Narcolepsy: Pathophysiology, Diagnosis, and Treatment

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Narcolepsy: Pathophysiology, Diagnosis, and Treatment

Narcolepsy Christian R. Baumann Claudio L. Bassetti Thomas E. Scammell Editors Narcolepsy Pathophysiology, Diagnosis,

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Narcolepsy

Christian R. Baumann Claudio L. Bassetti Thomas E. Scammell Editors

Narcolepsy Pathophysiology, Diagnosis, and Treatment

Editors Christian R. Baumann, MD Department of Neurology University Hospital of Zurich Zurich, Switzerland [email protected] Claudio L. Bassetti, MD Department of Neurology Neurocenter EOC of Southern Switzerland Ospedale Civico Lugano, Switzerland [email protected]

Thomas E. Scammell, MD Department of Neurology Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA, USA [email protected]

ISBN 978-1-4419-8389-3     e-ISBN 978-1-4419-8390-9 DOI 10.1007/978-1-4419-8390-9 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011926991 © Springer Science+Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, ­electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

Narcolepsy is characterized by excessive daytime sleepiness, cataplexy, fragmented sleep, and other symptoms. It affects approximately 1 in 2,000 people and can have a huge impact on their ability to succeed in school and work. Narcolepsy was first recognized by clinicians over 125 years ago, yet until recently, its cause remained a mystery. In 2000, two research groups discovered that narcolepsy is caused by a selective loss of neurons in the hypothalamus that produce the hypocretin neuropeptides (also known as orexins). With this groundbreaking perspective, narcolepsy research has advanced in large steps, with new discoveries every year that have enhanced our understanding of the disorder. In 1975, the First International Symposium on Narcolepsy was held in La Grande Motte in France, organized by William C. Dement, Christian Guilleminault, and Pierre Passouant. After a successful Fifth International Symposium on Monte Verità near Ascona (Switzerland) in 2004, many of the world’s leading narcolepsy researchers – including the authors of this book – gathered again in this inspiring landscape for the Sixth International Symposium on Narcolepsy in 2009. In the course of the meeting, it became clear that researchers and clinicians have learned much about narcolepsy, yet many key questions remain unanswered, even in light of recent advances. For instance, we still have no definite proof that narcolepsy is caused by an autoimmune attack or by another mechanism. The recent discovery that levels of specific antibodies are increased in some patients soon after the onset of narcolepsy provides some of the most compelling evidence for an autoimmune mechanism, but many questions remain unanswered. For example, it appears that narcolepsy is caused by a selective loss of the hypocretin­producing neurons, yet the target antigens are expressed by many non-hypocretin neurons. In addition, antibody titers appear normal in many narcolepsy patients. It remains possible that these antibodies are not pathogenic but are simply increased as a consequence of another process that kills the hypocretin neurons. Much more work is needed to determine what mechanism kills the hypocretin neurons in narcolepsy. Many questions remain about the pathophysiology of cataplexy, hypnagogic hallucinations, and sleep paralysis. These symptoms have many similarities to rapid eye movement (REM) sleep, such as muscle atonia and dreaming, and they may represent the intrusion of fragments of REM sleep into wakefulness. Theories have proposed an increase in REM sleep pressure, a reduction in the threshold to transition into REM sleep, or dysregulation of v

