, morning headaches raise a high suspicion of OSAS, PLMS, RLS, FMS, and other sleep disorders. The specific signs and diagnostic procedures to be used are summarized in Table 63.4.

HEADACHES

WITH A HIGHER RISK OF SLEEP

DISTURBANCE

Patients with cluster headache have a higher prevalence of sleep apnea; the risk increases in patients aged over 40 years who have a body mass index above 25 kg/m2 (Nobre et al., 2003). Migraine has a clear relationship with sleep and sleep disturbances, mainly insomnia. In sleep-related headaches (CPH and hypnic headache), a brief sleep questionnaire is also mandatory. In the remaining headache entities, sleep disturbances should be evaluated because poor sleep worsens the course of headache. Furthermore, over-the-counter sleep medications, often not mentioned by patients, should be known, as habituation is likely to develop and some may aggravate sleep apnea. Increasing headaches in shunted patients with low-pressure ventriculoperitoneal shunts

1082 T. PAIVA should raise the suspicion of obstructive sleep apnea (i.e., delta sleep or slow-wave sleep) affects the restor(Hanigan and Zallek, 2004). ative function of sleep with tiredness, lack of concentration, and performance difficulties the following RISK OF HEADACHES IN SLEEP DISTURBANCES morning, whereas increased amounts of these stages are associated with abnormal arousal functions seen In OSAS, RLS, PLMS, circadian sleep disorders, sleepin some of the parasomnias, such as sleep terrors and walking, and bruxism, an inquiry about headaches is somnambulism. Signs of cortical depression in the mandatory. This is still controversial in narcolepsy nights preceding a migraine attack (Goder et al., and other parasomnias. In addition, headaches should 2003; Strenge et al., 2001; Bruni et al., 2004) may be be investigated in all situations associated with a sleep premonitory manifestations of cortical spreading restriction. depression observed during an attack, and offer a possible explanation for the influence of sleep. FUNCTIONAL LINKS BETWEEN Abnormalities in REM sleep occur mainly in HEADACHES AND SLEEP depression and narcolepsy, with decreased REM sleep Sleep is a recurrent phenomenon during which a comlatency and abnormal distribution of REM sleep across plex set of functions occur that promote tissue repair the night. REM sleep is reduced in situations causing (Adam and Oswald, 1983), for example thermoregulafragmented sleep, such as sleep apnea and periodic limb tion (Parmeggiani, 1987), immune function (Moldofsky movements. Unpleasant REM sleep-related dreams may et al., 1986; Dinges et al., 1995), regulation of noradbe associated with migraine headaches (Heather-Greener renergic sensitivity (Siegel and Rogawski, 1988), and et al., 1996). maintenance of memory (Davis, 1985; Maquet, 1995). Sleep and pain regulation share common anatomical However, many sleep functions are either incompletely pathways within the central nervous system (Jensen, understood or are still unknown. 2001; Jones, 2005; Mason, 2005), namely in what conSleep researchers usually focus on the brain/body cerns the hypothalamus, the brainstem regions, and restorative effects of sleep. These effects are achieved cortical modulators. Appropriate knowledge of these by a sophisticated organization of nocturnal sleep, anatomicofunctional links that influence sleep and which implies a recurrent alternation of two basic sleep headache simultaneously is crucial. states intermixed with small amounts of the awake Several neuromodulators have been proposed in state. Awake is expressed in terms of transient awaorder to explain the association between sleep and headkenings or brief arousals; the two basic sleep stages aches, especially involving the restorative function of are REM and NREM sleep. Minimal sleep disturslow-wave sleep. Serotonin (5-hydroxytriptamine, 5HT) bances, as well as more severe disturbances, arise is implicated in the modulation of slow-wave sleep, whenever an imbalance of these states occurs. The and lesions of the raphe serotonin nuclei in animals basic effects of disturbed sleep, relevant to the producand humans induce insomnia. Furthermore, serotonin tion of headaches, can be summarized as follows. facilitates sleep onset, attenuating systems that normally Sleep deprivation induces sleepiness, fatigue and tiredactivate cortical activation and arousal (Jones, 2005). ness, headaches, anxiety, lack of concentration, confuSerotonin has opposite effects on migraine: 5HT-related sion, perception disturbances, learning deficits, growth compounds may induce migraine attacks, or prevent problems, and increased health risks and accidents them as prophylactic treatment or abort the acute epi(Bonnet, 2005). sodes. These discrepancies may be explained by the Sleeplessness may present either as an initiation, interaction with multiple 5HT receptors, and may conmaintenance, or early morning insomnia or as sleep tribute to our understanding of the relationship between fragmentation, i.e., sleep is frequently interrupted by sleep and headaches (Hamel, 2000). short awakenings. Insomnia shares some of the feaAdenosine, a central neuroprotector (Ribeiro et al., tures of sleep deprivation and is often associated with 2002), is another possible neuromodulator, as it is a fatigue and tiredness, headaches, lack of concentrasleep-inducing factor that accumulates in the brain durtion, anxiety, and depression. For these reasons, in ing prolonged wakefulness, mainly in the extracellular patients with chronic headaches insomnia aggravates space of the basal forebrain. This increase reduces the and perpetuates the complaints. activity of wakefulness-promoting cell groups, mostly In normal subjects, sleep propensity increases in the basal forebrain cholinergic cells. Adenosine receptor course of wakefulness, and the longer the previous antagonists, such as caffeine and theophylline, induce wakefulness the longer and deeper is the following higher vigilance, promoting wakefulness (Porkkasleep, namely delta activity of stages 3 and 4 (Borbe´ly Heiskanen, 1999). Caffeine is known to abort headet al., 1981). Lack of the deep stages of NREM sleep aches, whereas, conversely, headaches can be induced

SLEEP AND HEADACHE by caffeine withdrawal (Van Dusseldorp and Katan, 1990). The proposed mechanism of action is by blocking adenosine receptors (Sawynok, 1995). Adenosine also plays a role in migraine, as its extracellular brain concentration increases during a migraine episode and infused adenosine induces migraine-like symptoms or precipitates migraine attacks (Guieu et al., 1998). The treatment effect of caffeine in hypnic headache raises the possibility of adenosine involvement. Several headache disorders have clear chronobiological influences (migraine, CH, CPH, hypnic headache) (Peres, 2005). They are explained by the temporal profile of attacks, the presence of low plasma levels of melatonin, and treatment benefits of melatonin. The mechanisms of action of metatonin are still under discussion, but it is clear that it interferes in the sleep– headache relationship (Peres, 2005). Genetic influences in sleep and headache interaction are likely but not well understood. Some familial disorders, such as migraine and somnambulism, seem to be associated, but no recent studies are available.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 64

Sleep and breathing in neuromuscular disorders S. CHOKROVERTY * New Jersey Neuroscience Institute, JFK Medical Center, Seton Hall University, Edison, NJ, USA

INTRODUCTION Neuromuscular disorders traditionally include all diseases caused by dysfunction of the motor units (anterior horn cells, brainstem motor neurons, motor roots, neuromuscular junctions, peripheral nerves and muscles). Sleep dysfunction related mostly to sleeprelated breathing disorders or sleep-disordered breathing (SDB) is very common in neuromuscular diseases, particularly in the advanced stage, but occasionally occurs as a presenting symptom (Labanowski et al., 1996; Langevin et al., 2000; Guilleminault and Shergill, 2002; Chokroverty et al., 2005a). The most common neuromuscular disorders causing SDB and sleep dysfunction consist of: ● ● ● ● ● ● ●

motor neuron disease (amyotrophic lateral sclerosis) poliomyelitis and postpolio syndrome myasthenia gravis including myasthenic syndrome acute inflammatory demyelinating polyradiculoneuropathy (Landry–Guillain–Barre´–Strohl syndrome) phrenic neuropathy muscular dystrophies including myotonic dystrophies congenital myopathies.

Many of these conditions are treatable whereas others show relentless progression of the disease, but even in those conditions quality of life may be improved with prolongation of the natural course of the illness by timely and adequate treatment of SDB. It is therefore incumbent upon the physicians managing patients with neuromuscular disorders to have a basic idea about these disorders and a high index of suspicion for SDB, so that they can be referred to specialists or treated adequately in a timely manner. This chapter gives a brief overview of the control of breathing during sleep and wakefulness in normal

individuals, its alteration in various neuromuscular disorders, types of SDB, mechanism and pathogenesis of respiratory failure in neuromuscular diseases, clinical features including impact on breathing during sleep causing SDB and sleep dysfunction, and an approach to patients with suspicion of SDB, laboratory techniques and principles of treatment.

CONTROL OF BREATHING DURING WAKEFULNESS AND SLEEP An understanding of the control of breathing requires a basic knowledge about alveolar ventilation and diffusion across the alveolar capillary membranes (i.e., elimination of carbon dioxide and supply of oxygen from atmospheric air, which contains 21% oxygen, 78% nitrogen, and 1% other inert gases); an adequate pulmonary circulation is essential to complete these processes. Three interrelated and integrated components constitute the respiratory control system (Table 64.1): central controllers located in the medulla aided by the supramedullary including forebrain influence, peripheral chemoreceptors, pulmonary and upper airway receptors; thoracic bellows consisting of respiratory and other thoracic muscles, and their innervation and bones; and the lungs including the airways (Chokroverty, 2009a).

The central control of breathing This is dependent on two separate but independent systems: the metabolic (automatic) and the voluntary (behavioral) system (Plum, 1966; Mitchell and Berger, 1975; Berger et al., 1977; Phillipson, 1978a, b; Mitchell, 1980; Phillipson and Bowes, 1986). Both metabolic and voluntary systems are active during wakefulness whereas only the metabolic system participates during sleep. The wakefulness stimulus, probably derived

*Correspondence to: Professor S. Chokroverty, New Jersey Neuroscience Institute, JFK Medical Center, Seton Hall University, 65 James Street, Edison, NJ 08818, USA. E-mail: [email protected]

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Table 64.1 Respiratory control systems ●

● ●

Central controllers in the medulla: ○ The dorsal respiratory group (mainly for inspiration) ○ The ventral respiratory group (for both inspiration and expiration) including Botzinger complex and pre-Botzinger region (for respiratory rhythmicity) The thoracic bellows including respiratory and other thoracic muscles and bones The lungs including the airways

from the ascending reticular activating system, also represents a tonic stimulus to ventilation during wakefulness (Hugelin and Cohen, 1963; Cohen and Hugelin, 1965). The central control of breathing depends mainly on two groups of automatic respiratory neurons in the medulla (Nathan, 1963; Merrill, 1970; Mitchell and Berger, 1975; Berger et al., 1977; Phillipson, 1978a, b; Mitchell, 1980; Cherniack and Longobardo, 1986; Phillipson and Bowes, 1986; Chokroverty, 1990). The dorsal respiratory group (DRG), located in the nucleus tractus solitarius (NTS), is responsible principally, but not exclusively, for inspiration, projecting mainly to the contralateral spinal cord with a small ipsilateral projection, and probably also responsible for rhythmic respiratory drive to phrenic motor neurons. The ventral respiratory group (VRG) located in the region of the nucleus ambiguus and retroambigualis is responsible for both inspiration and expiration. The VRG contains the Botzinger complex in the rostral region and the preBotzinger region immediately below the Botzinger complex, responsible mainly for the automatic respiratory rhythmicity as these neurons have intrinsic pacemaker activity. Two groups of neurons located in the rostral pons in parabrachial and Ko¨lliker–Fuse nuclei (pneumotaxic center) and in the dorsolateral region of the lower pons (apneustic center) exert strong influence on the medullary respiratory neurons. The DRG and VRG neurons send axons that decussate below the obex and descend with the reticulospinal tracts in the ventrolateral cervical spinal cord to synapse with the spinal respiratory neurons innervating various respiratory muscles. There is tonic afferent input to the pontine and the medullary respiratory centers from forebrain and midbrain as well as sympathetic and vagal fibers from the respiratory tract, the carotid and aortic body peripheral chemoreceptors, and central chemoreceptors located in the ventrolateral medulla (Lumsden, 1923; Wang et al., 1957; Sullivan, 1980; Cherniack and Longobardo, 1986; Chokroverty, 1993, 1990).

The voluntary breathing system, which is the second respiratory controlling system, originates in the forebrain and the limbic system and descends with the corticobulbar and corticospinal tracts, controlling respiration during wakefulness (Plum, 1966; Sullivan, 1980). These projections descend partly to the automatic medullary respiratory neurons but descend mainly with the corticospinal tract to the spinal respiratory motor neurons where the fibers integrate with the reticulospinal fibers originating from the medullary respiratory neurons (Newsom-Davis, 1974; Berger et al., 1977; Mitchell, 1980; Phillipson and Bowes, 1986). The voluntary and automatic respiratory systems thus finally integrate in the high cervical spinal cord for smooth coordinated functioning of the respiration during wakefulness. The function of breathing is to maintain arterial homeostasis by maintaining normal partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2). PaCO2 depends predominantly on the central chemoreceptors with some influence from the peripheral chemoreceptors. Both hypoxia and hypercapnia stimulate breathing (Read, 1967; Weil et al., 1970). The hypoxic ventilatory response in normal individuals is a hyperbolic curve, showing a sudden increase in ventilation when PaO2 falls below 60 mmHg (Douglas et al., 1982a, b; White et al., 1982). In contrast, the hypercapnic ventilatory response is linear (Read, 1967; White, 1990). When PaCO2 falls below a certain minimum level, which is called apnea threshold, ventilation is inhibited.

The chest bellow component This consists of thoracic bones, connective tissues, pleural membranes, the intercostal and other respiratory muscles (see Table 64.1), the nerves, and blood vessels. Respiratory muscle weakness plays a critical role in causing sleep dysfunction and SDB in neuromuscular disorders. Table 64.2 lists the respiratory muscles. The main inspiratory muscle is the diaphragm (innervated by phrenic nerve formed by motor roots of C3, C4, and C5 anterior horn cells), assisted by the external intercostal muscles (innervated by the thoracic motor roots and nerves) which expand the core of the thoracic cavity and lungs during quiet, normal breathing. Expiration is passive, resulting from elastic recoil of the lungs. During forced and effortful breathing (e.g., dyspnea and orthopnea), accessory muscles of respiration assist the breathing. Accessory inspiratory muscles include sternocleidomastoideus, trapezius, and scalenus (anterior, middle and posterior), as well as pectoralis, serratus anterior, and latissimus dorsi. Accessory expiratory muscles consist of internal intercostals and abdominal muscles (e.g., rectus abdominis,

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS Table 64.2 Respiratory muscles Inspiratory muscles ▪ Diaphragm ▪ External intercostal Accessory inspiratory muscles ▪ Sternocleidomastoideus ▪ Scalenus (anterior, middle, posterior) ▪ Pectoralis major ▪ Pectoralis minor ▪ Serratus anterior ▪ Serratus posterior superior ▪ Latissimus dorsi ▪ Alae nasi ▪ Trapezius Expiratory muscles (Silent during quiet breathing but contract during moderately severe airway obstruction or during forceful and increased rate of breathing) ▪ Internal intercostal ▪ Rectus abdominis ▪ External and internal oblique ▪ Transversus abdominis

external and internal oblique, and transversus abdominis), innervated by thoracic motor roots and nerves. Normally, these three components (central controllers, chest bellows, and lungs) function smoothly in an automatic manner to permit gas exchange (transfer of oxygen into the blood and elimination of carbon dioxide into the atmosphere) for ventilation, diffusion, and perfusion. Minute ventilation is defined as the amount of air breathed per minute, which equals about 6 liters (about 2 liters stay in the anatomic dead space consisting of the upper airway and the mouth, and 4 liters participate in gas exchange in the millions of alveoli constituting alveolar ventilation). Respiratory failure (see below) may occur as a result of dysfunction anywhere within these three major components of respiratory control systems.

Changes in breathing during sleep During both nonrapid eye movement (NREM) and rapid eye movement (REM) sleep, respiratory neurons in the medullary region decrease their firing rates. Changes are noted in respiratory rate and rhythm, alveolar ventilation, tidal volume, chemosensitivity, and blood gases. Respiratory homeostasis is unprotected during sleep. Respiratory rate decreases during NREM sleep and becomes irregular during REM sleep. Minute ventilation and alveolar ventilation decrease due to a reduction of tidal volume (Tabachnik et al., 1981; Douglas et al., 1982a, b; Hudgel et al., 1984; White, 1990).

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Sleep-related alveolar hypoventilation results from a combination of the following factors (White, 1990): loss of wakefulness stimuli, increased upper airway resistance as a result of muscle hypotonia of the upper airway dilator muscles, diminished thoracic movement due to intercostal muscle hypotonia, impaired hypoxic and hypercapnic ventilatory responses due to decreased number of functional medullary respiratory neurons (central controller), and falling metabolic rate (reduced VO2 and VCO2). The upper airway dilating and intercostal muscles show mild hypotonia during NREM sleep but marked hypotonia or atonia during REM sleep. The diaphragm maintains phasic activities but tonic activity is reduced in REM sleep (Phillipson and Bowes, 1986). The functional residual capacity decreases in the supine position due to hypotonia of the intercostal muscles. As a result of sleep-induced mild alveolar hypoventilation, the normal individual’s arterial oxygen tension falls, causing less than a 2% reduction of oxygen saturation, and arterial carbon dioxide tension rises slightly. Hypoxic and hypercapnic ventilatory response is decreased mildly during NREM sleep with a more marked decrement during REM sleep (Berthon-Jones and Sullivan, 1982; Douglas et al., 1982a, b; Hedemark and Kronenberg, 1982; White et al., 1982). These sleep-related ventilatory changes (Table 64.3) do not have any significant effect in normal individuals. However, they become critical, transforming physiological nocturnal hypoventilation into pathological sleep-related hypoventilation, and may trigger life-threatening hypoxemia, abnormal breathing patterns, and respiratory failure in patients with neuromuscular disorders associated with respiratory muscle weakness.

CLINICAL MANIFESTATIONS OF SLEEP DYSFUNCTION IN NEUROMUSCULAR DISORDERS In neuromuscular disorders, sleep disturbances are most commonly secondary to involvement of the respiratory pump, which includes upper airway muscles (genioglossus, palatal, pharyngeal, laryngeal, hyoid, and masseter muscles), intercostal and other accessory muscles of respiration, and the diaphragm as a result of affection of the motor neurons, the phrenic and intercostal nerves or the neuromuscular junctions of the respiratory and oropharyngeal muscles, and primary muscle disorders affecting these muscles. The most common complaint is excessive daytime sleepiness resulting from repeated arousals and sleep fragmentations due to transient nocturnal hypoxemia and hypoventilation. The important clinical clues (Chokroverty, 2001; Chokroverty and Montagna, 2009) include:

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Table 64.3 Physiological changes in breathing during sleep Physiology

Wakefulness

NREM sleep

REM sleep

Parasympathetic activity Sympathetic activity Heart rate Blood pressure Cardiac output Peripheral vascular resistance Respiratory rate Alveolar ventilation Upper airway muscle tone Upper airway resistance Hypoxic and hypercapnic

þþ þþ Normal sinus rhythm Normal Normal Normal

þþþ þ Bradycardia Decreases Decreases Normal or decreases slightly Decreases Decreases þ þþþ Decreases

þþþþ Decreases or variable (þþ) Bradytachyarrhythmia Variable Decreases further Decreases further

Normal Normal þþ þþ Normal

Variable; apneas may occur Decreases further Decreases or absent þþþþ Decreases further ventilatory response

NREM, nonrapid eye movement; REM, rapid eye movement; þ, mild; þþ, moderate; þþþ, marked; þþþþ, very marked.

● ● ● ● ● ● ● ● ●

nocturnal restlessness frequent unexplained arousals excessive daytime sleepiness and fatigue shortness of breath orthopnea morning headaches intellectual deterioration unexplained dependent edema failure to thrive and declining school performance in children.

Signs of impending cor pulmonale include severe insomnia, morning lethargy, headaches, and unexplained dependent edema. The evaluation of SDB should begin with a detailed sleep history, which must specifically include clues suggestive of SDB as described above. Clinical approaches must also include a history of present and past illnesses, family, social, and medication histories. Physical examination including neurological and medical examination should assess the underlying cause of SDB. Special attention should be paid to uncovering bulbar weakness and respiratory muscle weakness, use of accessory muscles of respiration, and paradoxical breathing. Patients with neuromuscular disorders showing these clinical symptoms or findings must be investigated further to evaluate for nocturnal hypoventilation in order to prevent serious consequences of chronic respiratory failure, such as pulmonary hypertension, congestive cardiac failure, and cardiac arrhythmia. In addition to the sleep-related respiratory dysrhythmias, some patients, particularly those with painful polyneuropathies, muscle pain, muscle cramps,

and immobility due to muscle weakness, may complain of insomnia. Those complaining of sleeplessness may have the following features: insufficient sleep; difficulty initiating sleep; repeated awakenings including early morning awakenings; nonrestorative sleep; excessive daytime fatigue, tiredness or sleepiness; irritability, anxiety, lack of concentration; and sometimes depression related to sleep deprivation. The complaints from patients with hypersomnia generally include: excessive sleepiness and falling asleep at inappropriate places or under inappropriate circumstances; excessive daytime fatigue; absence of relief of symptoms following additional sleep at night; sometimes morning headaches; lack of concentration and listlessness, and impairment of daytime function; and impaired motor skills and cognition. Patients with obstructive sleep apnea may also complain of excessive snoring, cessation of breathing at night, and waking up fighting for breath. Persons with neuromuscular disease often complain of breathlessness, particularly in the supine position (orthopnea). Alveolar hypoventilation associated with neuromuscular disease may present acutely or insidiously. The acute form presents with progressive rapid reduction in vital capacity followed by respiratory failure. Symptoms and signs of acute respiratory failure are characterized by shortness of breath, irregular rapid, shallow or periodic breathing, cyanosis, and tachycardia. However, nocturnal hypoventilation and chronic respiratory failure in neuromuscular disease may present insidiously, and sometimes remain asymptomatic. Thus a high index of suspicion is needed.

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS

SLEEP

IN POLIOMYELITIS AND POSTPOLIO SYNDROME

Patients with bulbar poliomyelitis may develop respiratory disturbances and sleep dysfunction in acute and convalescent stages, and some patients have sequelae of respiratory dysrhythmia, particularly sleep-related hypoventilation or apnea requiring ventilatory support (Chokroverty and Montagna, 2009). The poliovirus infection directly affects the medullary respiratory and hypnogenic neurons and this explains the patient’s sleep-related respiratory difficulties. Sleep disorders, however, in postpolio syndrome are less well known; such patients may present with sleep-related hypoventilation or apnea causing excessive daytime somnolence (Codd et al., 1987; Speier et al., 1987; Chokroverty and Montagna, 2009). Postpolio syndrome is manifested by increasing weakness in previously affected or unaffected muscles of the subject with a past history of poliomyelitis. Based on questionnaire studies, sleep disturbances were noted in 31% of postpolio patients in one series (Cosgrove

Staging Movement Time Awake REM Stage 1 Stage 2 Stage 3 Stage 4 12 AM

1 AM

2 AM

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et al., 1987), and in another series (Van Kralingen et al., 1996) sleep complaints were noted in almost 50% of 43 postpolio patients. Steljes et al. (1990) performed polysomnographic (PSG) examinations in 13 postpolio patients and showed respiratory abnormalities consisting of hypoventilation, apneas, and hypopneas associated with significant obstructions and desaturation. Figure 64.1 shows a hypnogram and Figure 64.2 a sample of PSG recording from a patient with postpolio syndrome with REM-related hypopneas, apneas, and hypoventilation.

SLEEP

AND MOTOR NEURON DISEASE

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is the most common degenerative disease of the motor neurons in adults affecting the spinal cord, brainstem, motor cortex, and corticospinal tracts. It is characterized by progressive degeneration of both upper and lower motor neurons, manifesting as a varying combination of lower motor

3 AM

4 AM

5 AM

6 AM

7 AM

Position Left Right Supine Prone Upright Respiratory Events Mixed Apnea Obstructive Apnea Central Apnea Hypopnea Snore

SaO2 %

100 85 50

ECG Heart Rate 300 bpm 30 Arousal

Fig. 64.1. Hypnogram from a patient with postpolio syndrome. bpm, Beats per minute; ECG, electrocardiogram; REM, rapid eye movement; SaO2, oxygen saturation. (From Chokroverty et al., 2005b. # Elsevier.)

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S. CHOKROVERTY PSG limbs - PFLOW

High Cut :

70 Hz

Low Cut :

0.53 Hz

Sensitivity :

7 mV / mm

Speed :

120 s/page

F3 - C3 F7 - T3 T3 - T5 T5 - O1 F4 - C4 F8 - T4 T4- T6 T6- O2 C3- A2 C4- A1 LT EOG

RT EOG

Chin EMG

Lt. Tib EMG Rt. Tib EMG

P Flow Oronasal

Chest

Abdomen

Snore EKG SaO2-A

94 %

93 %

86 %

88 %

80 %

91 %

80 %

77 %

Fig. 64.2. Sample polysomnographic recording from a patient with postpolio syndrome. Chin EMG, submental electromyogram; ECG, electrocardiogram; EMG, electromyogram; EOG, electro-oculogram; REM, rapid eye movement; PFLOW, nasal pressure recording for air flow; SaO2, oxygen saturation; L, left; R, right. (From Chokroverty et al., 2005b. # Elsevier.)

neuron (e.g., muscle weakness, wasting, fasciculation, dysarthria, and dysphagia) and upper motor neuron (e.g., spasticity, hyperreflexia, and extensor plantar responses) signs. The World Federation of Neurology published El Escorial clinical diagnostic criteria for ALS (Table 64.4) after convening a workshop (Brooks, 1994). ALS can be associated with profound sleep disturbances characterized by excessive daytime somnolence as a result of repeated arousals and sleep fragmentation due to nocturnal hypoventilation, recurrent sleep apneas, hypopneas, hypoxemias, and hypercapnias (Figures 64.3 & 64.4). Some patients present with insomnia related to other factors (e.g., decreased mobility, muscle cramps, anxiety, and swallowing difficulties). There is no significant relationship between bulbar involvement and severity of SDB or other types of respiratory event (Kimura et al., 1999; Arnulf et al., 2000). Manifestations of SDB in ALS may result from

weakness of the upper airway, diaphragmatic, and intercostal muscles due to involvement of the bulbar, phrenic, and intercostal motor neurons. In addition, degeneration of central respiratory neurons may occur, causing central and upper airway obstructive sleep apneas. Respiratory failure in ALS generally occurs late, but occasionally is a presenting feature requiring mechanical ventilation (Parhad et al., 1978; Sugie et al., 2006). Diaphragmatic weakness as a result of degeneration of phrenic motor neurons is noted frequently in patients with ALS, and appears to be mainly responsible for nocturnal hypoventilation initially during REM sleep. SDB causing sleep disturbance and daytime symptoms has also been noted in other types of motor neuron disease, such as Kugelberg–Welander syndrome, a variant of juvenile type of motor neuron disease, as well as in spinal muscular atrophy type 1 and 2 in children (Testa et al., 2005; Petrone et al., 2007).

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS Table 64.4 El Escorial clinical diagnostic criteria for amyotrophic lateral sclerosis ALS status

Clinical criteria

Definite

Lower motor and upper motor neuron signs in multiple regions (e.g., bulbar or at least two of the spinal or three spinal regions) Lower motor and upper motor neuron signs in at least two regions; some upper motor neuron signs must be rostral to lower motor neuron signs Lower motor and upper motor neuron signs in one region only or upper motor neuron signs alone in two or more regions or lower motor neuron signs rostral to upper motor neuron signs Only lower motor neuron signs in two or more regions

Probable

Possible

Suspected

ALS, amyotrophic lateral sclerosis.

SLEEP

DYSFUNCTION AND PERIPHERAL NEUROPATHY

Polyneuropathies are characterized by bilaterally symmetrical, distal sensory symptoms and signs, and muscle weakness and wasting affecting the legs more than the arms; they may be caused by a variety of heredofamilial and acquired lesions. Disturbance of the phrenic, intercostal, and other nerves supplying the respiratory muscles can cause SDB, which becomes worse during sleep causing sleep fragmentation and daytime somnolence. Painful peripheral neuropathies may cause insomnia. The most common polyneuropathy causing respiratory dysfunction is acute inflammatory demyelinating polyradiculoneuropathy (Landry–Guillain– Barre´–Strohl syndrome). This entity is manifested most commonly by rapidly progressive ascending paralysis beginning in the legs and becoming maximal in 2–3 weeks. In about 20–25% of cases, severe respiratory involvement has been reported; the critical period is usually in the first 3–4 weeks of the illness, and it is important to recognize and treat ventilatory dysfunction early. Other causes of polyneuropathies include diabetic autonomic neuropathy, Charcot–Marie–Tooth disease, and paraneoplastic syndrome. Unilateral phrenic neuropathy may be asymptomatic, but bilateral disorder may be life threatening and is the main cause of SDB in polyneuropathies. Other causes of phrenic neuropathy include varicella zoster infection, diphtheria, brachial plexopathy, and Charcot–Marie–Tooth disease (Tanner, 1980; Chan et al., 1987).

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Diaphragmatic weakness is suspected in the presence of breathlessness and excessive daytime somnolence, paradoxical inward movement of the abdomen and intercostal spaces with epigastric retraction instead of protrusion during inspiration, and a significant fall in vital capacity (e.g., 70% of the predicted value) from erect to supine position. This can be confirmed by documenting an elevated diaphragm on chest radiography, and paradoxical movement or decreased excursion of the diaphragm on fluoroscopy.

SLEEP

IN NEUROMUSCULAR JUNCTIONAL DISORDERS

Neuromuscular junction transmission disorders (e.g., myasthenia gravis, myasthenic syndrome, botulism, and tic paralysis) may give rise to respiratory failure as a result of easy fatigability of the muscles, including the bulbar and other respiratory muscles due to failure of transmission of the nerve impulses at the neuromuscular junctions of these muscles. This respiratory failure becomes worse in sleep causing central, upper airway obstructive and mixed apneas and hypopneas, accompanied by oxygen desaturation, disturbed nocturnal sleep, and a sense of breathlessness (Shintani et al., 1989; Quera-Salva et al., 1992; Stepansky et al., 1996; Nicolle et al., 2006). The most important of these conditions is myasthenia gravis, an autoimmune disease characterized by a reduction in the number of functional acetylcholine receptors in the postjunctional regions. Acute respiratory failure is often a dreaded complication of myasthenia gravis, and patients need immediate assisted ventilation for life support. SDB and nocturnal desaturation may improve following treatment with thymectomy or prednisone. Older myasthenic patients and those with increased body mass index, abnormal pulmonary function, and abnormal daytime blood gas values are at particular risk for sleep-related respiratory dysrhythmia. SDB has also been described in Eaton–Lambert myasthenic syndrome, a disorder of the neuromuscular junction in the presynaptic region, and is often a paraneoplastic manifestation, mostly of oat cell carcinoma of the lungs.

SLEEP

AND BREATHING DYSFUNCTION IN PRIMARY

MUSCLE DISORDERS

Primary muscle disorders or myopathies manifest as symmetrical proximal limb muscle weakness and wasting without sensory impairment or fasciculation, and result from a defect in the muscle membrane or the contractile elements that are not secondary to a dysfunction of the lower or upper motor neurons. Respiratory disturbances are generally noted in the advanced stage of the illness, but sometimes

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Fig. 64.3. Overnight polysomnographic recording from a patient with amyotrophic lateral sclerosis presenting with upper and lower motor neuron signs including bulbar palsy. Recurrent periods of central apneas can be seen, many of which are prolonged, followed by irregular ventilatory cycles resembling ataxic breathing accompanied by severe oxygen desaturation and sleep hypoxemia during rapid eye movement sleep. Top four channels show international electrode placement system (electroencephalogram). LOC, left electro-oculogram; ROC, right electro-oculogram; Chin, submental electromyogram (EMG); ECG, electrocardiogram; L gast. EMG, left gastrocnemius EMG; R gast. EMG, right gastrocnemius EMG; Oronasal, oronasal air flow; PFLOW, nasal pressure recording for air flow; Thorax, thoracic breathing effort; Abdomen, abdominal breathing effort; SaO2, oxygen saturation by finger oximetry; Snore, snoring recording (From Chokroverty and Montagna, 2009. # Elsevier.)

respiratory failure appears in the early stage. Sleep complaints and sleep-related respiratory dysrhythmias are common in Duchenne and limb-girdle muscular dystrophies, myopathies associated with acid maltase deficiency, and may also occur in other congenital myopathies (e.g., nemaline rod, centrotubular and central core disease, merosin deficiency myopathy, and congenital muscular dystrophy) or acquired myopathies, mitochondrial encephalopathies, and polymyositis (Chokroverty, 1986; Howard et al., 1993; Labanowski et al., 1996; Chokroverty and Montagna, 2009). Acid maltase deficiency, a variant of glycogen storage disease, may present very early with diaphragmatic weakness causing hypoventilation, initially during REM sleep and later causing respiratory failure even during the daytime (Rosenow and Engel, 1978; Sivak et al., 1981; Martin et al., 1983; Margolis et al., 1994). Correct diagnosis in this condition can be established by performing electromyographic (EMG),

biochemical, histochemical, or morphological examination of muscle biopsy samples and respiratory function testing. Sleep architecture in Duchenne muscular dystrophy appears to be better preserved compared with the architecture in ALS.

SLEEP

DYSFUNCTION IN MYOTONIC DYSTROPHY

In 1954, Benaim and Worster-Drought were probably the first to describe alveolar hypoventilation in myotonic dystrophy, an autosomal dominant muscular dystrophy of adult onset associated with myotonia (myotonic dystrophy type 1, DM1). Alveolar hypoventilation associated with hypoxemia and impaired hypercapnic and hypoxic ventilatory responses may be present in both early and late stages of myotonic dystrophy. Sleep-related problems in this condition may be due to two factors: SDB and primary hypersomnia unrelated to SDB. SDB in myotonic dystrophy may

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS

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Fig. 64.4. Overnight hypnogram from the patient in Figure 64.3, showing obstructive, central, and mixed apneas–hypopneas accompanied by repeated arousals and oxygen desaturation throughout the night, except during periods of wakefulness in the middle of the sleep period. Note oxygen desaturation throughout the sleep period (sleep hypoxemia) with more marked desaturation during rapid eye movement (REM) sleep, suggesting hypoventilation. Stage, nonrapid eye movement sleep stages; PLMS, periodic limb movements of sleep; A/H, apneas–hypopneas; SaO2, oxygen saturation by finger oximetry.

be due to weakness and myotonia of respiratory and upper airway muscles as well as an inherent abnormality of the central control of ventilation, most likely related to a membrane abnormality of muscles and other tissues, including the brainstem neurons that regulate breathing and sleep (Guilleminault et al., 1978; Harper, 1979; Hansotia and Frens, 1981; Striano et al., 1983). Central, mixed, and upper airway obstructive sleep apneas have been described in patients with myotonic dystrophy (Coccagna et al., 1975; Guilleminault et al., 1978; Hansotia and Frens, 1981; Labanowski et al., 1996). A correction of sleep apnea or hypoventilation does not necessarily lead to improvement in excessive daytime sleepiness in this condition, suggesting other causes of hypersomnia in such patients. In addition, there may be an impairment of circadian and ultradian rhythms involving neuroendocrine abnormalities in sleep, contributing to excessive daytime somnolence (Culebras et al., 1977). Park and Radtke (1995) demonstrated the presence of sleep-

onset REMs in patients with myotonic dystrophy without any evidence of SDB, suggesting other causes for hypersomnia. It is, therefore, important to evaluate patients who have myotonic dystrophy with overnight PSG followed by multiple sleep latency tests, as excessive daytime somnolence may not be related to SDB. Martinez-Rodriguez et al. (2003) measured cerebrospinal fluid hypocretin-1 levels in six patients with DM1 complaining of excessive daytime sleepiness who were HLA-DQB1*0602 negative and found to have significantly lower hypocretin-1 levels compared with control values. The authors concluded that a dysfunction of the hypothalamic hypocretin system may be responsible for hypersomnia in DM1. Sleep disturbances have also been reported in proximal myotonic myopathy (PROMM), also known as myotonic dystrophy type 2 (DM2). PROMM is a hereditary myotonic disorder that is differentiated from DM1 by the absence of the chromosome 19 CTG trinucleotide repeat, which is associated with myotonic

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dystrophy (Ricker et al., 1994; Sander et al., 1996; Chokroverty et al., 1997; Lucchiari et al., 2008). In PROMM there is a mutation of the gene encoding for zinc finger 9 of chromosome 3q21. Sleep disturbances in these patients include excessive daytime sleepiness, snoring, frequent awakenings, sleep onset and maintenance insomnia, and alpha intrusion into NREM sleep on PSG which may be related to involvement of REM–NREM-generating neurons as part of a generalized membrane disorder (Chokroverty et al., 1997). In some patients with DM2 upper airway obstructive sleep apneas and REM-related hypoventilation have also been observed (S. Chokroverty, unpublished observations).

TYPES OF BREATHING PATTERN IN NEUROMUSCULAR DISORDERS The term sleep-disordered breathing encompasses all disorders of breathing during sleep and includes a variety of patterns (Figure 64.5) based on analysis of breathing patterns during overnight PSG recordings (Chokroverty and Montagna, 2009). The most common SDB in neuromuscular disorder is sleep-related alveolar hypoventilation, defined as a reduction of alveolar

ventilation resulting in hypoxemia and hypercapnia, manifesting initially during REM sleep and later, as the disease advances, also noted during NREM and even during the daytime (see below). In addition to alveolar hypoventilation, the following also occur (Figure 64.5): ● ● ●

upper airway obstructive, mixed, and central apneas sleep-related hypopneas paradoxical breathing.

Upper airway obstructive apneas are defined as complete cessation of air flow at the nose and mouth lasting at least 10 seconds with persistence of thoracic and abdominal efforts (Chokroverty and Sharp, 1981). Cessation of air flow with no respiratory effort constitutes central apnea. In mixed apnea, initially airflow and respiratory effort cease, followed by a period of upper airway obstructive sleep apnea. Hypopnea is defined as a greater than 50% reduction in airflow and effort as compared to the preceding or following respiratory cycles, lasting at least 10 seconds, accompanied by arousals and/or more than 3% oxygen desaturation (Iber et al., 2007). Apneas and hypopneas are

AIR FLOW AIR FLOW EFFORT EFFORT

A

D

AIR FLOW FLOW THOR. EFFORT EFFORT

B

ABD. EFFORT

E AIRFLOW AIR FLOW EFFORT EFFORT

C F

Fig. 64.5. Schematic diagram showing the most common types of breathing pattern in patients with neuromuscular disorders. (A) Normal breathing pattern, (B) upper airway obstructive apnea, (C) central apnea; (D) mixed apnea (initially central followed by obstructive apnea), (E) paradoxical breathing, (F) hypopnea.

