Narcolepsy (eBook)

A Clinical Guide
eBook Download: PDF
2009 | 2010
XXII, 330 Seiten
Springer New York (Verlag)
978-1-4419-0854-4 (ISBN)

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Narcolepsy serves as a prototype of how the interaction of high quality clinical research and groundbreaking basic science can collaborate to defne the cause of a disease and change forever how we evaluate and treat it. There is scarcely a topic in this book that would have been covered in the same way 10 years ago as it is d- cussed today. We are also fortunate that many of the players in this dramatic tu- around have contributed to this volume, so that the result is a tapestry of the events that have transformed the feld over the last decade that is both authentic and detailed. The frst section of the book provides much of the basic science background. As described in the frst two chapters, the dramatic convergence of lines of evidence from two different laboratories frst demonstrated in 1999 that narcolepsy is a disease of loss of neurotransmission by lateral hypothalamic neurons making the peptides that have been called orexins or hypocretins. These fndings did much to clarify and unify a feld that had puzzled for decades over the fundamental nature of this puzzling disease, as refected in the chapters that review its epidemiology and neuroanatomical and imaging fndings.

Meeta Goswami, BDS, PhD, MPH, has been the director of the Narcolepsy Institute since its inception in 1985 and serves as an Assistant Professor of Neurology, Albert Einstein College of Medicine. Her general area of research interest includes narcolepsy and psychosocial issues.

S.R. Pandi-Perumal, M.Sc, is the President and Chief Executive Officer of Somnogen Inc, a New York Corporation. He is a well-recognized sleep researcher both nationally and internationally, and has authored many publications. His general area of research interest includes sleep and biological rhythms. He is a well-known editor in the field of sleep medicine and has edited over 15 volumes dealing with various sleep-related topics.

Michael J Thorpy, MD, has won many awards for his research including one of the sleep field's highest honors: the Nathaniel Kleitman Award. He is a well-published researcher and a board-certified sleep physician. He serves as a Professor of Neurology at Albert Einstein College of Medicine and the Director of the Sleep-Wake Disorders Center at Montefiore Medical Center, Bronx, New York.


Narcolepsy serves as a prototype of how the interaction of high quality clinical research and groundbreaking basic science can collaborate to defne the cause of a disease and change forever how we evaluate and treat it. There is scarcely a topic in this book that would have been covered in the same way 10 years ago as it is d- cussed today. We are also fortunate that many of the players in this dramatic tu- around have contributed to this volume, so that the result is a tapestry of the events that have transformed the feld over the last decade that is both authentic and detailed. The frst section of the book provides much of the basic science background. As described in the frst two chapters, the dramatic convergence of lines of evidence from two different laboratories frst demonstrated in 1999 that narcolepsy is a disease of loss of neurotransmission by lateral hypothalamic neurons making the peptides that have been called orexins or hypocretins. These fndings did much to clarify and unify a feld that had puzzled for decades over the fundamental nature of this puzzling disease, as refected in the chapters that review its epidemiology and neuroanatomical and imaging fndings.

Meeta Goswami, BDS, PhD, MPH, has been the director of the Narcolepsy Institute since its inception in 1985 and serves as an Assistant Professor of Neurology, Albert Einstein College of Medicine. Her general area of research interest includes narcolepsy and psychosocial issues. S.R. Pandi-Perumal, M.Sc, is the President and Chief Executive Officer of Somnogen Inc, a New York Corporation. He is a well-recognized sleep researcher both nationally and internationally, and has authored many publications. His general area of research interest includes sleep and biological rhythms. He is a well-known editor in the field of sleep medicine and has edited over 15 volumes dealing with various sleep-related topics. Michael J Thorpy, MD, has won many awards for his research including one of the sleep field's highest honors: the Nathaniel Kleitman Award. He is a well-published researcher and a board-certified sleep physician. He serves as a Professor of Neurology at Albert Einstein College of Medicine and the Director of the Sleep-Wake Disorders Center at Montefiore Medical Center, Bronx, New York.