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Preface

the brainstem mechanisms that normally coordinate REM sleep phenomena. However, there is little evidence that these symptoms are influenced by manipulations of REM sleep, and gamma hydroxybutyrate strongly suppresses cataplexy yet it has no effect on REM sleep. Thus, the pathways underlying cataplexy and other narcolepsy symptoms remain elusive. Furthermore, people and animals with narcolepsy transition frequently and rapidly between wakefulness and sleep. For over 20 years, this pattern has been referred to as behavioral state instability but its cause remains unknown. It is possible that hypocretin/orexin stabilizes the neural pathways that regulate sleep/wake transitions; so a loss of the hypocretin neurons would destabilize this mechanism, leading to frequent transitions between wakefulness and sleep. This could account for both excessive daytime sleepiness and fragmented nocturnal sleep in narcolepsy. However, this hypothesis is not yet proven, and the electrophysiological basis of this instability is still poorly understood. Last but not least, narcolepsy is often accompanied by a variety of metabolic and psychiatric symptoms, including obesity and depression. These symptoms are unappreciated by many clinicians and their fundamental cause remains unknown. For instance, there is still no clear explanation why narcolepsy patients are often overweight. Hypocretin can enhance appetite, yet individuals with narcolepsy probably eat normal amounts. Their obesity may result from low physical activity or low basal metabolic rate. Thus, despite much recent progress, many large questions remain about the causes, neurobiology, and physiology of narcolepsy. To provide a unified resource for clinicians and basic scientists, dozens of researchers with expertise in nearly all facets of narcolepsy have contributed to this book. Our intent is to provide a comprehensive and up-to-date overview on the pathophysiology and neurobiology of narcolepsy and to describe new clinical research on narcolepsy and the best approaches for treatment. The supplementary DVD offers a unique and large collection of movies displaying the symptoms of narcolepsy in people and animals. We have also highlighted many of the outstanding questions about narcolepsy, and hope this book will spark new perspectives and inspire new discoveries. Finally, we thank the funders of the Sixth International Meeting on Narcolepsy, and above all the Centro Stefano Franscini on Monte Verità, the Swiss Federal Institute of Technology, Zurich, and also Actelion, Boehringer Ingelheim, Cephalon, and UCB Pharma. The production of the supplemental DVD was made possible by the funding from UCB. Special thanks go to Yvonne Fernandez and Sarah Eisenstein, the meeting secretaries. Zurich, Switzerland Lugano, Switzerland Boston, MA, USA

Christian R. Baumann Claudio L. Bassetti Thomas E. Scammell

Contents

Part I  Etiology of Narcolepsy Etiology and Genetics of Human Narcolepsy.................................... Emmanuel Mignot

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Narcolepsy: Autoimmunity or Secondary to Infection?................... Adriano Fontana, Heidemarie Gast, and Thomas Birchler

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Is Narcolepsy a Neurodegenerative Disorder?.................................. Christelle Peyron

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Part II  Neurochemistry of Narcolepsy The Roles of Hypocretin/Orexin in Narcolepsy, Parkinson’s Disease, and Normal Behavior....................................... Jerome Siegel Histamine in Narcolepsy and Excessive Daytime Sleepiness........... Seiji Nishino Dopaminergic Substrates Underlying Hypersomnia, Sleepiness, and REM Sleep Expression............................................. David B. Rye and Amanda A.H. Freeman

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The Serotoninergic System in Sleep and Narcolepsy........................ Chloé Alexandre and Thomas E. Scammell

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Sleep Homeostasis, Adenosine, Caffeine, and Narcolepsy............... Hans-Peter Landolt

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Prostaglandin D2: An Endogenous Somnogen.................................. Yoshihiro Urade and Osamu Hayaishi

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Part III The Role of the Hypocretins in Sleep–Wake Regulation The Neurobiology of Sleep–Wake Systems: An Overview............... 107 Pierre-Hervé Luppi and Patrice Fort The Hypocretins/Orexins: Master Regulators of Arousal and Hyperarousal................................................................................. 121 Matthew E. Carter, Antoine Adamantidis, and Luis de Lecea Optogenetic Probing of Hypocretins’ Regulation of Wakefulness...................................................................................... 129 Antoine Adamantidis and Luis de Lecea Hypocretin/Orexin Receptor Functions in Mesopontine Systems Regulating Sleep, Arousal, and Cataplexy.......................... 139 Christopher S. Leonard, Mike Kalogiannis, and Kristi A. Kohlmeier Afferent Control of the Hypocretin/Orexin Neurons........................ 153 Thomas S. Kilduff, Junko Hara, Takeshi Sakurai, and Xinmin Xie The Neural Basis of Sleepiness in Narcoleptic Mice......................... 163 Thomas E. Scammell and Chloé Alexandre Mathematical Models of Narcolepsy.................................................. 175 Cecilia Diniz Behn Part IV  The Key Role of the Hypothalamus The Hypothalamus and Its Functions................................................ 191 Giovanna Zoccoli, Roberto Amici, and Alessandro Silvani The Prehistory of Orexin/Hypocretin and Melanin-Concentrating Hormone Neurons of the Lateral Hypothalamus.............................................................. 205 Clifford B. Saper Metabolic Influence on the Hypocretin/Orexin Neurons................. 211 Denis Burdakov Endocrine Abnormalities in Narcolepsy............................................ 217 Thomas Pollmächer, Marietta Keckeis, and Andreas Schuld Appetite and Obesity........................................................................... 227 Alice Engel and Norbert Dahmen