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS usually accompanied by oxygen desaturation and terminated by an arousal. Thus, recurrent apneas, hypopneas, arousal and oxygen desaturation result in sleep disruption and fragmentation with subsequent hemodynamic changes in systemic and pulmonary circulation. Apneas and hypopneas are combined and expressed as the apnea–hypopnea index (number of apneas– hypopneas per hour of sleep), which should be at least 5 to be significant. Most people consider an apnea– hypopnea index of 10–15 to be significant, necessitating treatment. Recurrent arousals related to respiratory effort (RERAs) as a result of increasing upper airway resistance due to decreased tone of the upper airway dilator muscles as well as sleep fragmentation without apnea, hypopnea, or oxygen desaturation are believed to constitute upper airway resistance syndrome (UARS). Finally, some patients may have paradoxical breathing (movements of the thorax and abdomen in opposite directions, as noted in PSG recordings), suggesting upper airway obstructive sleep apnea or UARS. The other types of breathing pattern (Chokroverty and Montagna, 2009) included within the term SDB (e.g., periodic breathing, including Cheyne–Stokes’ breathing, ataxic breathing, Biot’s breathing, inspiratory gasp, apneustic breathing, and dysrhythmic breathing) are not generally seen in patients with neuromuscular disorders.

PATHOGENESIS AND MECHANISM OF SDB AND RESPIRATORY FAILURE IN NEUROMUSCULAR DISORDERS Respiratory failure is defined as an inability of the lungs to exchange gas effectively and to maintain a normal acid–base balance as a result of failure of the respiratory system anywhere from the medullary respiratory controllers to the chest bellows and the lungs, including the upper airways. As a result of this failure, there is reduction in PaO2 and increased PaCO2. PaO2 of less than 60 mmHg and/or a PaCO2 of more than 45 mmHg at sea level are commonly considered criteria for respiratory failure. Most neuromuscular disorders characteristically cause ventilatory failure, defined as inadequate alveolar ventilation with reduced tidal volume causing low PaO2 and high PaCO2. How does sleep initiate the onset of respiratory failure in neuromuscular disorders? The events that occur during sleep in neuromuscular disorders are the end of the beginning of respiratory failure and gradual or relentless progression unless interrupted by ventilatory support at night during sleep. A variety of changes occur in the respiratory system (both in the central control of breathing and in the respiratory muscles) during sleep that are responsible for initiating respiratory

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failure in sleep in patients with neuromuscular disorders. In addition, there may be a comorbid upper airway obstruction not related to neuromuscular disorders. However, in many patients with neuromuscular disorders, upper airway muscles are also affected, causing upper airway obstructive sleep apneas. The accessory muscles of respiration maintain ventilation during NREM sleep in patients with weakness of the diaphragm, the main muscle of ventilation; however, during REM sleep there is hypotonia or atonia of these accessory muscles and ventilation then depends exclusively on the diaphragm. Therefore, in patients with diaphragmatic weakness, ventilation is severely affected during REM sleep, causing REM hypoventilation. This is the first stage of respiratory failure in neuromuscular disorders (Piper and Sullivan, 1994). As the disease advances, even the accessory muscles of respiration are affected severely, thus causing ventilatory disturbance during NREM sleep. In the final stage of neuromuscular disorder, ventilation is affected even during the daytime, producing altered blood gases (e.g., hypoxemia and hypercapnia) during wakefulness. Stage two of respiratory failure may be related to either progression of the neuromuscular disorders or superimposed intercurrent infection (e.g., pneumonia), or both. Several authors have performed studies to identify daytime predictors of SDB and nocturnal hypoventilation at its onset (Lyall et al., 2001; Ragette et al., 2002; Mellies et al., 2003). These authors concluded that progressive ventilatory restriction in neuromuscular diseases correlates with respiratory muscle weakness and can be predicted from daytime lung and respiratory muscle function. Inspiratory vital capacity (IVC) and maximum inspiratory muscle pressure (PImax) are the two important predictors for onset of respiratory failure. IVC of less than 60% and PImax below 4.5 kPa predicted onset of REM hypoventilation; IVC of less than 40% and PImax below 4.0 kPa predicted both REM and NREM hypoventilation; and IVC of less than 25% and PImax below 3.5 kPa predicted daytime respiratory failure (Ragette et al., 2002; Mellies et al., 2003). It has also been suggested that a significant (70% of the predicted value) fall in vital capacity from erect to supine position indicates the presence of diaphragmatic weakness (Varrato et al., 2001; Lechtzin et al., 2002; Czaplinski et al., 2006). Fluoroscopy will confirm the weak movement of the dome of the diaphragm during inspiration. In addition, PImax will be supportive evidence. A serial blood gas determination is important for detecting impending respiratory failure. It should be remembered that a normal daytime PaO2 and PaCO2 does not exclude REM-related hypoventilation.

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In patients with weak respiratory muscles, regardless of cause, the waking breathing difficulties may worsen during sleep. During wakefulness, both voluntary and metabolic respiratory assistance are intact. In order to drive the weak respiratory muscles in neuromuscular disorders, the central respiratory neurons increase the firing rate or recruit additional respiratory neurons during wakefulness to maintain adequate ventilation (Chokroverty, 1986). During sleep, this voluntary control is entirely lacking, aggravating the existing ventilatory problems and causing more severe hypoventilation and even apnea and hypopneas. Functional impairment of the sensitivity of the central respiratory neurons causing decreased metabolic respiratory control may also give rise to apnea and hypopnea during both REM and NREM sleep. Oropharyngeal (upper airway) muscle weakness coupled with REM-related hypotonia or atonia of the muscles may contribute to possible upper airway obstructive sleep apnea. In summary, breathing disorders causing sleeprelated hypoventilation in neuromuscular disorders may be related to the following factors (Chokroverty and Montagna, 2009): ● ●

●

●

● ●

●

●

● ●

Impaired chest bellows caused by weakness of the respiratory and chest wall muscles Increased work of breathing due to altered chest mechanics and reduced forced vital capacity caused by weakness of the chest wall muscles and the diaphragm so that breathing is less efficient Hyporesponsive chemoreceptors which may be secondarily acquired or related to altered afferent inputs from skeletal muscle spindles, causing functional alteration of the medullary respiratory neurons Weakness of upper airway muscles that increases upper airway resistance, adding respiratory muscle load or even upper airway obstructive sleep apnea from complete closure of the upper airway Decreased minute and alveolar ventilation during sleep REM-related marked hypotonia or atonia of all the respiratory muscles except the diaphragm, causing increased diaphragmatic workload Respiratory muscle fatigue due to increased demand on the respiratory muscles during sleep, particularly REM sleep Kyphoscoliosis secondary to neuromuscular disorders, causing extrapulmonary restriction of the lungs with impairment of pulmonary functions, breathlessness, sleep apnea, and hypoventilation Failure of central control of ventilation Alteration in respiratory reflexes from upper airway and lung receptors, and arousal responses.

All of these factors lead to respiratory failure in neuromuscular disorders. As a result of alveolar

hypoventilation and ventilation–perfusion mismatching, hypoxemia and hypercapnia occur, giving rise to chronic respiratory failure even during the daytime at an advanced stage of the illness.

CLINICAL APPROACH TO DIAGNOSIS OF RESPIRATORY FAILURE IN NEUROMUSCULAR DISORDERS The initial approach to patients with sleep dysfunction in neuromuscular disorder is clinical. A careful history including present and past sleep history, family, drug, alcohol, medical, and psychiatric histories is essential. When clinical clues strongly suggest SDB, physical examination must be directed to uncover bulbar and respiratory muscle weakness including diaphragmatic dysfunction, in addition to detailed neurological and general medical examination to exclude other causes of SDB including nocturnal hypoventilation (Langevin et al., 2000; Chokroverty and Montagna, 2009). Clinical diagnosis of acute respiratory failure, as may be seen in patients with acute inflammatory demyelinating polyneuropathy (Guillain–Barre´ syndrome), myasthenia gravis, or acute anterior poliomyelitis, is quite obvious. Patients may have irregular, rapid, shallow, or periodic breathing, intermittent cessation of breathing, and cyanosis; however, nocturnal hypoventilation and chronic respiratory failure in neuromuscular disorders may present insidiously and may initially remain asymptomatic (Martin and Sanders, 1995; Labanowski et al., 1996; Attarian, 2000; Langevin et al., 2000; Chokroverty, 2001; Chokroverty, 2003). A high index of clinical suspicion is needed. The clinical scale called the Epworth Sleepiness Scale (ESS) is often used to assess the general level of persistent sleepiness. This scale measures propensity to sleepiness assessed by the patient under eight situations on a scale from 0 to 3, with 3 indicating a situation where chances of dozing off are highest. The maximum score is 24, and a score of 10 suggests the presence of excessive daytime sleepiness. The test has been weakly correlated with Multiple Sleep Latency Test scores (see below).

LABORATORY INVESTIGATIONS Laboratory investigations are simply an extension of the history and physical examination described above. Laboratory tests should include those needed to diagnose primary neuromuscular disorders and those directed at the evaluation of sleep disturbance and SDB. The description of the tests to diagnose primary neuromuscular disorders is beyond the scope of this chapter and the reader is referred to standard

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS neurological and neuromuscular texts. Tests to evaluate SDB include the following: ●

● ● ● ● ● ● ● ●

Pulmonary function tests including maximal inspiratory (PImax) and expiratory (PEmax) mouth pressure Arterial blood gases: PaO2, PaCO2 Oxygen saturation (SaO2) by finger oximetry End-tidal (EtCO2) or transcutaneous (TcCO2) carbon dioxide Overnight polysomnography (PSG) Multiple Sleep Latency Test (MSLT) Chest fluoroscopy Phrenic nerve conduction Diaphragmatic needle EMG.

Chest radiographs are important to identify intrinsic bronchopulmonary diseases and diaphragmatic paralysis.

Overnight polysomnographic (PSG) recording The single most important laboratory test in patients with hypersomnia and nocturnal sleep disturbances is PSG recording, which must be performed in all patients with excessive daytime somnolence unless the patient is so severely impaired by the neuromuscular condition that the diagnosis and treatment of sleep problems will not alter the outcome of the illness. Overnight PSG is important in patients with sleep complaints secondary to neuromuscular diseases to prevent a fatal sleep-related respiratory arrest at night and to treat dangerous nocturnal hypoventilation and hypoxemia. PSG findings in various neuromuscular disorders may include the following: increased number of awakenings; sleep fragmentation and disorganization; reduced total sleep time and decreased sleep efficiency; central, mixed, and upper airway obstructive sleep apneas or hypopneas associated with oxygen desaturation; nonapneic oxygen desaturation becoming worse during REM sleep. Additionally, in painful polyneuropathies and in neuromuscular disorders associated with muscle pain and muscle cramps, PSG may show sleep-onset insomnia and reduced sleep efficiency.

Multiple Sleep Latency Test (MSLT) This may be performed to document the presence and severity of daytime sleepiness and to diagnose comorbid narcolepsy. A mean sleep-onset latency of less than 8 minutes is consistent with pathological sleepiness, and the presence of sleep-onset REM in two or more of four to five nap recordings during MSLTs may suggest a diagnosis of comorbid narcolepsy in patients

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with neuromuscular disease (American Academy of Sleep Medicine, 2005). As stated above, many patients with DM1 may have hypersomnia not related to SDB, and therefore hypersomnia in these patients may have other explanations or may indicate comorbid narcolepsy, particularly when there is a history of cataplexy (Park and Radtke, 1995).

Pulmonary function tests The definitive test for alveolar hypoventilation is an analysis of arterial blood gases showing hypercapnia and hypoxemia (Martin and Sanders, 1995; Langevin et al., 2000). In early stage of neuromuscular disorder, awake arterial blood gas values remain normal; only in advanced stages with chronic respiratory failure are these values abnormal. To detect abnormal nocturnal arterial blood gases and hypoventilation, an indwelling arterial catheter needs to be placed throughout the night – this is invasive and rather impractical. Therefore, some investigators advocate noninvasive monitoring of oxygen saturation and carbon dioxide tension alone to detect hypoventilation; however, there are pitfalls to this line of investigation (Martin and Sanders, 1995). There is limitation to usefulness of finger oximetry alone because of the hyperbolic shape of the oxyhemoglobin dissociation curve, which may show minor oxygen desaturation in the presence of significant hypoventilation and reduced PaO2. The noninvasive end-tidal and transcutaneous carbon dioxide tension measurements are also unreliable and correlate poorly with actual PaCO2. Pulmonary function tests assess respiratory and ventilatory muscle function (Martin and Sanders, 1995; Gold, 2005). They include measurement of lung volumes (quantities of air within the lungs) and lung capacities (derived from lung volumes) (Table 64.5 & Figure 64.6), PaO2 and PaCO2 obtained by arterial (radial or femoral) punctures, oxygen saturation (SaO2) by finger oximetry and end-tidal carbon dioxide (PaCO2) or transcutaneous carbon dioxide (TcCO2) (Varrato et al., 2001; Lechtzin et al., 2002; Gold, 2005; Morgan et al., 2005; Czaplinski et al., 2006). Spirometry, the most important pulmonary function test, measures most of the lung volumes and capacities, except residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC), which require nonspirometric techniques (e.g., gas dilution technique). Important spirometric measurements include forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and the ratio of FEV1 to FVC. Patient cooperation and good patient– technician interaction are essential for obtaining valid spirometric measurements. Values are expressed as the percentage predicted. Values of FVC, FEV1, and

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Table 64.5 Lung volumes and capacities Parameter

Description

Lung volumes Tidal volume (TV)

Volume (ml) of air per normal inspiration or expiration Inspiratory reserve Volume of air during maximal volume (IRV) inhalation following a normal breath Expiratory reserve Volume of air during maximal volume (ERV) exhalation following a normal breath Residual volume (RV) Volume of air remaining after maximum exhalation Lung capacities (derived from lung volumes) Vital capacity (VC) Volume of air that can be exhaled maximally after maximum inspiration (IRV þ TV þ ERV) Inspiratory Inspiratory reserve volume capacity (IC) plus tidal volume (IRV þ TV) Functional residual Volume of air remaining after capacity (FRC) a normal expiration (ERV þ RV) Total lung capacity Vital capacity plus residual volume (TLC) (VC þ RV)

5

Volume (Liters)

4 3

IRV

VC (IRV + TV + ERV)

TV

2

FRC (ERV + RV)

1

ERV

RV

0

Fig. 64.6. Schematic diagram to show lung volumes and capacities. ERV, expiratory reserve volume; FRC, functional residual capacity; IRV, inspiratory reserve volume; RV, residual volume; TV, tidal volume; VC, vital capacity. (From Chokroverty and Montagna, 2009. # Elsevier.)

peak expiratory flow rate (PEFR) of less than 80% predicted is considered abnormal. A value of less than 70% predicted for the ratio of FEV1 and FVC is abnormal.

In neuromuscular disorders, the characteristic abnormalities include decreased FVC, FEV1, and TLC, but increased RV. The airway obstruction shows less than predicted values of the ratio of FEV1 to FVC, whereas restrictive lung disease shows an increase in the ratio of FEV1 to FVC combined with an absolute reduction in FVC and FEV1. The strength of respiratory muscles must be severely reduced before a significant reduction in lung volumes is appreciated, as pressure/ volume characteristics of the respiratory system are not linear. Thus, static respiratory pressure measurements are often used to assess respiratory muscle strength, such as maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) (Black and Hyatt, 1971). These measurements, however, require the cooperation of patients, and the normal values have large ranges and variability which may be related to factors such as lung volume, type of mouthpiece, variable effort, and learning. In patients with bulbar muscle weakness, it may not be possible to measure PImax and PEmax. In order to reduce the effects of these variables in the measurement of PImax, investigators have used respiratory pressures during maximal sniff maneuvers (Lyall et al., 2001; Morgan et al., 2005). The maximal sniff pressure (SMP) may be measured using transdiaphragmatic (TPdi), esophageal (Pes), or nasal (Pn) methods. Pn is often measured rather than Pes because it is much less invasive. Noninvasive sniff pressure is reported to be more sensitive than VC and PImax in predicting respiratory muscle strength and the risk of ventilatory failure in these patients (Lyall et al., 2001; Morgan et al., 2005). In patients suspected to have diaphragmatic paralysis, chest fluoroscopy and measurement of transdiaphragmatic pressure using esophageal and gastric balloons inserted via the nasogastric route may be necessary (Lourenco and Mueller, 1967; Lopata et al., 1978; Baydur et al., 1982). This may be difficult to perform. Chest radiography is noninvasive and permits visualization of the diaphragm dome, but provides little information regarding diaphragm function. Diaphragm fluoroscopy provides real-time examination of the start of diaphragm dome motion but carries the disadvantage of exposure to ionizing radiation and poor sensitivity and specificity. Phrenic (Markand et al., 1984) and intercostal (Chokroverty et al., 1995) nerve conduction by electrical or magnetic stimulation may detect phrenic or intercostal neuropathy causing respiratory muscle weakness. Needle EMG of the diaphragm may reveal diaphragmatic denervation, suggesting neurogenic dysfunction of the diaphragm (Bolton et al., 1992; Saadeh et al., 1993; Sander et al., 1999).

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS

PRINCIPLES OF TREATMENT OF SLEEP DYSFUNCTION IN NEUROMUSCULAR DISORDERS Treatment of primary neuromuscular disorder should be the first line of treatment; however, in many of these conditions there is no specific treatment and only symptomatic measures are available. The goal of treatment in sleep disturbances related to SDB is to improve arterial blood gases, eliminate daytime symptoms, improve quality of life, prevent life-threatening cardiac arrhythmias, pulmonary hypertension, and congestive cardiac failure, and possibly prolong the patient’s longevity. Table 64.6 lists principles of treatment of sleep dysfunction and SDB in neuromuscular diseases.

GENERAL

MEASURES

In obese patients, weight reduction should be encouraged, as excess weight might contribute to upper airway obstructive sleep apnea syndrome. Alcohol, sedatives, hypnotic drugs, and other medications that may contribute to sleep disturbances and cause depression of breathing during sleep should be reduced or eliminated.

INTERVENTIONAL

TREATMENT USING MECHANICAL

DEVICES

In the past, the mainstay of treatment was invasive ventilation via a tracheostomy, but this has now been largely replaced by noninvasive methods of ventilatory support for patients with SDB including hypoventilation consisting of negative and positive pressure Table 64.6 Principles of treatment of sleep-disordered breathing and sleep dysfunction in neuromuscular diseases ● ●

● ●

●

General measures Intervention with mechanical devices ○ CPAP ○ BiPAP ○ IPPV Supplemental oxygen therapy Surgical treatment ○ Tracheostomy ○ Diaphragm pacing Pharmacological treatment ○ For sleep apnea ○ For insomnias ○ For myotonic dystrophy

BiPAP; bilevel positive airway pressure; CPAP, continuous positive airway pressure; IPPV, intermittent positive airway pressure.

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ventilators (Strumpf et al., 1990; Tobin, 1994; Martin and Sanders, 1995; Chokroverty and Montagna, 2009). Ventilators were developed during the early polio epidemics in the 1950s and 1960s. Negative-pressure ventilators include “iron lung” or tank respirator, “rain coat” or “pneumo-wrap ventilator”, and cuirass or “tortoise shell” (Collier and Affeldt, 1954; Spalding and Opie, 1958; Hill, 1986; Strumpf et al., 1990; Hillberg and Johnson, 1997; Rabatin and Gay, 1999). The tank respirator, although a most effective negative pressure ventilator, is bulky, limiting the patient’s acceptance (Hill, 1986; Strumpf et al., 1990). Furthermore, negative-pressure ventilators may be associated with upper airway obstructive sleep apnea syndrome with oxygen desaturation in patients with neuromuscular disease (Ellis et al., 1987). The contemporary standard of management for chronic ventilatory failure in neuromuscular disorders is noninvasive intermittent positive pressure ventilation (IPPV) using a nasal mask or prongs. Positive-pressure ventilation includes continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), and IPPV. For upper airway obstructive sleep apnea syndrome, nasal CPAP is the ideal treatment. Following such treatment, sleep quality and daytime hypersomnolence often improve due to the reduction or elimination of sleep-related obstructive or mixed apneas and oxygen desaturation. In patients with relentlessly progressive disease, however, such treatment has not been very useful, and therefore the role of CPAP in such diseases requires further study. Some patients may not be able to tolerate the same high pressure during both inspiration and expiration, and feel comfortable using BiPAP. BiPAP uses higher inspiratory positive airway pressure than expiratory positive airway pressure. Both types can be used, but studies have found no significant difference between the two types of ventilator in terms of survival (Janssens et al., 2003) and correction of hypoventilation (Meechan Jones and Wedzichia, 1993). The beneficial effects of nocturnal IPPV may be summarized as follows: improvement of nocturnal gas exchange as reflected in SaO2 and TcCO2 as well as improvement in daytime arterial blood gases; slight improvement in total sleep duration without significant improvement in quality of sleep; improvement in FVC and PImax; reduction in the number of days of hospitalization; improvement in quality-of-life measures and long-term survival. Numerous studies have proven the benefit of noninvasive ventilation through a nasal mask for 6–8 hours during sleep in neuromuscular disorders (Bye et al., 1985; Howard et al., 1989; Leger et al., 1989; Newsom-Davis et al., 2001; Sivak et al., 2001; Bourke

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and Gibson, 2002; Bourke et al., 2003; Butz et al., 2003; Gruis et al., 2005; Ward et al., 2005; Bourke et al., 2006; Mustfa et al., 2006; Petrone et al., 2007). IPPV generally uses no expiratory positive airway pressure, but in some patients positive end-expiratory pressure (PEEP) of up to 5 cmH2O may be required. In some patients during initial nights of IPPV, there may be upper airway closure for the first time during the expiratory phase (Piper and Sullivan, 1994, 1996). The mechanism for such closure may include driving of carbon dioxide levels below the apnea threshold, and marked reduction of muscle tone as a result of REM rebound. Treatment of these patients is the addition of a PEEP valve by maintaining a positive pressure (up to 5 cmH2O) during expiration. Noninvasive IPPV can be used even in those with bulbar muscle weakness, utilizing the full face mask. Either pressurecycled (delivering air at a fixed pressure) or volumecycled (delivering a fixed volume of air) ventilators may be used, but many clinicians prefer pressurecycled ventilators to deliver IPPV. However, in terms of long-term survival (Janssens et al., 2003) or shortterm correction of hypoventilation (Meechan Jones and Wedzichia, 1993) there is no difference between the two types of ventilator. The volume-cycled ventilators deliver tidal volume and pressure-cycled ventilators deliver a fixed pressure (usually 10–20 cmH2O) set by the clinician. Ventilator modes could be one of the following three: control mode where the ventilator starts and ends inspiration according to prescribed setting; assist-control mode where either patient’s effort or programmed setting initiates inspiration; and spontaneous assist where patient’s effort starts and ends inspiration. Following such treatment, patients show improvement in daytime somnolence, arterial blood gases, sleep efficiency, and sleep architecture, a reduction in the need for prolonged hospitalization, and increased longevity. Long-term follow-up and prospective randomized controlled trials in neuromuscular disorders such as ALS are limited. In one of the largest prospective, although not randomized or blinded, studies, Mustfa et al. (2006) showed efficacy of noninvasive ventilation in patients with ALS. There were striking improvements in blood gases and in a variety of quality-of-life measurements following noninvasive ventilation within 1 month which were maintained for up to 12 months in 26 patients with ALS showing respiratory muscle weakness. These authors also studied, in parallel, 15 age-matched patients without respiratory muscle weakness but with similar severity of ALS. Despite the progression of ALS, they showed improvement in qualityof-life measures. They had also shown that noninvasive ventilation in patients had no impact on most aspects

of quality-of-life measures in caregivers, and did not increase caregiver burden or stress. Twenty-six patients with congenital neuromuscular or chest wall diseases having daytime normocapnia and nocturnal hypercapnia were randomized to either nocturnal noninvasive ventilation or to a control group without ventilatory support by Ward et al. (2005). They found increased mean arterial oxygen saturation and a decreased mean percentage of nights with peak transcutaneous carbon dioxide tension in the group using noninvasive ventilation compared with controls. These authors suggested that such patients may benefit from nocturnal IPPV before daytime hypercapnia ensues. In the only randomized controlled trial, Bourke et al. (2006) selected 41 ALS patients who had orthopnea with maximum inspiratory pressure less than 60% of predicted value or symptomatic hypercapnia. They then randomly assigned 22 patients to noninvasive ventilation and 19 patients to standard care. They found survival benefit with improvement in quality-of-life measures in patients receiving noninvasive ventilation. In patients with severe bulbar involvement, however, no survival benefit was found.

INDICATIONS

FOR INTERMITTENT POSITIVE

PRESSURE VENTILATION

A European consensus conference (Robert et al., 1993) listed the following criteria for long-term noninvasive nasal ventilation for patients with neuromuscular disorders: presence of clinical symptoms (see above), PaCO2  45 mmHg or above, PaO2 < 60 mmHg in the daytime arterial blood gas analysis or pronounced nocturnal oxygen desaturation. The patients’ obstructive symptoms and arterial blood gases should be monitored. A later USA consensus conference report (Consensus Conference, 1999) listed the criteria for noninvasive positive pressure ventilation for patients with neuromuscular disorders (Table 64.7). First, the diagnosis must be established by a history and physical examination, followed by appropriate laboratory tests. The patient should also have received treatment for associated (e.g., obstructive sleep apnea syndrome diagnosed by PSG) or underlying conditions. The suggested indications for use of noninvasive ventilation include clinical symptoms (see above) and one of the following physiological criteria: (1) PaCO2  45 mmHg; (2) nocturnal oxygen desaturation (by finger oximetry)  88% for 5 consecutive minutes; (3) in cases of progressive neuromuscular diseases, PImax < 60 cmH2O or FVC < 50% predicted. Follow-up in 1–3 months for assessment of compliance and monitoring of awake arterial blood gases is also suggested. Overnight oximetry may be helpful for monitoring such patients. It should be remembered that different neuromuscular

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS Table 64.7 Indications for intermittent positive pressure ventilation: consensus criteria ● ●

Appropriate clinical symptoms and signs One of the following physiological criteria: ○ PaCO2  45 mmHg ○ Nocturnal oxygen desaturation (finger oximetry)  88% for 5 consecutive minutes ○ PImax < 60 cmH2O or ○ FVC < 50% predicted (in cases of progressive disease)

FVC, forced vital capacity; PaCO2, arterial partial pressure of carbon dioxide; PImax, maximum inspiratory muscle pressure.

disorders evolve and progress at different and varying speeds depending on the etiology of the disease process and other associated variables, and, therefore, this set of guidelines may need further modifications depending upon the disease process involved. There have been some attempts to document daytime predictors that will indicate nocturnal hypoventilation and hence the need for IPPV; these were discussed in the previous section. To evaluate progression of disease and efficacy of treatment, there is no control study to implement this but finger oximetry is the most widely used. In addition, transcutaneous or end-tidal carbon dioxide concentration can also be used. EMG of the accessory respiratory muscles may help in indicating evidence of ventilatory failure; however, repeat PSG remains the best test for evaluating quality of sleep and effectiveness of IPPV. Guilleminault and Shergill (2002) suggested that, even if there is no change in clinical symptomatology, PSG is recommended at least once a year as respiratory changes can occur without accompanying clinical symptoms. There are, however, no standard guidelines for this recommendation.

PROBLEMS

WITH

IPPV

The complications of IPPV are similar to those noted for CPAP or BiPAP (Chokroverty, 2009b). One particularly annoying complication is nasal stuffiness or rhinorrhea, which may be relieved by using a warm humidifier or nasal corticosteroids. Some patients complain of claustrophobia with the use of nasal masks, particularly those with breathing problems. In such patients, a nasal pillow instead of a nasal mask may be useful. Leaks around the mask causing arousals, sleep fragmentation, and a subsequent decrease in the efficiency of IPPV are also common; correction of these leaks is important to improve sleep quality and architecture. Long-term use of a nasal mask can lead

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to a maxillary hypoplasia in young subjects. Children using nasal ventilation should be seen monthly to adjust mask size, particularly in the first 2 years of life, as a child’s face grows quickly during infancy and childhood. Airways develop and remodel during this time and, therefore, frequent repetition of nocturnal PSG has been suggested, approximately every 3 months (Guilleminault and Shergill, 2002).

MECHANISM

OF IMPROVEMENT FOLLOWING

IPPV

Several mechanisms have been suggested, but not proven (Martin et al., 1983; Martin and Sanders, 1995; Kramer et al., 1996; Langevin et al., 2000). Improvement of respiratory muscle fatigue and restoration of the sensitivity of the respiratory center to carbon dioxide are the two important mechanisms cited. Changes in pulmonary mechanics (e.g., increasing lung volume, improvement of lung compliance, and reduction of dead space) may also contribute to improvement in symptoms and gas exchange.

SUPPLEMENTAL

OXYGENATION

The role of supplemental oxygen treatment using lowflow oxygen (1–2 liters per minute) in SDB in neuromuscular diseases remains controversial. Supplemental oxygen therapy is mostly ineffective in patients with neuromuscular disorders and may even be dangerous, leading to marked carbon dioxide retention and making symptoms worse (Chokroverty et al., 1969; Motta and Guilleminault, 1978; Gay and Edmonds, 1995; Masa et al., 1997).

TRACHEOSTOMY For patients who have failed noninvasive positivepressure ventilation or who cannot cooperate with such treatment, tracheostomy may be beneficial. In patients with severe bulbar weakness, effective IPPV may not be possible. Tracheostomy remains the only effective emergency measure for those patients with marked respiratory failure with severe hypoxemia, and for those with sudden respiratory arrest after resuscitation by intubation. Such patients may later be weaned from tracheostomy and may later require positive-pressure treatment. However, a decision about tracheostomy should be weighed carefully in many of these neuromuscular disorders with relentless progression and an overall unfavorable prognosis.

DIAPHRAGMATIC

PACING

In the treatment of SDB in neuromuscular disorders, diaphragmatic pacing has a very limited application. If central apnea or alveolar hypoventilation persists

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during wakefulness despite appropriate ventilation during sleep, diaphragmatic pacing may be indicated (Chervin and Guilleminault, 1994; Guilleminault and Shergill, 2002). This requires surgery for placement of subcutaneous stimulator and phrenic nerve electrodes, and careful follow-up. IPPV via a tracheostomy or nasal mask may be used in association with diaphragmatic pacing. There are many potential complications of diaphragmatic pacing (e.g., nerve fibrosis, infection, unit malfunction, and other surgical complications). The Food and Drug Administration in the USA recently approved the NeuRx Diaphragm Pacing System (Onders et al., 2008) for patients with spinal cord injury who depend on ventilators because of a paralyzed diaphragm. Whether patients with neuromuscular disorders will benefit from this will depend on future clinical trials.

PHARMACOLOGICAL

TREATMENT

Pharmacological treatment for central or upper airway obstructive sleep apnea or nocturnal hypoventilation is unsatisfactory. However, in patients with myotonic dystrophy, additional treatment with stimulants for treatment of excessive daytime sleepiness may be required as these patients may have hypersomnia unrelated to alveolar hypoventilation. Modafinil, a novel wake-promoting stimulant, may be initiated at 100 mg per day, increasing to a maximum of 400 mg per day in two divided doses (Damian et al., 2001; MacDonald et al., 2002; Talbot et al., 2003). Armodafinil (Roth et al., 2008), with longer half-life than modafinil, may also be used (150 or 250 mg once daily in the morning). Methylphenidate and amfetamines may be used if modafinil or armodafinil is not effective. Patients complaining of insomnia should follow general sleep hygiene measures, such as a regular sleep schedule, avoidance of alcohol and caffeine in the evening, and other measures. Analgesics may be prescribed for pain and, occasionally, patients may need hypnotics, which should be used judiciously in low doses, no more than two to three nights per week.

CONCLUSION SDB is a common and serious consequence of neuromuscular disorders associated with respiratory muscle weakness, which unfortunately remains underdiagnosed or undiagnosed, as it presents as nocturnal hypoventilation in its early stage. A high index of clinical suspicion is needed so that appropriate diagnostic tests may be designed to diagnose nocturnal hypoventilation and other sleep-related disorders in the early stage of the illness. Some recent studies suggested possible

daytime predictors (e.g., reduced FVC and maximal inspiratory mouth pressure) for nocturnal hypoventilation, and, therefore, further studies are needed to develop optimal criteria for detecting SDB and nocturnal hypoventilation in its early stages. Noninvasive nasal IPPV remains the mainstay of treatment for SDB in neuromuscular disorders, providing an improvement in quality of life without always altering the natural history of the illness. Further studies are needed to answer many critical questions outlined in the USA consensus criteria document, such as when to treat, whom to treat, what type of equipment and what types of ventilator settings to use, what is the long-term outcome, how frequently the patient should be followed, what are the physiological mechanisms of benefit with noninvasive IPPV, what is patient tolerance and compliance to IPPV, and what are the longterm effects on outcome.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 65

Sleep-related epilepsy MARCO ZUCCONI * Sleep Disorders Center, Department of Clinical Neurosciences, H San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy

INTRODUCTION A seizure is a paroxysmal event caused by a sudden excessive discharge of the neurons of the cerebral cortex. Epilepsy is a condition of recurrent unprovoked seizures; it is not a single disorder nor a single syndrome, but rather encompasses a number of heterogeneous entities. Seizures often occur during sleep, mainly because sleep facilitates epileptic activity. Both ictal events (IEs) and interictal discharges (IDs) tend to be highly state dependent. Nonrapid eye movement (NREM) sleep is associated with an increased incidence and spread of IDs, and has a permissive effect for IEs. Rapid eye movement (REM) sleep has a suppressive effect both on IDs, more localized than spread, and on IEs. Both occur less frequently in REM than in NREM sleep. This facilitating effect of NREM sleep depends in part on the common basic brain circuitry generating NREM oscillations, in terms of physiological elements (e.g., K-complexes, spindles, slow waves), prolonged fluctuation of arousability (e.g., microarousals, cyclic alternating pattern, CAP), and electrical seizures or spike-and-wave complexes. From studying sleep and epilepsy with neurophysiological techniques and video-recording, it has become clear that the state dependency of IEs and IDs involves the complex interactions of different neural networks, neuromodulators, peptides, neurotransmitters, and many sleep-promoting substances, often resulting in mixed and oscillating states. This oscillatory system, with dissociation states, may be one of the causes facilitating seizures during sleep, but it is also involved in other behavioral episodes that mimic epileptic episodes, such as parasomnias or paraphysiological phenomena. Therefore, sleep and sleep disorders may influence seizures and epileptic

activity, but both IEs and IDs themselves have an impact on sleep structure, the sleep–wake cycle, the restorative effect of sleep, and daytime sleepiness and efficiency.

HISTORICAL PERSPECTIVES The close relationship between sleep and epilepsy has been recognized since antiquity, but it was not studied until the end of the 19th century and the first half of the 20th century. Before and after the discovery of the human electroencephalogram (EEG), the link between IE, interictal activity (IA), and sleep was reported, and it was found that the amount of IE and IA both increase during sleep (Dinner and Luders, 2001). Considering wake epilepsy, sleep epilepsy, and diffuse epilepsy, the authors observed clinically that at least 20% of epileptic patients experienced seizures only during sleep, and approximately 30% experienced IEs during both daytime and nighttime hours. At the same time, an increase in IDs during sleep compared with the wake state was reported by Gibbs and Gibbs (1947). Only after the 1960s did researchers start to study, by means of polysomnography (PSG), sleep-related episodic phenomena. These studies allowed researchers to differentiate sleep disorders such as sleepwalking and sleep terrors from epileptic seizures, and showed that, although sleep disorders share some common features with epileptic seizures (e.g., abrupt onset, confusion, disorientation, and amnesia), these episodes could be related to arousal disorder rather than to epilepsy (Broughton, 1968). After the introduction of videorecording during PSG, the characteristics of nocturnal episodes during sleep were better defined and, mainly due to the work of the Lugaresi group, some new findings appeared suggesting the possibility that arousal

*Correspondence to: Marco Zucconi, M.D., Sleep Disorders Center, Department of Clinical Neurosciences, H San Raffaele Institute, Via Stamira d’Ancona, 20, 20127 Milan, Italy. Tel: þ39 02 26433364-3476, Fax: þ39 02 26433394, E-mail: zucconi. [email protected]

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disorders could provoke, represent, or be caused by epileptic disorders. Nocturnal paroxysmal dystonia, as described by Lugaresi and Cirignotta (1981), showed the possible existence of nocturnal attacks, stereotypic in motor pattern, repetitive almost every night, with more episodes per night and emerging from NREM sleep, without clearcut electroencephalographic (EEG) epileptic activity both ictally and interictally. For the dystonic–dyskinetic pattern of movements, a possible new movement disorder was suggested. Subsequently, with the aid of audio–video recordings and deep electrodes, the same group and others were able to confirm the epileptic origin of the motor attacks, with possible frontal lobe origin, similar to the classical partial frontal seizures. These attacks included complex, bizarre motor patterns with bipedal–bimanual activity; rocking axial and pelvic torsion; occasional deambulation; jumping, shouting, and screaming; and the vocalizing of guttural sounds with a frightened expression (Meierkord et al., 1992; Vigevano and Fusco, 1993; Tinuper et al., 2007). More recently, different groups have described nocturnal frontal lobe epilepsy (NFLE) in both familial and sporadic forms, reinforcing the concept of peculiar nocturnal seizures emerging from NREM sleep that are brief in duration, repetitive, sometimes with secondarily generalized tonic–clonic seizures (GTCSs), that are often misdiagnosed as nightmares, parasomnias, or hysteria (Montagna, 1992; Oldani et al., 1996, 1998; Provini et al., 2000). Genetic studies have identified different loci as responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), most of these coding for different subunits of the ligand-gated neuronal nicotinic acetylcholine receptor (nAChR) (Phillips et al., 1995, 1998; Gambardella et al., 2000). Very recent neurophysiological and stereo-EEG studies have confirmed the epileptic origin not only of complex motor repetitive behaviors such as nocturnal wanderings and nocturnal paroxysmal dystonia, but also of minor attacks, present alone or associated with major episodes, such as paroxysmal arousals of very short duration, with repetitive, stereotypic, and quasiperiodic characteristics (Sforza et al., 1993; Plazzi et al., 1995; Zucconi et al., 1997; Nobili et al., 2002, 2003).