Foreword 5
Credits and Acknowledgments 7
Preface 8
Contents 11
Contributors 14
Biographies 18
Section I Etiology 20
Chapter 1 21
Narcolepsy: Genetic Predisposition and Pathophysiology 21
Prevalence Studies 21
Animal Models 22
Twin Studies and Environmental Factors in Narcolepsy 24
Familial Aspects of Human Narcolepsy 25
Hypocretin (Orexin) Deficiency and Human Narcolepsy–Cataplexy 26
HLA-DR2, Narcolepsy and Autoimmunity 26
DQB1*0602 and DQA1*0102 Are the Main HLA Narcolepsy Susceptibility Genes 27
HLA Typing in Clinical Practice 28
Genetic Factors Other Than HLA 29
CSF Hypocretin-1 as a Diagnostic Tool for Narcolepsy 30
Secondary Narcolepsy Cases 31
Pharmacological Studies: Monoaminergic and Cholinergic Interactions in Hypocretin Deficiency 32
Hypocretin Compounds as Therapeutic Targets 34
Conclusion and Perspectives 34
References 35
Chapter 2 40
Animal Models of Narcolepsy: Development, Findings and Perspectives 40
Introduction 40
Narcolepsy for the Veterinarian 41
Canine Narcolepsy 41
The Canine Narcoleptic Phenotype 42
Neurotransmitter Differences and Imbalances in the Canine Narcoleptic 43
The Genetics of Canine Narcolepsy 44
Rodent Narcolepsy 45
Vigilance State Characterization of Orexin- and Orexin-Receptor Deficient Rodents 46
The Orexin / Mouse 46
Orexin/Ataxin-3 Transgenic Mice and Rats 48
The Orexin Receptor Null Mice: OX1R-/-, OX2R.-/- and OX1R.-/- OX2R-/-
Summary 49
Current Research Issues 50
Etiology 50
Cataplexy 50
References 51
Chapter 3 55
Neuroimaging of Narcolepsy 55
Introduction 55
Functional Neuroimaging Studies of Healthy Human Sleep 55
Narcolepsy 56
Narcolepsy Pharmacotherapy and Neuroimaging 57
Receptor Ligand Studies 58
Summary 58
References 58
Section II Clinical Considerations 60
Chapter 4 61
Epidemiology of Narcolepsy 61
Introduction 61
Narcolepsy Has a Variable Phenotype 61
Difficulties with Diagnosis Complicate Epidemiological Estimates 61
Prevalence and Incidence Estimates Vary by Methods and Populations 62
Age of Onset Generally Begins in the First Two Decades 63
Narcolepsy Without Cataplexy Is More Common Among Men than Women 63
Narcolepsy Has Few Links to Lifestyle Characteristics 64
Narcolepsy Impairs Quality of Life and Increases Accident Risks 64
Narcolepsy Overlaps with a Variety of Co-morbidities 64
Narcolepsy Has Both a Genetic and Environmental Link 64
Seasonality of Birth Gives Clues to Environmental Origins of Narcolepsy 65
Treatment Options Are Developing Rapidly 65
Looking Ahead: The Future of Epidemiology of Narcolepsy 65
References 66
Chapter 5 68
Narcolepsy in Childhood 68
Historical Notes 68
Introduction 68
Prevalence 68
Clinical Presentation 69
Pre-School-Age Children 69
School-Age Children 69
Histocompatibility Antigens and Human Narcolepsy 71
Hypocretin Deficiency 71
Two Threshold Hypothesis 71
Secondary Narcolepsy 72
Physical Examination 72
Diagnosis 72
Evaluating Sleepiness 72
Sleep Laboratory Testing 72
Differential Diagnoses 73
Management 75
Immunotherapy 77
Conclusions 77
References 77
Chapter 6 81
Narcolepsy in the Older Adult 81
Introduction 81
Narcolepsy Onset After Age 35 81
Delayed Diagnosis 82
Secondary or Symptomatic Narcolepsy 83
Implications of Narcolepsy in the Older Adult and Therapeutic Challenges 84
Conclusion 85
Case Example 86
References 87
Chapter 7 89
Diurnal and Nocturnal Sleep in Narcolepsy with Cataplexy 89