Contents

Contents

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Part V Reward, Addiction, Emotions and the Hypocretin System Effects of Orexin/Hypocretin on Ventral Tegmental Area Dopamine Neurons: An Emerging Role in Addiction............. 241 Stephanie L. Borgland Orexin/Hypocretin, Drug Addiction, and Narcolepsy...................... 253 Ralph J. DiLeone, Maysa Sarhan, and Ruth Sharf Emotional Processing in Narcolepsy.................................................. 261 Sophie Schwartz Depression in Narcolepsy.................................................................... 271 Michael Lutter Part VI REM Sleep Dysregulation and Motor Abnormalities in Narcolepsy The Clinical Features of Cataplexy.................................................... 283 Sebastiaan Overeem Parasomnias in Narcolepsy with Cataplexy...................................... 291 Yves Dauvilliers and Régis Lopez The Motor System and Narcolepsy: Periodic Leg Movements and Restless Legs Syndrome............................................................... 301 Luigi Ferini-Strambi Part VII  The Borderlands of Narcolepsy Spectrum of Narcolepsy...................................................................... 309 Claudio L. Bassetti Secondary Narcolepsy......................................................................... 321 Philipp O. Valko and Rositsa Poryazova Posttraumatic Narcolepsy................................................................... 341 Christian R. Baumann and Rositsa Poryazova The Hypocretin System and Sleepiness in Parkinson’s Disease...... 347 R. Fronczek Idiopathic Hypersomnia...................................................................... 357 Ramin Khatami

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Part VIII The Diagnosis of Narcolepsy and the Assessment of Fitness to Drive Current Diagnostic Criteria for Adult Narcolepsy........................... 369 Alex Iranzo The Arguments for Standardized Diagnostic Procedures................ 383 Geert Mayer Fitness to Drive in Narcolepsy............................................................ 389 Johannes Mathis Part IX  Treatment of Narcolepsy Treatment of Narcolepsy..................................................................... 401 G.J. Lammers Treatment of Narcolepsy in Children................................................. 411 Michel Lecendreux Index...................................................................................................... 419

Contents

Contributors

Antoine Adamantidis, PhD McGill University, Department of Psychiatry, Douglas Mental Health University Institute, Montréal, Canada Chloé Alexandre, PhD Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA Roberto Amici, MD Department of Human and General Physiology, University of Bologna, Bologna, Italy Claudio L. Bassetti, MD Department of Neurology, Neurocenter EOC of Southern Switzerland, Ospedale Civico, Lugano, Switzerland Christian R. Baumann, MD Department of Neurology, University Hospital of Zurich, Zurich, Switzerland Cecilia Diniz Behn, PhD Department of Mathematics, University of Michigan, Ann Arbor, MI, USA Thomas Birchler, MD Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland Stephanie L. Borgland, PhD Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, BC, Canada Denis Burdakov, PhD Department of Pharmacology, University of Cambridge, Cambridge, UK Matthew E. Carter Departments of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

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Norbert Dahmen, MD Department of Psychiatry, University of Mainz, Mainz, Germany Yves Dauvilliers, MD Centre de Référence Nationale Maladie Rare – Narcolepsie et Hypersomnie Idiopathique, Service de Neurologie, Hôpital Gui-de-Chauliac, Montpellier, France Luis de Lecea, PhD Departments of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA Ralph J. DiLeone, PhD Department of Psychiatry, Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, USA Alice Engel Department of Psychiatry, University of Mainz, Mainz, Germany Luigi Ferini-Strambi, MD, PhD Department of Neuroscience, Sleep Disorders Center, Università Vita-Salute San Raffaele, Milan, Italy Adriano Fontana, MD Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland Patrice Fort, PhD Institut Fédératif des Neurosciences de Lyon, Université de Lyon, Lyon, France Amanda A.H. Freeman, PhD Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA R. Fronczek, PhD Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands Heidemarie Gast, MD Department of Neurology, University Hospital Berne, Inselspital, Berne, Switzerland Junko Hara Biosciences Division, SRI International, Menlo Park, CA, USA Osamu Hayaishi, MD Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan

Contributors

Contributors

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Alex Iranzo, MD, PhD Hospital Clínic and Institut D’Investigació, Neurology Service and Multidisciplinary Sleep Unit, Barcelona, Spain Mike Kalogiannis, DMD, DDS Department of Physiology, New York Medical College, Valhalla, NY, USA Marietta Keckeis Max Planck Institute of Psychiatry, Munich, Germany Ramin Khatami, MD Center of Sleep Medicine, Klinik Barmelweid AG, Barmelweid, Switzerland Thomas S. Kilduff, PhD Biosciences Division, SRI International, Menlo Park, CA, USA Kristi A. Kohlmeier, PhD Department of Physiology, New York Medical College, Valhalla, NY, USA G.J. Lammers, MD, PhD Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands Hans-Peter Landolt, PhD Institute of Pharmacology & Toxicology, Zürich Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland Michel Lecendreux, MD Pediatric Sleep Center and Narcoleptic Reference Center, Hospital Robert Debré, Paris, France Christopher S. Leonard, PhD Department of Physiology, New York Medical College, Valhalla, NY, USA Régis Lopez Centre de Référence Nationale Maladie Rare – Narcolepsie et Hypersomnie Idiopathique, Service de Neurologie, Hôpital Gui-de-Chauliac, Montpellier, France Pierre-Hervé Luppi, PhD Institut Fédératif des Neurosciences de Lyon, Université de Lyon, Lyon, France Michael Lutter, MD, PhD Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

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Johannes Mathis, MD Sleep Disorders Centre and Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Switzerland Geert Mayer, MD Hephata Klinik, Schwalmstadt, Germany Emmanuel Mignot, MD, PhD Stanford Center for Sleep Sciences, Stanford University School of Medicine, Palo Alto, CA, USA Seiji Nishino, MD, PhD Stanford Center for Sleep Sciences, Stanford University School of Medicine, Palo Alto, CA, USA Sebastiaan Overeem, MD, PhD Department of Neurology, Donders Institute for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Christelle Peyron, PhD Centre de Recherche en Neurosciences de Lyon, Faculté de Médecine Laennec, Université Lyon1, Lyon, France Thomas Pollmächer, MD Center of Mental Health, Klinikum Ingolstadt, Ingolstadt, Germany Rositsa Poryazova, MD Department of Neurology, University Hospital of Zurich, Zurich, Switzerland David B. Rye, MD, PhD Department of Neurology and Program in Sleep, Emory University School of Medicine, Atlanta, GA, USA Takeshi Sakurai, MD, PhD Department of Molecular Neuroscience and Integrative Physiology, Kanazawa University, Kanazawa, Japan Clifford B. Saper, MD, PhD Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA Maysa Sarhan, PhD Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Thomas E. Scammell, MD Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA Andreas Schuld, MD Max Planck Institute of Psychiatry, Munich, Germany

Contributors

Contributors

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Sophie Schwartz, PhD Department of Neuroscience, University of Geneva, Geneva, Switzerland Ruth Sharf Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Jerome Siegel, PhD Department of Psychiatry, University of California at Los Angeles, North Hills, CA, USA Alessandro Silvani, MD Department of Human and General Physiology, University of Bologna, Bologna, Italy Yoshihiro Urade, PhD Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan Philipp O. Valko, MD Department of Neurology, University Hospital of Zurich, Zurich, Switzerland Xinmin Xie, MD AfaSci, Inc., Burlingame, CA, USA Giovanna Zoccoli, MD Department of Human and General Physiology, University of Bologna, Bologna, Italy

Part I Etiology of Narcolepsy

Etiology and Genetics of Human Narcolepsy Emmanuel Mignot

Keywords

Human leukocyte antigen • Mutation • Autoimmunity • Genetics • Prevalence • Narcolepsy