EPIDEMIOLOGY The data on the prevalence of seizures during sleep are not definitive, and questionnaires based on patient interviews have not been able to distinguish parasomnias from seizure disorders because of their highly similar symptoms (especially those of partial complex seizures). The estimated prevalence of patients who have seizures predominantly or exclusively during

sleep is 10–45%, reflecting the heterogeneity of the seizures and syndromes associated with sleep-related epilepsy (Dinner and Luders, 2001). Localization-related epilepsies – in particular, partial complex seizure disorders followed by tonic–clonic attacks – are the more frequent type of sleep seizure, with both frontal and temporal foci. No significant gender prevalence is noted, and the age of onset overlaps with the onset of parasomnias (i.e., arousal disorders). In addition, hereditary information is not completely available, as studies mostly refer to ADNFLE, and arousal disorders have an evident large familial aggregation (Hublin et al., 1997). Because seizures have many clinical characteristics similar to those of parasomnias, it is possible that the rarity of nocturnal seizures described in the literature may be more apparent than real, attributable to the difficulty in making a correct diagnosis without the aid of instrument examinations.

PATHOGENESIS Sleep not only activates clinical seizures but also may lead to activation of IDs. Thus, EEG with an adequate period of sleep increases the chances of detecting such discharges. Both sedated and spontaneous sleep (or after sleep deprivation) are similarly effective (Rowan et al., 1982). Moreover, sleep has an effect on the morphology of IDs. The exact mechanisms of these interactions are not completely understood, but many things are known. For example, it is well known that in virtually all seizure disorders and in experimental epilepsy models, IDs are more likely to occur and to propagate during NREM sleep than in any other state, and that IDs are less likely to propagate and lead to a clinically evident seizure during intact REM sleep than in any other state (Shouse et al., 1989, 1996). This state-specific differentiation, affecting seizures and discharges, is caused by the alternating tonic and phasic firing components of hypothalamic and brainstem generators and projections regulating sleep and wake states. In NREM sleep and drowsiness, EEG activity is synchronized, and long-lasting oscillations of rhythmic burst-phase firing patterns, through synchronous synaptic effects, increase the magnitude and propagation of postsynaptic responses, including epileptic discharges (Steriade et al., 1993). During REM sleep and waking (alert waking, in particular) the discharges are prevalently asynchronous, leading to an inhibitory effect on the amplitude and propagation of epileptic discharges (Siegel, 1994). Also, the different state dependency of skeletal muscle tone justifies the different distribution and susceptibility of NREM and REM sleep concerning seizures: in NREM sleep, muscle tone is

SLEEP-RELATED EPILEPSY 1111 diminished but still preserved, with the possibility and CLINICAL AND VIDEOpermissibility of movement-related episodes (both POLYSOMNOGRAPHIC FEATURES parasomnias and seizures). In contrast, in REM sleep, In all types of epilepsy, some types of epileptic synan important postural muscle atonia allows hardly drome have a marked tendency to manifest only or any movement disorders (Siegel, 1994; Shouse et al., predominantly during sleep: NFLE, benign epilepsy of 1996). Only when the EEG and skeletal motor activity childhood with centrotemporal spikes (BECTS), earlydissociate, experimentally or pathologically, are there onset or late-onset childhood occipital epilepsy, juvedifferent motor manifestations as well as ID propaganile myoclonic epilepsy (JME), GTCSs on awakening, tion both in NREM and REM sleep. Animal models a subgroup of temporal lobe epilepsy, tonic seizures and experimental studies indicate that, beside the (as a component of Lennox–Gastaut syndrome), constate-specific modulation of events and EEG epileptic tinuous spikes waves during NREM sleep (CSWS), abnormalities, neuromodulators play an important role and Landau–Kleffner syndrome. in determining the frequency of discharges and electroclinical manifestations: agents that synchronize the EEG (cholinergic or noradrenergic antagonists) have Nocturnal frontal lobe epilepsy convulsant effects, whereas cholinergic and noradrenergic agonists, acting on a central benzodiazepine NFLE is a distinct form of paroxysmal sleep-related receptor, reduce the EEG epileptic firing (Velasco and disorder that includes a spectrum of presentations of Velasco, 1982; Applegate et al., 1986; Shouse et al., presumed frontal lobe origin. NFLE is characterized 1996). At the same time, modulation of skeletal muscle by repetitive attacks with a predominantly motor comtone inducing atonia diminishes motor activity assoponent, a high frequency of attacks per night, interciated with IEs or IDs. The different pattern of cellular night repetition, stereotypy of the episodes, and a discharge and the alteration in tone may affect both tendency to start in childhood and persist into young EEG and clinical manifestations in different epilepsies adulthood, with uncommon EEG ictal and interictal (Shouse et al., 1989, 1996). paroxysms during sleep (Scheffer et al., 1995; Oldani NREM and REM sleep effects on ID may also vary et al., 1996, 1998; Provini et al., 1999). as a function of epilepsy syndrome, and in particular The common features characterizing NFLE consist as a function of the pathophysiology of the specific of the following: age of onset during infancy or childseizure disorder. Cholinergic and noradrenergic pathhood with persistence in adulthood; a family history of ways in the brainstem, when reduced in firing, promote possible similar nocturnal frontal lobe seizures and ID generation and propagation during NREM sleep in nocturnal episodes simulating NREM parasomnias primary generalized epilepsies, enhancing the thala(e.g., sleep terrors or sleepwalking); a generally absence mocortical EEG synchronization via an increase in gof morphological substrates based on clinical history aminobutyric acid (GABA) release (Gloor and Fariello, and brain imaging; motor dystonic–dyskinetic attacks 1988). However, the peak in GABA release seems to suddenly emerging from NREM sleep; repetitive and reduce clinically evident seizures as generalized myostereotypical features seen in the same patient and clonic and tonic–clonic convulsions (Shouse et al., across different patients; usually normal ictal or inter1996). Otherwise, moderate levels of reticular formaictal EEGs without clearcut epileptic paroxysms in tion activation (with low thalamocortical discharge) more than 50% of the cases; and benefit from some are conductive to IDs in drowsiness (Shouse et al., antiepileptic drugs (AEDs) but occasional resistance 1996). Increased levels of activation of ascending to AEDs in some severe forms. The different types brainstem afferents (in both the wake state and REM of NFLE seizure may cause a severe sleep disruption sleep) seem to suppress ictal and interictal events via affecting both the macrostructure and microstructure GABA effects in primary generalized epilepsies of sleep, resulting in some patients experiencing poor (Siegel, 1994). In frontal or temporal lobe IEs or IDs, sleep quality, daytime tiredness, and sleepiness. The the reduced activity in reticulolimbic discharge promovements may also be so severe that injuries caused motes the propagation and activation of epileptic by a patient’s striking a hard object can occur. Oneabnormalities (Applegate et al., 1986). Increased excitthird to one-half of the patients experiencing NFLE ability of seizure foci may lead focal epileptic cells to also have occasional attacks during the day (not necesbe hyperresponsive to synchronous inputs, and consesarily of the same type as those occurring at night) quently justifies the propagation of IDs with possible and secondarily GTCSs; neurological examination is clinical manifestations during NREM sleep (Shouse generally normal (Scheffer et al., 1995; Oldani et al., et al., 1994). 1996, 1998; Provini et al., 1999).

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CLINICAL

M. ZUCCONI AND PATHOPHYSIOLOGICAL SUBTYPES

The variable duration, types, and semiology of the seizures can be used to divide the attacks into three subgroups: paroxysmal arousals (PAs) with short, sudden paroxysmal motor attacks or behaviors; major shortlasting episodes with complex dystonic–dyskinetic components (formerly known as nocturnal paroxysmal dystonia, NPD); and episodic complex attacks consisting of deambulation, wandering or agitation, violent somnambulism, and epileptic nocturnal wanderings (ENW) (Montagna, 1992; Sforza et al., 1993; Plazzi et al., 1995; Provini et al., 1999). PAs consist of brief (less than 20 seconds), sudden, and often very frequent arousals associated with minimal or minor stereotyped motor activity with apparently purposeful or semipurposeful behavior, such as the abrupt elevation of the head, neck, and sometimes trunk from the bed; and screaming, moaning, or

looking around with a fearful expression. Stereotypic and dystonic arm or leg movements are frequent, as is facial grimacing and chewing (Montagna, 1992; Sforza et al., 1993) (Figures 65.1–65.3). The episodes previously known as NPD may sometimes start as PAs but usually include complex motor behavior with a dystonic–dyskinetic component, an asymmetrical posture, cycling and kicking of the legs, repetitive and rhythmic limb or arm movement, and pelvic or body rocking accompanied by guttural sounds or unspecified words and a frightened expression of the face (Figures 65.4 & 65.5). The duration of the episodes varies from 30 to 100 seconds. The intraindividual repetitiveness is still a characteristic feature (Montagna, 1992; Provini et al., 1999, 2000). ENWs are rare attacks characterized in the beginning by a typical NFLE episode (either brief or more prolonged) followed by agitation, sudden standing, walking around the bed or toward the exit of the room,

Fig. 65.1. Short (less than 10 seconds) paroxysmal arousal in a patient with nocturnal frontal lobe epilepsy: sudden elevation of the head and sudden opening of the eyes with fear. Interictal and ictal electroencephalogram (EEG) shows left hemisphere spikes with prevalence in frontocentral and vertex leads, but extending to parietal leads. The montage is EEG, electrooculogram (EOG) (LOC–A2, ROC–A2), submental electromyogram (EMG) (Chin1–Chin2), and electrocardiogram (EKG). LOC, left electro-oculogram; ROC, right electro-oculogram.

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1113

Fig. 65.2. (A) Paroxysmal arousal in a patient with nocturnal frontal lobe epilepsy, emerging from stage 3–4 NREM (slowwave sleep) and characterized by screaming, head elevation, eyes opening, and fear. Note the absence of clearcut electroencephalographic (EEG) abnormalities before and during the episode. (B) The same seizure with a low speed (1 min) epoch. Note the EEG fluctuation (cyclic alternating pattern) during slow-wave sleep and the seizure relationship with the A phase (arousal). The montage is EEG, electro-oculogram (EOG) (LOC Pg1–Pg2, ROC Pg2–A2), submental electromyogram (EMG) (24–35), and electrocardiogram (EKG) (32–A1). LOC, left electro-oculogram; ROC, right electro-oculogram.

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M. ZUCCONI

aimless movements, a sudden change of direction, or walking and jumping around the bed as in a bizarre kind of dance. Dystonic posture and dyskinetic movements may be limited to a single arm or leg. The duration may be more prolonged than the other NFLE episodes and may last for up to 3 minutes. Sometimes all three types of episode may occur in the same patient in a continuum. More commonly, the patients

present one or two types of recurrent episode during the night (Plazzi et al., 1995; Provini et al., 2000).

AGE

OF ONSET, COURSE, AND COMPLICATIONS

Onset may occur anytime in infancy or adulthood, but generally occurs when the patient is between 10 and 16 years of age (median age 12 years). As the condition

Fig. 65.3. Paroxysmal arousal in a patient with nocturnal frontal lobe epilepsy with sudden elevation of head and trunk, loud and prolonged shouting, turning on right of trunk, with no other tonic, dystonic, or motor component. (A) Emergence of the episode from stage 3–4 NREM sleep, with a brief burst of spikes preceding the arousal, more evident in frontocentral and parietal right leads. (B) The electroencephalogram (EEG) during episodes is normal with a spread alpha rhythm corresponding to a wake state of the patient during shouting. (Continued)

SLEEP-RELATED EPILEPSY

1115

Fig. 65.3—cont’d (C) Interictal EEG diffuse abnormalities (spike, and spike and wave) with prominence in right frontocentral and vertex leads. The montage is EEG, electro-oculogram (EOG) (LOC–A2, ROC–A2), submental electromyogram (EMG) (Chin1–Chin2), and electrocardiogram (EKG). LOC, left electro-oculogram; ROC, right electro-oculogram.

Fig. 65.4. Complex motor seizure (hypermotor seizure) in a patient with drug-resistant nocturnal frontal lobe epilepsy, characterized by head turning towards left side, eye opening, vocalization followed by loud screaming, elevation and tonic– dystonic contraction of right arm, then pedalling and bicycling movements of both legs, with elevation of trunk, and finally an attempt to get out of bed. (A) Seizure starting from stage 2 NREM sleep, with slow activity mixed with spikes on the left side (in both temporal and frontal leads). (Continued)

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Fig. 65.4—cont’d (B) Persistence of 3–4-Hz activity in left hemisphere leads during vocalization and dystonic posture of right arm. (C) Elevation of trunk with pedalling movements and maintenance of consciousness. The montage is electroencephalogram (EEG), electro-oculogram (EOG) (LOC Pg1–A2, ROC Pg2–A2), submental electromyogram (EMG) (24–35), and electrocardiogram (EKG) (32–A2). LOC, left electro-oculogram; ROC, right electro-oculogram.

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1117

Fig. 65.5. Another seizure of the previous patient with nocturnal frontal lobe epilepsy (see Figure 65.4), similar in semiology, emerging from stage 3–4 NREM sleep but not preceded by epileptiform abnormalities. The montage is electroencephalogram (EEG), electro-oculogram (EOG) (LOC–A2, ROC–A2), submental electromyogram (EMG) (Chin1–Chin2), and electrocardiogram (EKG). LOC, left electro-oculogram; ROC, right electro-oculogram.

has been characterized recently, definite data on natural history are not available. For some cases, a spontaneous remission in adulthood may be expected. A positive response to antiepileptic drugs (e.g., carbamazepine, topiramate) is reported in most cases. However, more than one-third of patients, particularly those with more complex forms, are resistant to antiepileptic medications. Surgery may be a choice in very severe and drug-resistant forms. Due to the predominantly nocturnal occurrence of the seizures and the consequent limited impact they have on patients’ social interaction, patients with few and minor attacks often refuse treatment altogether (Oldani et al., 1998; Provini et al., 1999).

PATHOLOGY

AND PATHOPHYSIOLOGY

Electrophysiological recordings of these attacks with sphenoidal or zygomatic leads showed epileptic activity over the mesiotemporal regions, and video-PSG analysis has confirmed that the motor pattern of at least the major seizures (NPD and ENW) resembles that noted in orbital and mesial frontal seizures (Tinuper et al., 1990; Meierkord et al., 1992; Vigevano and Fusco, 1993; Provini et al., 2000). Recent data, gathered by means of stereo-EEG studies, seem to show that in some cases the seizures, in particular those involving nocturnal wanderings, may arise from the temporal regions (rather than frontal regions), with a secondary spread to the cingulate regions (Degen, 1980). No specific lesions or abnormalities have been found in

patients with NFLE (Oldani et al., 1998; Provini et al., 1999). A form of ADNFLE has been delineated in reports from many countries, and a genetic heterogeneity has also been reported by different groups (Scheffer et al., 1995; Oldani et al., 1996, 1998). In ADNFLE, different mutations have been described in chromosome 20q13, all in the second transmembrane domain (M2) of the nAChR a4 subunit (Ser248Phe, 776lns3) and in chromosome 1q21 in the M2 of the nAChR b2 subunit (V287L, V287M) (Phillips et al., 1995; Steinlein et al., 1997; Gambardella et al., 2000). A third locus in chromosome 15q24 has been described, but the mutation has not yet been found (Phillips et al., 1998). The mutations affect the functional properties of the receptor controlling the ion channel gating and alter electrophysiological properties. In vitro studies have shown that those localized in the a4 subunit generally have a hypoactivity effect (i.e., loss of function mutations), whereas b2 subunit mutations show an increase in the sensitivity of the receptor to cholinergic stimuli (i.e., gain of function mutations). Therefore, mutations may modulate the neurotransmitter release affecting the excitability of a particular group of neurons (for a review see Rozycka and Trzeciak, 2003; Combi et al., 2004). Alternative mutations may produce disorganization of the neuronal circuits. The lack of involvement in the pathogenesis of the disease of all the genes coding for nAChR subunits has been shown in some families, and consequently new ADNFLE genes not belonging to the nAChR may be hypothesized

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(Bonati et al., 2002). Recently, two new putative ADNFLE loci were identified (chromosomes 3p22–24 and 8q11.2-q21.1) in one family, and new nucleotide variations in the promoter region of the gene coding for the corticotropin-releasing hormone have been found in four families, opening new perspectives on the genetic form of NFLE (Combi et al., 2005). In any case, it remains to be explained why this form of epilepsy has as its main characteristic seizures that occur during sleep and rarely in wakefulness. It has been hypothesized that the genetic basis of the condition may facilitate the appearance of the seizures during the synchronizing state (NREM sleep) that activates oscillations between thalamocortical loops and the brainstem activating system (Gloor, 1978). These very slow oscillations may manifest in different forms of EEG elements (e.g., delta waves, K-complexes, spindles, or arousal fluctuations in a CAP), all of them with major expression in the frontal lobe. These oscillations may activate epileptogenic foci and seizures or, alternatively, arousal disorders that cause motor behaviors (often indistinguishable from seizures) across common pathway of the central motor pattern generator (Tassinari et al., 2005; Parrino et al., 2006). This finding suggests that arousal oscillation, an increase in microarousals, the periodic instability of sleep microstructure as measured by a CAP rate increase, and the relationship of the

nocturnal motor attacks to phase A of the CAP are more than an epiphenomenon of NFLE or ADNFLE. Thus, it is conceivable that a genetic alteration observed in NFLE might be responsible for both epileptic susceptibility and arousal instability, causing both parasomnias and frontal lobe seizures during sleep (Nobili, 2007). A recent observation using deep electrodes in nocturnal hyperkinetic seizures demonstrated that the preseizure sleep spindles are longer than and different from the interictal ones, with no relation to wake activity (12 Hz as alpha activity) and acting independently of the spatial relationship of the ictal onset, suggesting and emphasizing the importance of the thalamus and the thalamocortical circuit in generating seizures in NFLE (Picard et al., 2007). This mechanism of a thalamocortical loop dysfunction may be related to the genetic alteration at the nicotinic acetylcholine receptor level, as defects at this level have been demonstrated in family members with NFLE (Picard et al., 2006).

POLYSOMNOGRAPHIC

AND OTHER OBJECTIVE

FINDINGS

Nocturnal video-PSG is the main diagnostic test for NFLE. Most seizures appear during NREM sleep, with the preponderance occurring in stage 1–2 NREM sleep (more than 60%) (Figure 65.6). Seizures rarely emerge

Fig. 65.6. Focal motor seizure emerging from stage 2 NREM sleep with ictal activity mainly in right leads. Clinically tonic elevation of right arm and dystonic posture of left arm, divaricating and tonic contraction of lower limbs, vocalization with no significant impairment of conscience The montage is electroencephalogram (EEG), electro-oculogram (EOG) (ROC Pg1–A2, LOC Pg2–A2), and submental electromyogram (EMG) (24–25), EKG (32–A1).

SLEEP-RELATED EPILEPSY

Fig. 65.6—cont’d

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M. ZUCCONI

during REM sleep. In some cases, particularly PA, motor attacks may show a periodicity (occurring every 20 seconds to 2 minutes). Due to the presence of muscle artifacts, EEG during the attacks is uninformative in almost half the cases (Figure 65.7). Rhythmic theta or delta waves; sharp waves predominantly in the frontal regions; attenuation of the background activity; and, in a minority of cases, classic spike-and-wave activity or small-amplitude fast activity have been recorded during seizures, sometimes with a clearcut focal pattern (frontal or frontotemporal). The recording

using intracranial or deep electrodes confirmed the paroxysms during or preceding the motor components (Sforza et al., 1993; Plazzi et al., 1995; Oldani et al., 1996, 1998; Zucconi et al., 1997; Provini, 1999). They helped definitively to confirm the increasing complexity and duration of different motor seizures caused by the different spreading and propagation of the discharges within the frontal lobe in patients with NFLE and drug-resistant seizures (Nobili et al., 2003). However, deep electrode recordings showed also that short-lasting minor motor events (2–4

Fig. 65.7. Focal motor seizures starting from slow-wave sleep without interictal epileptiform electroencephalographic (EEG) activity preceding or during the attack. (A) Arousal preceded by high-amplitude slow activity and characterized by electromyographic (EMG) tonic and phasic activity covering EEG leads (B), in particular in right frontotemporal leads. (Continued)

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Fig. 65.7—cont’d (C) Artifact EMG activity which continues with an awakening (alpha EEG activity masked by EMG fast activity). Clinically sudden elevation of trunk and head, tonic–dystonic contraction of right arm, and version of the head towards the right side.

seconds in duration), often related to brief intracerebral epileptic discharges, may not be differentiated from physiological behaviors from a clinical and video-PSG point of view. The epileptic discharges may increase sleep fluctuations, evoking and possibly

modulating physiological phenomena as well as parasomnic episodes or periodic leg movements, and the arousal instability may increase the epileptic discharges (Figure 65.8). The result is that normal motor behaviors or periodic small movements (periodic leg movements

Fig. 65.8. Same patient as in Figure 65.1. (A) Interictal epileptic paroxysms in right hemisphere, with maximal amplitude in F4–C4 lead during stage 2 NREM sleep. (Continued)

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Fig. 65.8—cont’d (B) The same discharges during arousal, corresponding to A phase of the cyclic alternating pattern, during stage 2 NREM sleep. (C) Interictal focal discharges in median regions of right hemisphere, during slow-wave sleep. The montage is electroencephalogram (EEG), electro-oculogram (EOG) (ROC Pg1–A2, LOC Pg2–A2), submental electromyogram (EMG) (24–25), and electrocardiogram (EKG) (32–A1). LOC, left electro-oculogram; ROC, right electro-oculogram.

in sleep, bruxism, sleep-talking) are similar in those with or without IDs (Nobili et al., 2005; Terzaghi et al., 2007). Sometimes sleep-related seizures similar to those observed in NFLE may arise from temporal lobe rather than from orbitofrontal zones, particularly some of those characterized by affective symptoms such as agitated ambulatory behaviors (known as epileptic nocturnal wanderings). They may involve large neuronal networks and sometimes emerge from the frontal zone (orbitofrontal, anterior cingulated) but

also spread to temporal limbic cortices (Nobili et al., 2002; Ryvlin et al., 2006). Some episodes emerge during the unstable microstructural phase of the EEG (e.g., a phase of the CAP) (Terzano et al., 1997; Zucconi and Ferini-Strambi, 2000). The interictal sleep EEG is generally normal, but in 30–40% of subjects focal epileptic abnormalities are seen, predominantly in the anterior regions. Autonomic changes such as tachycardia, tachypnea, or respiratory abnormalities and irregularities, as well as

SLEEP-RELATED EPILEPSY 1123 electrodermal changes, are frequently present during Bologna, Italy (Tinuper et al., 2007) tried to delineate the attacks. Video-recording of the different types of some practical points to differentiate or correlate attack permits categorization of the seizures and charNFLE and NREM parasomnias. acterization of the main features (Oldani et al., 1996, The Australian group tried to establish the reliability 1998; Zucconi et al., 1997; Provini et al., 1999). of anamnestic characteristics to distinguish the two Classical imaging studies (i.e., using computed entities when video-PSG is unavailable or unhelpful. tomography or magnetic resonance imaging, MRI) On the basis of previous analyses and practical experiare typically normal, and may be useful to exclude rare ence, they developed a scale, the Frontal Lobe Epilepsy symptomatic forms. However, in some cases of ADNand Parasomnias (FLEP) Scale, with questions and posFLE, minor nonspecific features have been noted. sible answers determining a score. Responses favoring More sophisticated techniques such as positron emisepilepsy score positively, and those favoring parasomsion tomography (PET) and single-photon emission nias score negatively. These authors compared the clincomputed tomography (SPECT) may be helpful in ical diagnosis on the FLEP Scale with a standard identifying the most active brain zones during ictal diagnostic test (video-PSG, expert interviews) in a manifestations or in detecting interictal hypoactivity. group of patients with nocturnal episodes of uncertain A recent PET study showed a reduction of the nicotinic definition. Three groups were defined: NFLE, typical receptors in the prefrontal cortex of patients with parasomnias, and atypical parasomnias. The scale ADNFLE, suggesting a possible role of arousal and thareached a sensitivity of 1 and a specificity of 0.9, with lamocortical circuits in the pathogenetic mechanisms of a Cohen kappa score of 0.97 between different interseizures during sleep (Picard et al., 2007). Genetic analviewers. Notwithstanding the retrospective nature of ysis with a finding of possible mutations in particular the study and the lack of video-PSG confirmation for pedigrees may identify an individual genetic form of typical parasomnias, use of the FLEP Scale seems ADNFLE (Oldani et al., 1998; Provini et al., 1999). promising for the differential diagnosis of NFLE and parasomnias, if the results are confirmed in a larger group of subjects and with video-PSG control for all DIFFERENTIAL DIAGNOSIS subjects (Derry et al., 2006). NFLE should be differentiated from parasomnias, in The indications for guidelines in differentiating particular from NREM parasomnias such as arousal epileptic from nonepileptic motor phenomena during disorders (e.g., sleepwalking, sleep terrors, and confusleep provided by the Italian group started from some sional arousals). The clinical/anamnestic features of observed and verified statements: the behavior patterns the two conditions are quite similar, but the older age may be similar; semeiological characteristics are not of onset in NFLE, the tendency of the episodes to be present in all the episodes, and the description by a witof high frequency and short duration, the partial preserness may be not complete and adequate; and, finally, vation of consciousness during episodes, and the tenclinical diagnostic tools are unreliable (e.g., EEG, somedency of the episodes to persist in adulthood times video-PSG, video-recording at home) (Tinuper differentiate NFLE from arousal disorders. The motor et al., 2007). Tinuper and colleagues reviewed the clinipattern during sleep and the semiology of the attacks cal aspects and features of the major motor phenomena (e.g., stereotypy, dyskinetic and dystonic component, during sleep and elaborated on possible still-open issues: abrupt and sudden onset, dancing or jumping features video-PSG analysis is of utmost importance, but due to for the more complex seizures) may be helpful in dislack of ictal and interictal scalp EEG, abnormalities are tinguishing the episodes, although the definite boundsometimes difficult to interpret, and debate is still open aries between the two types are still not completely on the etiopathogenesis of different (epileptic and noneunderstood. Differentiating paroxysmal arousals from pileptic) motor phenomena during sleep; ADNFLE has confusional arousal is difficult because of the lack of been linked to different mutations in the genes coding paroxysmal EEG discharges in PAs, and requires for nAChRs, but the exact mechanisms by which these video-PSG (Provini et al., 2000; Zucconi and Ferinimutations may modify the firing of neurons giving oriStrambi, 2000). gin to seizures is not completely understood (Combi Notwithstanding the spread of video-PSG and the et al., 2004). Moreover, arousal disorders are often wide acceptance of the concept of NFLE, the differenaggregated on a family basis; indeed, in patients with tial diagnosis between some types of sleep-related seiboth sporadic and genetic NFLE, coexistence of nocturzure and paroxysmal nonepileptic motor events is still nal parasomnic episodes or seizure attacks in family a challenge, and no definite guidelines have been members was found (Oldani et al., 1996, 1998; Provini approved in this field (Table 65.1). Recently, groups et al., 1999; Nobili, 2007; Tinuper et al., 2007). Considerin Melbourne, Australia (Derry et al., 2006) and ing the central motor pattern generator theory, it is also

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Table 65.1 Clinical and video-polysomnographic features of nocturnal frontal lobe epilepsy (NFLE) and NREM parasomnias (arousal disorders)

Age at onset (years) Attacks/month (n) Attack distribution in the night Sleep stage at onset of attack Duration of the attacks

Attacks per night Repeated and stereotypic attacks Vocalization

Dystonic or tonic posturing Brief burst of running or jumping in the bed or around the bed Awareness Recall Consciousness if awakened Sleep fragmentation Daytime sleepiness Family history

Response to treatment

Follow-up and clinical course

NFLE

Arousal disorders

> 10 (generally during or after adolescence but any age is possible) Almost every night (>30) but with possible variation At any time NREM sleep (>60% in stage 2) Less than 1 min (excluding complex prolonged dystonic or wandering seizures) Several Generally present May be present, generally very rapid and loud (screaming or shouting)

<10 (generally during school age, 3–8 years) Sporadic (1 to 4 or fewer)

Very common Characteristic of some complex seizures (nocturnal epileptic wanderings, even though of possible extrafrontal origin) May be present in a proportion of seizures. Typical aura: breath stuck in the throat May be present in a proportion of attacks Present and normal Present Common (often related to the high number of seizures and sleep fragmentation) Frequent (for both seizures and parasomnias, sometimes clinically indistinguishable) Good response to AEDs (carbamazepine, topiramate, etc.) in at least 60–70% of cases Stable or increasing (unknown)

Generally first third of night NREM sleep stage 3–4 Some minutes (1–10)

Generally one Generally absent Generally present (brief and unintelligible, or comprehensible and prolonged) Uncommon Generally absent (calm or quiet ambulation, even out of room or house) Generally absent Generally absent Impaired and slower May be present, sometimes related only to SWS microstructure instability Infrequent Frequent (for parasomnias)

Not known (improvement with sleep stabilization) Symptoms generally reduced or absent

AED, antiepileptic drug; NREM, nonrapid eye movement; SWS, slow-wave sleep.

possible that the genetic or sporadic alteration resides in the mechanisms controlling the arousal system, explaining why sometimes, or in some subjects, we can expect arousal disorders (parasomnias) or epileptic seizures by the same activation but with different triggers: epileptic abnormalities or sleep-related dysfunctions (Tassinari et al., 2005; Nobili, 2007). In support of this hypothesis, Tinuper and coworkers (2007) collected some data on familial aggregation of patients with diagnosed NFLE and found a higher frequency of arousal parasomnias (clinically defined) in NFLE probands and their relatives compared with a control population. The features that differentiate REM parasomnias (REM sleep behavior disorder) from NFLE include later

age of onset, motor episodes occurring during the night and with a strict relationship to a dream-enacting behavior, less stereotypical behaviors, polysomnographic characteristics of REM without electromyographic (EMG) atonia, and an increase in EMG activity of the limb or arm muscle (Ferini-Strambi and Zucconi, 2000). Other motor phenomena during sleep or sleep transitions, such as rhythmic movement disorder, hypnic myoclonus, or physiological body movements, are easier to recognize. Nocturnal panic attacks are characterized by sudden awakening with complex autonomic activities and an unpleasant sensation of fear or imminent death,

SLEEP-RELATED EPILEPSY usually lasting longer than NFLE and not recurring, unlike NFLE. The presence of the same attacks during the day may also be helpful in differentiating REM parasomnias from NFLE (Oldani et al., 1998; Provini et al., 1999).

TREATMENT According to data in the literature, in about two-thirds of patients with NFLE who are treated pharmacologically, low-dose carbamazepine is reported to reduce greatly the frequency and complexity of seizures (Oldani et al., 1998; Provini et al., 1999). However, seizures mostly occur during nocturnal sleep; thus, patients are often unaware of the response to treatment, and without the aid of video-PSG it is difficult to collect useful information on treatment results. We recently described the effectiveness of topiramate in about 90% of a sample of 24 patients with NFLE utilizing seizure diaries, and in a subgroup using video-PSG recording (Oldani et al., 2006). Topiramate (dose range 50–300 mg daily at bedtime) was administered as single or add-on therapy, and patients were followed for a mean of 2.3 years (range 0.5–6 years). The mean effective dose in responders and seizure-free subjects was 102 mg. Other reported treatments include acetazolamide (Varadkar et al., 2003) and transdermal nicotine (Willoughby et al., 2003). Because of possible mutations in nAChRs, an effect of nicotine on the expression of seizures may be postulated, and a transdermal nicotine patch, associated with carbamazepine, has been showed to reduce seizures in an open and double-blind placebo-controlled study in a single patient (Willoughby et al., 2003). Moreover, a significant association between tobacco use and seizure control, and a parallel persistence of seizures in nonsmokers, were demonstrated in a group of subjects affected by ADNFLE (Brodtkorb and Picard, 2006). Finally, because around 30% of patients in the larger sample were resistant to AEDs, in particular those with more numerous and complex attacks (Kobayashi et al., 1990; Oldani et al., 1998), surgical treatment may have an indication, especially in patients with a high number of nocturnal attacks, sleep fragmentation, nonrestorative sleep, important daytime sleepiness, and side-effects from AEDs. An accurate presurgical evaluation, including invasive EEG recording, is mandatory for resective surgery in drug-resistant and severe forms of NFLE (Ryvlin et al., 2006; Nobili et al., 2007).

Benign epilepsy of childhood with centrotemporal spikes (BECTS) BECTS is the most common epilepsy in children, accounting for 15–20% of childhood epilepsy (Dinner and Luders, 2001). In BECTS, seizures are unilateral

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focal motor (clonic) attacks involving the face, arms, and, rarely, legs, but with frequent secondary tonic– clonic generalization. The seizures may have a sensory component and may provoke speech impairment, a feeling of dysphagia and suffocation, and noise when pharyngeal and laryngeal muscles are involved. They occur in sleep in 51–80% of cases, and tend to be grouped in clusters with prolonged seizure-free intervals (Dinner and Luders, 2001). The seizures of BECTS are usually easily distinguishable from movement disorders and psychogenic disorders on the basis of the patient’s history, EEG, and response to medication (Luders et al., 1987). The other important and typical characteristic is the activation of epileptic discharges during NREM sleep, with a typical morphology of a triphasic sharp wave of high amplitude localized to the centrotemporal regions, but sometimes with spread to the contralateral hemisphere. In some reports, the ID appears only during sleep, in 2.5–35% of cases (Luders et al., 1987). The spectral analysis of EEG reveals a positive correlation of spike distribution with 18–22-Hz spindle activity (Nobili et al., 1999). Prognosis in BECTS is excellent, with satisfactory response to treatment and remission before 16 years of age in the majority of the patients on discontinuation of AEDs.

Early-onset or late-onset childhood benign epilepsy with occipital paroxysms Benign epilepsy with occipital paroxysms (BEOP), in particular the form defined as early-onset BEOP (Panayiotopoulus, 2002), is a syndrome characterized by partial seizures marked by deviation of the eyes and vomiting. It is the second most frequent benign syndrome of childhood after rolandic epilepsy, which primarily affects 15% of children at a peak onset at age 7–9 years (Panayiotopoulus, 2002). Another epileptic syndrome categorized with BEOP and rolandic epilepsy is the Gastaut-type childhood occipital epilepsy (Gastaut, 1982), manifesting frequent and brief visual seizures. However, this type is rare, of uncertain prognosis, and markedly different from Panayotopoulus syndrome, despite common interictal EEG manifestations of occipital spikes (Panayiotopoulus, 2002). Sleep is the main precipitating factor, with 84% of the seizures occurring soon after the child goes to sleep or in the early hours of the morning. Seizures during sleep frequently evolve to hemiconvulsion and generalized tonic–clonic fits. The EEG has occipital paroxysms of high-amplitude spike waves or sharp waves with shape and amplitude similar to the centrotemporal spikes found in the benign epilepsy with rolandic spikes. Eye closure induces a strong increase of paroxysmal activity, which recurs rhythmically on

1126 M. ZUCCONI posterior areas. Although not so consistently as in consists of synchronized EEG elements such as a BECTS, occipital spikes can be activated by NREM K-complexes, spindles, and delta bursts (Parrino sleep: there is an activating effect of NREM sleep on et al., 2000; Parrino and Terzano, 2001). These oscillainterictal epileptiform discharge (IED) production, tions of sleep and wakefulness (microarousals and and the IEDs reduce to the wakefulness level during microsleep) may be considered a time window during REM sleep. The IED distribution during NREM sleep which IEA may easily appear and modify the sleep is similar to that found in patients with BECTS, in structure (Parrino et al., 2000). It is well known that symptomatic or cryptogenic epileptic children, and in the morphology of IEA varies during sleep; for examLandau–Kleffner syndrome (Nobili et al., 1999). No ple, polyspikes may appear, the bursts of IEA may differences between spike incidence during light sleep become fragmented, and focal and unilateral paroxand deep sleep stages were found. This seems to indiysms may occur. In JME, the IEA may be reduced to cate an independence between the promoting effect a single paroxysm intermingled with the delta activity of IEDs and slow-wave sleep (SWS). A significant corof SWS; otherwise, IEA may increase in the transirelation between IEDs and sigma activity was found tional phases and after awakening (Janz, 1962; Dinner using spectral analysis techniques, but not a correlation and Luders, 2001). with slow-wave activity (SWA), as is found in partial epilepsy of adulthood. This fact suggests that the neural Temporal lobe epilepsy mechanisms underlying spindles also facilitate the proNocturnal temporal lobe epilepsy (TLE) is not a well motion of IEDs. IEDs during sleep are more sensitive defined specific epilepsy but rather includes patients to the promoting action of the spindle-generating mechwith focal seizures that feature automatisms and expeanism of spindle activity than to the SWA-producing riential or sensory components occurring exclusively ones. This mechanism of IED modulation during sleep or predominantly during sleep. Frequently, the partial seems, therefore, an age-dependent phenomenon that seizures are followed by secondary generalization. is not peculiar to either a particular type of epilepsy or These patients have infrequent and nonclustered seiparticular brain region (Nobili et al., 1999). zures, patterns that are rarely familial, a low prevalence of febrile seizures, and a favorable response to surgery Early- and late-onset juvenile myoclonic when seizures are resistant to AED treatment (in up to epilepsy and idiopathic generalized epilepsy 35% of cases) (American Academy of Sleep Medicine, with variable phenotypes 2005). The seizures are characterized by brief periods In both JME and GTCSs, myoclonic and tonic–clonic of impaired consciousness with motionless staring or seizures may arise on awakening, during sleep, and automatisms, and sometimes complex motor activity randomly throughout the day. Myoclonic jerks may such as sleepwalking. A NREM facilitation is found precede GTCSs or predominate in the clinical context for seizures; almost all attacks are activated in stage of a patient with JME. More frequently, myoclonic sei2 NREM sleep and rarely in stage 3–4 NREM sleep zures occur during the early morning, with possible (Crespel et al., 1998). The ictal EEG pattern in nocturnal associated features of absence seizures and GTCSs partial seizures is not characteristically different from (Dinner and Luders, 2001). JME starts in the second the ictal EEG during the wake state. Recently, video-stedecade of life, has a genetic component, a generalized reo-EEG monitoring with intracerebral electrodes paroxysmal discharge pattern, and a positive response showed discharges confined to temporal lobe structures to treatment. Seizures are typical during sleep, in the and clinical features of epileptic nocturnal wandering or transition from sleep to awakening, or upon awakenhyperkinetic seizures, considered to be of frontal lobe ing. In patients with only sleep-related epilepsy, GTCSs origin (Nobili et al., 2004). The involvement of extraare restricted to sleep in the majority of instances, but temporal regions and structures, such as the cingulate 20% of patients may have a diffuse distribution (Janz, and frontal ones, is probably responsible for the similar1962). The characteristic interictal epileptiform activity ity of symptoms between NFLE and TLE in some (IEA) in idiopathic generalized epilepsies (symmetrical patients. In partial epilepsies, the IEA (spikes or sharp spike slow waves or polyspike slow-wave complexes at waves) occur in a localized distribution with an increase 1–4 Hz in frequency) usually increases during NREM in NREM sleep and a decrease in REM sleep. The spike sleep, with prominence at sleep onset, during the first frequency is increased in stage 2 NREM sleep, as well part of the night, and during NREM versus REM state as in stages 3 and 4 NREM sleep compared with REM transition. REM sleep and wakefulness have an inhibisleep, although in some forms of TLE a restriction of tory effect. IEA is associated with phasic arousals and the electrical field of epileptiform activity is reported in particular with the A phase of the CAP, which during REM sleep (Sammaritano et al., 1991). Spectral

SLEEP-RELATED EPILEPSY analysis studies have found that, in TLE, spiking is maximal during the oscillations in delta range present mainly during deep NREM sleep, as a consequence of preceding seizures during years spent with epilepsy (Sammaritano et al., 1991; Clemens et al., 2005). Thus, patients with an earlier onset of epilepsy more frequently show atypical spike distribution patterns with a lower rate in stage 3 and 4 NREM sleep. There are also indications that the spiking rate during REM sleep may be increased in patients with generalized nocturnal seizures (Clemens et al., 2005). The IEA may remain localized, may spread to adjacent areas, and may sometimes become secondarily generalized. Deep electrode recordings have shown maximal spiking rates during NREM sleep and a decrease during REM sleep (Sammaritano, 2001).