Introduction 89
Clinical Characteristics 89
Laboratory Characteristics 92
Daytime MSLT 92
Polysomnographical Findings 92
Sleep Structure 92
Sleep Microstructure 93
Periodic Limb Movements 93
Dissociated Sleep 93
Sleep Apnea/Hypopnea Syndrome 94
Conclusion 95
Diagn ostic criteria for narcolepsy with cataplexy [24] 95
References 96
Chapter 8 98
Hypnagogic Hallucinations and Sleep Paralysis 98
Introduction 98
Hypnagogic Hallucinations 99
Clinical Features 99
Hypnagogic Hallucinations and Dreams 99
Hypnagogic Hallucinations and Schizophrenia 100
Hypnagogic Hallucinations and other Neurological Disorders 100
Sleep Paralysis 101
Clinical Features 101
Isolated Sleep Paralysis and Culturally Determined Interpretations 101
Neurobiology of Hypnagogic Hallucinations and Sleep Paralysis 102
General View 102
Neurobiology of Hallucinations 102
Neurobiology of Sleep Paralysis 103
Dissociated REM Phenomena in the AIM State Space Model 103
Hypnagogic Hallucinations in the AIM Model 104
Sleep Paralysis in the AIM Model 104
Treatment of Hypnagogic Hallucinations and Sleep Paralysis 105
Sodium Oxybate 105
Antidepressant Medications 106
Conclusive Remarks 106
References 107
Chapter 9 109
REM Sleep Behavior Disorder in Narcolepsy with Cataplexy 109
Introduction 109
Diagnostic Criteria for RBD 110
RBD in Narcoleptic Patients 111
References 112
Chapter 10 114
Narcolepsy and Other Comorbid Medical Illnesses 114
Introduction 114
Comorbid Eating Disorders and Obesity 114
Diabetes Mellitus 116
Psychiatric Disorders 117
Fibromyalgia 118
Migraines and Other Headaches 118
Cognitive Dysfunction 119
Psychosocial Comorbidities 120
Conclusion 120
References 121
Chapter 11 123
Humor Processing in Human Narcolepsy with Cataplexy 123
Introduction 123
Emotional Triggers of Cataplexy 123
Weak with Laughter 124
Anatomical Findings in Human Narcolepsy 125
Functional Abnormalities in Narcolepsy 126
Neural Correlates of Humor and Laughter 126
Neuroimaging of Humor Processing in Narcolepsy–Cataplexy 127
Abnormal Hypothalamic and Amygdala Activity 127
Implications for Models of Cataplexy 129
Conclusions 130
References 130
Chapter 12 133
Dreams in Patients with Narcolepsy 133
References 134
Chapter 13 136
Psychoanalysis and Narcolepsy 136
Psychoanalytic Approaches to Narcolepsy 136
Narcolepsy – The Rems Model 138
Narcolepsy and Neuroscientific Theory 139
Discussion 140
References 140
Chapter 14 142
Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency 142
Introduction 142
Definition of Symptomatic Narcolepsy and Its Overview 143
Anatomical Substrate for the Symptoms of Narcolepsy 150
Hypocretin Status in Various Neurological Conditions 151
Hypocretin Status in Symptomatic Narcolepsy–Cataplexy Associated with Distinct CNS Lesions 151
Status in Symptomatic Narcolepsy–Cataplexy and/or EDS Associated with Inherited Disorders 152
Prader-Willi Syndrome 152
Niemann-Pick Type C Disease 153
Myotonic Dystrophy 153
Status in Hypersomnia in Various Neurological Conditions: Focal/Generalized CNS Invasion 154
Cerebral Tumors 154
Infarctions 155
Encephalopathies 156
Wernicke’s Encephalopathy 156
Limbic Encephalopathy 156
Rasmussen’s Syndrome 157
Brain Stem Encephalitis 157
Neurodegenerative Disorders 158
Parkinson’s Disease 158
Dementia with Lewy Bodies 158
Progressive Supranuclear Palsy 158
Alzheimer’s Disease 159