Low levels of the neuropeptide hypocretin-1 (hcrt-1, also called orexin-A) are found in the cerebrospinal fluid (CSF) of most people with narcolepsy with cataplexy and in some without cataplexy [1–6]. As a result, in the most recent revision of the International Classification of Sleep Disorders (ICSD), narcolepsy with cataplexy and narcolepsy without cataplexy have been separated [7]. In this chapter, we will discuss the etiology of narcolepsy/hcrt deficiency, as there is a strong suggestion of homogeneity based on the very high association with human leukocyte antigen (HLA) DQB1*0602 and low CSF hcrt-1. References to narcolepsy without cataplexy, defined by sleepiness and a positive multiple sleep latency test (MSLT), will also be made, although the condition likely represents a constellation of problems and pathologies. We will also briefly discuss secondary narcolepsy cases. E. Mignot (*) Stanford Center for Sleep Sciences, Stanford University School of Medicine, 701-B Welch Road, Basement, Room 145, Palo Alto, CA 94304-5742, USA e-mail: [email protected]

Prevalence Studies Population-based prevalence studies of narcolepsy–cataplexy have been performed in multiple countries. In Finland, 11,354 individual twins were asked to respond to a questionnaire. Subjects with answers suggestive of narcolepsy were contacted by phone and subjected to clinical interviews and polysomnography [8]. Three subjects with cataplexy and abnormal MSLT results were identified, leading to a prevalence of 0.026% [8]. Other studies have led to similar prevalence (0.013–0.067%) in Great Britain, France, Hong Kong, the Czech Republic, and in the USA [9–11]. A study performed in 1945 in African American Navy recruits also led to 0.02% in this ethnic group for narcolepsy–cataplexy, although this study concluded that narcolepsy was more frequent in this ethnic group because of “natural tendencies” [12]. Narcolepsy–cataplexy may be less frequent in Israel (0.002%) and more frequent in Japan (0.16–0.18%). It is of interest to note that DQB1*0602 is rare in Israel (4–6%), Japan (8%), and Korea (13%), but more common in most Caucasian (25%), Chinese (25%), and

C.R. Baumann et al. (eds.), Narcolepsy: Pathophysiology, Diagnosis, and Treatment, DOI 10.1007/978-1-4419-8390-9_1, © Springer Science+Business Media, LLC 2011

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African American populations (38%). Thus, a direct correspondence between the prevalence of narcolepsy and the frequency of DQB1*0602 is not evident. The prevalence of narcolepsy without cataplexy is largely unknown, as a proper population-based study would require an MSLT of all subjects. In case series, narcolepsy without cataplexy represents 20–50% of cases [13]. Patients without cataplexy are, however, more likely to be underdiagnosed (e.g., narcolepsy plus sleep apnea), undiagnosed (no major complaint), or misdiagnosed (e.g., as depression or sleep apnea) [14]. Some studies have shown that 1–3% of the adult population have self-reported sleepiness and multiple SOREMPs during MSLT [15, 16]. A recent study identified all diagnosed narcoleptic patients in Olmsted County (MN, USA) using the medical records linkage system of the Rochester Epidemiology Project [17]. The study identified 0.036% of the population with narcolepsy–­ cataplexy and 0.021% with narcolepsy without cataplexy, suggesting a significant prevalence for narcolepsy without cataplexy [17]. In King County (WA, USA), a similarly designed recent study found 0.031% of the population with narcolepsy and only 0.009% without cataplexy (27% of DQB1*0602 positive) [11]. It is likely that registry-based estimations of prevalence of diagnosed cases underestimate, while population-based epidemiological studies that do not exclude other confounding factors overestimate the true population prevalence of narcolepsy without cataplexy, explaining the 300-fold range. What percent of narcolepsy without cataplexy cases have hcrt deficiency also remains unclear. When all other causes of daytime sleepiness have been excluded, 5–30% of patients with this diagnosis are hcrt deficient [4–6, 18], with a mean of 15% overall and 31% of HLA DQB1*0602positive subjects in a recent meta-analysis of 162 samples tested in our center [19]. This is also reflected by the % DQB1*0602 positivity in such samples, ranging from 27% (slightly above the 23% population frequency in Caucasians) to 40% in a large multicenter drug trial [13] and other samples [4, 19]. We have conducted systematic CSF hcrt-1 measurement in random samples of