Lennox–Gastaut syndrome (tonic seizures) and West syndrome These syndromes refer to seizures and mental disorders characterized by severe diffuse cerebral dysfunction, intractable seizures, and the presence of generalized slow spike and wave complexes in the form of slow spike and wave (2.5 Hz or less) sequences or hypsarrhythmia. The prognosis is poor, and spontaneous remission never occurs. In Lennox–Gastaut syndrome, the tonic seizures are present during sleep (NREM) and are associated with an increase of runs of generalized polyspikes and rhythmic bursts of 10–20 Hz fast activity (Dinner and Luders, 2001). When NREM and REM sleep can be differentiated, in NREM there is also an increase in the quantity of bursts of spike–wave complexes and a decrease in REM sleep (Kellaway et al., 1979). Concerning West syndrome, the infantile spasms tend to occur infrequently during sleep (in 2–5% of cases); EEG abnormalities may be increased in NREM sleep and the hypsarrhythmia pattern may become more apparent during sleep. In some patients, the bursts of spike and slow waves alternate with periods of generalized suppression of the EEG activity in a semiperiodic fashion, like a burst-suppression pattern, attenuated or with a tendency to disappear in REM sleep (Dinner and Luders, 2001).

Continuous spikes-waves during NREM sleep (CSWS) CSWS, formerly known as electrical status epilepticus of sleep (ESES), is characterized by continuous and diffuse slow spike and wave complexes persisting through NREM sleep, epilepsy, and neuropsychological and motor impairment. It is typically found in childhood, and the characteristic pattern consists of

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generalized slow spike and wave discharges occupying 85% of NREM sleep with relative suppression during REM sleep and wakefulness, and persisting on three or more records over a period of at least 1 month. It is now considered an epileptic encephalopathy of childhood consisting of motor impairment, regression of cognitive function, and epilepsy (Tassinari et al., 2001, 2005).

CLINICAL

AND PATHOPHYSIOLOGICAL SUBTYPES

Epilepsy with CSWS has a heterogeneous presentation consisting of various seizure types: generally, focal and motor seizures, but also tonic–clonic seizures, absence and complex partial seizures, or epileptic falls. Seizures generally predate the recognition of CSWS (i.e., they occur between 2 months and 4.5 years of age), are usually nocturnal, and persist with an increase in severity and frequency at the time of recognition of CSWS (Tassinari et al., 2001). Based on the seizure pattern, three types of presentation are recognized: patients with motor seizures only, which are rare and nocturnal (11%); patients with unilateral motor seizures with possible secondary generalization during sleep, in which absence at the time of CSWS has been detected (44%); and patients with rare nocturnal motor seizures, with atypical absence, frequently with atonic or tonic components, developing at the time of CSWS (45%) (Tassinari et al., 1992, 2005). Other types of seizure have been described, but tonic seizures have never been observed, and this may be considered a major feature of the syndrome. Some patients may not have clinically apparent seizures.

AGE

OF ONSET, COURSE, AND COMPLICATIONS

The average age of recognition of CSWS or ESES is around school age (i.e., between 4 and 14 years), but the appearance of the first seizure is early, occurring at between 2 months and 12 years of age (mean 4.5 years). Familial antecedents of epilepsy (including febrile convulsions) have been found in 15% of cases. Genetic factors have not been established and in general seem to play a minor role in CSWS. CSWS disappears in all cases within 3 years of appearance (Tassinari et al., 2001, 2005). Focal abnormalities during sleep may persist. Epilepsy also shows a benign course and responds well to AEDs, with disappearance of all seizures in almost all cases by the mid teens. Despite normalization of EEG and seizures, neuropsychological impairment persists. Neuropsychological dysfunction associated with language, mental, and psychiatric disturbance is considered part of the syndrome, and in about half of the patients may lead to an impairment of intellectual

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M. ZUCCONI

function, memory, and temporospatial orientation (Tassinari et al., 2001). Hyperkinesias, aggressiveness, and sometimes psychotic states may appear. When symptoms appear before CSWS is recognized, patients often show a worsening of their mental state. A recent study with long-term follow-up of children with ESES showed that despite control of seizures with therapy, cognitive dysfunction did not respond to valproate or benzodiazepines. ESES disappeared with puberty (in both CSWS and Landau–Kleffner syndrome), but good cognitive recovery was obtained only in 1 of 10 children, and partial recovery in 4 of 10 children. An unfavorable prognosis of cognitive deterioration seems to be related to a long duration of ESES and/or earlyonset epileptic activity. The earlier the epileptic activity occurs, the greater the functional deficit. Otherwise, behavior normalizes after the disappearance of ESES and is independent of the cognition evolution (Tassinari et al., 1992).

PATHOLOGY

AND PATHOPHYSIOLOGY

Secondary bilateral synchrony is the mechanism generating CSWS. This hypothesis is supported by EEG, intracranial recordings, EEG with coherence computerassisted analysis, and metabolic (PET and SPECT) studies. CSWS associated with Landau–Kleffner syndrome (an acquired epileptic aphasia) is probably secondary to an alteration of function over the temporal area (Kobayashi et al., 1990; Maquet et al., 1990; Hirsch et al., 1994; Morikawa et al., 1995; Tassinari et al., 2001). CSWS could be directly responsible for the appearance of neuropsychological impairment: there is a close temporal association between mental regression and CSWS, a relationship between CSWS duration and the neuropsychological outcome, and an association between patterns of neuropsychological disabilities and the location of the interictal focus. For the motor impairment, there is also an association between the predominant involvement of the motor area and continuous spike and wave activity. Interictal paroxysmal activity may induce prolonged cognitive and motor impairment (Tassinari et al., 2001).

POLYSOMNOGRAPHIC

During CSWS, the abnormalities increase in frequency and sometimes in extension: diffuse spike waves at 2–3 Hz are seen, organized in bursts with or without clinical manifestations. Sometimes cases with relatively focal but continuous discharges, mainly involving temporal or frontal regions, have been described. The discharges are continuous and occupy 85–100% of NREM sleep stages. Sometimes CSWS is diagnosed based on different criteria, even though the spike–wave index is below 85%. Abnormalities arise as soon as patients fall asleep, and disappear on awakening as abruptly as they appeared. Focal paroxysms with frontal predominance may also be observed during the infrequent few seconds of background activity that occur during the fragmented diffuse slow-wave discharges in NREM sleep (Kobayashi et al., 1990; Tassinari et al., 2001, 2005). REM sleep is typically preserved, and the spike– wave index is below 25%, but the frontal predominance of the infrequent bursts may become prominent. In general, EEG patterns during REM sleep are similar to those in awake periods. The sleep structure is normal, but the presence of almost continuous spike and wave discharges makes the recognition of normal sleep EEG elements such as K-complexes, spindles, or vertex sharp transients difficult (Tassinari et al., 2001). Routine daytime EEG recordings can show bursts of generalized spike and slow wave discharges, often associated with focal spikes or spikes and waves, involving the frontotemporal and centrotemporal regions. Neuropsychological tests are important in determining the type and extent of cognitive and mental impairment. Neuroimaging (in particular PET and SPECT) may be useful in correlating neuropsychological dysfunction with an altered metabolism in the frontotemporal areas (Maquet et al., 1990; Mourisden et al., 1993; Morikawa et al., 1995).

DIFFERENTIAL

DIAGNOSIS

The differential diagnosis is concerned with other epileptic syndromes with a marked activation of epileptic paroxysms during sleep. Landau–Kleffner syndrome

AND OTHER OBJECTIVE

FINDINGS

Before the recognition of CSWS, EEG and PSG recordings showed interictal abnormalities (focal and diffuse) during sleep such as 2–2.5-Hz spike and slow wave complexes and focal spikes. Sleep structure including NREM–REM cycling and percentages of NREM and REM sleep stages are normal (Tassinari et al., 2001, 2005).

The main characteristic of the syndrome is acquired aphasia or “developmental dysphasia”. There are many similarities between CSWS and Landau–Kleffner syndrome, but also some differences; for example, not all patients with Landau–Kleffner syndrome have the same EEG paroxysms during sleep, and the majority of patients with CSWS have no evidence of language dysfunction. However, the two syndromes are now considered to be two different aspects of the same

SLEEP-RELATED EPILEPSY 1129 entity, in which the type of the neuropsychological dysapproach for behavioral problems, with adequate function depends on the location of the discharges counseling and parental guidance. When AEDs are (frontal in CSWS and temporal in Landau–Kleffner ineffective, a further attempt with corticosteroids or syndrome). intravenous immunoglobulins can be considered. Lennox–Gastaut syndrome Because of the presence of atypical absence, falling seizures, and mental retardation, CSWS may be similar to Lennox–Gastaut syndrome. However, in Lennox– Gastaut syndrome the spike and wave activation during sleep is less marked (not more that 50%), and tonic seizures are typical, which are never observed in CSWS. Moreover, polyspikes and waves and bursts of fast activities, which are observed in Lennox–Gastaut syndrome, are not observed in CSWS. Benign epilepsy of childhood with centrotemporal spikes Generally, sleep enhances the discharges in BECTS, but these discharges are not present during 85% of NREM sleep, unlike the discharges seen in CSWS. CSWS has been described in patients with BECTS (atypical BECTS), accompanied by neurocognitive and motor dysfunction, and the term “typical CSWS with epilepsy” has been used. The localization of discharges is frontocentral in CSWS and characteristically centrotemporal in BECTS. Neuropsychological deterioration is generally absent in BECTS. A familial pattern of occurrence is frequent in BECTS but rare in CSWS. Finally, signs of encephalopathy are rare in BECTS and common in CSWS. Atypical benign partial epilepsy The clinical features of atypical benign partial epilepsy are very similar to those of CSWS, but without intellectual deterioration. The activation of paroxysms is important, but not present in up to 85% of NREM sleep, and no duration of the EEG pattern during sleep has been mentioned.

TREATMENT Valproate and/or benzodiazepines such as clonazepam and clobazam are the treatments of choice, with positive response in CSWS. Other treatments of EEG abnormalities include corticosteroids, adrenocorticotropic hormone, ethosuximide, clomipramine, and amphetamine. Other drugs such as carbamazepine, phenytoin, and phenobarbital have been shown to fail. Also, seizures, when present, are generally responsive to AEDs. The effects of AEDs on cognitive function are generally disappointing. It is important to start the treatment rapidly and to consider a psychological

EFFECT OF EPILEPTIC PHENOMENA ON SLEEP That nocturnal seizures disrupt sleep structure is a well known concept, as is the improvement in sleep efficiency and sleep architecture seen with treatment of seizures. Less known is the effect of epilepsy per se (also during nights without seizures) on sleep. The works of Touchon et al. (1987) have shown sleep architecture fragmentation, at least for temporal epilepsy, supporting a hypothesis that the presence of epilepsy per se, not just the occurrence of seizures or the effects of AEDs, predisposes a patient to sleep disruption. However, during nights with seizures, a significant decrease in sleep efficiency and REM sleep, and an increase in stage 1 NREM sleep in respect to seizure-free nights, more pronounced when seizures occur early in the night, have been demonstrated. Considering the immediate effects of an epileptic attack, we can expect at least an arousal or brief awakening with a more superficial sleep that follows, and, depending on the number of epileptic attacks, an increase in sleep fragmentation, wake after sleep onset (WASO), and stage 1–2 NREM sleep with a decrease of stage 3–4 NREM and REM sleep (Crespel et al., 1998). Moreover, sleep may be instable and fragmented, without seizures but with the presence of IDs; in general, sleep-related attacks mostly affect the sleep macrostructure parameters, whereas nocturnal interictal abnormalities have an effect on sleep microstructure with an increase in the instability of the CAP (Touchon et al., 1987). CAP is increased in generalized epilepsy also in the absence of nocturnal seizures and with classical sleep parameters unchanged (Terzano et al., 1981; Gigli et al., 1992). In patients with NFLE, when daytime sleep complaints such as sleepiness and tiredness are present, an enhanced degree of unstable sleep, expressed by an increase in CAP rate, has been demonstrated in comparison with that in patients with NFLE without daytime symptoms and in controls (Zucconi et al., 2000). These data are particularly significant if we consider that all the patients and controls had no significant difference in sleep macrostructure. The majority of episodes occur during phase A of the CAP cycle, confirming the modulator and gating functions as activating properties of this phase (mainly subtypes A1, the more desynchronized phases A with mostly rapid EEG waves). In patients with NFLE, apart from major seizures, the high number of minor motor

1130 M. ZUCCONI events lasting 2–4 seconds is related to the CAP epileptic abnormalities (Gloor, 1978). The spike and phases, with an increase in sleep instability expressed wave activity is triggered by the slow cortical oscillaby the high values of the CAP rate (Terzano et al., tion, which disappears after decortication and survives 1997; Zucconi et al., 2000). Not only minor or minimal after thalamectomy (Steriade and Contreras, 1995). At events have a destabilizing effect on sleep; in addition, the same time, it has been suggested that SWAs may the occurrence of epileptic discharges, when periodic, also trigger epileptic discharges in some forms of epimay play a major role in the mechanisms inducing lepsy, manifesting as focal temporal lobe epilepsy or arousal instability: interictal discharges could act as a Lennox–Gastaut syndrome (Malow et al., 1998; Eisennonspecific internal trigger able to act directly on the sehr et al., 2001). Slow oscillations probably play a role arousal mechanisms operating during sleep (Terzano in the control of cortical excitability, but the presence et al., 1997). A recent description of a drug-resistant of a great amount of epileptic activity in light NREM NFLE case, recorded with intracerebral electrodes, sleep (where slow activity is scarcely represented) indishowing subcontinuous and periodically recurrent cates that other mechanisms such as infraslow oscillaepileptic discharges (without scalp EEG evidence of tions are implicated (Vanhatalo et al., 2004). epileptic abnormalities), and mostly linked to the Infraslow or ultraslow oscillations (0.025 Hz) have A phases of the CAP, gave power to this possible recently been observed to modulate excitability and mechanism (Nobili et al., 2006). IEA in the human cortex during sleep (Penttonen et al., 1999). These infraslow oscillations coincide with an alternation of states (fluctuation of the synaptic MODULATION OF SLEEP release at the cortical level which powerfully entrains MICROSTRUCTURE ON INTERICTAL thalamic neurons) expressed in the scalp EEG by the EPILEPTIC DISCHARGES AND SEIZURES CAP, oscillations of different rhythms as a conseAccording to the historical perspective of seizures and quence of the interaction of different physiological sleep, Janz (1962) classified them in waking epilepsies, subsystems, and also other polygraphic features (elecsleep epilepsies, and diffuse epilepsies, with the result trocardiography, blood pressure, motor activity, and that most of the epileptic syndromes may be grouped behavior). This alternation of specific transient EEG into sleep and diffuse epilepsies. Besides this, the relaactivity (phase A) and of a rebound deactivation tionship between single specific elements of the sleep EEG/polygraphic activity (phase B) means oscillation structure, microstructural organization of sleep, and between greater arousal (phase A) and lesser arousal seizures/interictal epileptic activity has recently been (phase B). In opposition to this unstable state of EEG studied and analyzed in different ways (Parrino and activation, the absence of CAP reflects a condition of Terzano, 2001). stable consolidated sleep with a great stability of the Ictal and interictal discharges are definitely more process (Parrino and Terzano, 2001). frequent in NREM than they are in REM sleep, in Regarding the activation effect on EEG epileptic sleep stage changes, or during the transition from discharges, the enhancement is caused by the activating NREM to REM sleep. Both in animal models and in properties of phase A (mainly A1 subtypes with slow human epilepsy, discharges and seizures are influenced activity), whereas phase B exerts a powerful and proby a rapid shift of EEG synchrony and are thought to longed inhibitory action (Terzano et al., 1989). The actirepresent a pathological cortical response to afferent vation property is not similar in all CAP sequences: it thalamocortical volleys, normally involved in spindling. depends on the branch of the buildup process of EEG The close relationship between spikes, polyspikes, synchrony. Terzano et al. (2000) showed the highest spike and wave complexes, and K-complexes or spindischarge rate in the descending branch of the sleep dles confirmed that a common basic mechanism and process (from light NREM to deep NREM sleep) in transmission circuitry may be shared by epileptic patients with primary generalized epilepsy, compared phenomena and the normal phasic events of sleep with the trough and the ascending slope progressing (Passouant et al., 1962; Niedermeyer, 1965; Nobili toward REM sleep. Most of the epileptic abnormalities et al., 2001). According to Steriade and Amzica occurred during a CAP sequence and, inside the cycle, (1998), epileptic discharges are driven by slow cortical within the phase A (A1 subtypes). This means that disoscillation (less than 1 Hz), similar to the frequency charges depend largely on slow EEG waves and, as of K-complexes, becoming as recurrent and periodic well as occupying the A1 phases, they tend to occupy as the phasic events of sleep. According to the Gloor the slow portion of A2 and A3 phases (almost always hypothesis, the generalized spike and wave discharges starting with a K-complex or a delta burst). The same utilize the same circuits that generate sleep spindles, activating effect of the CAP sequence (A phase) has with cortical transformation of the spindle waves in been described for focal frontal and temporal

SLEEP-RELATED EPILEPSY epilepsies (Parrino et al., 2000). In contrast, in BECTS, rolandic spikes seem to be modulated by sigma activities of sleep spindles (Nobili et al., 1999, 2001). Sleep instability also facilitates ictal phenomena, and also IEs (i.e., focal seizures of both temporal and frontal origin) appear to be modulated by CAP (Terzano et al., 1991, 1997; Arunkumar et al., 1997; Parrino et al., 2006) and related to phase A, confirming that seizure manifestations are strictly connected to fluctuations of arousals. The particular relationship between frontal lobe seizures and the EEG synchronized pattern of phase A (A1 and the starting part of A2 sequences) seems to be due to the prevalence over the prefrontal and frontal regions for the slow EEG band frequency (0.25–2.5 Hz) source, as demonstrated by Ferri et al. (2005). These findings suggest a causal relationship between NFLE and microstructure oscillations during sleep.

EFFECT OF SLEEP DEPRIVATION Since the second half of the 20th century, the activating effect of sleep deprivation on IEs and IDs (Rodin et al., 1962; Bennet, 1963) has been well known. Depending on the conditions (complete or partial sleep loss), the age of the subject, and the duration of the recording, the activation with sleep deprivation has very few false positives (1.2–2.2%) (Kotagal, 2001). The advantage of sleep deprivation compared with drug-induced sleep has not been proven. However, recent papers considered the EEG after sleep deprivation to be more activated (Rowan et al., 1982; Aguglia et al., 1994). Moreover, in children, EEGs after sleep deprivation are more activated than they are in adolescents or young adults (Degen, 1980). It is important for a wake EEG to be followed by an adequate period of sleep, because IDs following sleep deprivation are more frequent in sleep than in wakefulness (El Ad et al., 1994). Generally, with sleep deprivation, the percentage of clinical seizures in persons with no prior history of seizures is very low (2.4%) (Rodin et al., 1962; Bennet, 1963; Ellingson et al., 1984), and the risk of seizures is higher within 48 hours of sleep deprivation, considering some factors such as physical or emotional stress, fatigue, and alcohol or substance use (Kotagal, 2001). Sleep deprivation may also affect the morphology of the seizures, leading to more intense and prolonged attacks and to clonic and secondary generalized seizures, allowing the onset of the seizure to lateralize in presurgical evaluation (Benbadis et al., 1995; Kotagal, 2001). Recent findings contrast with the theory that sleep deprivation is a powerful activating agent for both IDs and IEs, reporting that acute sleep deprivation (24 hours) does not affect seizure frequency in

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patients with intractable complex partial seizures and secondary generalization (Malow et al., 2002). However, at least for some forms of epilepsy (JME and generalized seizures at awakening), the clinical evidence of activation from sleep deprivation is well known, probably on the basis of increased cortical and corticospinal excitability in the motor area, as documented by transcranial magnetic stimulation in comparison with nonepileptic control subjects (Manganotti et al., 2006). It is otherwise true that most of the studies including sleep deprivation have been clinical and observational in nature, and studies on animals did not separate the effect of sleep deprivation per se from the stress effect (Malow, 2004). The association of sleep deprivation with physical, mental, and emotional stress makes things complicated, and it is difficult to extrapolate the real and relative contribution of sleep deprivation in the activation of IDs and IEs. However, it is certain that sleep deprivation may be useful in getting epileptic patients to sleep when sleep on demand is needed for undertaking special procedures such as ictal SPECT, PET, postictal magnetic resonance spectroscopy, or diffusion-weighted MRI, and transcranial magnetic stimulation.

EFFECT OF SLEEP DISORDERS Sleep disorders may coexist with epilepsy, and different groups have found this relationship to be more than casual (Foldvary, 2001; Parrino et al., 2006). In particular, some sleep disorders, such as obstructive sleep apnea syndrome (OSAS), periodic limb movements during sleep (PLMS), REM sleep behavior disorder (RBD), and narcolepsy, may contribute to the challenge not only of diagnosis but also of treatment of seizures during sleep. The more frequent comorbidity in sleep epilepsies is OSAS: the coexistence of the two syndromes ranges between 10% and 30% in different case series (Malow et al., 2000; Foldvary, 2001). In general, patients with epilepsy and OSAS are older, sleepier, heavier, and more frequently male than are non-OSAS epileptic patients. Moreover, they frequently have seizures during sleep. OSAS is sometimes underdiagnosed in these epileptic patients, but by means of polysomnography or cardiorespiratory monitoring it has been proven to be quite common in old men. Another interesting feature is that the start of seizures in old age seems to be related to the comorbidity of OSAS. Therefore, it is important from a clinical and practice point of view to exclude or confirm OSAS by clinical interview and instrument examinations in these categories of epileptic patients (Manni et al., 2003). PLMS are frequent in epilepsy, showing up in 30% of 50 epileptic patients

1132 M. ZUCCONI screened by PSG (Beran et al., 1999; American Acadfragment sleep, but it also increases SWS, whereas emy of Sleep Medicine, 2005), and they may be related in epileptic patients it reduces the duration of REM to sleep fragmentation. RBD may coexist in old epilepsleep and increases REM sleep fragmentation. Other tic patients, and for RBD diagnosis by video-PSG an data do not confirm these findings, demonstrating epileptic disorder has to be excluded (American Acadthe absence of effects on epileptics or shorter sleep emy of Sleep Medicine, 2005). cycle duration in normal subjects (Yang et al., 1989; Regarding the mechanisms by which sleep disorders Gigli et al., 1997; Placidi et al., 2000a), and long-term may worsen epilepsy, and nocturnal seizures in partictreatment seems not to cause significant modificaular, chronic sleep deprivation and fragmentation, noctions of nocturnal sleep and daytime sleepiness turnal hypoxemia, and arousal-linked activation of IEs (Ellingson et al., 1984; Aguglia et al., 1994). Primidone and IDs play a combined role, in particular in OSAS. produces an increase in SWS and a decrease in REM Improvement in control of seizures, during both the sleep and sleep latency. Among the older drugs, valnight and the day, have been described with treatment proic acid has been studied extensively in both normal of OSAS by continuous positive airway pressure subjects and epileptics: a reduction of REM sleep per(Vaughn et al., 1996; Malow et al., 1997). Drug treatcentage and an increase in SWS in controls, and an ment of PLMS or restless leg syndrome associated increase in stage 1 NREM sleep and a slight reduction with gabapentin or clonazepam may be considered a or no alteration of stage 2 NREM and REM sleep in reasonable choice, as well as treatment of RBD in patients, has been found (Declerck and Wauquier, patients with concomitant RBD. 1991; Manni et al., 1993; Placidi et al., 2000a, c). Concerning the new AEDs, their effect on sleep structure is less impressive and of more importance, EFFECT OF ANTIEPILEPTIC daytime sleepiness is less frequently reported to be DRUGS ON SLEEP associated with their use. Levetiracetam produces an Sleepiness and sedation are the most common sideincrease in NREM sleep (both stages 2 and 3–4 effects of AEDs in patients with epilepsy. However, NREM) in both healthy subjects and patients, with before giving all the responsibility for such side-effects a significant increase in total sleep time and sleep to drugs, one should exclude their concomitance with efficiency and a significant decrease in WASO and other sleep disorders that have potential daytime sleepnumber of stage shifts (Bell et al., 2002; Cicolin iness effects. Moreover, AEDs may improve daytime et al., 2006). Moreover, no changes in Epworth Sleepivigilance in patients with sleep-related seizures, ness Scale or Multiple Sleep Latency Test scores have reducing IEs and IDs, and, as described in the section been reported. An increase in SWS and sleep efficiency on the effect of seizures on the microstructure of has also been reported for tiagabine and gaboxadol, sleep, ameliorate sleep instability and fragmentation two GABA agonists (Faulhaber et al., 1997; Mathias during the night sleep. et al., 2001) that act on the GABA type A receptor difThe choice of the correct AED, considering the posferently from benzodiazepines or other modulators. sible concomitant sleep disorders, is another issue. Gabapentin and pregabalin, acting on a different subAEDs with sedating properties (such as valproate, leveunit of the calcium channel, also produce an increase tiracetam, or gabapentin) may be useful for patients in SWS and sleep efficiency, with no effect on REM with insomnia, whereas AEDs with stimulating propersleep duration but with a slight reduction in the REM ties (such as lamotrigine) may be useful in patients sleep percentage in relation to the total sleep time (Folcomplaining of daytime sleepiness. Valproate or other vary-Schaefer et al., 2002; Hindmarch et al., 2005). In AEDs that promote weight gain may not be indicated chronic drug-resistant epileptic patients, gabapentin in patients with respiratory disturbances during sleep showed an increase in REM sleep and SWS associated (for the contribution made to the increase in obstrucwith a reduction in stage 1 NREM sleep and the numtion), and other new AEDs such as topiramate or ber of awakenings (Placidi et al., 2000a). The effect oxcarbazepine may be more useful. of an increase in the duration of NREM episodes and AEDs determine different effects and alterations the delta power band of frequency, but with a signifiin sleep architecture. Older drugs such as phenobarbicant decrease in REM sleep, has also been shown in tal and phenytoin shorten sleep latency, but phenobaranimals, at least for pregabalin (Kubota et al., 2001). bital reduces REM sleep, increasing stage 2 NREM Lamotrigine may decrease REM sleep and increase sleep, whereas phenytoin reduces stage 1–2 NREM wakefulness in rats (Bertorelli et al., 1996), while as sleep, increasing stage 3–4 NREM sleep and possibly an add-on in drug-resistant epileptics it resulted in an decreasing REM sleep (Yang et al., 1989; Bazil, increase in REM sleep with a decrease in SWS and 2003). Carbamazepine in normal subjects seems to substantial preservation of other sleep parameters

SLEEP-RELATED EPILEPSY (Placidi et al., 2000b). Data are scarce regarding the effect of other AEDs such as felbamate, tiagabine, and topiramate on sleep structure; only for felbamate has a substantial modification of sleep parameters in rats been shown (Placidi et al., 2000a). Summarizing these observations, it could be stated that AEDs may have important and sometimes detrimental effects on sleep structure, but the effects of stabilizing sleep and reducing ictal and interictal events have a substantial positive effect on the sleep of epileptic patients. The new AEDs, with possible different mechanisms, including the enhancement of the GABAergic system, have in general positive effects on sleep or, at least, no significant detrimental activities on sleep structure. Analyses of sleep microstructure (considering CAP and SWA in the function of the sleep cycles) and analyses of the effect of new AEDs on daytime alertness (by means of the Multiple Sleep Latency Test or Maintenance Wakefulness Test) should be added to classical sleep analysis when testing the effect of a new AED on normal subjects or in patients.

OVERVIEW AND GENERAL STATEMENTS There is a reciprocal relationship between sleep and epilepsy, with sleep and sleep disorders affecting seizures and IDs, and seizures and IDs during sleep affecting sleep itself, modifying sleep microstructures more than they do the classical sleep architecture. The proportion of patients who have seizures occurring either exclusively or predominantly during sleep range between 7.5% and 45% (Sammaritano, 2001). When seizures remain stable (nocturnal) for at least 6 months, they are very likely to remain nocturnal over time. Moreover, seizures entrained to a specific sleep–wake rhythm or state (sleep/arousal) usually respond better to treatment than do randomly timed seizures (Shouse et al., 1996). Both focal frontal and temporal seizures may occur during sleep, but frontal lobe seizures are more frequent (Crespel et al., 1998). In contrast, temporal seizures that occur during sleep show secondary generalization more frequently than do frontal seizures (Bazil and Walczak, 1997). NREM sleep allows the propagation of IDs, both focal and generalized spikes, recorded as an extension of an electrical field with maximal spiking rates (in focal epilepsies) during deeper stages of sleep (stage 3–4 NREM), and REM sleep shows a suppression or focalization of IDs as a restriction of an electrical field (Rowan et al., 1982; Rossi et al., 1984; Montplaisir et al., 1987; Sammaritano, 2001). Usually, more spiking

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foci are seen in NREM than in REM sleep, where foci are usual unilateral (Sammaritano et al., 1991). The mechanisms involved in the close relationship between sleep and seizures include NREM synchronization of the EEG waves, arousal and awakening from sleep, microstructure oscillation and regulation, circadian and ultradian factors influencing sleep– wake rhythms, and anatomical localization of the epileptogenic zone.

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Velasco M, Velasco F (1982). Brainstem regulation of cortical and motor excitability: effects on experimental focal motor seizures. In: MB Sterman, MN Shouse, P Passounant (Eds.), Sleep and Epilepsy. Academic Press, New York, pp. 53–61. Vigevano F, Fusco L (1993). Hypnic tonic postural seizures in healthy children provide evidence for a partial epileptic syndrome of frontal lobe origin. Epilepsia 34: 110–119. Willoughby JO, Pope KJ, Eaton V (2003). Nicotine as an antiepileptic agent in ADNFLE: an N-of-one study. Epilepsia 44: 1238–1240. Yang JD, Elphick M, Sharpley AL et al. (1989). Effects of carbamazepine on sleep in healthy volunteers. Biol Psychiatry 26: 324–328. Zucconi M, Ferini-Strambi L (2000). NREM parasomnias: arousal disorders and differentiation from nocturnal frontal lobe epilepsy. Clin Neurophysiol 111: S129–S135. Zucconi M, Oldani A, Ferini-Strambi L et al. (1997). Nocturnal paroxysmal arousals with motor behaviors during sleep: frontal lobe epilepsy or parasomnia? J Clin Neurophysiol 14: 513–522. Zucconi M, Oldani A, Bizzozero D et al. (2000). The macrostructure and microstructure of sleep in patients with autosomal dominant nocturnal frontal lobe epilepsy. J Clin Neurophysiol 17: 77–86.

Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 66

Sleep disorders in multiple sclerosis LUIGI FERINI-STRAMBI * Sleep Disorders Center, Università Vita-Salute San Raffaele, Milan, Italy

INTRODUCTION Sleep disorders are common, although clinically underrecognized, in patients with multiple sclerosis (MS). Approximately half of all patients with MS report sleep-related problems (Tachibana et al., 1994; Figved et al., 2005). Some physical and psychological factors such as pain, anxiety and mood disorders, sleepdisordered breathing, and nocturnal discomfort may all contribute to sleep disturbances. Common sleep disorders in patients with MS include insomnia, sleep apnea, restless legs syndrome (RLS), narcolepsy, and rapid eye movement (REM)-sleep behavior disorder (RBD). Disrupted sleep leads to daytime somnolence, increased fatigue, worsening depression, and a lowered pain threshold (Saunders et al., 1991; Achiron et al., 1995). In a recent cross-sectional epidemiological survey, Patel et al (2006) evaluated 60,028 middle-aged women who reported a habitual sleep duration of 7 hours or more. MS was the factor most strongly associated with prolonged sleep (odds ratio 3.7, 95% confidence interval 3.0 to 4.5). An increased clinical awareness of sleep-related problems is warranted in MS population because they are extremely common and have the potential to impact negatively on overall health and quality of life. As reported recently by Attarian (2009), getting a good nocturnal sleep may not cure or even improve the neurological damage of MS, but it would certainly help patients face it with a better outlook and give them a better chance at a fuller life.

INSOMNIA IN MULTIPLE SCLEROSIS Insomnia is a widespread complaint, estimated to affect at least 10% of the adult population (Ohayon, 2002). It is characterized by difficulty falling asleep, difficulty maintaining sleep, or waking up sooner than

desired, or by a nonrestorative sleep. More than 50% of patients with MS complain of sleep-related problems, and 40% have insomnia with difficulty initiating or maintaining sleep (Fleming and Pollack, 2005). Causes of insomnia common in the MS population include pain associated with muscle spasms, periodic limb movements, RLS, nocturia, medication effect, and psychiatric illness such as depression. Chronic insomnia can also predispose an individual to the development of major depression (Breslau et al., 1996). In patients with MS, sleep difficulties have been shown to be associated with the yearly exacerbation rate and with disease severity (Achiron et al., 1995). Long-term treatment of insomnia is best directed toward addressing the underlying cause.

Pain Pain is a common complaint, but often underrecognized, in patients with MS. More than 50% of patients with MS describe pain as a significant problem (RaeGrant et al., 1999). In a large study that examined 364 patients with MS (Osterberg et al., 2005), 57.5% reported pain during the course of their disease (21% nociceptive, 2% peripheral neuropathic, and 1% related to spasticity); 27.5% had central pain. It has been reported that chronic pain in MS is not significantly related to age, disease duration, or disease course, but correlates with aspects of health-related quality of life (Kalia and O’Connor, 2005). Pain has the potential to disrupt sleep, causing daytime somnolence, worsening fatigue, and a lower pain threshold (Onen et al., 2001). Indeed, the presence of chronic pain can be associated with a vicious cycle pattern. A day with intense pain may be followed by a night of poor sleep quality, and a night of poor sleep may increase pain the next day.

*Correspondence to: Luigi Ferini-Strambi, M.D., Department of Neuroscience, Universita` Vita-Salute San Raffaele, Via Stamira d’ Ancona 20, 20127 Milano, Italy. Tel: þ39 02 2643 3363, Fax: þ39 02 2643 3394, E-mail: [email protected]

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Treatment options include medications such as gabapentin, which has been shown to improve nocturnal pain and promote restorative sleep (Solaro et al., 2000). Other medication options include carbamazepine and pharmacotherapy directed at treating muscle spasticity (baclofen, dantrolene, tizanidine, botulinum toxin, diazepam). It has been observed recently that cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with MS who have central neuropathic pain (Rog et al., 2005).

Nocturia Bladder dysfunction is a common problem for patients with MS. The severity of symptoms often correlates with the degree of spinal cord involvement, and hence the patient’s general level of disability (Kalsi and Fowler, 2005). Nocturia or urinary incontinence affects 70–80% of patients with MS (Amarenco et al., 1995). Spasticity or involuntary contraction of the bladder causing nocturia and incontinence can cause frequent awakenings and sleep fragmentation (Fleming and Pollack, 2005). Leo et al (1991) surveyed 47 patients with MS and 63 matched controls. Correlational analyses demonstrated an increased frequency of nocturnal awakenings, prolonged sleep latency, and early morning awakenings caused by bladder spasticity in these patients. Moreover, increased nocturnal awakenings were associated with increased daytime fatigue. In addition to frequent awakenings and fragmented sleep, nocturia may also impose an extreme demand on caregivers and may lead to early institutionalization (Nuotio et al., 2003). Awareness and treatment of this sometimes underrecognized cause of sleep disruption may lead to significant improvements in the quality of life of patients with MS. Treatment options for nocturnal bladder spasticity include fluid restriction, intermittent catheterization, anticholinergic agents such as propantheline or oxybutynin, and the hormone desmopressin (Valiquette et al., 1996). A recent study evaluated the use of botulinumA toxin injections into the bladder as an alternative approach in patients with MS with drug-refractory overactive bladder symptoms (Schulte-Baukloh et al., 2006). At 4 weeks, and 3 and 6 months after the injection, nocturia diminished by 33%, 72%, and 40% respectively.

Depression The association between MS and depression has been well established. The lifetime prevalence of major depression in patients with MS is as high as 50.3% – three times the prevalence reported for major

depression and psychiatric comorbidity in the general population (Sadovnick et al., 1996). McGuigan and Hutchinson (2006) performed a study to assess the point prevalence of previously unrecognized symptoms of depression in a community-based population with MS. They found that one in four patients had unrecognized and therefore untreated symptoms of depression. These data are consistent with the findings of another recent study (Mohr et al., 2006) that evaluated 260 patients with MS and found that 25.8% had major depressive disorder; some 65.6% of these depressed patients received no antidepressant medication, and 4.7% received subthreshold doses. Depression in patients with MS has a complex and multifactorial pathogenesis, including the psychosocial impact of a chronic, usually progressive, disabling illness, cerebral demyelination, lack of family support, and the possible depressogenic effects of drugs such as corticosteroids and interferon (Feinstein et al., 1992; Goeb et al., 2006). Depression has the potential to cause insomnia, leading to excessive daytime somnolence and worsening fatigue. Early recognition and treatment can prevent psychiatric sequelae and improve sleep and the overall quality of life (Fruehwald et al., 2001). Treatment options for patients with depression and MS include psychotherapy and medications such as the selective serotonin reuptake inhibitors, tricyclic antidepressants, and nontricyclic antidepressants. However, it should be borne in mind that several studies have found antidepressant use to be associated with increased periodic limb movements in sleep (PLMS), a possible cause of sleep fragmentation (Picchietti and Winkelman, 2005).