Hungtington’s Disease 159
Head Trauma 159
CNS Diseases Mediated with Neuroimmune Mechanisms 161
Demyelinating Diseases 161
Multiple Sclerosis 161
Pathophysiological Considerations of MS Cases 162
Neuromyelitis Optica and Anti-AQP4 Antibody 163
Pathophysiological Considerations of MS Cases and NMO Cases 164
Acute Disseminated Encephalomyelitis 164
Pathophysiological Considerations of MS Cases and ADEM Cases 165
Conclusions of Demyelinating Disease 165
Guillain-Barre’s Syndrome 165
Paraneoplastic Syndrome 166
Conclusion 166
References 168
Chapter 15 173
Hypersomnias Other than Narcolepsy: Differential Diagnosis 173
Introduction 173
Positive Diagnosis of Hypersomnia 173
Differential Diagnosis of Hypersomnia 173
Clinical Approach 173
Laboratory Tests 174
Neurophysiological Tests 174
Multiple Sleep Latency Test 174
Maintenance of Wakefulness Test 174
Prolonged Polysomnographic Recording 175
Brain Imaging 175
Psychometric/Psychiatric Evaluation 175
Various Causes of Hypersomnia 175
Hypersomnia as a Direct Consequence of a Behaviour or of the Use of a Drug or Substance 175
Behaviorally Induced Insufficient Sleep Syndrome 175
Hypersomnia Due to Drug or Substance 175
Psychotropic Drugs 175
Anxiolytics and Hypnotics 175
Antidepressants 176
Neuroleptics 176
Stimulants 176
Cardiovascular Drugs 176
Antihypertensive Drugs 176
Drugs Used in Neurology 176
Antiparkinsonian Drugs 176
Antiepileptic Agents 176
Analgesics 176
Opioïds 176
Substances 176
Hypersomnias in the Context of Sleep-Related Breathing Disorders 176
Obstructive Sleep Apnoea Syndrome 176
Central Sleep Apnoea Syndrome 177
Hypersomnias of Central Origin 177
Idiopathic Hypersomnia 178
Recurrent Hypersomnias 179
Hypersomnias Associated with Various Medical Disorders 180
Hypersomnia Associated with Neurological Diseases 180
Brain Tumours 180
Stroke 180
Neurodegenerative Diseases 180
Neuromuscular Diseases 180
Multiple Sclerosis 181
Epilepsy 181
Chiari Malformation 181
Rare Inherited Disorders 181
Hypersomnia Associated with Infectious Disease 181
Hypersomnia Associated with Metabolic and Endocrine Diseases 181
Post-traumatic Hypersomnia 181
Hypersomnia not due to Substance or Known Physiological Condition (Psychiatric Hypersomnia) 182
The Issue of Periodic Limb Movements in Sleep (PLMS) and Excessive Daytime Sleepiness 182
Conclusion 182
References 182
Section III Psychosocial Considerations 185
Chapter 16 186
Psychosocial Impact of Narcolepsy in Children and Adolescents 186
Preamble 186
Introduction 186
Review of the Literature 187
General Accounts 187
Childhood 188
Problems Related to Sense of Self and Others 188
Problems with Social Functioning 188
Problems with Mood and Family 188
Problems at School 188
Adolescence 188
Empirical Research Studies 188
Issues Arising 189
What Do We Know About the Psychosocial Problems of Children with Narcolepsy in General? 189
What Aspects Need to Be Considered in Describing Narcoleptic Children’s Psychosocial Problems and How Should They Be Assessed? 190
Which Aspects of Narcolepsy Determine the Likelihood, Nature and Extent of Psychosocial Difficulties? 190
What Resources Are Needed to Prevent or Offset the Psychosocial Difficulties to Which Children and Adolescents Are Apparently P 191
Are Preventive or Intervention Measures Effective in Reducing Psychosocial Complications to the Lives of Young People with Na 191