E. Mignot

healthy individuals (approximately 250 subjects total) and have been unable to detect a single subject with CSF hcrt-1 below 110  pg/ml, the best diagnostic cut-off distinguishing narcolepsy–cataplexy vs. controls. Interestingly, using 162 patients without cataplexy tested in our center since 2000, we found that a cut-off of 200 pg/ml improved sensitivity for this test to 41% in the presence of HLA-DQB1*0602 and 9% in the absence of HLA-DQB1*0602 [19] (Table  1). It is, therefore, possible that some subjects without cataplexy have less pronounced hcrt cell loss, as reflected by intermediate (110–200  pg/ml) or normal CSF hcrt-1 [19, 20]. The notion is also supported by the slightly increased HLA frequency observed in narcolepsy without cataplexy subjects with normal CSF hcrt [21], although it is difficult in this case to exclude that some patients were diagnosed after HLA positivity was established, thus creating a bias.

Twin Studies and Environmental Factors in Narcolepsy As mentioned above, the only systematic twin study available was performed by Hublin et al. in Finns [8], but the three twin pairs identified with narcolepsy were dizygotic and so are uninformative to establish concordance. Approximately 20 monozygotic twin reports are available in the literature (see [10] for review). Five to seven pairs are concordant for narcolepsy, depending on how strictly concordance is determined clinically [10, 22–24]. Most cases of human narcolepsy, therefore, require the influence of environmental factors for the pathology to develop. This is also substantiated by the fact that onset is not at birth but rather in adolescence, suggesting the existence of triggering factors. The nature of the environmental factor(s) involved is still uncertain. Frequently cited factors have been head trauma [25–27], sudden change in sleep/wake habits [23, 28], or various infections [29, 30]. These factors may be involved, but these studies all used retrospective designs, limiting the value of any reported difference. A recent study found increased antistreptolysin O antibodies, a

Etiology and Genetics of Human Narcolepsy

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Table  1  Sensitivity (SE) and specificity (SP) of various diagnostic tests for narcolepsy/cataplexy and narcolepsy without cataplexy

HLA MSLT hcrt £ 110 pg/ml hcrt £ 200 pg/ml

SE SP SE SP SE SP SE SP

Narcolepsy with cataplexy 89.3%(822/1291) 76.0% (1,291) 87.9% (964/1,095) 96.9% (1,095) 83.3% (233/182) 100% 85.0%(233/182) 98.9%

Narcolepsy without cataplexy 45.4% (306/1,291) 76.0%(1,291) Not applicable 96.9%(1,095) 14.8%(162/182) 100% 22.8%(162/182) 98.9%

Idiopathic hypersomnia 17.7% (62/1,291) 76.0%(1,291) Not applicable 96.9% (1,995) 0.0%(49/182) 100% 6.1%(49/182) 98.9%

Not applicable because it is part of the clinical definition. Numbers in parentheses indicate the number of patients and corresponding number of controls used to calculate sensitivity (SE). For specificity (SP), only the number of controls is reported. Narcolepsy with atypical or no cataplexy is grouped as narcolepsy without cataplexy as per ICSD-2 [7]. Idiopathic hypersomnia includes both patients as defined by a positive MSLT or with prolonged sleep time independent of MSLT results. A positive MSLT is a mean sleep latency £8 min and ³2SOREMP for narcolepsy without cataplexy, or a mean sleep latency £8 min and 2 affected members Healthy relatives

DQB1*0602, n (%) 498/574 (87%)‡ 83/210 (40%)‡ 358/1,416 (25%) 51/74 (70%)**,‡ 21/39 (54%) 36/47 (77%)*,‡ 15/27 (56%)†,** 78/164 (48%)

Sporadic cases are patients with narcolepsy without a family history. Data reported for multiplex cases include multiple cases in each multiplex family. Results are identical when only one proband per family (n = 35 families) is included, data not shown. Typical cataplexy is defined as muscle weakness triggered at least sometimes by laughing or joking. *P = 0.05 vs. sporadic cases; **p