Nocturnal movement disorders The incidence of PLMS and RLS is higher in patients with MS than in the general population (Ferini-Strambi et al., 1994; Despault-Duquette et al., 2002). RLS is characterized by uncomfortable and unpleasant sensations in the legs, that are relieved by movement (Tachibana et al., 1994). According to the recently revised diagnostic criteria, RLS is a clinical diagnosis; the four minimal criteria for the diagnosis of RLS are: (1) a desire to move the legs associated with a sensory discomfort; (2) a motor restlessness that consists of moving; (3) leg discomfort occurring predominantly at rest with at least temporary relief of discomfort occurring with movement; and (4) leg discomfort that is worse in the evening and at night. RLS can lead to severe sleep disruption, with daytime fatigue and other functional consequences (Montplaisir et al., 2005). The patients may feel forced to get out of bed several times during the night to walk or engage in other physical

SLEEP DISORDERS IN MULTIPLE SCLEROSIS activities, in order to relieve discomfort or pain. Moreover, PLMS occur in more than 80% of patients with RLS. PLMS have the ability to awake the patient or to cause brief arousals, resulting in unrefreshing sleep (Montplaisir et al., 2005). In the general population, conservative estimates report RLS as affecting between 5% and 15% (Montplaisir et al., 2005) and PLMS as affecting 5% between the ages of 30 and 50 years (Coleman et al., 1988). In patients with MS, the incidence of PLMS is reported to be as high as 36% (Ferini-Strambi et al., 1994). RLS is also reported to be more prevalent than in the general population. Despault-Duquette et al. (2002) found that 32 of 100 patients with MS had RLS. Another study (Manconi et al., 2008b) estimated the prevalence of RLS in 82 patients with MS, and compared the neurological damage in patients with and without RLS using conventional and diffusion tensor magnetic resonance imaging MRI. Thirty patients were affected by RLS. Patients affected by RLS showed a higher disability according to the Expanded Disability Status Scale (EDSS) score than patients without RLS. No difference between the two groups was found in whole brain, cerebellar and brainstem T2 lesion loads, or T2 lesion loads of the two cerebral and cerebellar hemispheres when considered separately. Among the MRI metrics analyzed, cervical cord fractional anisotropy was significantly reduced in patients with RLS compared with that in patients with MS without RLS, suggesting that cervical cord damage might represent a significant risk factor for RLS among patients with MS. Previous studies have already reported a relation between cord involvement caused by different pathologies (e.g., intramedullary lesions, schwannoma, MS) and RLS and/or PLMS (Yokota et al., 1991; de Mello et al., 1999; Hartmann et al., 1999; Winkelmann et al., 2000; Lee et al., 2005). A possible explanation is that cord damage may interrupt descending or ascending pathways, resulting in a brain–spinal cord disconnection, which in turn leads to the appearance of RLS. The hypothesis that an impairment of a descending cerebrospinal inhibitory pathway could lead to a higher spinal motor excitability in patients with RLS is indeed supported by clinical and neurophysiological studies (Bara-Jimenez et al., 2000; Provini et al., 2001). A possible target of the spinal lesion could be represented by the dopaminergic descending neurons projecting from the A11 hypothalamic area to D3 receptors located in the dorsal and intermediolateralis spinal nuclei (Ondo et al., 2000). Several findings support the notion that this nerve pathway is central in RLS genesis: the A11 area receives a diffuse innervation from the suprachiasmatic nucleus, which is the main physiological

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drive for the circadian rhythm; the artificial lesion of A11, as well the systemic administration of selective D3 antagonists, increases locomotor activity in rats; knockout mice for D3 receptors exhibit hyperactivity; and D3 agonists are the first-choice drugs in RLS (Ondo et al., 2000; Leriche et al., 2003). Moreover, the hypothesis that the spinal lesion related to RLS is a consequence of ascending pathway damage cannot be excluded. The RLS may indeed be the result of a central somatosensory processing dysfunction due to an abnormal peripheral afferent input (Schattschneider et al., 2004). Some recent epidemiological studies have suggested that MS-related RLS should be considered among the symptomatic RLS forms secondary to neurological disorders, and it should be always investigated in patients with MS. Table 66.1 shows all published epidemiological studies of RLS in the MS population. The highest prevalence of RLS was reported in the first paper by Auger et al. (2005), which evaluated 200 FrenchCanadian patients and found RLS in 37.5% of patients with MS and 16% of controls. The age at onset of MS was 31 years, and the age at onset of RLS was 35 years. High prevalence of RLS has been confirmed in the majority of the other epidemiological studies (Gomez-Choco et al., 2007; Manconi et al., 2007, 2008a, b; Moreira et al., 2008; Deriu et al., 2009; Douay et al., 2009). Treatment options for RLS and PLMS are similar and include dopaminergic agents (levodopa/carbidopa, pramipexole, ropinirole), anticonvulsants (gabapentin, clonazepam), and opioids. These compounds should be considered for the treatment of RLS and PLMS in patients with MS.

Medication Immunomodulating therapy for the treatment of MS has been associated with hypersomnolence, increasing fatigue, depression, and insomnia. In patients with relapsing MS, 5% of those treated with interferon b-1a three times a week in one series had hypersomnolence, compared with 1% of controls (Fleming and Pollack, 2005). In another study (Huber et al., 1996), 3–17% of patients treated with interferon b-1b for 1 month had insomnia and described fatigue as a common (33%) side-effect. Corticosteroids are widely believed to disrupt sleep. The most consistent effect of corticosteroids on polysomnographic data in normal subjects is a marked decrease in REM sleep (Born et al., 1987). Approximately 50% of patients treated with prednisone for optic neuritis reported sleep disturbance, compared with 20% on placebo (Chrousos et al., 1993). Preliminary data (Antonijevic and Steiger, 2003)

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Table 66.1 Epidemiological studies of restless legs syndrome in multiple sclerosis RLS prevalence rate (%)* Reference

Country

MS

Controls

Odds ratio

Risk factors associated with RLS

Auger et al., 2005 Manconi et al., 2007

Canada Italy

37.5 (200) 32.7 (156)

16 (100) N/A

N/A N/A

Gomez-Choco et al., 2007 Manconi et al., 2008b

Spain Italy

13.3 (135) 36.5 (82)

9.3 (118) N/A

1.49 N/A

Manconi et al., 2008a

Italy

19 (861)

4.2 (649)

5.4

Moreira et al., 2008 Douay et al., 2009 Deriu et al., 2009

Brazil France Italy

27 (44) 18 (242) 14.4 (202)

N/A N/A 2.8 (212)

N/A N/A 5.76

None Age, disability, familiality for RLS, insomnia, leg jerks None Age, gender, disability, familiality for RLS, insomnia, leg jerks, EDS, hypnotic therapy, cervical cord damage Age, disability, PP, MS duration, familiality for RLS, insomnia, leg jerks, snoring, EDS, hypnotic therapy Insomnia, fatigue, disability RR None

*Size of population is given in parentheses. EDS, excessive daytime sleepiness; MS, multiple sclerosis; N/A, data not available; PP, primary progressive form of MS; RLS, restless legs syndrome; RR, relapsing–remitting form of MS.

have also demonstrated that treatment of MS patients with methylprednisolone causes sleep electroencephalogram changes typically seen in patients with depression (reduced REM sleep latency, decreased REM sleep density, decreased slow-wave sleep). Earlier data suggesting that treatment with interferon b predisposes patients to depression has been questioned. However, Mohr et al (2006) recently suggested that, considering the uncertainty of a link between interferon and depression, as well as the complete remission of psychiatric complications after discontinuation of interferon, physicians should monitor the psychiatric status of patients closely. To date, disrupted sleep, depression, and increased fatigue have not been described with the use of glatiramer acetate (Vallittu et al., 2005), mitoxantrone (Fox, 2006), or immunoglobulins (Haas et al., 2005).

found sleep apnea syndrome in two patients and episodes of nocturnal desaturations in three. In another polysomnographic study of 25 patients with definite MS, central sleep apneas were found in only two patients (Ferini-Strambi et al., 1994). However, central nervous system (CNS) and brainstem-related nocturnal respiratory abnormalities such as paroxysmal hyperventilation, hypoventilation, respiratory muscle weakness, and respiratory arrest have all been described (Howard et al., 1992; Auer et al., 1996). The coexistence of respiratory abnormalities and PLMS (Figure 66.1) is not a rare condition and it should be considered in patients with MS who present with symptoms of daytime somnolence and nonrestorative sleep.

SLEEP-DISORDERED BREATHING

Narcoleptic symptoms have long been recognized in patients with MS. Studies published in the first half of the 20th century reported cases of MS associated with sleep attacks termed “narcolepsy” (Jacobson, 1926; Guillain and Alajouanine, 1928). Symptoms of narcolepsy may appear before or after other symptoms of MS (Bonduelle and Degos, 1976). There is a coincidence of genetic susceptibility between narcolepsy and MS (Schrader et al., 1980). Studies involving Caucasian Americans, Japanese, African Brazilians, and African Americans show a strong association (>90%) between narcolepsy with

The medullary reticular formation is responsible for controlling automatic breathing during sleep. In patients with MS, demyelinating lesions in this area could affect nocturnal respiratory effort, leading to sleep-disordered breathing and even nocturnal death (Ondine’s curse) (Auer et al., 1996). It has been reported that the incidence of obstructive sleep apnea in patients with MS is no higher than in the general population (Wunderlin et al., 1997). In a study of 28 consecutive patients with MS, Tachibana et al (1994)

NARCOLEPSY

SLEEP DISORDERS IN MULTIPLE SCLEROSIS

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Fig. 66.1. Periodic limb movements in sleep and central sleep apneas in a patient with multiple sclerosis.

cataplexy and certain human leukocyte antigens: HLADR2, -DQB1*0602, -DQA1*0102, and -DQw1 (Mignot, 2005). The susceptibility to MS is coded by genes within or close to the HLA-DR-DQ subregion. Indeed, in MS populations an increased prevalence (50–70%) of HLA-DR2, -DQB1, -DQA1, -A3, -DQw1, and -B7 has also been found (Duquette et al., 1985). The finding that both narcolepsy and MS are strongly linked to similar HLA expression, a hallmark of most autoimmune diseases, suggests that similar autoimmune factors may play a role in the development of both diseases and may be partially responsible for similar symptoms of fatigue and somnolence. Hypocretin-1 and -2 (orexin A and B) are neuropeptides released by lateral hypothalamic neurons that are involved in wake promotion and sleep regulation (Mignot, 2005). These neurons are reduced in patients with idiopathic narcolepsy. Most sporadic, HLA-DQB1*0602-positive narcoleptic patients with cataplexy have undetectable levels of hypocretin-1 (orexin A) in the cerebrospinal fluid (CSF). This evidence, taken in the context of a strong narcolepsy–HLA association, suggests the possibility of an autoimmune disorder directed against hypocretin-containing cells in the lateral hypothalamus, although no direct cause and effect relationship has been established. The symptoms of narcolepsy can occur during the course of several neurological conditions (i.e., symptomatic or secondary narcolepsy). Symptomatic narcolepsy defines all the cases that meet the criteria for narcolepsy, according to the International Classification of Sleep Disorders, and that are also associated with a significant underlying

neurological disorder that accounts for excessive daytime sleepiness and temporal associations. Hypoxic– ischemic injury, brain trauma, and hypothalamic MS plaques have been shown to cause hypersomnia and narcoleptic symptoms in the context of low CSF hypocretin-1 (orexin A) levels (Iseki et al., 2002). Additionally, preliminary data demonstrate abnormally low levels of hypocretin-1 (orexin A) in patients with MS when hypothalamic plaques are present. Therefore, it is possible for CNS inflammation and demyelination, in this area, to cause somnolence by altering CSF hypocretin-1 (orexin A) levels (Kato et al., 2003). Modafinil is a CNS-activating agent. It is histaminergic and pharmacologically distinct from other CNS stimulants. Preclinical studies have demonstrated that modafinil can selectively activate lateral hypothalamic neurons that produce wake-promoting hypocretin-1 (orexin 1) (Scammell et al., 2000). It is well known that modafinil significantly improves excessive daytime somnolence associated with narcolepsy (Guilleminault and Fromherz, 2005), and a preliminary study showed that modafinil can be used effectively to manage fatigue associated with MS (Rammohan et al., 2002). However, a randomized placebo-controlled doubleblind study in 115 patients with MS showed no improvement of fatigue in patients treated with modafinil versus placebo (Stankoff et al., 2005). This finding casts doubt on the proposal that the symptoms of somnolence and fatigue seen in patients with MS have a common immunopathophysiological mechanism. Indeed, Vetrugno et al (2007) found normal sleep–wake and body temperature rhythms in six patients with MS and chronic fatigue.

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RAPID EYE MOVEMENT BEHAVIOR DISORDER RBD is a parasomnia characterized by complex motor behaviors, such as kicking, punching, and dream enactment, which occur during REM sleep. RBD may be idiopathic or, according to the International Classification of Sleep Disorders diagnostic criteria for RBD, it can be associated with various neurological conditions such as brainstem neoplasm, multiple sclerosis affecting the brainstem, olivopontocerebellar atrophy, Lewy body disease, Alzheimer dementia, progressive supranuclear palsy, or Shy–Drager syndrome and pure autonomic failure (Mahowald and Schenk, 2003; Ferini-Strambi et al., 2005). RBD has been described as an initial presenting symptom in a 25-year-old woman with MS, and subsequently resolved after treatment with adrenocorticotropic hormone (Plazzi et al., 2002). However, in that study no MRI images documenting the described pontine and bilateral periventricular cerebral lesions were presented. More recently, another RBD case in a 51-year-old woman with MS has been reported (Tippmann-Peikert et al., 2006). The RBD onset was attributed to the large MS plaque in the dorsal brainstem: MRI showed a large confluent area of increased T2 signal in the dorsal pons lesion, similar to those provoked in animal models (cats) with bilateral peri-locus coeruleus lesions inducing REM sleep without atonia accompanied by motor behaviors. In relation to the reported association between MS and depression, it should be remarked that the literature over the past three decades has evidenced severe sideeffects of tricyclic antidepressants on REM sleep muscle atonia, and induction of RBD in healthy subjects and in patients with neuropsychiatric disorders (Nofzinger and Reynolds, 1994; Mahowald and Schenck, 2005). There are similar reports of RBD symptoms being triggered by serotonergic synaptic reuptake inhibitors, and a systematic polysomnographic study of patients taking serotonergic antidepressants, such as fluoxetine, paroxetine, citalopram, sertraline, and venlafaxine, found an increase in REM sleep electromyographic tonic activity compared with that in control subjects (Winkelman and James, 2004; Mahowald and Schenck, 2005). Patients with MS taking such medications may be at increased risk of developing RBD, particularly with increasing age. In conclusion, the association between MS and sleep disorders is common. More than 50% of patients with MS complain of chronic sleep disturbance resulting in daytime somnolence, worsening fatigue, depression, and a lowered pain threshold. An increased clinical awareness and appropriate treatment of sleep disorders in the MS population may significantly improve the overall quality of life in these patients.

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Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 67

Violent parasomnias: forensic implications MARK W. MAHOWALD 1, 3 *, CARLOS H. SCHENK 1, 2, AND MICHEL A. CRAMER BORNEMANN 1, 3 1 Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, Minneapolis, MN, USA 2

Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA

3

Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA

In all of us, even in good men, there is a lawless, wild-beast nature which peers out in sleep. (Plato, The Republic) Acts done by a person asleep cannot be criminal, there being no consciousness. (Fitzgerald, 1961)

INTRODUCTION Increasingly, sleep medicine practitioners are asked to render opinions regarding legal issues pertaining to violent or injurious behaviors purported to have arisen from the sleep period. Such acts, if having arisen from sleep without conscious awareness, would constitute an “automatism”. Automatic behaviors (automatisms) resulting in acts that may result in illegal behaviors have been described in many different medical, neurological, and psychiatric conditions. Those medical and psychiatric automatisms arising from wakefulness are reasonably well understood. Recent advances in sleep medicine have made it apparent that some complex behaviors, occasionally violent or injurious with forensic science implications, are exquisitely state dependent, meaning that they arise exclusively, or predominately, from the sleep period. Violent behaviors arising from the sleep period are more common than previously thought, being reported by 2% of the adult population (Ohayon et al., 1997).

CASE EXAMPLE A recent, highly publicized, case in Canada underscores interesting and difficult forensic issues raised by violent behavior arising from the sleep period.

A 33-year-old man met a woman at a party. Both had been drinking and fell asleep on a couch. She awakened to find that he was having sex with her. She pushed him off. He claimed no awareness until he woke up as he fell to the floor. He told police that he only suspected that he had had sex when he went to the bathroom to discover that he was still wearing a condom. Subsequently she filed a criminal complaint resulting in his arrest and charge of sexual assault. At trial, sleep experts testified that this behavior was due to a condition termed “sexsomnia”, which is similar to sleepwalking, and therefore without conscious awareness or culpability, and the man was exonerated. This judgment has enraged women’s groups.

VIOLENCE ARISING FROM THE SLEEP PERIOD Violence may be state dependent Sleep is not simply the passive absence of wakefulness. Not only is sleep is an active, rather than passive, process, it is now clear that sleep is comprised of two completely different states: nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. Recent studies have indicated that bizarre behavioral syndromes can, and do, occur as a result of the incomplete declaration or rapid oscillation of these states (Mahowald et al., 1990; Mahowald and Schenck, 1992). Sleep inertia may also play a role in state admixture-related complex behaviors (Mahowald and Schenck, 2000; Wertz et al., 2006). Although the automatic behaviors of some “mixed states” are relatively benign (e.g., shoplifting in narcolepsy) (Zorick et al., 1979), others may be associated with very violent or injurious behaviors.

*Correspondence to: Mark W. Mahowald, M.D., Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA. Tel: 612-872-6201, Fax: 612-904-4207, E-mail: [email protected]

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There are a number of factors that permit the appearance of violent or injurious behaviors in the absence of conscious wakefulness and without conscious awareness. Animal experimental studies provide preliminary answers. The widely held concept that the brainstem and other more “primitive” neural structures participate primarily in elemental/vegetative rather than behavioral activities is inaccurate. There are overwhelming data documenting that highly complex emotional and motor behaviors can originate from these more primitive structures – without involvement of higher neural structures such as the cortex (Berntson and Micco, 1976; LeDoux, 1987; Bandler, 1988; Cohen, 1988; Grillner and Dubic, 1988; Siegel and Pott, 1988; Corner, 1990).

Sleep-related disorders associated with violence Violent sleep-related behaviors have been reviewed recently in the context of automatic behavior in general (Mahowald et al., 1990; Mahowald and Schenck, 2000). There are well documented cases of: somnambulistic homicide, filicide, attempted homicide, and suicide; murders and other crimes with sleep drunkenness (confusional arousals); and sleep terrors/sleepwalking with potential violence/injury. A wide variety of disorders may result in sleep-related violence (Mahowald et al., 1990, 2003). Conditions associated with sleep periodrelated violence are listed in Table 67.1. These

Table 67.1 Conditions associated with automatic behavior arising from the sleep period Sleep disorders Disorders of arousal (confusional arousals, sleepwalking, sleep terrors) REM sleep behavior disorder Nocturnal seizures Automatic behavior: Narcolepsy and idiopathic CNS hypersomnia Sleep apnea Sleep deprivation (including jetlag) Hypnagogic hallucinations Psychogenic disorders Dissociative states (may arise exclusively from sleep): Fugues Multiple personality disorder Psychogenic amnesia Posttraumatic stress disorder Malingering Munchausen by proxy CNS, central nervous system; REM, rapid eye movement.

conveniently fall into two major categories: neurological and psychiatric.

NEUROLOGICAL CONDITIONS ASSOCIATED WITH SLEEP-RELATED VIOLENT BEHAVIORS Disorders of arousal (confusional arousals, sleepwalking/sleep terrors) The disorders of arousal comprise a spectrum ranging from confusional arousals (sleep drunkenness) to sleepwalking to sleep terrors (Mahowald and CramerBornemann, 2005). Although there is usually amnesia for the event, vivid dream-like mentation may occasionally be experienced and reported (Schenck et al., 1989). Contrary to popular opinion, these disorders may persist into or actually begin in adulthood, and are most often not associated with significant psychopathology (Mahowald and Cramer-Bornemann, 2005). Recent population surveys indicate that disorders of arousal in adults are much more prevalent than previously appreciated, being reported by 3–4% of all adults, occurring weekly in 0.4% (Hublin et al., 1997). Febrile illness, prior sleep deprivation, and emotional stress may serve to trigger disorders of arousal in susceptible individuals (Bonkalo, 1974; Vela Bueno et al., 1980; Raschka, 1984). Sleep deprivation is well known to result in confusion, disorientation, and hallucinatory phenomena (Brauchi and West, 1959; Shurley, 1962; Williams et al., 1962; Belenky, 1979; Babkoff et al., 1989; Nielsen et al., 1995). Medications such as sedative/hypnotics, neuroleptics, minor tranquilizers, stimulants, and antihistamines, often in combination with each other or with alcohol, may also play a role (Luchins et al., 1978; Charney et al., 1979; Huapaya, 1979). It has recently been shown that alcohol does not serve as a trigger for disorders of arousal (Pressman et al., 2007). Confusional arousals, a milder form of sleepwalking or sleep terrors (also termed “sleep drunkenness”), occur during the transition between sleep and wakefulness, and represent a disturbance of cognition and attention despite the motor behavior of wakefulness, resulting in complex behavior without conscious awareness (Guilleminault et al., 1975a; Roth et al., 1981; Lipowski, 1987). As in other disorders of arousal, these may be potentiated by prior sleep deprivation or by the ingestion of sedative/hypnotics before sleep onset (Roth et al., 1972). These episodes of “automatic behavior” occur in the setting of chronic sleep deprivation or other conditions associated with state admixture (shoplifting has been reported during a period of automatic behavior in a narcoleptic) (Zorick et al., 1979; Parkes, 1985; Mahowald and Schenck, 1994).

VIOLENT PARASOMNIAS: FORENSIC IMPLICATIONS

PATHOPHYSIOLOGY

OF DISORDERS OF AROUSAL

The behavioral similarities between documented sleepwalking or sleep terror-related violence in humans and “sham rage”, as seen in the “hypothalamic savage” syndrome, are striking (Glusman, 1974). Although it has been assumed that the “sham rage” animal preparations are “awake”, there is some suggestion that similar preparations are behaviorally awake and yet (partially) physiologically asleep, with apparent “hallucinatory” behavior possibly representing REM sleep dreaming occurring during wakefulness, dissociated from other REM-state markers (Kitsikis and Steriade, 1981). Animal studies indicate a clear anatomical basis for some forms of violent behavior (Siegel and Shaikh, 1997). The prosencephalic system may serve to control and elaborate, rather than initiate, behaviors originating from deeper structures (Berntson and Micco, 1976). In humans, confusional arousals that can result in confusion or aggression may be associated with electroencephalographic (EEG) evidence of rapid oscillations between wakefulness and sleep (Guilleminault et al., 1975b; Roth et al., 1981). Such behaviors occurring in states other than wakefulness may be the expression of motor/affective activity generated by lower structures – unmonitored and unmodified by the cortex. Clearly, psychobiological and sociocultural factors also play a role in both wakeful and sleep-related violence (Golden et al., 1996; Greene et al., 1997). Treatment of the disorders of arousal include both pharmacological (benzodiazepines and tricyclic antidepressants) and behavioral (hypnosis) approaches (Mahowald and Schenck, 2005a). Importantly, there are various associations between obstructive sleep apnea and confusional arousals. Patients suffering from obstructive sleep apnea may experience frequent arousals which may serve to trigger arousal-induced precipitous motor activity (Guilleminault and Silvestri, 1982). Disorders of arousal may also be precipitated by adequate or incomplete treatment of sleep apnea with nasal continuous positive airway pressure (Millman et al., 1991; Pressman et al., 1995).

DISORDERS

OF AROUSAL AND HUMAN VIOLENCE

The commonly held belief that disorders of arousal are always benign is erroneous: the accompanying behaviors may be violent, resulting in considerable injury to the individual, others, or damage to the environment (Schenck et al., 1989; Mahowald et al., 1990). Such behaviors have been described in the medical literature for over a century (Hammond, 1869). Sleepwalking

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resulting in injury to self or others has been termed “Elpenor’s syndrome”, after an incident in Homer’s Odyssey. A youth named Elpenor became intoxicated and fell asleep on the roof of a house. He was suddenly awakened by noise of others preparing to leave the island of Aeaee (A´iai Z), and ran off the rooftop rather than taking the staircase, sustaining a fatal cervical fracture (Homer, 800 BC). Keeping in mind that not only is sleep a very active process, that the generators or effectors of many components of both REM and NREM sleep reside in the brainstem and other “lower” centers, and that there are multiple state transitions occurring every night, it is actually surprising that such behaviors do not occur more often than they do. Specific incidents include (Mahowald and Schenck, 2005b): ● ● ● ● ●

Somnambulistic homicide, attempted homicide, filicide Murders and other crimes with sleep drunkenness, including sleep apnea and narcolepsy Suicide, or fear of committing suicide Sleep terrors/sleepwalking with potential violence/ injury (these episodes may be drug induced) Inappropriate sexual behaviors during the sleep state, presumably the result of an admixture of wakefulness and sleep.

Violent sleep-related behaviors can also result in posttraumatic stress in a spouse (Baran et al., 2003). Very dramatic cases have been tried in the court system using confusional arousal as defense. In one, the “Parks” case in Canada, the defendant drove 23 kilometers, killed his mother-in-law, and attempted to kill his father-in-law. Somnambulism was the legal defense, and he was acquitted (Broughton et al., 1994). In another, the “Butler, PA” case, a confusional arousal attributed to underlying obstructive sleep apnea was offered as a criminal defense for a man who fatally shot his wife during his usual sleeping hours. He was found guilty (Nofzinger and Wettstein, 1995). Accidental death resulting from self-injury incurred during sleepwalking may be erroneously attributed to suicide (“parasomnia pseudo-suicide”) (Shatkin et al., 2002; Mahowald et al., 2003).

REM sleep behavior disorder (RBD) RBD represents an experiment of nature, predicted in 1965 by animal experiments (Jouvet and Delorme, 1965) and recently identified in humans (Schenck et al., 1986). Normally, during REM sleep, there is active paralysis of all somatic muscles (sparing the

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diaphragm and extraocular muscles). In RBD, there is the absence of REM sleep atonia, which permits the “acting out” of dreams, often with dramatic and violent or injurious behaviors. These oneiric behaviors displayed by patients with RBD are often misdiagnosed as manifestations of a seizure or psychiatric disorders. RBD is often associated with underlying neurological disorders, most notably the synucleinopathies and narcolepsy (Schenck and Mahowald, 2002; Boeve et al., 2003, 2004; Nightingale et al., 2005). The overwhelming male predominance (90%) of RBD (Schenck et al., 1993) raises interesting questions relating sexual hormones to aggression and violence (Moyer, 1968; Goldstein, 1974). The violent and injurious nature of RBD behaviors has been reviewed extensively elsewhere (Schenck and Mahowald, 1991; Gross, 1992; Schenck et al., 1993; Dyken et al., 1995; Morfis et al., 1997). Interestingly, there is no evidence of aggression during wakefulness in patients with RBD (Fantini et al., 2005). Treatment with clonazepam is highly effective (Schenck and Mahowald, 2002). Other sleep disorders, such as the parasomnia overlap syndrome, disorders of arousal, underlying sleep apnea, and nocturnal seizures, may perfectly simulate RBD, again underscoring the necessity for thorough formal polysomnographic (PSG) evaluation of these cases (Nalamalapu et al., 1996; D’Cruz and Vaughn, 1997; Schenck et al., 1997; Iranzo and Santamaria, 2005).

Nocturnal seizures The association between seizures and violence has long been debated. Rarely, nocturnal seizures may result in violent, murderous, or injurious behaviors (Hindler, 1989; Mahowald et al., 1990). Of particular note is the frantic, elaborate, and complex nocturnal motor activity that may result from seizures originating in the orbital, mesial, or prefrontal region (Tharp, 1972; Quesney et al., 1984; Williamson and Spencer, 1986; Ludwig et al., 1987; Waterman et al., 1987; Collins et al., 1988). “Episodic nocturnal wanderings”, a condition clinically indistinguishable from other forms of sleep-related motor activity such as complex sleepwalking, but which is responsive to antiepileptic therapy, has also been described (Pedley and Guilleminault, 1977; Maselli et al., 1988; Plazzi et al., 1995). Aggression and violence may be seen preictally, ictally, or postictally. Postictal wanderings may result in confused or violent behaviors (Mayeux et al., 1979; Borum and Appelbaum, 1996). Some postictal violence is often induced or perpetuated by the good intentions of bystanders trying to “calm” the patient following a seizure (Fenwick, 1989). As mentioned above, other

sleep disorders such as obstructive sleep apnea or RBD may masquerade as nocturnal seizures (Houdart et al., 1960; Kryger et al., 1974; Guilleminault, 1983; D’Cruz and Vaughn, 1997).

Compelling hypnagogic hallucinations Conversely, recurrent sexually oriented hypnagogic hallucinations experienced by patients with narcolepsy may be so vivid and convincing to the victim that they may serve as false accusations (Hays, 1992). It has been suggested that some cases of “repressed memories” of childhood abuse may actually be due to compelling hypnagogic hallucinations (McNally and Clancy, 2005a, b).

Sleeptalking Sleeptalking has also been addressed by the legal system; it is interesting to speculate whether utterances made during sleep are admissible in court (Regina v. Warner, 1995).

PSYCHIATRIC CONDITIONS ASSOCIATED WITH SLEEP-RELATED VIOLENT BEHAVIORS Psychogenic dissociative states Waking dissociative states may result in violence (McCaldon, 1964). It is now apparent that dissociative disorders may arise exclusively or predominately from the sleep period (Fleming, 1987; Schenck et al., 1989). Virtually all patients with nocturnal dissociative disorders evaluated at our center were victims of repeated physical and/or sexual abuse beginning in childhood (Schenck et al., 1989).

Posttraumatic stress disorder (PTSD) Dissociative states and injury related to “nightmare” behaviors have been reported in association with PTSD (Bisson, 1993; Coy, 1996). The “limbic psychotic trigger reaction” in which motiveless unplanned homicidal acts occur is speculated to represent partial limbic seizures that are “kindled” by highly individualized and specific trigger stimuli, reviving past repetitive stress (Pontius, 1997). If so, this would be an example of environmentally induced changes in brain function.

Malingering Although uncommon, malingering must also be considered in cases of apparent sleep-related violence. Our center has seen a young adult male who developed progressively violent behaviors apparently arising from sleep directed exclusively at his wife. This behavior

VIOLENT PARASOMNIAS: FORENSIC IMPLICATIONS 1153 included beating her and chasing her with a hammer. Although the medical concept of automatism is Following exhaustive neurological, psychiatric, and relatively straightforward (complex behavior in the PSG evaluation, it was determined that this behavior absence of conscious awareness or volitional intent), represented malingering. It was suspected that he was the judicial concept is quite different. Legally, there attempting to have the sleep center “legitimize” his are two forms of automatism: “sane” and “insane”. behaviors, should his wife be murdered during one of The “sane” automatism results from an external or these episodes. extrinsic factor, the “insane” from an internal or endogenous cause. This choice results in two very difMunchausen syndrome by proxy ferent consequences for the accused: commitment to a mental hospital for an indefinite period of time if In this recently described syndrome, a child is reported “insane”, or acquittal without any mandated medical to have apparently medically serious symptoms that, in consultation or follow-up if “sane”. For example, a fact, are induced by an adult, usually a caregiver, often criminal act resulting from altered behavior due to a parent. The use of surreptitious video-monitoring hypoglycemia induced by injection of too much insuin sleep disorder centers during sleep (with the parlin would be a “sane” automatism, whereas the ent present) has documented the true etiology for same act, if due to hypoglycemia caused by an insulireported sleep apnea and other unusual nocturnal noma, would be an “insane” automatism. By this spells (Rosenberg, 1987; Griffith and Slovik, 1989; unscientific paradigm, criminal behavior associated Light and Sheridan, 1990; Samuels et al., 1992; Byard with epilepsy is, by definition, an “insane” automatism and Beal, 1993; Skau and Mouridsen, 1995; Bryk and (Fenwick, 1990b, 1997). In the USA, the approach to Siegel, 1997; Mydlo et al., 1997). automatism varies from state to state (McCall Smith and Shapiro, 1997). MEDICOLEGAL EVALUATION The current legal system, unfortunately, must consider a sleep-related violence case strictly in terms of Automatisms and the law choosing between “insane” and “non-insane” autoActus non facit reum nisi mens sit rea – the deed matism, without any stipulated deterrent concerning a does not make a man guilty unless his mind is recurrence of sleepwalking with criminal charges that guilty was induced by a recurrence of the high-risk behavior. (Fenwick, 1996) If sleepwalking is deemed an “insane” automatism, then a significant percentage of the population at large In the USA and the UK, a criminal act (actus reus), is “legally insane.” Clearly, dialogue between the medin order to be criminal, must be paired with a culpable ical and legal professions regarding this important area mental state (mens rea), meaning knowing intent to would be helpful both to the professions and to those commit a crime. The legal definition of automatism arrested during automatisms (Thomas, 1997). is based upon this doctrine. A book has been published One reasonable approach in dealing with the abovethat is devoted to the various forensic aspects of sleep mentioned automatisms from a legal standpoint would medicine (Shapiro and McCall Smith, 1997). be to add a category of acquittal that allowed for Most of the above-mentioned conditions resulting innocence based on lack of guilt consequent to set in violent or injurious behaviors are termed “autodiagnoses – specific illnesses that could be categorized matisms.” Automatism is difficult to define (Fenwick, by a group of subspecialty clinicians in consultation 1990a, b; Jang and Coles, 1995). Fenwick (1996) has with the legal profession (Beran, 1992). proposed the following definition: Another suggestion has been a two-stage trial, An automatism is an involuntary piece of behavwhich would first establish who committed the act, ior over which an individual has no control. and then deal separately with the issue of culpability. The behavior is usually inappropriate to the The first part would be held before a jury, the second circumstances, and may be out of character for in front of a judge with medical advisors present the individual. It can be complex, coordinated, (Fenwick, 1990a, b). and apparently purposeful and directed, though One fortunate, and unexplained, fact is that noclacking in judgment. Afterwards the individual turnal sleep-related violence is seldom recurrent may have no recollection or only partial and (Guilleminault et al., 1995). Rarely, recurrence is confused memory for his actions. In organic reported, and possibly should be termed a “non-insane automatisms there must be some disturbance of automatism.” Thorough evaluation and effective treatbrain function sufficient to give rise to the above ment are mandatory before the patient can be regarded features. as no longer a menace to society (Schenck and

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Mahowald, 1995). In some cases, clear precipitating events can be identified, and must be avoided to be exonerated from legal culpability. These concepts have led to the proposal of two new forensic categories: (1) “parasomnia with continuing danger as a non-insane automatism” and (2) “(intermittent) state-dependent continuing danger” (Schenck and Mahowald, 1992, 1995, 1998).

The role of the sleep medicine specialist With the identification of ever increasing causes, manifestations, and consequences of sleep-related violence comes an opportunity for sleep medicine specialists to educate the general public and practicing clinicians as to the occurrence and nature of such behaviors, and their successful treatment. More importantly, the onus is on the sleep medicine professional to educate and assist the legal profession in cases of sleep-related violence that result in forensic medicine issues. This often presents difficult ethical problems, as most “expert witnesses” are retained by either the defense or the prosecution, leading to the tendency for expert witnesses to become an advocate or partisan for either one side or the other. Historically, this has been fertile ground for the appearance of “junk science” in the courtroom (Huber, 1991) – from Bendectin to triazolam to breast implants. Junk science leads to junk justice, and altered standards of care (Weintraub, 1995). Recently, much attention has been paid to the existence and prevalence of junk science in the courtroom, with recommendations to minimize its occurrence. There is some hope that the judicial system is paying more attention to the process of authentic science and may move to accept only valid scientific evidence (Foster et al., 1993; Loevinger, 1995).

Forensic sleep medicine experts as impartial friends of the court (amicus curiae) One infrequently employed tactic to improve scientific testimony is to use a court-appointed “impartial expert” (Huber, 1991). When approached to testify, volunteering to serve as a court-appointed expert, rather than one appointed by either the prosecution or the defense, may encourage this practice. Other proposed measures include the development of a specific section in scientific journals dedicated to expert witness testimony extracted from public documents with request for opinions and consensus statements from appropriate specialists, or the development of a library of circulating expert testimony that could be used to discredit irresponsible, professional, witnesses (Huber, 1991). Good science is not determined by the credentials of the expert witness, but, rather, by scientific

consensus (Weintraub, 1995). Interestingly, in Europe, expert witnesses are court-appointed – often from lists of faculties of universities, compensated from a standard scale – and remain independent of both parties (Deftos, 1999). To address the problem of junk science in the courtroom, many professional societies are calling for, and some have developed, guidelines for expert witness qualifications and testimony (Committee on Medical Liability, 1989; American College of Physicians, 1990; Bone and Rosenow, 1990). Similarly, the American Sleep Disorders Association and the American Academy of Neurology have adopted their own guidelines detailing: elements of medical expert testimony, qualifications of a medical expert, and guidelines for the conduct of the medical expert (American Sleep Disorders Association, 1993; Beresford et al., 2006; Williams et al., 2006). Familiarizing oneself with these guidelines may be helpful in a given case, as the expert witness from each side should be held to the same standards (Mahowald and Schenck, 1995).

Clinical and laboratory evaluation of waking, sleep/violence The history of complex, violent, or potentially injurious motor behavior arising from the sleep period should suggest the possibility of one of the above-mentioned sleep disorders or psychiatric conditions. It is likely that violence arising from the sleep period is more frequent than previously assumed (Broughton and Shimizu, 1995). Our experience with a large number of adult cases of sleep-related injury/violence has repeatedly indicated that clinical differentiation, without formal PSG study, among RBD, disorders of arousal, sleep apnea, and sleep-related psychogenic dissociative states and other psychiatric conditions is often impossible (Mahowald et al., 1992; Mahowald and Schenck, 2005a, b). As mentioned above, the legal implications of automatic behavior have been discussed and debated in both the medical and legal literature (Prevezer, 1958; Fitzgerald, 1961; Williams, 1961; Whitlock, 1963; Shroder and Mather, 1976). As with nonsleep-related automatisms, the identification of a specific underlying organic or psychiatric sleep/violence condition does not establish causality for any given deed. Two questions accompany each case of purported sleep-related violence: (1) Is it possible for behavior this complex to have arisen in a mixed state of wakefulness and sleep without conscious awareness or responsibility for the act? and (2) Is that what happened at the time of the incident? The answer to the first is usually “yes.” The second can never be determined with surety after the fact.