Conclusion 191
References 192
Chapter 17 193
Quality of Life and Psychosocial Issues in Narcolepsy 193
Introduction 193
QOL, Health-Related Quality of Life, and Health Status 193
Measuring Health-Related Quality of Life in Narcolepsy 195
The Short Form 36 195
Sickness Impact Profile 196
Functional Outcomes of Sleep Questionnaire 196
Points to Consider in Critical Appraisal of Research on HRQOL in Narcolepsy 196
Quality of Life in Narcolepsy 196
Health-Related Quality of Life 198
Narcolepsy and Support Groups 201
Why Do Some Members Not Attend Support Group Meetings? 202
What Characteristics Differentiate Those Who Attend Support Groups from Those Who Don’t? 203
Implications for Management of Narcolepsy 203
Social Support and Counseling 203
Transportation 204
Employment 204
Research Implications 205
References 205
Chapter 18 209
Narcolepsy, Intimacy and Sexuality 209
Symptoms 209
Impact of Symptoms as a Function of Developmental Stage 210
Case History: MAG 211
Case History: RIL 212
Case History: PR 213
Case History: Mrs. L. 215
Case History: Mr. B. 215
References 218
Chapter 19 220
Narcolepsy, Driving and Traffic Safety 220
Introduction 220
Narcolepsy and Accident Risk 220
Driving Performance of Untreated Narcolepsy Patients 220
Treatment Effects on Driving Performance 221
Interpretation of Driving Simulator Results 222
Decisions on Fitness to Drive 222
References 223
Chapter 20 225
Memory and Cognition in Narcolepsy 225
Main Symptoms of Narcolepsy 225
Dysfunction of the Hypocretin System in Narcolepsy 225
Neurotransmitter Dysfunction 225
Cognitive Deficits in Narcolepsy 226
Memory 226
Attention 227
Executive Functions 228
Summary and Discussion 229
References 230
Chapter 21 232
Medico-Legal Aspects of Disability in Narcolepsy 232
Introduction 232
Disability and Work Disability 232
Work Limitations in Narcolepsy 233
Impairment Variability 234
The Lack of a Clinical Severity Scale 234
The Contribution of Sleep Disorder Experts to Work Disability Determination 235
Conclusions 236
References 237
Chapter 22 239
Narcolepsy and Mental Health 239
Introduction 239
Cognitive Function 239
Methodological Issues 239
Attention 239
Memory 240
Executive Function 240
Mood Disorders 240
Anxiety and Depression 240
Psychosis 241
Other Psychological Aspects 241
Dreams and Hallucinations 241
Pain 241
Food Cravings 241
Functional Impairment 242
Age 242
Gender 243
Social Activities 243
Recreational Activities 243
Accidents 243
Education 243
Employment 243
Treatment 243
Explanation 243
Lifestyle Aspects 244
Drugs 244
Amphetamines 244
Modafinil 244
Sodium Oxybate 245
References 246
Section IV Management 248
Chapter 23 249
Overview of Management of Narcolepsy 249
Introduction 249
Symptoms of Narcolepsy 249
Sleepiness or Excessive Daytime Sleepiness (EDS) 250
Cataplexy 250
Hypnagogic or Hypnopompic Hallucinations 250
Sleep Paralysis 251
Treatments of Narcolepsy 251
Pharmacological Treatment of Daytime Sleepiness with Amphetamine-Like Compounds 251
Modafinil and Armodafinil 254
Other Wake Promoting Agents 255
Sodium Oxybate and Treatment of Disturbed Nocturnal Sleep 255
Antidepressants and the Pharmacological Treatment of Cataplexy 256
Treatment of Sleep Paralysis and Hypnagogic Hallucinations 258
Future Treatment Options 258
Conclusion 260
References 260
Chapter 24 264
Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics 264
Introduction 264
Neurobiology of Wakefulness and Modes of Action of Amphetamines and Modafinil on EDS 264
Neurobiology of Wakefulness 265
Modes of Action of Amphetamines 266
Molecular Targets of Amphetamine Action 266
Dopaminergic Neurotransmission and EEG Arousal 269
Anatomical Substrates of Dopaminergic Effects 271
Modes of Action of Modafinil/Armodafinil 271
Other Wake-Promoting Compounds 274
Mechanisms of Action of Tricyclic anti-Cataplectics 275
Preferential Involvement of Adrenergic Neurotransmission in the Control of Canine Cataplexy 275
Receptor Subtypes Involved in the Control of Cataplexy 277
MAOIs 277
GHB 278
Conclusion 280
References 280
Chapter 25 284
Modafinil/Armodafinil in the Treatment of Narcolepsy 284
The Introduction of Modafinil/Armodafinil 284
Treatment of Narcolepsy by Modafinil 284
Armodafinil 286
Efficacy of Armodafinil in Narcolepsy 286
Mode of Action of Modafinil/Armodafinil 287
Safety and Adverse Event Data with Modafinil/Armodafinil 287
Summary 289
References 289
Chapter 26 292
Sodium Oxybate in the Treatment of Narcolepsy 292
Conservative Treatment of Narcoleptic Symptoms 292
Gammahydroxybutyrate (GHB)/Sodium Oxybate (SO) 292
Pharmacology 292
Pharmacokinetics 293
Efficacy of SO in Treating Symptoms of Narcolepsy 293
Cataplexy 293
Excessive Daytime Sleepiness 293
Sleep 294
Quality of Life 294
Adverse Events 294
Contraindications 295
Treatment Recommendations 295
Conclusion 296
References 296
Chapter 27 297
Emerging Treatments for Narcolepsy 297
Introduction 297
Hypocretin-Based Treatments 297
Hypocretin Gene Therapy 299
Hypocretin Cell Transplants 299
Stem Cell Transplantation 300
Hypocretin-Receptor Agonists 300
Immunotherapy 300
Thyrotrophin Releasing Hormone Agonists 301
Histamine 3 Receptor (H3) Antagonists 302
Modified Current Medical Therapies 303
Combination Therapies 303
Others 304
Conclusions 305
References 305
Chapter 28 308
Non-pharmacologic Treatments of Narcolepsy 308
Introduction 308
Excessive Daytime Somnolence and Involuntary Sleep Episodes 308
Scheduled Naps and EDS 309
Dietary Manipulation in Managing Excessive Daytime Sleepiness 310
Exercise 311
Disrupted Nighttime Sleep 311
Cataplexy 312
Sleep Paralysis 312
Hypnagogic Hallucinations and Nightmares 312
Cognitive Complaints 312
Psychiatric Co-morbidities and Management 313
Interpersonal Difficulties and Limited Psychosocial Support 314
Work and Education Difficulties 314
Difficulties with Driving and Home Chores 315
Conclusion 315
References 315
Index 318

Erscheint lt. Verlag 11.11.2009
Zusatzinfo XXII, 330 p. 29 illus.
Verlagsort New York
Sprache englisch
Themenwelt Medizin / Pharmazie Medizinische Fachgebiete Allgemeinmedizin
Medizin / Pharmazie Medizinische Fachgebiete Gynäkologie / Geburtshilfe
Medizin / Pharmazie Medizinische Fachgebiete Innere Medizin
Medizin / Pharmazie Medizinische Fachgebiete Neurologie
Medizin / Pharmazie Medizinische Fachgebiete Pädiatrie
Schlagworte attention • cataplexy • daytime sleepiness • Diagnosis • hypersomnias • hypnagogic • hypnopompic hallucinations • modafinil • narcolepsy • Psychoanalysis • sleep medicine • sleep paralysis • sodium oxybate
ISBN-10 1-4419-0854-4 / 1441908544
ISBN-13 978-1-4419-0854-4 / 9781441908544
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