VIOLENT PARASOMNIAS: FORENSIC IMPLICATIONS To assist in the determination of the putative role of an underlying sleep disorder in a specific violent act, we have proposed guidelines, modified from Bonkalo (1974) (sleepwalking), Walker (1961) (epilepsy), and Glasgow (1965) (automatism in general), and formulated from our clinical experience (Mahowald et al., 1990): 1.

2. 3.

4.

5.

6. 7.

8.

There should be reason (by history or formal sleep laboratory evaluation) to suspect a bona fide sleep disorder. Similar episodes, with benign or morbid outcome, should have occurred previously. (It must be remembered that disorders of arousal may begin in adulthood.) The duration of the action is usually brief (minutes). The behavior is usually abrupt, immediate, impulsive, and senseless – without apparent motivation. Although ostensibly purposeful, it is completely inappropriate to the total situation, out of (waking) character for the individual, and without evidence of premeditation. The victim is someone who merely happened to be present, and who may have been the stimulus for the arousal. Immediately following return of consciousness, there is perplexity or horror, without attempt to escape, conceal or cover up the action. There is evidence of lack of awareness on the part of the individual during the event. There is usually some degree of amnesia for the event; however, this amnesia need not be complete. In the case of sleep terrors/sleepwalking or sleep drunkenness, the act may: a. occur upon awakening (rarely immediately upon falling asleep) – usually at least 1 hour after sleep onset. b. occur upon attempts to awaken the subject. c. have been potentiated by sedative/hypnotic administration or prior sleep deprivation. Intoxication with alcohol or other substances precludes the use of the sleepwalking defense (Pressman et al., 2007).

Most conditions associated with sleep-related violence are diagnosable and treatable. Clinical evaluation should include a complete review of sleep/wake complaints from both the victim and the bed partner (if available). This should be followed by a thorough general physical, neurological, and psychiatric examination. The diagnosis may be suspected only clinically. Extensive polygraphic study employing an extensive scalp EEG, electromyographic monitoring of all four extremities, and continuous audiovisual recording are mandatory for correct diagnosis in atypical cases.

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PSG studies may be of value in establishing a diagnosis of RBD or nocturnal seizures. There are absolutely no PSG findings that serve as reliable markers of disorders of arousal (Schenck et al., 1998; Pressman, 2000, 2004; Pilon et al., 2006). Even if a sleepwalking episode were captured during a PSG study of an individual claiming sleepwalking as a defense, the high prevalence of sleepwalking in normal adults would render that finding worthless in attributing a remote episode of sleep-related violence to sleepwalking. The proposition that sleep disorders may be a legitimate defense in cases of violence arising from the sleep period has understandably been met with immense skepticism (Guilleminault et al., 1995). For credibility, evaluations of such complex cases are best performed in experienced sleep disorders centers with interpretation by a veteran clinical polysomnographer. Due to the complex nature of many of these disorders, a multidisciplinary approach is highly recommended (Mahowald et al., 2005).

SUMMARY AND FUTURE DIRECTIONS It is abundantly clear that violence may occur during any of the three states of being. That which occurs during REM or NREM sleep may have occurred without conscious awareness and may be due to one of a number of completely different disorders. Violent behavior during sleep may result in events that have forensic science implications. The apparent suicide (e.g., leap to death from a second-story window), assault, or murder (e.g., molestation, strangulation, stabbing, shooting) may be the unintentional, nonculpable but catastrophic result of disorders of arousal, sleep-related seizures, RBD, or psychogenic dissociative states. The majority of these conditions are diagnosable and, more importantly, are treatable. The social and legal implications are obvious. More research, both basic science and clinical, is urgently needed to identify and elaborate further upon the components of both waking and sleep-related violence, with particular emphasis upon neurobiological, neuroplastic, genetic, and socioenvironmental factors (Elliott, 1992; Blake et al., 1995; Greene et al., 1997). The study of violence and aggression will be greatly enhanced by close cooperation among clinicians, basic science researchers, and social scientists.

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Subject Index NB: Page numbers in italics refer to boxes, figures and tables

A Absolute risk reduction, 281 Acetazolamide, 342, 444, 478, 1081, 1125 Acetylcholine (ACh), 79, 134, 179, 268–269 agonists, 155 Acetylcholinesterase (AChE), 134, 135 inhibitors, 876 Acoustic perturbation, 704–705, 705 Actigraphic monitoring, 55–60 acceleration signal, 56 applications, 55 circadian/diurnal rhythms, 59–60, 60 perspectives, 60–61 placement, 56, 56 sleep-wake state/sleep parameters, 56–58, 57, 58 versus polysomnography, 58–59, 59, 61 Active wakefulness (AW), 837 Acupuncture, 5, 366 Acute insomnia, 670 Acute-phase response (APR), 229, 233–234 Adenosine, 776, 1082–1083 Adie, William John, 19 Adjustment insomnia, 670 Adrenergic uptake inhibition, 804 Adrenocorticotropic hormone (ACTH), 241, 627–628, 1129 Adult obstructive sleep apnea syndrome (OSAS), 671–672 Adults, thermoregulation, 220–222 Advanced sleep phase syndrome (ASPS), 690, 958 Aerophagia, 465 African trypanosomiasis (sleeping sickness), 19 Age aging effects, 653, 1011–1015 circadian rhythm changes, 1012, 1013–1014 EEG patterns, 704, 705 headache and, 1077 melatonin and, 1012–1013, 1017 pharmacological treatment and, 758 restless-legs syndrome (RLS) and, 925–926, 927 sleep structure and, 218 sleep-related erections (SREs) and, 358 ‘Agrypnia excitata’, concept of, 990–991

AIDS (acquired immunodeficiency syndrome), 231 Air pollution, 503 Airways see Upper-airway Akinetic mutism, 1051 Akira Amemiya, 16 Alarm devices, enuresis, 365–366 Alcmaeon, 6–7, 11–12 Alcohol abuse, 442–443, 587–588 alcoholism, 757 dreaming and, 552 in pregnancy, 503–504 relapse, 589 sleep-disordered breathing (SDB) and, 589 withdrawal, 588, 990 Alertness, 919 Alice in Wonderland syndrome, 894 Alligator mississippiensis (American alligator), 102, 102 Allopregnanolone, 250 Almitrine bismesylate, 478 Alpha2 agonists, 600–601 Alternating leg muscle activation (ALMA), 889, 890 Alveolar hypoventilation, 472–473, 475, 1089, 1090, 1094 Alzheimer’s disease (AD), 656, 830, 1011, 1144 circadian dysrhythmias, 972, 1016–1021 hallucinations and, 1024–1025 insomnia and, 59, 60 medication-induced insomnia and, 1025–1026 obstructive sleep apnea syndrome (OSAS) and, 1026–1027, 1026 prevalence, 1015, 1016 see also Dementia Amantadine, 1060 Ambulatory monitoring, 385–386 American Academy of Sleep Medicine (AASM), 17, 21, 34, 712 actigraphy and, 55, 58 bright light and, 966 Manual for the Scoring of Sleep and Associated Events, 34 Multiple Sleep Latency Test (MSLT) and, 49 polysomnographic systems recommendations, 41, 42 psychological/behavioral therapy and, 731

American Academy of Sleep Medicine (AASM), (Continued) video polysomnography (VPSG) and, 65, 66 American alligator, 102, 102 American Association of Sleep Technologists, 21 American Board of Otolaryngology, 21 American Board of Pediatrics, 21 American Board of Psychiatry and Neurology, 21 American Cancer Society, 285 American College of Graduate Medical Education, 21 American Electroencephalographic Society, 66 American Sleep Disorders Association, 21, 33 American Sleep Medicine Foundation, 21 Amphetamines, 592, 1059, 1104, 1129 Aminergic systems, 373, 374–375 Amitriptyline bruxism and, 909 efficacy, 755 insomnia and, 734, 739, 755 isolated sleep paralysis (ISP) and, 895 sleep-related painful erections and, 359 Amnesia, 752 Amphibians, 101–102 Amplifiers, analog, 38–40, 40 Amyotrophic lateral sclerosis (ALS), 1035, 1091–1092, 1093, 1094, 1095, 1102 Anabolic androgenic steroids, 603 Analog amplifiers, 38–40, 40 Analytical studies, 275–276 Anemia theory, 12 ‘Animal spirits’, 10, 11, 16 Ankle dorsiflexion myoclonus, 888 Antiadrenergics, 600 Antiallergy drugs, 47 Antibiotics, 47 Anticholinergics, 366 Anticonvulsants elderly and, 754 excessive daytime sleepiness (EDS) and, 47 insomnia and, 735, 740–741, 749, 749 periodic limb movement disorder (PLMD) and, 827

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-2

SUBJECT INDEX

Anticonvulsants (Continued) posttraumatic stress disorder (PTSD) and, 568 restless-legs syndrome (RLS) and, 937, 939–940 Antidepressants bruxism and, 902 elderly and, 754 enuresis and, 366 excessive daytime sleepiness (EDS) and, 47 hypersomnia and, 1059 insomnia and, 705–706, 734, 749, 1025 narcolepsy and, 803, 804 psychiatric diseases and, 564, 568 restless-legs syndrome (RLS) and, 1028 sleep dysfunction and, 593–596 see also Sedating antidepressants Antiepileptic drugs (AEDs), 1125, 1132–1133 continuous spikes waves during NREM sleep (CSWS) and, 1129 sleep dysfunction and, 596–597 Antihistamines, 601–602, 741, 749, 756, 1025 Antihypertensives, 47 Antiparkinsonian agents, 47, 597–598, 1001 Antipsychotics, 598–599 atypical, 740 excessive daytime sleepiness (EDS) and, 47 insomnia and, 735, 749, 756 mechanisms of action, 598 specific agents, 598–599 Antireflux medication, 47 Anxiety, 566, 583 Anxiolytics, 599–600, 749, 749 Apathy, 1057–1058 Apis mellifera (honey bee), 99–100, 100 Aplysia californica (sea slug), 99 Apnea-hypopnea index (AHI), 441, 657, 658, 689, 1060, 1061, 1097 Apparent life-threatening event (ALTE), 501–502 Aqtuqsinniq, 894 Aristotle, 7, 10, 13, 231 Armodafinil, 829, 1104 Arousability, 363, 364 Arousal, 33–34 cyclic alternating pattern (CAP) and, 708, 708, 709 cyclic nature of, 701, 702, 703, 703 diffuse projection systems, 135–136, 138–141 effects, 316, 392–393, 393 hypothesis, 510 reactivity and, 700–701, 701, 702 responses, modulation, 617 slow-wave sleep, 858–859 thresholds, 378–379 Arousal disorders, 1150–1151 classification, 674 confusional, 674, 853, 1150–1151

Arousal disorders, (Continued) paroxysmal, 1112, 1112, 1113, 1114–1115 pathophysiology, 1151 violence and, 1151 see also Parasomnias Arrhythmias, 334 Artemidorus of Daldis, 5 Arterial hypertension, 294–295, 1064 pulmonary, 332–333 systemic, 331–332 Arteries, cerebral blood flow (CBF), 319 Artifacts actigraphy and, 56 video polysomnography (VPSG) and, 70 Ascending reticular activating system (ARAS), 18, 154, 766, 1057 Aschoff, Jules, 19 Asclepiades of Bithynia, 7, 20 Asclepios, 6, 6 Aserinsky, Eugene, 17 Association of Polysomnographic Technologists, 21 Association of Professional Sleep Societies, 21 Association for the Psychophysiological Study of Sleep, 20–21 Association of Sleep Disorder Centers (ASDC), 19, 21 Asthma, 482 Astrology, 9 ‘Athalamic’ cats, 989 Atherogenesis, 1064 Atomism, 7, 10 Atomoxetine, 803, 804 Attention, 494 Attention deficit hyperactivity disorder (ADHD), 489, 490, 493–494, 826 Atypical benign partial epilepsy, 1129 Augmentation, 939 Autonomic control hypothesis, 509–510 Autonomic dysfunction, 874–875 Autonomic nervous system (ANS), 689 Autonomisms, law and, 1153–1154 Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), 1110, 1117–1118, 1123, 1125 Avicenna, 9 Awakening concept of, 700 scoring, 33–34

B ‘Baby blues’, 645 Bacon, Francis, 9–10 Barbiturates, 19, 748, 754, 827 Barthel Index, 1067 Basal forebrain, 137, 141 Basalocortical projection system, 132, 135, 136, 137 Bayes theorem, 279–280 Beck depression inventory scores, 561 ‘Bedridden by the witch’, 894 Bed-sharing, 505

Bee, 99–100, 100 Behavioral factors, 1014–1015, 1020 arousal/quiescence, 132, 133 problems, 493–494 theories, 3, 16, 20 treatment, insomnia, 654–655 see also Rapid eye movement (REM) sleep behavior disorder (RBD) Behavioral insomnia of childhood, 671 Behavioral Sleep Medicine (Journal), 21 Behaviorally induced insufficient sleep syndrome, 673 Bekhterev, Vladimir Michailovich, 16 Belgian Association for the Study of Sleep, 21 ben Maimon, Moses (aka Maimonides), 9 Benign epilepsy of childhood with centrotemporal spikes (BECTS), 1125, 1129, 1131 Benign epilepsy with occipital paroxysms (BEOP), 1125–1126 Benign sleep myoclonus of infancy, 887–888 classification, 676 Benzodiazepine receptor agonists (BzRAs) daytime function, 751–752 dependence liability, 753 discontinuation effects, 752–753 efficacy, 737–738, 748, 749–751, 750 elderly and, 753–754 indications/limitations, 738 insomnia and, 734, 736–738, 741, 747, 749–754, 750 safety, 752–754, 756, 757 side-effects, 738 substance abuse and, 758 Benzodiazepines arousal disorders and, 1151 continuous spikes waves during NREM sleep (CSWS) and, 1129 effect on sleep, 1132 elderly and, 655, 661, 753, 754 excessive daytime sleepiness (EDS) and, 47 insomnia and, 705, 734, 736, 741, 748 NREM parasomnias and, 863 periodic limb movement disorder (PLMD) and, 827 REM behavior disorder (RBD) and, 875–876 restless-legs syndrome (RLS) and, 940, 1028 sleep-related eating disorder (SRED) and, 583 withdrawal, 990, 1080 Benztropine, 598 Berger, Johannes (Hans), 17 Bermuda reef fish, 101 Beta-agonists, 601 Beta-blockers, 552, 600, 601, 909, 1024 Bible, 8 Bilevel positive airway pressure (BiPAP), 463, 1101

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

SUBJECT INDEX Billiard, Michel, 20 Binge eating, 583 Biological clocks, 18–19 Birds, 97, 103–105 Bite splint, 908, 909 ‘Black box warning’, 740, 1024 ‘Blip’ syndrome, 885 Blood pressure, 1065, 1066 Bloodletting, 4, 8, 9, 10 Blumenbach, Johann Fredreich, 12 Bmal1 genes, 954, 956 Board of Internal Medicine, 21 Board of Sleep Medicine, 21 ‘Body sleep’, 991 Body temperature, 216–218, 1018 Bodyrocking, 889 Bodyrolling, 889 Boerhaave, Hermann, 11, 12 Bootzin, Richard, 20 Botulinum toxin, 909 Bouchard, Abel, 13 Bovine spongiform encephalopathy, 981 Boyle, Robert, 10 Brain anatomy, 152–157 ‘brain sleep’, 991 damage, dreaming, 553 neuropathological examination, 818–819 obstructive sleep apnea syndrome (OSAS), changes, 81–83 organization theory, 234–236 pain processing, 617 serial reaction time (SRT), 263, 264 -signaling, 234 stimulation, 75 stress adaptation, 121–122 Brainstem aminergic systems, 373 caudal, 838–840, 839 electrical stimulation, 131 enuresis and, 365 lesions, 528 neoplasm, 1144 pontine reticular formation (PRF), 153–154, 153, 154 REM sleep-generating system, 767–768 sleep-wake cycle regulation, 773, 773 Breaking Point: How Female Midlife Crisis is Transforming Today’s Women (Shellenbarger), 647 Breath of Life (Catlin), 15, 15 Breathing, control of, 1087–1089, 1088 behavioral control, 373 central control, 371–375, 1087–1088 changes during sleep, 1089, 1090 chemical regulation, 375–377 chest bellow component, 1088–1089, 1089 control hypothesis, 509 wakefulness/sleep influences, 374–375, 374 see also Sleep-disordered breathing (SDB); Sleep-related breathing disorders (SRBDs)

Breathing pattern types, 1096–1097, 1096 Bremer, Fre´de´ric, 18 Bright light exposure circadian rhythm sleep disorders, 966, 967, 969, 971, 972 dementia and, 1020–1021, 1021 elderly and, 1014, 1019, 1025 British Sleep Society, 21 Broadbent, William Henry, 15 Bromocriptine, 1059 Bronchial irritation, 379 Bronchodilators, 478, 601, 1025 Brotizolam, 705, 708 Broughton, Roger, 20 Brown-Se´quard, Charles Edouard, 13 ‘Brux index’, 904, 907 Bruxism, 901–909 classification, 675 diagnosis, 903–905, 904 epidemiology, 901–902 genetics, 901–902 headache and, 1077 management, 907–909, 908 pathophysiology, 904, 905–907, 906 risk factors, 902–903 ‘Bruxomanie’, 905 Bufo boreas (western toad), 102 Bullfrog, 102, 102 Bunning, Erwin, 18 Bupropion, 78, 595 Burwell, Charles Sidney, 20 Buspirone, 599–600, 909

C

Cabergoline, 937, 938 Caffe, P., 14 Caffeine headache and, 1082–1083 restless-legs syndrome (RLS) and, 940 slow release, 972 wakefulness and, 590, 776 withdrawal, 1080 Caiman sclerops (caiman), 102 Cajal, Santiago Ramo´n y, 12–13 Calcium, 1014 Calcium channel blockers, 601, 1025 Canadian Continuous Positive Airway Pressure for patients with central sleep apnea and heart failure (CANPAP) study, 415, 434 Cancer patients, 231 Canine narcolepsy models, 787–788, 789, 790, 791 Cannabidiol, 590 Cappie, James, 12 Carassius auratus (goldfish), 101 Carbamazepine effect on sleep, 1132 hallucinations and, 1023 Kleine–Levin syndrome and, 830 nocturnal frontal lobe epilepsy (NFLE) and, 1125 REM behavior disorder (RBD) and, 1023

I-3 Carbamazepine (Continued) restless-legs syndrome (RLS) and, 937, 939 sleep dysfunction and, 596 Carbidopa, 597 Carbon dioxide, cerebral blood flow (CBF) and, 318–319, 319 Cardiac failure see Heart (cardiac) failure Cardiac pacing, 341–342 Cardiac resynchronization therapy (CRT), 341 Cardiac transplantation, 341 Cardiocerebrovascular disorders, 330, 331 Cardiorespiratory failure, 425–426 Cardiovascular diseases, 327–342 central sleep apnea (CSA) and, 322, 322, 338–339 congestive heart failure, 336–342 continuous positive airway pressure (CPAP) and, 330, 334–335, 341, 433 definitions, 327, 328, 329 obstructive sleep apnea syndrome (OSAS) and, 320–321, 321, 329–336, 329, 330, 331, 335 polysomnography, 329 Cardiovascular effects of arousal, 316 Cardiovascular events, 316–317, 317 Cardiovascular medications, 600–601 Cardiovascular physiology neural circulatory regulation, 315, 316 NREM sleep, 315, 316, 317 REM sleep, 315–316, 316, 317 Caretta caretta L. (loggerhead sea turtle), 103 Carskadon, Mary, 17 Cartoon face scale, 48 Case-control studies, 276 Casein Kinase 1 epsilon gene, 956 Castration, 250, 359 Cataplexy, 14, 16, 289, 672, 785, 828 atonia, 845 narcolepsy with, 672, 785, 786, 793–794, 796 Cataracts, 1013 Catathrenia (groaning), 674, 891–892, 891 Catlin, George, 15, 15 Caton, Richard, 17 Caudal brainstem, 838–840, 839 Cellular aspects, 191, 261–262 stress, 193–194, 194 Cellular prion protein (PrPC), 981–982, 991 Central nervous system (CNS) hypersomnia and, 830 pain and, 614 stimulants, 592–593, 783, 802, 1025 Central pattern generator (CPG) neuronal network, 906 Central sensitization, 627 Central sleep apnea (CSA), 411–417 at altitude, 413, 413

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-4

SUBJECT INDEX

Central sleep apnea (CSA), (Continued) cardiovascular diseases and, 322, 322, 338–339 Cheyne-Stokes breathing (CSB), 413–415, 414, 415–417, 416 classification, 671 complex sleep apnea, 417 continuous positive airway pressure (CPAP) and, 415–416, 416, 422, 422, 433–434 defined, 411 dementia and, 1028 hemodynamic changes, 321–322, 322 hypercapnic, 411–412 hypocapnic, 412–417, 412 idiopathic, 413 periodic breathing, 338 sleep hypoventilation syndrome, 411–412, 412 stroke and, 322, 322, 1060, 1063 treatment, 340, 340 Cerebral blood flow (CBF) intrinsic vasogenic autoregulation, 317–318, 318 major arteries, 319 metabolic regulation, 318 oxygen/carbon dioxide concentration, 318–319, 319 regional (rCBF), 72–73, 72, 78, 319 regulation, 317–319 Cerebral glucose metabolism (CMRGlu), 74, 76, 76, 81, 81 Cerebral reactions, experiencedependant, 263–264, 264 Cerebrospinal fluid (CSF), 16, 320, 771–773, 775, 930–932, 1143 narcolepsy and, 789–790, 792, 794–796, 795, 799, 829 studies, 934 Cerebrovascular events, 316–317, 317 Cerebrovascular physiology, 317–319, 318 Cetirizine, 601–602 Charcot–Marie–Tooth (CMT) disease, 924, 1093 Charcot–Wilbrand syndrome, 1053 Chemical regulation, breathing, 375–377 Chemical theories, 13, 15–16 Chemoreceptors, 375 Chest bellow component, 1088–1089, 1089 Chester Beatty papyrus, 4 Cheyne–Stokes breathing (CSB), 295, 327 central sleep apnea (CSA) and, 413–415, 414, 415–417, 416, 671 stroke and, 1060–1061, 1061, 1063 ‘Chicago criteria’ (AASM), 411 Children, 489–496 behavioral insomnia of childhood, 671 behavioral problems, 490–493, 492, 493 child care setting, 505 epilepsy and, 1125–1126 headache and, 1075, 1077 psychobehavioral problems, 493–496

Children, (Continued) restless-legs syndrome (RLS) and, 916, 917, 940 snoring/sleep apnea, 294 see also Enuresis Children’s Sleep Habits Questionnaire, 49 China, ancient, 5 Chloral hydrate, 754 Chlordiazepoxide (LibriumÒ), 748 Choking syndrome, sleep-related, 892 Choline acetyltransferase (ChAT), 134, 135 Cholinergic agonists, 155–156 Cholinergic modulators, 805 Cholinergic neurons, 156, 838 Cholinergic pontomesencephalic neurons, 132, 134 Cholinergic projections, 152, 155, 155 Christianity, 8 Chronic fatigue syndrome (CFS) see Fibromyalgia (FM)/chronic fatigue syndrome (CFS) Chronic insomnia, 231 Chronic morning headache (CMH), 1073 Chronic obstructive pulmonary disease (COPD), 471–481 mechanisms, 473–476, 474 medications, 478–479 noninvasive intermittent positive pressure ventilation (NIPPV) and, 463 studies, 476–477 therapeutic intervention, 477 treatment, 477–480 Chronobiology, 14 Chronotherapy, 20, 966, 967 Chuang Tzu, 5 Cichlosoma nigrofasciatum (perch), 101 Cimetidine, 602 Circadian rhythm, 19, 963–964 actigraphic monitoring, 59–60, 60 age-related changes, 1012, 1013–1014 cardiovascular/cerebrovascular events, 316–317, 317 control, 167 cryptochromes, 954–955 elderly, 656–657, 656 genetics, 952–954, 955, 956 master neural clock, 951–952 molecular model, 956–957, 957 sleep regulation, 768 snoring and, 298 stroke and, 298, 1054, 1059–1060 women, 641–642 Circadian rhythm sleep disorders, 20, 673–674, 686, 826 advanced sleep phase type, 673, 865, 966–967, 967, 1017 delayed sleep phase type (DSPT), 673, 964–966, 964, 965, 1017 free-running type (nonentrained), 673, 968–969, 968 genetics, 690 irregular sleep-wake type, 673, 969–970, 969

Circadian rhythm sleep disorders, (Continued) jet lag type, 673, 971–972, 971 mental condition and, 972, 972 shiftwork type, 673–674, 970–971, 970 Cirignotta, F., 20 Citalopram, 1024 Clapare`de, Edouard, 16 Classification, 669–676 development of new, 669 history, 669–670 Climate, 503 Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimer’s disease (CATIE-AD), 1024 Clinical Journal of Sleep Medicine (Journal), 21 Clinical Sleep Society, 21 Clobazam, 1129 Clock genes, 953–954, 953 Clomipramine, 803, 803, 1129 Clonazepam bruxism and, 908 continuous spikes waves during NREM sleep (CSWS) and, 1129 elderly and, 661 REM behavior disorder (RBD) and, 875–876, 1023 restless-legs syndrome (RLS) and, 937, 940 Clonidine, 600, 909, 940 Clozapine, 598–599, 1023 Cluster headache (CH), 1076, 1078, 1079 Cocaine, 592–593 Cognition, 1022 Cognitive impairment, 916 Cognitive-behavioral therapy (CBT) bruxism and, 908 elderly and, 655 insomnia and, 731, 733, 736, 758 Cohort studies, 276 Color vision dysfunction, 874 Comorbid insomnia, 698, 725, 757 treatment, 732–733 Complex motor seizure, 1115–1116, 1117 Computerization, 40–41 Confusional arousals, 674, 853, 1150–1151 Congenital central hypoventilation syndrome, 672 Congestion theory, 12 Congestive heart failure, 336–342 central sleep apnea (CSA) and, 414, 415–417, 416 Cheyne-Stokes breathing (CSB) and, 415–417 Continuous positive airway pressure (CPAP), 20, 82, 83 autotitrating, 426–428 cardiac failure, 433–434 cardiovascular diseases, 330, 334–335, 341, 433 central sleep apnea (CSA), 415–416, 416, 422, 422, 433–434

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

SUBJECT INDEX Continuous positive airway pressure (CPAP), (Continued) chronic obstructive pulmonary disease (COPD), 476, 479 compliance, 430–432 elderly and, 659 health outcomes, 432–433 home setting, 426 interface, 429 long-term, 431 management, failure, 432 mode of action, 422, 422 neuromuscular disorders, 1101 obstructive sleep apnea syndrome (OSAS), 421–434, 1027, 1066, 1076 practical aspects, 422–426, 424, 425 pressure level/airflow, 427, 429–430 side-effects, 428–430, 428 sleep-related breathing disorder (SRBDs), 1030–1031 technologists, 432 treatment comparisons, 430 upper-airway resistance syndrome (UARS), 407 usage, 431–432 vascular effects, 1065, 1066 Continuous spikes waves during NREM sleep (CSWS), 1127–1129 age of onset/complications, 1127–1128 differential diagnosis, 1128–1129 pathology/physiology, 1128 polysomnographic findings, 1128 subtypes, 1127 treatment, 1129 Continuous ventilation, 464 Coronary artery disease, 334 Coronary disease, 1064 Corpus Hippocraticum (Hippocrates), 7 Cortical activation, 131, 132, 133 episodic, 33 Cortical pathology, 934–935, 935 Cortical silent period (CSP), 934–935 Corticobasal degeneration (CBD), 1033 Corticosteroids, 1025, 1129, 1141 Corticotropin-releasing factor (CRF), 839 Corticotropin-releasing hormone (CRH), 245–246, 685–686 Cortisol, 241, 245 ‘Cosinor’ method, 59 Cramp, 675, 888 Crayfish, 99 Creutzfeldt–Jacob disease (CJD), 981, 983, 985, 987–988 CRY protein, 955, 956, 957, 957 Cryptochromes, 954–955 cryptochrome genes, 685 Cuirass ventilator, 1101 Culture, 503 Cuttlefish, 99 Cyclic alternating pattern (CAP), 701–705, 702, 705, 709, 855 arousal and, 708, 708, 709

Cyclic alternating pattern (CAP), (Continued) effects of zolpidem, 705 scoring, 32, 33–34, 33, 718–719, 720, 721 Cyclobenzaprine, 756 Cyproheptadine, 601 Cystic fibrosis, 482 Cytokines, sleep regulation and, 229–232, 231 Czeisler, C.A., 19

D

Danio rerio (zebrafish), 101 Davey, James George, 14 Daytime light exposure, elderly, 1014, 1019, 1025 see also Bright light exposure de Candolle, Augustin Pyramus, 14 de Lecea, Luis, 16 de Mairan, Jacques, 10, 14, 18 de Manace´¨ıne, Marie, 13 De Humani Corporis Fabrica (Vesalius), 9 ‘Deafferentation’ theory, 17–18 ‘De-arousal’, 990 Death, sudden, 299, 740, 1062 see also Sudden infant death syndrome (SIDS) Decongestants, 1025 Dehydroepiandrosterone (DHEA), 250 Dejerine, Joseph Jules, 17 Delayed sleep phase syndrome (DSPS), 20, 958 Delirium tremens, 710–711, 990 Delta brush patterns, 113 Delta wave patterns, 114, 115, 115, 116 Delta-9-tetrahydrocannabinol (THC), 590–591 Dement, William, 17, 19, 20, 21 Dementia, 661–662, 830, 1015–1027, 1015, 1016 causes, 1016 circadian dysrhythmias, 1016–1021 hallucinations and, 1024–1025 insomnia and, 284, 710 with Lewy bodies (DLB), 1011, 1021–1024, 1145 medication-induced insomnia and, 1025–1026 medications for, 47 multiple system atrophy (MSA) and, 1028–1032 neurodegenerative diseases and, 1022, 1027–1028, 1033–1035 obstructive sleep apnea syndrome (OSAS) and, 1026–1027, 1026 prevalence, 1015, 1016 progressive supranuclear palsy (PSP) and, 710, 1032–1033, 1144 snoring/sleep apnea and, 299 see also Alzheimer’s disease (AD) Democritus of Abdera, 7 Dental appliances, 445–448, 908, 909

I-5 Dental appliances, (Continued) cost, 448 efficacy, 447 mechanism of action, 446 side effects, 448 treatment adherence, 447–448 types, 445–446, 446 vs continuous positive airway pressure (CPAP), 448 Depression, 557–565 elderly and, 654 multiple sclerosis (MS) and, 1140 neuroimaging, 76–78 psychophysiological relationships, 558–560 sleep complaints, 557 sleep variables, 557–558, 560–564, 560, 561, 563 treatment, 564, 593, 594, 756 Descartes, Rene´, 10 Descriptive studies, 275–276 Desert iguana, 104 Desipramine, 803, 804 Desmopressin, 366 Detrusor overactivity, 364 Detrusor relaxants, 366 Dextroamphetamine, 804, 829 Diabetes mellitus, type II, 1064–1065 Diabetic autonomic neuropathy, 1093 Diagnostic Classification of Sleep and Arousal Disorders (DCSAD), 19, 20, 670 Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) circadian rhythm sleep disorders, 963 depression, 76 insomnia, 706, 724, 725, 748 nightmare disorder, 547 NREM parasomnias, 860, 861 sleep-related eating disorder (SRED), 577 sleep-wake cycle, 1025 Dialysis, 922–923 Diaphragmatic pacing, 1103–1104 Diastolic heart failure, 336–337 Diazepam, 908 Dichotomy of sleep, 16 Dickens, Charles, 14–15, 20, 383 ‘Diencephalic’ cats, 989 Dim-light melatonin onset (DLMO), 964 Diogenes, 7 Diphenhydramine, 601–602, 735, 741, 754, 756 Dipsosaurus dorsalis (desert iguana), 104 Diurnal rhythms, actigraphic monitoring, 59–60, 60 Doll, Eric, 20 Donders, Frans Cornelius, 12 Donepezil hallucinations and, 1024 insomnia and, 1025 REM behavior disorder (RBD) and, 876, 1023 Dopamine (DA), 138, 552

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-6

SUBJECT INDEX

Dopamine (DA) agents, 876 restless-legs syndrome (RLS) and, 937, 938–939, 1028 Dopamine (DA) agonists, 828 elderly and, 660, 660 excessive daytime sleepiness (EDS) and, 997, 998–999, 1000 restless-legs syndrome (RLS) and, 938 sleep dysfunction and, 583, 597–598 Dopamine (DA) system, 79, 932–934 transmission, 804–805 Dopaminergic antipsychotics, 902 Dopaminergic mesencephalic neurons, 138–139 Dorsal raphe (DR), 767 Dorsal raphe nucleus (DRN), 162, 163, 165, 166, 776, 840 Dorsal raphe serotonergic neurons, 139, 158–159, 159 Dorsal respiratory group (DRG) neurons, 1088 Dorsomedial nucleus of hypothalamus (DMH), 768, 769 Doxepin, 734, 739, 741 Doxylamine, 741 Dreaming, 519–540 Biblical dreams, 8 Charcot–Wilbrand syndrome, 519–520 conditions for, 539–540 excessive, 530, 534–536 functional neuroanatomy, 540 global loss/suppression, 520, 522, 523–527 headache and, 1076 historical perspective, 4, 8, 16, 17 neurobiology, 546 neurochemical/psychopharmacological findings, 533, 539, 5533 neuroimaging, 531–533, 539 pontine brainstem lesions, 528 prefrontal leukotomy, 522, 528, 528, 529–530, 531, 532, 533 psychology, 546–547 REM behavior disorder (RBD), 869–870 sleep cycle and, 545 theoretical considerations, 539–540 visual imagery, loss of, 520, 521 Dreaming, abnormal, 545–554 clinical disorders, 547–552 lucid dreaming, 553–554 nightmares, recurring, 530–531, 537–539 non-clinical disorders, 552–553 see also Nightmare disorder Drosophila, 100, 105, 106, 768, 952, 953, 954, 955 Drosophila doubletime gene, 956 Drosophila melanogaster (fruit fly), 99, 100 Drug abuse, 587–593, 588 addiction, 503 bruxism and, 902 central sleep apnea (CSA) and, 671

Drug abuse, (Continued) circadian rhythm sleep disorders and, 674 dreaming and, 552 hypersomnia and, 673 insomnia and, 671, 757 movement disorder and, 675 parasomnias and, 675 prescribed medications, 593–603 Drug-induced REM behavior disorder (RBD), 873 Dubois, Raymond Emil, 13 Duchenne muscular dystrophy, 1094 Duloxetine, 596 Dupuy General Wellbeing, Vitality subscale, 645 Du¨rer, Albrecht, 9 Durham, Arthur Edward, 12 Duval, Marie Mathias, 12 Dynes, John Burton, 19 Dystonia, 1034–1035

E

Eating disorders, 581, 583 see also Sleep-related eating disorder (SRED) Eaton–Lambert myasthenic syndrome, 1093 Echidna, short-beaked, 104, 105 Ecstasy (3,4-methylenedioxy methamphetamine), 591 Edison, Thomas A., 20 EEG of Human Sleep: Clinical Applications (Williams), 38 Effect size, 281 Effector neurons, 153–154, 153, 154 Egypt, ancient, 4–5 Eichler, Victor B., 18–19 Elderly, 653–662 aging effects, 653, 1011–1015 benzodiazepine receptor agonists (BzRAs) and, 753–754 circadian rhythm, 656–657, 656 daytime light exposure and, 1025 dementia and, 661–662 insomnia and, 653–655 institutionalized, 661–662, 662 obstructive sleep apnea syndrome (OSAS) and, 1026 primary sleep disorders and, 657–661 restless-legs syndrome (RLS) and, 940 snoring/sleep apnea and, 294 thermoregulation, 220–222 Electrical status epilepticus of sleep (ESES), 1127 Electrical stimulation, 131 Electroencephalography (EEG), 19, 30–38 aging, patterns and, 38, 39 behavior episodes, 856, 857 data reduction, 34–37, 35 depression and, 558 discontinuity, 113, 114 electrode placement, 65, 66

Electroencephalography (EEG), (Continued) familial fatal insomnia (FFI) and, 983–985, 984, 985 night patterns, 37–38, 37, 38 pattern maturity, 112–116 power spectral analysis, 403–404 recurrent hypersomnias and, 817 REM sleep analysis, 151–152, 152 sleep homeostasis and, 208–210, 209, 210, 211 sleep terrors and, 859 traditional recording technique, 29–31, 30 waveforms, 31–34, 31 women and, 640 Electromyography (EMG), 30, 34, 35 Electro-oculography (EOG), 34, 35 Electrophysiology, 11, 17 Elementa Physiologiae (von Haller), 11 ‘Elpenor’s syndrome’, 1151 Empedocles, 7 Emys orbicularis (pond turtle), 103 ‘Encephalitis lethargica’, 830 Endocrine/metabolic changes, 241–251 galanin, 248–249 gonadal hormones, 249 hypothalamo-pituitary-adrenocortical (HPA) system, 241, 242, 244–246 hypothalamo-pituitary-somatotrophic (HPS) system, 241–244 hypothalamo-pituitary-thyroid (HPT) system, 246–247 insulin, 247–248 leptin/ghrelin, 247 melatonin, 249 neuroactive steroids, 250 neuropeptide Y, 249 prolactin, 248 End-stage renal disease, 922–923 Energy metabolism, 193–194, 194 Enuresis, 355–356, 363–368 classification, 674 defined, 363 epidemiology, 363 etiology/pathogenesis, 363–365 management, 366–368 treatment, 365–366 Environmental factors light exposure, 1014, 1019 narcolepsy, 784 sudden infant death syndrome (SIDS) and, 504–505, 508, 511–512, 511 Ephedra (Ma Huang), 5 Epic dreaming, 551–552 Epicurus, 7 Epidemiological methods, 275–282 confounding, 278–279 data collection, 276 information bias, 278 P-value, 277 population size, 277 population surveys, 276 population-based rates, 279–282

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

SUBJECT INDEX Epidemiological methods, (Continued) power calculations, 277 randomized controlled trials, 279 selection bias, 278 standardization/matching, 279 studies, 275–276 validity, 277–278 Epidemiology, sleep disorders, 282–303 bruxism, 901–902 enuresis, 363 epilepsy, 1110 excessive daytime sleepiness (EDS), 286–289, 287–288, 997–998 insomnia, 282–285, 723 narcolepsy, 289, 290, 784 parasomnias, 300 REM behavior disorder (RBD), 1001 restless-legs syndrome (RLS), 300, 301–302, 303, 1142 sleep-related breathing disorder (SRBD), 286, 291 smoking, 589 snoring/sleep apnea, 289–300 upper-airway resistance syndrome (UARS), 402 Epilepsy, 1109–1133 antiepileptic drugs (AEDs) and sleep, 1125, 1132–1133 dreaming and, 552 effect on sleep, 1129–1130 epidemiology, 1110 focal, 68–69 generalized syndromes, 68, 1110, 1126 historical perspectives, 1109–1110 insomnia and, 710 interictal epileptiform discharge (IED), 1126, 1130–1131 overview, 1133 pathogenesis, 1110–1111 sleep deprivation and, 1131 sleep disorders and, 1131–1132 subtypes, clinical/polysomnographic features, 1111–1129 see also Nocturnal frontal lobe epilepsy (NFLE) Epileptic nocturnal wanderings (ENW), 1112 Episodic nocturnal wanderings, 1152 Epworth Sleepiness Scale (ESS), 48, 48, 598, 999, 1051, 1098 antiepileptic drugs (AEDs) and, 1132 Erectile dysfunction (ED), 357, 358–359, 359 Erections (SREs), sleep-related, 357–359 Errera, Leo, 13 Estazolam, 734, 736, 749, 750 Estrogen levels, 642–643 Estrogen replacement therapy (ERT), 603, 646, 647 Eszopiclone circadian sleep disorders and, 826 elderly and, 655 insomnia and, 734, 738, 749, 750, 751 restless-legs syndrome (RLS) and, 940

Ethnic differences, 294 Ethosuximide, 1129 European data format (EDF), 43 European Neurological Society, 383 European Sleep Research Society, 21 Event-related desynchronization (ERD), 935–936 Event-related synchronization (ERS), 935 Evoked potentials, 51 Excessive daytime sleepiness (EDS), 45–52, 825–830 clinical characteristics, 1051–1052 elderly and, 653, 658, 659 epidemiology, 286–289, 287–288, 997–998 etiology, 46, 998–999 evaluation, 999, 1000 hallucinations and, 1002–1003 historical perspective, 45–47 Maintenance of Wakefulness Test (MWT), 50–51 medications, 47 Multiple Sleep Latency Test (MSLT), 48–49, 49–50 narcolepsy and, 783, 784–785, 786, 788, 792, 800 neurological basis, 825 nocturnal polysomnography, 49 obstructive sleep apnea syndrome (OSAS) and, 231 orexin (hypocretin) and, 769, 770, 800 Parkinson’s disease (PD) and, 997–1000 pathophysiology, 998–999, 1057–1058 physical examination, 47–48 practical applications, 51–52 sleepiness syndromes, 825–830 special tests, 51 subjective testing, 48–49, 48 treatment, 802, 802, 999–1000 Excessive fragmentary myoclonus, 676 hypnic (EFHM), 884–885, 885 Exorcism, 9 Exploding head syndrome, 885, 1075, 1077, 1079 classification, 674 Eye motility, 30

F ‘Factor S’, 16 Familial advanced sleep phase syndrome (FASPS), 198 Familial sleep disorders, genetics, 686–690 Famotidine, 602 Fatal familial insomnia (FFI), 20, 198, 710–711, 981, 982–988, 1035 ‘agrypnia excitata’, concept of, 990–991 clinical features, 982–983, 983 genetics, 198 laboratory findings, 983–985, 984, 985 molecular neurobiology, 987–988 neuroimaging, 985–988, 986

I-7 Fatal familial insomnia (FFI), (Continued) neuropathological aspects, 986–987 prion protein and, 991–992 thalamus and, 988–990 Fatigue, 231, 919 clinical characteristics, 1051–1052 pathophysiology, 1057–1058 see also Fibromyalgia (FM)/chronic fatigue syndrome (CFS) Fatigue Severity Scale (FSS), 1051 Fear and Avoidance Scale, 431 Feet movement foot tremors, hypnagogic, 676, 889 rhythmic, 889 Felbamate, 596, 1132 Ferritin, 930–932 Fetal growth retardation, 503 Fibromyalgia (FM)/chronic fatigue syndrome (CFS), 231, 621–631, 1080 associated conditions, 624–625 background, 621–622 definitions, 622–623 diagnosis, 622, 628–629 pathogenesis/pathophysiology, 627–628 prevalence/risk factors, 623–624 recommendations, 630–631 sleep disturbance and, 614, 625–626 treatment, 629–630 Filter settings, 39, 40 Finley, Knox H., 19 Finnish Twin Cohort, 275 ‘First-night effect’, 58 Fischer, Franz, 14 Fish, 100–102 Flamingos, 104 Fleming, Alexander, 12 ‘Flip-flop’ switch, 712, 776 Flourens, Marie Jean Pierre, 11, 13 Flower clock, 10 Fluoxetine, 595, 706, 803, 804 Flurazepam bruxism and, 909 insomnia and, 708, 734, 736, 749, 750 Fluvoxamine, 803 Focal epilepsy, 68–69 Focal temporal lobe epilepsy, 1130 Follicle-stimulating hormone (FSH), 644 Food allergy insomnia, 20 Food deprivation, 777 Food and Drug Administration (FDA), 657, 736, 741, 748, 754, 938, 971, 1020, 1028, 1104 Foot tremors, hypnagogic, 676, 889 Forebrain basal, 137, 141 modulation, 840–842, 841 reticular activating system, 134–135, 766 reticular neuron projection, 132, 133 Forel, Auguste Henri, 18 Forensic experts, 1154 Framington Cohort, 275

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-8

SUBJECT INDEX

Freud, Sigmund, 15, 16, 19 Frogs, 102 Frontal Lobe Epilepsy and Parasomnias (FLEP) Scale, 1123 Frontal lobe lesions, 529–530 Frontotemporal dementia (FTD), 1017 Fruit fly, 99, 100 Fu Hsi, 5 Fujita, Shiro, 20 Functional magnetic resonance imaging (fMRI), 71 memory and, 263, 266 narcolepsy, 79–80 obstructive sleep apnea syndrome (OSAS), 83 periodic limb movement, 85 Functional Outcomes of Sleep Questionnaire, 49 Functional residual capacity (FRC), 475

G GABAergic influences dorsal raphe nucleus (DRN)/locus caeruleus (LC), 163, 166 pontine reticular formation (PRF), 165 REM sleep, 161–164, 164–167, 165 Gabapentin, 596–597 bruxism and, 909 effect on sleep, 1132 insomnia and, 735, 740 restless-legs syndrome (RLS) and, 828, 937, 939, 1028 Gaboxadol, 1132 Galanin, 248–249 Galantamine, 1025 Galbraith, J.J., 19 Galen, 8 Galvani, Luigi, 11 Gamma-aminobutyric acid (GABA), 133, 591, 726, 1111 agonists, 1132 complex, 749 GABAergic neurons, 141–143, 166–167, 178, 179–181, 767 hypnotic drugs and, 143 REM sleep disinhibition, 163–164, 164 system, 740–741 see also GABAergic influences Gamma-hydroxybutyrate (GHB), 591, 802–803 modes of action, 805 ‘Gas’, 10 Gastaut, Henri, 20 Gastroesophageal reflux (GER), 348–350, 348, 349, 350 clinical aspects, 350–351 disease (GERD), 348, 350–351 Gastrointestinal functioning, 348–353 intestinal motility, 351–353 Gating, sensory transmission, 618–619 Gayet, Maurice Edouard Marie, 13 Ge´lineau, Jean Baptiste Edouard, 14, 19 Gender differences bruxism, 901–902

Gender differences (Continued) restless-legs syndrome (RLS), 924–925 see also Women Generalized anxiety disorder (GAD), 566, 728 Generalized epilepsy syndromes, 68 Generalized tonic-clonic seizures (GTCSs), 1110, 1126 Genetics, 681–690 bruxism, 901–902 circadian rhythm, 690, 952–954, 955, 956 familial sleep disorders, 686–690 fatal familial insomnia (FFI), 198 gene expression, 191–196, 196 Kleine–Levin syndrome (KLS), 690 memory, 268–269 narcolepsy, 198, 688–689, 784 normal sleep regulation, 681–686, 682, 684, 685 obstructive sleep apnea syndrome (OSAS), 689 periodic leg movements (PLMs), 687 restless-legs syndrome (RLS), 686–688, 929–930 of sleep, 106 sleep disorders, 197–198, 197 sleep terrors, 858 somnambulism (sleepwalking), 854 studies, 196–199, 197 sudden infant death syndrome (SIDS), 507–508 Genitourinary systems, 355 Georg Ebers papyrus, 4 German Migraine and Headache Society Study Group, 1077 Gerstmann–Straussler–Sheinker syndrome (GSS), 981 ‘Ghost oppression phenomenon’, 894 Ghrelin, 242, 247 Ginseng, 5 Glutamatergic neurons, 178–179 Glycine, 838 Goldfish, 101 Golgi, Camillo, 12 Gonadal hormones, 249 Gopherus flavomarginatus (tortoise), 103 Greece, ancient, 6–7 Griesinger, Wilhelm, 16 Groaning, nocturnal (catathrenia), 674, 891–892, 891 Growth hormone (GH), 241–242, 243 Growth hormone-releasing hormone (GHRH), 241–243 Guilleminault, Christian, 20

H

Habitual snoring see under Snoring Hallucinations, 674 complex nocturnal visual, 893–894 dementia and, 1024–1025 hypnagogic, 787, 828, 893–894, 1052, 1152 hypnopompic, 787, 893–894 Lhermitte’s peduncular, 1053

Hallucinations, (Continued) Lilliputian, 894 Parkinson’s disease (PD) and, 1002–1003 stroke and, 1053, 1055 treatment, 1024–1025 Haloperidol, 599, 902 Hamilton Depression Rating Scale (HDRS), 77 Hammond, William Alexander, 12, 14 Harvey, E. Newton, 17 Harvey, William, 9, 10 Hauri, Peter, 20 Headache, 1073–1083 causes, 1080–1081 clinical evaluation, 1074–1076, 1074 comorbidity, 1079–1081 functional aspects, 1082–1083 insomnia and, 711 prevalence, 1073–1074 sleep disturbances, associated, 1076–1081, 1078, 1081–1082 sleep duration, 1075 sleep pattern, 1075 sleep stage, 1075 sleep-relieved, 1075–1076 sleep-triggered, 1074 Headbanging, 889 Headrolling, 889 Heart (cardiac) failure, 333, 336–342, 433–434, 1064 pathophysiologic sequelae, 337–338 Heart disease, 295 Heart rate variability (HRV), 121 Hemispheric stroke, 1055, 1057, 1059 Henneberg, Richard, 14 Heraclitus, 7 Herbal medicines, 5 Heredity, enuresis and, 363 Hering–Breuer reflex, 372 Herodotus, 4–5 Hess, Walter Rudolph, 17 Heubel, E., 13 High-altitude headache, 1081 High-altitude periodic breathing, 671 Hill, Sir Leonard Erskine, 12 Hill, William, 15 Hippocrates, 7, 9, 11 Histamine (HA), 139 -orexin (hypocretin) interactions, 774–775 Histaminergic tuberomammillary neurons, 139–140 Historical perspective, 3–21 prehistoric and ancient times, 3–8 middle ages and Renaissance, 8–9 17th and 18th centuries, 9–11 19th century, 11–15 20th century, 15–21 classification, 669–670 dreaming, 4, 8, 16, 17 epilepsy, 1109–1110 excessive daytime sleepiness (EDS), 45–47, 46

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

SUBJECT INDEX Historical perspective, (Continued) neurobiology, waking/sleeping, 131, 132, 133 nocturnal eating/drinking syndrome (NEDS), 577–578 recurrent hypersomnias, 815–816 sleep-related eating disorder (SRED), 577–578, 578 Hobart, Garret, 17 Hobson, J. Allan, 18 ‘Hoffman’s anodyne of opium’, 11 Homeostasis see Sleep homeostasis Homer, 3, 6 Homovanillic acid (HVA), 934 Honey bee, 99–100, 100 Hormone replacement therapy (HRT), 445, 603, 643, 647 Hormones, 602 levels, 817, 818 studies, 933 thyroid, 1025 women and, 642–643 Huang Ti, Yellow Emperor, 5 Human leukocyte antigen (HLA), 688 narcolepsy and, 783, 796–800, 797, 798, 829 recurrent hypersomnias and, 817 Humoral factors, sleep regulation, 229, 230, 769 Humoralism, 7 Huntington’s disease, 1034 5-Hydroxytryptamine (5-HT) levels, 158–159, 159, 161, 755, 776, 895, 1082 Hydroxyzine, 601–602, 756 Hygiene see Sleep hygiene Hyla squirella (tree frog), 102 Hyoscyamine, 4 Hyperalgesia, sickness-induced, 617 Hypercapnia, 375–376, 376, 379 Hypercapnic central sleep apnea, 411–412 Hyperhydrosis, sleep, 892–893 Hypersomnias central origin, 828–830 classification, 672–673 clinical characteristics, 1051–1052, 1053–1054, 1056–1057 diagnosis, 1059–1060 headache and, 1077 menstrual-related, 830 nervous system disorder-related, 830 pathophysiology, 1057–1058 primary, 1032 sleep disorder-related, 826–828 treatment, 1059–1060 unspecified, 673 see also Recurrent hypersomnias Hypersomnolence, 1028 Hypersynchronous delta (HSD) waves, 855, 859 Hypertension see Arterial hypertension Hyperthermia, 505 Hypnagogic foot tremors, 676, 889

Hypnagogic hallucinations, 787, 828, 893–894, 1052, 1152 Hypnic headache, 1075, 1076, 1078, 1079 Hypnic jerks, 300, 675, 885–886 Hypnopompic hallucinations, 787, 893–894 Hypnosis, 864 Hypnotic drugs, 709–710 gamma-aminobutyric acid (GABA) and, 143 insomnia and, 705, 708, 748–749, 756–757, 1036 restless-legs syndrome (RLS) and, 937, 940 warnings, 739 Hypnotoxins, 16 Hypocapnic central sleep apnea, 412–417, 412 Hypocretin see Orexin (hypocretin) Hypothalamic orexinergic neurons, 374 Hypothalamic sleep-wake regulation system, 773, 773 sleep-promoting system, 775–776 vigilance control links, 776–777 wake-promoting system, 769–770, 770, 775–776 Hypothalamo-pituitary-adrenocortical (HPA) system, 241, 242, 244–246, 627–628 Hypothalamo-pituitary-somatotrophic (HPS) system, 241–244 Hypothalamo-pituitary-thyroid (HPT) system, 246–247 Hypothalamus, 765–766 posterior, 181 Hypoventilation alveolar, 472–473, 475, 1089, 1090, 1094 signs and symptoms, 460 sleep-related, 411–412, 412, 672 Hypoxemia, 672, 1089 nocturnal, 476–477 Hypoxia, 375, 378

I Ictal events (IEs), 1109, 1111, 1130, 1132 Idiopathic central sleep apnea, 413 Idiopathic hypersomnia, 786, 792, 829 with long sleep, 673 without long sleep, 673 Idiopathic insomnia, 75–76, 76, 670, 725 Idiopathic REM behavior disorder (RBD), 874–875, 1022–1023 Idiopathic sleep-related nonobstructive alveolar hypoventilation syndrome, 672 Iguanas, 102–103, 104 Iliad (Homer), 3, 6 Illness see Medical illness Imagery rehearsal therapy (IRT), 550 Imhotep, 4 Imipramine, 803, 803 Immediate early genes (IEGs), 192, 192 Immune system, 798–799

I-9 Immunomodulating therapy, 1141 Incidence, 280 India, ancient, 5 Indiplon, 750 Infants see Neonates and infants; Sudden infant death syndrome (SIDS) Infections, 505–506 Inflammatory pain models, 620–621 Infratentorial stroke, 1057 Inhalants, 591 Inhibitory postsynaptic potentials (IPSPs), 837–838 Inhibitory theory, 13 Insects, 99–100 Insomnia, 826 autonomic costs, 708–709 behavioral approaches, 654–655, 655, 729–733, 730, 736 biological basis, 726 chronic, 231 classification, 670–671, 699 consequences of, 654 course/prognosis, 725–726 cyclic alternating pattern (CAP) and, 712–713 daytime findings, 724–725 defined, 697–698, 747–748 diagnosis, 698–699, 699, 1060 differential diagnosis, 727–728 elderly and, 653–655 epidemiology, 57, 282–285, 723 etiology, 726 evaluation, 727, 727, 728, 729 food allergy, 20 headache and, 1076, 1077 idiopathic, 75–76, 76, 670, 725 medication-induced, 1025–1026 multiple sclerosis (MS) and, 1139–1142 neurological causes, 709–711, 709 neurological/somatic diseases and, 284–285 neurophysiological bases, 699–705 occupations and, 283 pathophysiology, 726, 1058 pharmacotherapy, 705–706, 733, 734–735, 736–741, 747–759, 1036–1037, 1060 polysomnographic (PSG) findings, 724 presenting complaints, 723–724 psychiatric disorders and, 283–284, 670–671 psychological approaches, 726, 729–733, 730 rebound, 752–753 seasonal differences, 283 secondary, 699, 757 stroke and, 1052, 1055, 1056 subtypes, 725 symptoms, 747–748 underlying factors, 711–712 unspecified, 671 women and, 647

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-10

SUBJECT INDEX

Insomnia, (Continued) see also Fatal familial insomnia (FFI); Primary insomnia; Sporadic fatal insomnia (SFI) Insomnia disorder, 698 Insomnia Severity Index, 727, 729 Insomnia symptom, 698 Inspiratory muscle training, 479 Inspiratory vital capacity (IVC), 1097 Institutionalized elderly, 661–662, 662 Insufficient sleep, 825 Insulin, 247–248 Intelligence, children, 495 Interferons, sleep regulation and, 232–233 Interictal discharges (IDs), 1109, 1110–1111, 1130, 1132 Interictal epileptiform activity (IEA), 1126, 1127 Interictal epileptiform discharge (IED), 1126, 1130–1131 International Classification of Diseases (ICD), 501, 669–670 ICD-9-CM, 669–670 ICD-10, 669 International Classification of Headache Disorders (ICHD), 1073, 1076, 1079 International Classification of Sleep Disorders (ICSD-1), 21, 670, 892 International Classification of Sleep Disorders (ICSD-2), 21, 669, 670–676 bruxism, 901, 903 categories, 883 circadian rhythm sleep disorders, 963, 967 excessive fragmentary hypnic myoclonus (EFHM), 884 headache, 1073 insomnia, 697, 698, 699, 706, 725, 725, 748 narcolepsy, 289, 547, 783, 788, 792, 795 parasomnias, 860, 861, 893 recurrent hypersomnias, 816 REM behavior disorder (RBD), 871–872, 871 sleep-related abnormal sexual behaviors (SRASBs), 860 sleep-related eating disorder (SRED), 578, 578, 580, 859 International Restless-Legs Syndrome Study Group (IRLSSG), 913, 924, 927 Interpretation of Dreams (Freud), 19 Interstitial lung disease, 481–482 Intervention studies, 275–276 Intracellular mechanisms, 269 Intracortical facilitation (ICF), 935 Intracortical microstimulation (ICMS), 906 Intracranial pressure (ICP), 1076–1077 Invertebrates, 99 IPPV see Noninvasive intermittent positive pressure ventilation (NIPPV) Iron deficiency, 921, 940

‘Iron lung’, 1101 Iron metabolism, 930 Iron regulatory proteins (IRPs), 931 ‘Irreminiscence’, 520, 522 Irritable bowel syndrome (IBS), 351–353 Isolated sleep paralysis (ISP), 674, 785, 787, 894–895

J Jackson, John Hughlings, 12, 18 Jactatio capitis, 889 Jactatio corporis nocturna, 889 Janota, Otakar, 19 Japanese Society for Sleep Research, 21 Jaw movements (RJMs), rhythmic, 906–907, 906 Jet lag disorder, 673, 971–972, 971 Jouvet, Michel, 18 Jung, R., 20 ‘Junk science’, 1154 Juvenile dystonia, 1035 Juvenile myoclonic epilepsy, 1126

K Kahn, Andre, 20 Kales, Anthony, 17, 20 ‘Kanashibari’, 894 Karolinska scale, 48 Ketamine, 591 Kilduff, Thomas, 16 Kleine–Levin syndrome (KLS), 815, 830 behavioral/cognitive abnormalities, 819 clinical features, 816 demographics, 816 diagnostic criteria, 816–817 genetics, 690 hormonal levels, 817, 818 laboratory tests, 817 neuroimaging, 818 orexin (hypocretin) levels, 817 pathophysiology, 820 treatment, 820 Kleitman, Nathaniel, 17, 18, 19 Konopka, R., 19 Kuhlo, Wolfgang, 20 ‘Kuru’, 981 Kyphoscoliosis, 481

L Lamotrigine, 597, 939 Landau–Kleffner syndrome, 1111, 1128–1129 Laryngospasm, sleep-related, 892 Laser-assisted uvulopalatoplasty (LAUP), 450 Lateral preoptic area (LPOA), 173–174 Lateral vestibular nucleus, 836 Laterodorsal tegmental nucleus (LDT), 174 cholinergic projections, 152, 155, 155 discharge activity, 156 lesion/stimulation effects, 156 serotonergic inhibition, 159–160, 160, 161 Laterodorsal tegmentum (LDT), 766, 767

Latin American Sleep Society, 21 Laudanum, 9 Lavoisier, Antoine-Laurent, 11 Law, medicolegal evaluation, 1153–1155 ` Le probleme physiologique du sommeil (Pieron), 19 Learning, children, 495–496 Lee Fatigue Scale, 645 Leg cramps, 675, 888 Leg muscle activation, alternating, 676 Legendre, Rene´, 16 Lennox–Gastaut syndrome, 1127, 1129, 1130 Lepine, Raphael Jacques, 12 Leptin, 247 Lesion studies, 160–161 Leucippus of Miletus, 7 ‘Leucomaines’, 13 Levetiracetam, 597, 1132 Levodopa excessive daytime sleepiness (EDS) and, 999 hypersomnia and, 1059 restless-legs syndrome (RLS) and, 828, 937, 938, 939 sleep dysfunction and, 597, 598 Lewy bodies (DLB), dementia with, 1011, 1021–1024, 1145 Lhermitte, Jacques Jean, 17 Lhermitte’s peduncular hallucinosis, 1053 LibriumÒ, 748 Lifestyle modification, 442–444 Light dim-light melatonin onset (DLMO), 964 sensitivity, 1013–1014 transmission dysfunction, 1013, 1018–1020 see also Bright light exposure Lilliputian hallucinations, 894 Limb movements see Periodic leg movements (PLMs); Periodic limb movement disorder (PLMD); Periodic limb movement disorder of sleep (PLMS) Linnaeus, C., 10 Lions, 104 Lithium (Li), 596, 830, 1028 Lizards, 102, 102 Locus caeruleus (LC), 156–157, 157–158, 767, 776 GABAergic influences and, 165, 166 neurons, 138, 839–840 REM sleep phenomena and, 160–161, 162–163 Loggerhead sea turtle, 103 Loomis, Alfred L., 17 Loratadine, 601 Lorazepam, 705, 908 Lucid dreaming, 553–554 Lucretius Carus, Titus, 7 Lugaresi, E., 20 Lugaro, Ernesto, 13 Lumbar punctures (LPs), 794

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

SUBJECT INDEX Lung capacities/volumes, 1099–1100, 1100 Lung inflation reflex, 372 Lymnaea stagnalis (pond snail), 99

M McCarley, Robert William, 18 McGregor, Peter Anderson, 21 Machado–Joseph disease, 1033–1034 MacNish, Robert, 12 Maculopathy, 1013 ‘Mad cow disease’, 981 Magnetic resonance imaging (MRI), 86 see also Functional magnetic resonance imaging (fMRI) Magnetic resonance spectroscopy, proton, 80–81, 82–83 Magoun, Horace W., 18 Maimonides, 9 Maintenance of Wakefulness Test (MWT), 50–51, 792, 999, 1133 Malingering, 1152–1153 Malpighi, Marcello, 9 Mammals, 97, 98, 103–105 Mandibular surgery, 450–451 Mania, 565–566 Marijuana, 590–591 Mauthner, Ludwig, 13, 17 Maxillary surgery, 450–451 Medians, 280 Medical illness, 654 central sleep apnea (CSA) and, 671 circadian rhythm sleep disorders and, 674 hypersomnia and, 673 hypoventilation/hypoxemia and, 672 insomnia and, 671 movement disorder and, 675 narcolepsy and, 672 parasomnias and, 675, 860 Medical schools, establishment of, 9 Medication, 19, 20, 654 respiratory-depressant, 442–443 specialists, 1154 see also specific drugs Medroxyprogesterone, 444, 478 Melanin-concentrating hormone (MCH), 777 peptidergic neurons, 182–183 Melanopsin, 1013 Melatonin age-related changes, 1012–1013, 1017 circadian rhythm and, 966, 967, 969, 971, 972 dementia and, 1020 insomnia and, 735, 738, 741 REM behavior disorder (RBD) and, 876 secretion, 769 studies, 249 Melatonin receptor agonists, 734, 738–739, 754–755 Melatonin replacement therapy, 657 Memantine, 1024

Membrane trafficking, 195 Memory, 259–270 biological/genetic factors, 268–269 children, 495 experiments, 259–260 impairment, 752 implications, 269–270 NREM sleep and, 264–268 REM sleep and, 261–264, 263, 264, 266–268 ‘topographical’, 520 types of, 260 Menopause, 249, 360, 645–646 Menstrual cycle, 249, 360, 643–644 hypersomnia and, 830 Mental disorder see Psychiatric diseases Meprobamate, 908, 990 Mesencephalic locomotor region (MLR), 843 Metabolic regulation cerebral blood flow (CBF), 318 see also Endocrine/metabolic changes Metabolic syndrome, 1064–1065 Metal neurotoxicity, 603–604 Methadone, 937, 939 Methamphetamine, 804 Methyldopa, 600–601 3,4-Methylenedioxymethamphetamine (ecstasy), 591 Methylphenidate hypersomnia and, 1059 insomnia and, 1037 narcolepsy and, 804, 829 neuromuscular disorders and, 1104 recurrent hypersomnias and, 820 Methylprednisolone, 1142 Metu (system of channels), 4 Mianserin, 1060 Michelangelo, Buonarroti, 9 Microarrays, 686 Micturition, 355–357 Midlife crisis, 646–647 Midline alpha/theta activity, 115, 117 Mignot, Emmanuel, 16 Migraine, 711, 1075, 1077, 1078, 1078, 1081–1082 Milnacipran, 803 Mink encephalopathy, 981 transmissible (TME), 992 Minnesota Multiphasic Personality Inventory (MMPI), 561 Mirtazapine efficacy, 755–756 insomnia and, 734, 740, 755 safety, 756 sleep dysfunction and, 595 Mitchell, Robert A., 20 Mobile phone radiation, 1081 Modafinil cataplexy and, 803 excessive daytime sleepiness (EDS) and, 1000 hypersomnia and, 1059 narcolepsy and, 804

I-11 Modafinil (Continued) neuromuscular disorders and, 1104 obstructive sleep apnea syndrome (OSAS) and, 445 Parkinson’s disease and, 1028 recurrent hypersomnias and, 820 sleep dysfunction and, 592 Molecular neurobiology, 191–200 cellular function, 191 gene expression, 191–196, 196 genetic studies, 196–199, 197 Moniz, Egas, 17 Monoamine oxidase inhibitors (MAOIs), 593–594, 595, 598, 827 Monoaminergic modulators, 805 Monoaminergic neurons, 176–178, 179–181 Montgomery–Asberg Depression Rating Scale, 1067 Mood disorders, 581, 583, 919–920 Mood stabilizers, 820 Moore, Robert Y., 18 Morning headache, 1081, 1081 Mortality rates, 280 Moruzzi, Giuseppe, 18 Morvan’s chorea, 710–711 Mosso, Angelo, 12 Motility patterns, 117 Motor behaviors, neuroimaging, 84–87 Motor control, 835–845 caudal brainstem, 838–840, 839 disturbances, nocturnal, 1031–1032 early studies, 836–837 forebrain modulation, 840–842, 841 motor neuronal activity, 837–838, 837 motor suppression, 835–836 REM sleep characteristics, 843–845, 845 REM sleep without atonia, 842–843, 844 Motor neuron disease, 1091–1092, 1093, 1094, 1095 Mouth dryness, 465 Movement disorders classification, 675 unspecified, 675 Moxibustion, 5 Multiple sclerosis (MS), 1139–1144 insomnia and, 1139–1142, 1142 medication and, 1141–1142 narcolepsy and, 1142–1143 REM behavior disorder (RBD) and, 1144 sleep-disordered breathing (SDB) and, 1142, 1143 Multiple Sleep Latency Test (MSLT), 17, 19 antiepileptic drugs (AEDs) and, 1132, 1133 children and, 489, 494 excessive daytime sleepiness (EDS), 48–49, 49–50, 999 idiopathic hypersomnia, 829 narcolepsy, 783, 786, 788–790, 792, 794–795, 800, 828–829

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-12

SUBJECT INDEX

Multiple Sleep Latency Test (MSLT), (Continued) neuromuscular disorders, 1099 obstructive sleep apnea syndrome (OSAS), 432 periodic limb movement index (PLMI) and, 1027 recurrent hypersomnias, 817, 830 stroke, 1059 Multiple system atrophy (MSA), 1028–1032 Munchausen syndrome by proxy, 1153 Munich-Composite International Diagnostic Interview (M-CIDI), 920 Muscle atonia, 156–157, 278, 842–843, 844, 845, 870, 1023 Muscle disorders cramps, 675, 888 primary, 1093–1094 Muscle relaxants, 47, 366, 756, 908 Muscle training, 479 Muslim world, 8–9 Mutation screening, 794 Myoclonus, 884–885, 885, 887–888 ankle dorsiflexion, 888 benign sleep, of infancy, 676, 887–888 epilepsy syndromes, 888 fragmentary, 676, 883–884, 884–885, 884, 885 nocturnal, 827 propriospinal (PSM), 676, 886–887, 887 Myofascial pain, 1080 Myotonic dystrophy, 1094–1096 Mysticism, 9

N Narcolepsy, 14, 16, 19, 783–807, 828–829 animal models, 787–788, 791 cataplexy, with, 672, 785, 786, 793–794, 796 cataplexy, without, 672, 786, 798, 799–800 classification, 672 defined, 783 diagnostic criteria, 788–792, 791 differential diagnosis, 792 dreaming and, 551 environmental factors, 784 epidemiology, 289, 290, 784 evaluation, 788–792 gene mutation, 765 genetics, 198, 688–689, 784 headache and, 1077, 1077 human leukocyte antigen (HLA) and, 796–798, 797, 798–799, 798, 800 immune system and, 798–799 multiple sclerosis (MS) and, 1142–1143 neuroimaging, 78–81, 81 neurological diseases and, 769, 770 orexin (hypocretin) and, 769, 770 pathophysiology, 793–802 REM behavior disorder (RBD) and, 873

Narcolepsy, (Continued) secondary, 786 symptomatic, 792, 800 symptoms, 784–787, 786 treatment, 802–805, 802, 803, 805–806, 806 unspecified, 672 ‘Narcoleptic tetrad’, 894 Narcotics, 754 Nasal congestion, 428–429, 464 Nasal dryness, 464 Nasal obstruction, 444 Nasal surgery, 450 National Academy of Sciences, 1020 National Institute of Mental Health, 757 National Institutes of Health State of the Science Conference on Insomnia, 655, 657 State of the Science Conference on Manifestation and Management of Chronic Insomnia, 698, 747 National Sleep Foundation, 21, 648 Nauta, Walle Jetz Harinx, 18 Nefazodone, 568, 595, 706 Negative-pressure ventilation, 479 ventilators, 1101 Nei Ching (Canon of Medicine) (Yu Hsiung), 5 Neonates and infants, 111–125 brain adaptation to stress, 121–122 electrographic pattern maturity, 112–116 neurophysiologic interpretation, 111–112 physiologic behaviors, 116–118, 116 recording techniques, 112 sleep ontogenesis, 119–121 sleep organization analysis, 122–125, 122, 123 state organization, 118–119 thermoregulation, 222–224, 223 see also Sudden infant death syndrome (SIDS) Neural circulatory regulation, 315, 316 Neural control, breathing, 371–375 Neural plasticity, 124–125 Neural theories, 12–13 Neuroactive steroids, 250 Neurobiology, REM sleep, 151–167 electroencephalography (EEG) analysis, 151–152, 152 GABAergic influences, 161–164 neurons, REM-off/REM-on, 157–161, 157, 165–167, 165, 176–179, 767–768 orexin (hypocretin) effects and circadian control, 167 physiology and brain anatomy, 152–157 promoting systems, 152–154, 153, 154–157 REM sleep generation model, 164–167, 165 suppressive systems, 157–161, 157

Neurobiology, waking and sleeping, 131–144 arousal systems, diffuse projection, 135–136, 138–141 dreaming, 546 forebrain relays, activating system, 134–135 historical perspective, 131, 132, 133 reticular activating system, 133–134, 134–135 sleep-promoting systems, 141–143 see also Molecular neurobiology Neurochemistry of sleep, 16, 173–184 dreams, 533, 539 models, 176, 176, 183, 184 REM sleep onset/maintenance, 176–183 sleep onset/maintenance, 173–176 Neurocognition, 494 Neurodegenerative diseases, 1022, 1027–1028, 1033–1035 comorbidity, 1027–1028 REM parasomnias and, 873–874 see also Dementia Neurogenic tachypnea, 892 Neuroimaging dreams, 531–533, 539 fatal familial insomnia (FFI), 985–988, 986 Kleine–Levin syndrome (KLS), 818 normal human, 71–75 recurrent hypersomnias, 818 sleep disorders, 75–87 Neuroleptics, 1028 Neurological diseases, 284–285, 769, 770, 1150–1152 Neuromelanin cells, 931 Neuromuscular disorders, 481, 711, 1087–1104 breathing, control of, 1087–1089, 1088 breathing pattern types, 1096–1097, 1096 junctional, 1093 respiratory failure, 1097–1100 sleep disorders and, 1089–1096 treatment in, 1101–1104, 1101 Neuropathy, 923, 1093 pain models, 621 Neuropeptide Y, 249 Neurophysiology, 17–18 insomnia, 699–705 neonates and infants, 111–112 Neurospora, 956 Neurospora crassa, 952 Neurotransmitters, 156, 592 ventrolateral preoptic area (VLPO) neurons, 174–176 Newborn Individualized Developmental Care and Assessment Program (NIDCAP), 223 Nicotine, 589–590 acute exposure to, 589–590 transdermal, 1125 withdrawal, 590 see also Smoking

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

SUBJECT INDEX Niemann–Pick type C disease, 792 Night sweats, 892–893 Nightmare disorder, 547–550, 894 classification, 674 diagnosis, 547–549 differential diagnosis, 549 medication-induced, 1025–1026 recurring, 530–531, 537–539 sleep terrors, 550–551 treatment, 549–550 see also Dreaming, abnormal Nighttime mental activity (NTMA), 267–268 N-methyl-D-aspartate (NMDA), 843 Nociception, 619–620 Nocturia, 356–357, 1140 Nocturnal eating/drinking syndrome (NEDS) differential diagnosis, 579–580, 579 historical perspective, 577–578 neuroendocrine studies, 582 prevalence, 580 treatment, 582–583 Nocturnal frontal lobe epilepsy (NFLE), 1110 age of onset/complications, 1114, 1117 clinical/pathophysiological subtypes, 1112–1114, 1112, 1113, 1114–1115, 1115–1116, 1117 differential diagnosis, 1123–1125, 1124 pathology/pathophysiology, 1117–1118 polysomnographic findings, 1118–1123, 1120–1121, 1121–1122 treatment, 1125 Nocturnal hypoxemia, 476–477 Nocturnal myoclonus, 827 Nocturnal oxygen therapy (NOT), 477–480 supplemental nasal, 342 Nocturnal polysomnography, 49 Nocturnal polyuria, 363–364 Nocturnal ventilation, 463–464 Nonbenzodiazepines excessive daytime sleepiness (EDS) and, 47 insomnia and, 734–735, 737, 741, 749 restless-legs syndrome (RLS) and, 940 Noninvasive intermittent positive pressure ventilation (NIPPV), 459–465 chronic obstructive pulmonary disease (COPD) and, 476, 479–480 complications, 464–465, 1103 continuous ventilation, 464 criteria for use, 460–461 diseases, potential treatment, 461, 461 effects, 465 indications for, 462–463, 462, 1102–1103, 1103 interfaces, 457 management, 463–464 methods/uses, 459–460 neuromuscular disorders and, 1101–1102, 1102–1103, 1103

Noninvasive intermittent positive pressure ventilation (NIPPV), (Continued) nocturnal ventilation, 463–464 survival and, 461–462 ventilator and mode, 459–460 Non-rapid eye movement (NREM) sleep memory and, 264–268 neuroimaging, 71–73, 72, 74, 78 scoring, 34, 36, 36 see also Parasomnias, NREM; Slowwave sleep (SWS) Nonrestorative sleep, 626–627 Nonsteroidal anti-inflammatory drugs (NSAIDs), 47, 602 Noradrenaline (NA) (norepinephrine), 136, 138, 776 Noradrenergic control, gene expression, 195–196 Noradrenergic locus caeruleus neurons, 138 NPPV see Noninvasive intermittent positive pressure ventilation (NIPPV) Nucleus magnocellularis (NMC), 838, 839, 843 Nucleus paramedianus (NPM), 838, 839 Nucleus pontis oralis (NPO), 838, 840, 842 Nucleus tractus solitarius (NTS), 1088 Number needed to treat (NNT), 281, 907, 908 Nurses’ Health Study, 297

O Obesity, 298, 577, 580–581, 776 Obsessive compulsive disorder (OCD), 566 Obstructive sleep apnea syndrome (OSAS), 14–15, 20, 826–827 behavioral problems, 493, 494 cardiocerebrovascular disorders and, 330, 331 cardiovascular complications, 331–334 cardiovascular diseases and, 320–321, 321, 329–336, 329, 330, 331, 335 children and, 489, 490, 491–493, 495–496 chronic obstructive pulmonary disease (COPD) and, 475–476, 477, 478 classification, 671–672 continuous positive airway pressure (CPAP) and, 421–434, 443–444, 1066, 1076–1077 dementia and, 1026–1027, 1026 dental appliances, 445–448 devices, treatment, 445 diagnosis, 384–386 epidemiology, 292, 384 epilepsy and, 1131–1132 evolution, 299–300 genetics, 689 headache and, 1076, 1077 hemodynamic changes, 319–320, 320 historical perspective, 383

I-13 Obstructive sleep apnea syndrome (OSAS), (Continued) lifestyle modification, 442–444 manifestations, 329–330, 330 mortality, cause of, 334–335, 335 neuroimaging, 81–84 oxygen and, 445 pathophysiology, 389–393 pharmacotherapy, 444–445 risk factors, 386–389, 386 stroke and, 320–321, 321, 1060, 1060, 1062–1063 treatment, 335–336, 335, 339–340, 441–451 upper-airway resistance syndrome (UARS) and, 404–407 upper-airway surgery, 448–451 women and, 647–648 Obstructive sleep apnea/hypopnea syndrome (OSAHS), 330, 330, 403, 1003 Occipital alpha/theta rhythms, 114, 114 Octopus vulgaris (octopus), 99 Odds ratio, 280 Ogle, William, 14 Olanzapine, 599, 735, 740, 756, 1024 ‘Old Hag’, 894 Olfactory dysfunction, 874 Olivopontocerebellar atrophy, 1144 Ondine (Giraudoux), 20 ‘Ondine’s curse’, 20 ‘Oneiric stupors’, 982, 982, 984 Oneirocritica (Artemidorus of Daldis), 5 Opiates, 1028 Opioids, 593, 937, 939 Opium poppy (Papaver somniferum), 4, 7 ‘Hoffman’s anodyne of opium’, 11 Oral guard, 908, 909 Orexin (hypocretin), 80, 167, 182, 765–766 behavioral state control, 770–775, 841–842 discovery of, 16 -histamine interactions, 774–775 interactions of HPS system, 243–244 narcolepsy and, 789–790, 792, 804, 829 neurons, 771, 771, 772, 773 receptors, 771, 771, 772, 773 recurrent hypersomnias and, 817 sleep regulation, 801–802 transmission deficiency, 794–796, 795 vigilance control, role, 773–774 see also Cerebrospinal fluid (CSF) Orexinergic posterior hypothalamic neurons, 140–141, 142 Orienting response, 858 Ornithorhynchus anatinus (platypus), 105 Orphan receptors, 765 Osamu Hayaishi, 16 Osborne, Jonathon, 13 Osler, Sir William, 20 Ovariectomy, 250

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-14

SUBJECT INDEX

Over-the-counter (OTC) drugs, 735, 736, 738, 741, 756–757 Oxcarbazepine, 597 Oxygen cerebral blood flow (CBF) and, 318–319, 319 chronic obstructive pulmonary disease (COPD) and, 476 discovery of, 11 nocturnal therapy (NOT), 342, 477–480 obstructive sleep apnea syndrome (OSAS)and, 445 pulmonary diseases, 477–478 therapy, supplemental, 1103 Oxytocin, 646

P Pain, 613–614 definitions, 614–615 medication, 47 multiple sclerosis (MS) and, 1139–1140 processing/modulation, 615–617 regulation, 1082 sleep disturbance studies, 620–621 sleep loss studies, 619–620 sleep modulation studies, 617–619 terminology, 615 see also Fibromyalgia (FM)/chronic fatigue syndrome (CFS) Palatal procedures, 450 Panayotopoulus syndrome, 1125 Panic disorders, 568–569 panic attacks, 893, 1061 Papaver somniferum see Opium poppy Paper tracings, 38–40 speed, 39–40 Pappenheimer, John, 16 Paracelsus, 9, 10 Paradoxical insomnia, 670, 707–708, 725 Paradoxical sleep (PS) see Rapid eye movement (REM) sleep Paralysis (ISP), isolated sleep, 674, 785, 787, 894–895 Paraneoplastic syndrome, 1093 Parasomnias, 583, 1052–1053, 1055 classification, 674–675 epidemiology, 300 unspecified, 675 see also Violent parasomnias Parasomnias, NREM, 851–864 clinical variants, 859–860 confusional arousals, 853 diagnosis, 860, 861, 862–863, 862 medical illness and, 860 polysomnographic features, 1124 primary sleep disorders and, 860 REM parasomnia comparisons, 852 sleep terrors, 856–859 somnambulism (sleepwalking), 853–856 treatment, 863–864 Parasomnias, REM, 869–878 NREM parasomnia comparisons, 852 Parkes, J. David, 20

Parkinson’s disease (PD), 61, 284, 597, 598, 830 bruxism and, 902 daytime alertness disorders and, 997–1000 insomnia and, 710 nocturnal sleep disorders and, 1000–1004 REM behavior disorder (RBD) and, 874–875 restless-legs syndrome (RLS) and, 923 Parkinson’s Disease Sleep Scale (PDSS), 999, 1000 Paroxysmal arousal, 1112, 1112, 1113, 1114–1115 Paroxysmal nocturnal dystonia, 20 Passouant, Pierre, 20 Pathology of sleep, 19–20 Pavlov, Ivan Petrovitch, 13, 16 Pavor nocturnus see Sleep terrors Pediatric Daytime Sleepiness Scale, 49 Pediatric Sleep Questionnaire, 49 Pediatrics obstructive sleep apnea syndrome (OSAS), 671–672 restless-legs syndrome (RLS) and, 926 Pedunculopontine nuclei (PPN), 766, 767, 839 Pedunculopontine tegmental nucleus (PPT), 174 cholinergic projections, 152, 155, 155 discharge activity, 156 lesion/stimulation effects, 156 serotonergic inhibition, 159–160, 160, 161 Pemoline, 804 Peptidergic sleep regulation model, 250, 251 PER protein, 952–953, 955, 956, 957, 957 period genes, 685, 952–953, 954 Perch, 101 Performance Vigilance Test, 51 Pergolide, 938 Periaqueductal gray, 163 Perimenopause, 645–646 Periodic leg movements (PLMs), 827 diagnosis, 915–916, 915 genetics, 687 studies, 932–933, 940 Periodic limb movement disorder (PLMD), 827, 828, 830 diagnosis, 915–916, 915 Parkinson’s disease and, 1003–1004 studies, 940 treatment, 940–941 Periodic limb movement disorder of sleep (PLMS), 84–86, 915–916 classification, 675 elderly and, 659–660, 660 epilepsy and, 1131–1132 headache and, 1077, 1077 motor control and, 1032 multiple sclerosis (MS) and, 1140–1141, 1142, 1143

Periodic limb movement disorder of sleep (PLMS), (Continued) neurodegenerative diseases and, 1027–1028 REM parasomnias and, 871 Periodic limb movement index (PLMI), 659, 827, 1027 ‘Periodic limb movements in wake’ (PLMW), 915 Periodische Schlafsucht (Kleine), 815 Peripheral afferents, pain processing, 616–617 Pettenkofer, Max, 13 Pfeffer, Wilhelm Friedrich Phillip, 14 Pflu¨ger, Eduard Friedrich Wilhelm, 13 Pharyngeal muscles, 390–391 Phencyclidine, 591 Phenobarbital, 596, 1129, 1132 Phenothyazines, 19 Phenotypes, sleep, 198–199, 199 Phenylpropanolamine, 592 Phenytoin, 596, 1132 Philosophy of Sleep (MacNish), 12 ‘Phrenitis’, 8 Phylogenic studies, 87, 105–106 Physiological fragmentary (partial) hypnic myoclonus (PFHM), 883–884, 884 Physiological (organic) hypersomnia, 673 ‘Pickwickian syndrome’, 20, 383 Pieron, Henri, 16, 19 Pineal gland, 1014 Pittsburg Sleep Quality Index, 1036 Plasma renin activity (PRA), 241 Platypus, 105 ‘Pneumo-wrap ventilator’, 1101 Podalirios, 6 Poliomyelitis, 1091, 1091, 1092 Polyglutamine diseases, 1022 Polyphasic sleep pattern, 4 Polysomnography (PSG), 20, 30 AASM recommendations, 41, 42 continuous spikes waves during NREM sleep (CSWS), 1128 neuromuscular disorders and, 1099 nocturnal, 49 nocturnal frontal lobe epilepsy (NFLE), 1118–1123, 1120–1121, 1121–1122 NREM parasomnias, 860, 862 obstructive sleep apnea syndrome (OSAS), 385 recurrent hypersomnias, 817 REM behavior disorder (RBD), 870–871, 870 upper-airway resistance syndrome (UARS), 403–404, 404, 405, 406 versus actigraphy, 58–59, 59, 61 see also Video polysomnography (VPSG) Polyuria, nocturnal, 363–364 Pond snail, 99 Pond turtle, 103 Pontine brainstem lesions, 528 Pontine inhibitory area (PIA), 838, 842, 843

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

SUBJECT INDEX Pontine reticular formation (PRF), 153–154, 153, 154, 767 acetylcholine agonists and, 155 cholinergic agonists and, 155–156 cholinergic projections and, 152, 155, 155 GABAergic influences, 165 neurons, 155–156 REM sleep disinhibition, 163–164, 164 ventral to locus caeruleus (LC), 156–157 Pontogeniculooccipital (PGO) waves, 73, 74, 153, 154, 158, 767, 844 Population factors, 275, 277, 279–282 Positional therapy, 443–444 Positive airway pressure (PAP) therapy, 827, 829 see also Continuous positive airway pressure (CPAP) Positive end-expiratory pressure (PEEP), 463, 480, 1102 Positron emission tomography (PET), 71, 86–87 cerebral blood flow (CBF) and, 319 dreams, 531–532 18F-fluorodeoxyglucose (FDG), 76, 77, 81 Postdialysis fatigue, 231 Posterior hypothalamus, 181 Posthumous Papers of the Pickwick Club (Dickens), 14, 15, 20, 383 Postpartum period, 644–645 Posttraumatic stress disorder (PTSD), 566–568 nightmare disorder and, 548, 550 pharmacological treatment, 568 violence and, 1152 Potassium channels, 199, 199 Power spectral analysis, 706 Practice of Physick (Willis), 10 Pramipexole REM behavior disorder (RBD) and, 876–877, 1023 restless-legs syndrome (RLS) and, 828, 937, 938 sleep dysfunction and, 598 ‘Predormitum’, 991 Pre-eclampsia patients, 231 Prefrontal leukotomy, 522, 528, 528, 529–530, 531, 532, 533 Pregabalin, 597, 735, 741 Pregnancy, 249, 644–645 pharmacotherapy and, 757 restless-legs syndrome (RLS) and, 921–922, 940 Pregnenolone, 250 Prematurity, 503, 508 Premenstrual dysphoric disorder (PMDD), 641, 644 Premenstrual syndrome (PMS), 644 Preoptic area (POA), 137, 141, 173 ‘Presleep behavior’, 990, 991 Prevalence, 279 Preyer, Thierry Wilhelm, 13 Priestley, Joseph, 11

Primary care settings, 927 Primary central sleep apnea (CSA), 671 Primary hypersomnia, 1032 Primary insomnia, 706–709 arousals, 708, 708, 709 classification, 699 diagnostic criteria, 724 psychological/behavioral therapy, 730 subtypes, 725 Primary muscle disorders, 1093–1094 Primary REM behavior disorder (RBD), 873 Primary sleep apnea of infancy, 671 Primary sleep disorders, 860 Principles and Practice of Sleep Disorders Medicine, 19 Prion diseases, 981–982 ‘Prion protein only’ theory, 988 Prionopathies, 1022 Procambarus clarkii (crayfish), 99 Process-C curve, 703–704, 768, 826, 963 Process-S curve, 38, 703, 768, 826, 963–964 Profile of Mood States, 645 Progesterone, 250, 603, 643 Progressive supranuclear palsy (PSP), 710, 1032–1033, 1144 Prokineticin 2 (PK2), 769 Prolactin, 248, 933 Prolactinoma, 248 Promethazine, 601 Prone sleeping position, 504 Propranolol, 909 Propriospinal myoclonus (PSM), 676, 886–887, 887 Prostaglandin, 16, 776 Protein synthesis, 195 Proton magnetic resonance spectroscopy, 80–81, 82–83 Protriptyline, 444, 478–479, 803, 804 Proximal myotonic myopathy (PROMM), 1095–1096 PRPN gene, 982, 985, 987, 988 Pseudoephedrine, 592 ‘Pseudo-hypersomnia’, 990 Psychiatric diseases, 557–571, 624 anxiety, 566 depression, 557–565 insomnia and, 283–284, 670–671 mania, 565–566 obsessive compulsive disorder (OCD), 566 panic disorders, 568–569 posttraumatic stress disorder (PTSD), 566–568 schizophrenia, 569–571, 571 violent parasomnias and, 1152–1153 Psychiatry, enuresis and, 364 Psychogenic dissociative states, 1152 Psychological distress, elderly and, 654 Psychology, dreaming, 546–547 Psychophysiological insomnia, 670, 725 Psychophysiological relationships, 558–560

I-15 Psychosocial issues, 646–648 Psychotherapy, 864 Public Health Service (US), 669 Pulmonary diseases, 471–483 alveolar hypoventilation, 472–473 etiologies, 473–476 sleep quality, 471–472 sleep studies, 476 treatment, 477–480 ventilatory abnormalities, 472 Pulmonary function tests, 1099–1100, 1100 Pupillometry, 51 ‘Pure’ insomnia, 706 Purgatives, 9, 10 Purkinje, Johannes Evangelista, 12 Python saebe (snake), 102

Q

Quazepam, 734, 736, 749, 750 Quetiapine, 735, 740, 756, 1023, 1024 Quiet wakefulness (QW), 836, 837, 838, 840

R Rabl-Ruckhardt, H., 12 Race, 503 ‘Rain coat’, 1101 Ramelteon dementia and, 1020 elderly and, 655 insomnia, 734, 738–739, 754–755 safety, 757 substance abuse and, 758 Rana catesbiana (bullfrog), 102, 102 Rana temporaria (frog), 102 Randomized controlled trials, 279 Ranitidine, 602 Ranson, Steven Walter, 18 Raphe nuclei, 157 dorsal raphe nucleus (DRN), 162, 163, 165, 166, 776, 840 Rapid eye movement (REM) sleep characteristics, 844–845, 845 depression, 78 elderly and, 660–661 -generating system, 767–768 historical perspective, 3, 17, 18 memory and, 261–264, 263, 264, 266–268 motor control, 838–840, 839 neuroimaging, 73–75, 74, 78 onset/maintenance, neuronal network, 176–183 parasomnias, 869–878 scoring, 36–37, 37 see also Neurobiology, REM sleep Rapid eye movement (REM) sleep behavior disorder (RBD), 20, 869–878 classification, 674 clinical features, 1001–1002, 1031–1032

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-16

SUBJECT INDEX

Rapid eye movement (REM) sleep behavior disorder (RBD), (Continued) defined, 869–871 dementia with Lewy bodies (DLB) and, 1021–1024 diagnosis, 871–873, 871, 872 dreaming and, 549, 551 epidemiology, 1001 epilepsy and, 1131–1132 hallucinations and, 1002–1003 idiopathic, 1022–1023 motor control and, 842, 843 multiple sclerosis (MS) and, 1144 neuroimaging, 84, 86–87 Parkinson’s disease (PD) and, 1001–1003 pathogenesis, 1023, 1032 pathophysiology, 1002 physiopathology, 877–878 progressive supranuclear palsy (PSP) and, 1033 secondary, 873 treatment, 875–877, 1002, 1023–1024, 1032 types, 873–874 violence and, 1151–1152 Rapid eye movement (REM) sleep without atonia (RWA), 842–843, 844, 1023 epidemiology, 1001 Parkinson’s disease (PD) and, 1001–1003 Rauwolfia serpentina, 5 Rebound, 939 Rechtschaffen, Allan, 17 Recording neonates and infants, techniques, 112 technology, evolution of, 38–43 see also Electroencephalography (EEG) Recurrent hypersomnias, 672–673, 815–821 clinical features, 816 clinical variants, 819 course, 819 demographics, 816 diagnostic criteria, 816–817 differential diagnosis, 819 historical perspective, 815–816 laboratory tests, 817 medical history, 816 pathophysiology, 820 predisposing factors, 819–820, 819 psychological investigations, 818 treatment, 820 Recurrent isolated sleep paralysis, 674 Red Emperor, Shen Nung, 5 Regulation see Sleep homeostasis; Sleep regulation; Thermoregulation Relative risk reduction, 281 Relaxation, 731, 731, 864, 908 REM behavior disorder see Rapid eye movement (REM) sleep behavior disorder (RBD)

Reptiles, 102–103 Respiratory disturbance index (RDI), 657 Respiratory effort related arousals (RERAs), 1097 Respiratory failure, neuromuscular disorders, 1097–1100 diagnosis, 1098 laboratory investigations, 1098–1100 Respiratory physiology, 371–379 airway resistance/muscle tone, 377–378, 378 arousal thresholds, 378–379 efferents, 372 feedback regulation, 375–377 muscles, 1088, 1089 neural control, 371–375 rhythm/pattern generation, 371–372, 372 tonic activation, 372–374, 373 Restless-legs syndrome (RLS), 913–941 classification, 675 clinical consequences, 918–920 clinical features, 913, 914 diagnosis, 913–915, 914, 916–918, 917, 925 elderly and, 659–660, 660 epidemiology, 300, 301–302, 303, 924–928, 924, 1142 excessive daytime sleepiness (EDS) and, 828 excessive fragmentary hypnic myoclonus (EFHM) and, 884, 885 genetics, 686–688, 929–930 headache and, 1077, 1077 motor control and, 1032 multiple sclerosis (MS) and, 1140, 1142 neurodegenerative diseases and, 1027–1028 neuroimaging, 84–85 Parkinson’s disease (PD) and, 1003–1004, 1004 pathophysiology, 930–937 phenotypes, 928 secondary, 920–924, 940 sleep-related eating disorder (SRED) and, 583 symptoms, 925 therapeutics, 937–941, 937 women and, 648 Reticular activating system, 133–134 forebrain and, 134–135 Reticular formation, 373, 374 neurons, 152, 155, 155 Retrorubral nucleus (RRN), 839 Rey Auditory Verbal Learning Test, 82 Rey-Osterrieth Complex Figure Design, 82 Rhines, Ruth, 18 Rhinitis, 464–465 Rhythmic movement disorders (RMD), 675, 889, 890 jaw movements (RJMs), 906–907, 906 masticatory muscle activity (RMMA), 901, 904, 905, 906, 909

Richardson, Gary, 17, 19 Richter, Curt P., 18 Risk absolute reduction, 281 ratio, 280 relative reduction, 281 Risperidone, 599, 1024 Rivastigmine, 876, 1025 Rodent narcolepsy models, 788, 791 Roentgen, Wilhelm Konrad, 15 Roffwarg, Howard, 19 Rolando, Luigi, 11, 13 Rome, ancient, 7–8 Ropinirole, 598, 828, 937, 938, 1028 Roth, Bedrich, 20 Rotigotine, 938 Rythmie du sommeil, 889

S Saccadic eye movements, 33 Sanctorious, 10 Scales for Outcomes in PD Sleep Scale (SCOPA-S), 999, 1000 Scandinavian Sleep Research Society, 21 Scheele, Karl, 11 Schenck, Carlos, 20 Schizophrenia, 569–571, 571 School performance, 495–496 Scopolamine, 4 ‘Scrapie’, 981 Sea slug, 99 Seasonal affective disorder (SAD), 958 Seasons, 503 Secondary insomnia, 757 classification, 699 Secondary narcolepsy, 786 Secondary REM behavior disorder (RBD), 873 Secondary restless-legs syndrome (RLS), 920–924, 940 Sedating antidepressants efficacy, 755–756 insomnia and, 739–740, 741, 755–756 safety, 756 Sedation, residual, 752 Seizures bruxism and, 902 complex motor, 1115–1116, 1117 diaries, 1125 generalized tonic-clonic (GTCSs), 1110, 1126 nightmare disorder and, 531–532, 537–539 tonic, 1127 violence and, 1152 Selective serotonin reuptake inhibitors (SSRIs) bruxism and, 902, 909 cataplexy and, 803 insomnia and, 706 nightmare disorder and, 552 periodic limb movement disorders and, 827, 1028 psychiatric diseases and, 568

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

SUBJECT INDEX Selective serotonin reuptake inhibitors (SSRIs) (Continued) safety, 756 sleep-related eating disorder (SRED) and, 583, 594 Selegiline, 598 Sensory transmission gating, 618–619 Sepia pharonis (cuttlefish), 99 Serial reaction time (SRT), 263, 264 Serotonergic inhibition, 159–160, 160, 161 Serotonergic raphe neurons, 139, 158–159, 159, 839 Serotonin, 1082 Serotonin norepinephrine reuptake inhibitors, 596 Severinghaus, John W., 20 Shen Nung, Red Emperor, 5 Sherin, J.E., 18 Shiftwork disorder, 673–674, 970–971, 970 Shiro Fujita, 20 Short-beaked echidna, 104, 105 Shy–Drager syndrome, 1144 Siffre, Michel, 19 Simpson, Sutherland, 19 Single-photon emission computed tomography (SPECT), 71 motor behaviors, 85–86 narcolepsy, 78–79 obstructive sleep apnea syndrome (OSAS) and, 83 recurrent hypersomnias, 818, 820 restless-legs syndrome (RLS) and, 934 Skala, A., 19 Sleep: Its Physiology, Pathology, Hygiene, and Psychology (Manace´¨ıne), 13, 14 Sleep architecture, 1012, 1054–1055 defined, 97–99 diary, 727, 728 fragmentation, 1001 insufficient, 825 length, 285–286, 675 parameters, 56–58, 57, 58, 855–856, 858–859 pattern, 1075 process of, 699–700, 700 Sleep apnea, 231 complex, 417 epidemiology, 289–300, 292 headache and, 1076, 1077 of infancy, primary, 671 pregnancy and, 645 risk factors, 293 threshold, 376–377, 377 see also Central sleep apnea (CSA); Obstructive sleep apnea syndrome (OSAS) ‘Sleep attacks’, 828, 997–998, 1000, 1051, 1142 ‘Sleep center’, 17, 769 Sleep deprivation depression, 77–78

Sleep deprivation (Continued) epilepsy and, 1131 gene expression, 196 nociception and, 619–620 REM (REMSD), 619–620 symptoms, 707 total (TSD), 564 Sleep disorders classification see Classification effects, assessing, 105–106 epidemiology see Epidemiology familial, 686–690 genetics see Genetics primary, 860 treatment models, 106 see also specific disorders Sleep disturbance headache and, 1076–1081, 1077–1079, 1078, 1081–1082 restless-legs syndrome (RLS) and, 919 ‘Sleep drunkenness’, 1150 Sleep Heart Cohort, 275 Sleep Heart Health Study, 333, 658 Sleep homeostasis, 205–211 defined, 205 electroencephalography (EEG) and, 208–210, 209, 210, 211 modeling, 207–208, 208 perspectives, 210–211, 211 physiological correlates, 205–207 two process model, 703–704, 704, 768 Sleep hygiene, 444, 671, 908, 1036 education, 730, 731 elderly and, 654, 655, 661 Sleep and its Derangements (Hammond), 14 Sleep (journal), 21, 670 Sleep Medicine (Journal), 21 Sleep Medicine Reviews (Journal), 21 Sleep paralysis (ISP), isolated, 674, 785, 787, 894–895 Sleep regulation, 229–236 acute-phase response (APR), 229, 233–234 brain organization theory, 234–236 cytokines in, 229–232, 231, 234–236 humoral, 229, 230 interferons and, 232–233 mechanisms of, 229 orexin (hypocretin) and, 801–802 Sleep regulatory substances (SRSs), 229, 234–235 Sleep Research Society, 21 Manual, 34 Sleep restriction, 20, 490–491, 707, 730, 730 Sleep Society of Canada, 21 Sleep starts see Hypnic jerks ‘Sleep state probability’ model, 221 ‘Sleep swimming’, 101 Sleep terrors, 550–551, 674, 856–859 clinical features, 856, 858 genetics, 858 orienting response, 858

I-17 Sleep terrors, (Continued) pathophysiology, 858 prevalence, 858 psychopathology, 858 sleep parameters, 858–859 violence and, 1150–1151 Sleep and Wakefulness (Kleitman), 19 Sleep-disordered breathing (SDB) alcohol and, 589 children, 489, 491–493, 492, 493 clinical characteristics, 1060–1062, 1060 diagnosis, 1065–1067 elderly, 657–659 epidemiology, 291 evaluation, 1090, 1099 multiple sclerosis (MS) and, 1142 neuromuscular disorders and, 1090, 1099, 1101, 1101 Parkinson’s disease (PD) and, 1003 pathophysiology, 1062–1065 psychobehavioral consequences, 493–495 pulmonary disease and, 475–476 smoking and, 589 stroke and, 1060–1067 treatment, 1065–1067, 1101 women and, 647–648 Sleeping sickness (African trypanosomiasis), 19 Sleep-onset REM periods (SOREMPs) hypersomnias and, 817, 828–829, 830 narcolepsy and, 783, 789–790, 792, 800 Sleep-promoting systems, 141–143 Sleep-related abnormal sexual behaviors (SRASBs), 860 Sleep-related breathing disorders (SRBDs), 830 classification, 671–672 epidemiology, 286, 291 multiple system atrophy (MSA) and, 1028–1032 pathogenesis, 1029–1030, 1031–1032 treatment, 1030–1031, 1030 Sleep-related dissociative disorder, 674 Sleep-related eating disorder (SRED), 577–583, 859 associated disorders, 581 characteristics, 578 classification, 674–675 consequences, 580–581 differential diagnosis, 579–580, 579 historical perspective, 577–578, 578 physiology, 581–582 prevalence, 580 treatment, 582–583, 583 Sleep-related erections (SREs), 357–359 painful, 359 Sleeptalking (somniloquy), 889–891, 1152 classification, 675 Sleep-Wake Activity Inventory (SWAI), 49

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-18

SUBJECT INDEX

Sleep-wake cycle actigraphic monitoring, 56–58, 57, 58 behavioral manipulations, 966 dreaming, 545 elderly, 656–657 free-running, 968, 968 hypothalamic/brainstem regulation, 773, 773, 775–776 patterns, 4, 19 regulation, 681–686, 682, 684, 685 substrates, 132 Sleep-wake disorders (SWDs) circadian rhythm factors, 1059–1060 clinical characteristics, 1051–1057 diagnosis, 1059–1060 pathophysiology, 1057–1059 stroke and, 1051–1060, 1059 treatment, 1059–1060 Sleep-Wake Disorders Unit, 21 Sleepwalking see Somnambulism (sleepwalking) Slow-wave activity (SWA), 855–856 epilepsy and, 1126 Slow-wave sleep (SWS), 3, 862, 862 arousals, 858–859 defined, 98–99 REM parasomnias and, 870–871 scoring, 33, 38 see also Non-rapid eye movement (NREM) sleep Smoking epidemiology, 589 obstructive sleep apnea syndrome (OSAS) and, 443 in pregnancy, 501, 503–504 sleep-disordered breathing (SDB) and, 589 see also Nicotine Snakes, 102 Snoring classification, 675 elderly and, 658 epidemiology, 289–300 habitual, 289, 291, 298, 493 headache and, 1076, 1077 risk factors, 293 Snyder, Frederick, 20 Socioeconomic class, 503 Sodium oxybate (GHB), 802–803, 805 Software, sleep analysis, 61 Somatic diseases, insomnia and, 284–285 Somatostatin, 243 Sommer, Wilhelm, 13 Somnambulism (sleepwalking), 853–856 clinical features, 853–854 genetics, 854 pathophysiology, 854–855 prevalence, 854 psychopathology, 854 sleep parameters, 855–856 violence and, 1150–1151 Somniloquy (sleeptalking), 675, 889–891, 1152 Spielman, Arthur, 20

Spinal cord, pain processing, 616–617 Spine pathology, 936–937 reflexes, 838 reticular neuron projection, 132, 133 Spinocerebellar ataxia, 923–924, 1033–1034 Split-night studies, 426 Sporadic fatal insomnia (SFI), 981, 988–992 thalamus and, 988–990 Stanford Sleepiness Scale, 48 Staphylococcus aureus, 233 Status cataplecticus, 785 Status dissociatus (SD), 895 Stephan, F.K., 19 Steroids, 250, 603 Stimulus control therapy, 20, 730–731, 730 Stress system dysregulation, 627–628 Stridor, 1030–1031, 1030 Stroke, 1051–1067 central sleep apnea (CSA) and, 322, 322 hemispheric, 1055, 1057, 1059 infratentorial, 1057 insomnia and, 285, 711 obstructive sleep apnea syndrome (OSAS) and, 320–321, 321 sleep apnea and, 298 sleep-disordered breathing (SDB) and, 1060–1067 sleep-wake disorders (SWDs) and, 1051–1060, 1059 snoring and, 295, 296, 297 supratentorial, 1055–1057, 1056, 1057 thalamic, 1053, 1055, 1055, 1056, 1057 Study of Women’s Health Across the Nation, 642 Subcortical pathology, 936 Sublaterodorsal nucleus (SLD), 178–179 Subparaventricular zone (SPZ), 768, 769 Substance abuse, 588 treatment, 595 ‘Subwakefulness’, 990 Sudden death, 299, 740, 1062 Sudden infant death syndrome (SIDS), 223, 501–512 critical development period, 507, 508 definitions, 501–502 environment, 504–505, 508, 511–512, 511 incidence, 502 mechanisms implicated, 508–510 model, 506–508, 507 pathologic examinations, 502 perinatal risk factors, 503–504 physiopathology, 510–511 prenatal vulnerability, 507–508 protective factors, 506, 511 recurrence rates, 504 risk factors, 502–506 sociodemographic/climatic factors, 503

Suggested immobilization test (SIT), 916, 932 Sullivan, Colin, 20 Suprachiasmatic nuclei (SCN), 60, 174, 765, 768, 769 circadian rhythms and, 951–952, 954–955, 956 neurodegenerative diseases and, 1013–1014, 1019 non-photic circadian inputs, 1014 Supratentorial stroke, 1055–1057, 1056, 1057 Swallowing, abnormal syndrome, 892 Sweats, night, 892–893 Sydenham, Thomas, 10 Symptomatic narcolepsy, 792, 800 Symptoms, isolated, 675–676 Synaptic depression, 195 Synaptic potentiation, 193–194, 194 Synchrony/asynchrony, 113 Synucleinopathies, 710, 1022, 1022 Systolic heart failure, 336–337

T

Tachyglossus aculeatus (short-beaked echidna), 104, 105 Takeshi Sakurai, 16 Tanenosuke, Ikematsu, 20 Tank respirator, 1101 Tau mutation, 956 Tauopathies, 1022 Technologists, sleep, 68 Temazepam efficacy, 751 elderly and, 753 insomnia and, 733, 734, 736, 749, 750 Temperature, body, 216–218, 219–220, 220, 1018 see also Thermoregulation Temporal lobe epilepsy (TLE), 1126–1127, 1130 Temporal theta rhythm, 114, 115 Tench, 101 Tension-type headache, 1075, 1077, 1078–1079, 1078 Terrors see Sleep terrors Testosterone, 643 Testudo marginata (tortoise), 103 Tetracyclic antidepressants, 593 Thalamic stroke, 1053, 1055, 1055, 1056, 1057 Thalamocortical projection system, 132, 134–135 Thalamocortical sleep oscillations, 766–767 Thalamus, 133, 986–987 sleep regulation and, 988–990 Theogony of Hesiod, 6 Theophylline, 342, 479, 601 Theriac, 9 Thermoregulation, 215–236 adults/elderly, 220–222 body temperature, 216–218, 219–220, 220

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

SUBJECT INDEX Thermoregulation, (Continued) neonates, 222–224, 223 sleep stage responses, 218–219, 219 sleep structure, age and, 218 thermal exchanges, 215–216 thermal load, 220 Thoth, 4 Thyroid hormones, 1025 Thyroid replacement therapy (TRT), 602 Thyroid-stimulating hormone (TSH), 246, 602 Tiagabine effect on sleep, 1132, 1133 insomnia and, 735, 740–741 TIM protein, 955 Timeless gene, 955 Tinca tinca (tench), 101 Titus Lucretius Carus, 7 Toads, 102 Toh, K., 19 Tokoloshis, 894 Tongue base surgery, 451 Tonsillectomy, 449 Tooth grinding see Bruxism Topiramate, 583, 597, 1133 ‘Topographical memory’, 520 ‘Tortoise shell’ ventilator, 1101 Tortoises, 98, 103 Total sleep deprivation (TSD), 564 Toxicity, drug, 752 Tracheostomy (tracheotomy), 20, 451, 1030, 1067, 1103 Tramadol, 937, 939 Transcranial magnetic stimulation (TMS), 934–935, 935 Transection studies, 152–154, 153 Transferrin, 930–931 Transforming growth factor (TGF)-a, 769 Transmissible mink encephalopathy (TME), 992 Trauma, decreased dream recall, 552–553 Trazodone efficacy, 755 hallucinations and, 1024 insomnia and, 734, 739–740, 741, 755 psychiatric diseases and, 568 safety, 756 sleep dysfunction and, 594–595 Tree frog, 102 Triazolam efficacy, 751 insomnia and, 705, 734, 736, 749, 750, 1037 primary insomnia and, 708 Tricyclic antidepressants (TCAs) arousal disorders and, 1151 bruxism and, 909 cataplexy and, 803, 803 enuresis and, 366 insomnia and, 739–740, 748 narcolepsy and, 804

Tricyclic antidepressants (TCAs) (Continued) NREM parasomnias and, 863 periodic limb movement disorder (PLMD), 827 safety, 756 sleep dysfunction and, 593 Trihexyphenidyl, 598 Trimipramine, 756 L-Tryptophan, 895 Tuberomammillary nucleus (TMN), 174, 770, 774–775 neurons, 776 Turtle headache, 1075, 1077, 1079 Turtles, 103 Two process model (Borbely), 38, 826 sleep homeostasis and, 703–704, 704, 768

U Ullanlinna Narcolepsy Scale (UNS), 289 Upper-airway narrow, 293 surgery, 448–451 Upper-airway resistance syndrome (UARS), 377–378, 401–407 clinical symptoms, 402 epidemiology, 402 neuromuscular disorders and, 1097–1098 pathophysiology, 404–407 physical examination, 402–404 treatment, 407 Uqumangirniq, 894 Uremia, 940 Urination see Enuresis Urotherapy, 366 ‘Urotoxins’, 13 Uvulopalatopharyngoplasty (UPPP), 20, 449–450

V Valproate, 596, 830, 1129, 1132 Valproic acid, restless-legs syndrome (RLS) and, 939 van Helmont, Jan Baptista, 10 Vascular theories, 11–12, 15 Vasoactive intestinal polypeptide (VIP), 248 Venlafaxine, 596, 803, 1028 Ventilation continuous, 464 negative-pressure, 479 nocturnal, 463–464 see also Noninvasive intermittent positive pressure ventilation (NIPPV) Ventilation-perfusion matching, 475 Ventilators, 459–460 negative-pressure, 1101 Ventilatory abnormalities, 472 Ventilatory control changes, 473–475 instability (loop gain), 392–393, 393

I-19 Ventilatory control (Continued) obstructive sleep apnea syndrome (OSAS), 83–84, 84 Ventilatory effort, 379 Ventral respiratory group (VRG) neurons, 1088 Ventrolateral preoptic area (VLPO), 142, 163–164 sleep-promoting neurons, 174–176, 775–776 Verispan Physician Drug Audit (2002), 748, 748 Vesalius, Andreas, 9 Video polysomnography (VPSG), 65–70 EEG electrode placement, 65, 66 interpretation, 68–70 montages, 65–68, 66–67 sleep stage effect, 69–70, 69 sleep technologist, 68 video recording, 68 viewing/reformatting, 68 Vigilance state-regulatory systems, 766–769, 766, 776–777 Vigilance testing, 51 Viloxazine, narcolepsy and, 804 Violent parasomnias, 1149–1155 case example, 1149 clinical/laboratory evaluation, 1154–1155 medicolegal evaluation, 1153–1155 neurological conditions and, 1150–1152 psychiatric conditions, associated, 1152–1153 sleep state-dependent, 1149–1150 sleep-related disorders, associated, 1150, 1150 Visual dream imagery, 894 loss of, 520, 521 Vitamin B12, 966 Vogel, Gerald, 19 von Economo, Constantin, 17–18, 769, 830 von Haller, Albrecht, 10, 11, 12 von Linne, Karl, 10 von Voit, Carl, 13 Voxel-based morphometry (VBM), 80, 82, 83, 85

W Wadd, William, 15 Wakefulness, 991 depression, 77 gene expression, 193–194, 194 scoring, 34, 36 ‘stimulus’, 374–375, 374 stroke and, 1062 transition to sleep, 32, 32 Wakefulness after sleep onset (WASO), 58–59, 59 ‘Waking center’, 17, 18, 769, 777 Waldeyer, Heinrich, 12 Wallenberg’s syndrome, 1062 Wanderings epileptic nocturnal (ENW), 1112

(Volume 1: pages 1–666; Volume 2: pages 667–1160)

I-20

SUBJECT INDEX

Wanderings (Continued) episodic nocturnal, 1152 Water fowl, 104 Weight loss, 442 Weitzman, Elliot David, 19, 20, 21 Wells, William Hughes, 15 West syndrome, 1127 Western toad, 102 Westphal, Carl Friedrich Otto, 14 Wever, Kurt, 19 White matter injury, 1064 Willis, Thomas, 10 Wisconsin Sleep Cohort Study, 275, 646 Women, 249, 639–648 circadian rhythmicity, 641–642 common sleep disorders, 640, 647–648 hormonal factors, 642–643 lifespan physiologic changes, 643–646 objective sleep differences, 639–642

Women, (Continued) psychosocial issues, 646–648 subjective sleep differences, 642 Women’s Health Initiative, 603 World Health Organization (WHO), 669

X Xe inhalation, 78–79

Y Yellow Emperor, Huang Ti, 5 Yin-yang symbol, 5 Yu Hsiung, 5 Yutaka Honda, 19

Z Zaleplon circadian sleep disorders and, 826 efficacy, 750

Zaleplon (Continued) elderly and, 655, 753 insomnia and, 734, 737, 738, 749, 750, 758 restless-legs syndrome (RLS) and, 940 Zebrafish, 101 Zolpidem circadian rhythm sleep disorders and, 826, 972 cyclic alternating pattern (CAP) and, 705 efficacy, 750 elderly and, 655 insomnia and, 734, 737, 738, 740, 749, 750 long-term efficacy, 705 primary insomnia and, 708 restless-legs syndrome (RLS) and, 940 Zopiclone, 705, 708 Zucker, Irving, 19

(Volume 1: pages 1–666; Volume 2: pages 667–1160)