Narcolepsy and excessive daytime sleepiness
http://www.100md.com
《英国医生杂志》
Adam Zeman, consultant neurologist1, Tom Britton, consultant neurologist2, Neil Douglas, professor of respiratory and sleep medicine3, Andrew Hansen, general practitioner4, Jane Hicks, specialist registrar in neuropsychiatry5, Robin Howard, consultant neurologist6, Andrew Meredith, consultant ENT surgeon7, Ian Smith, consultant physician8, Gregory Stores, emeritus professor of developmental neuropsychiatry9, Sue Wilson, psychopharmacology research fellow10, Zenobia Zaiwalla, consultant in clinical neurophysiology11
1 Western General Hospital, Edinburgh EH4 1PU, 2 King's College Hospital, London, 3 Royal Infirmary, Edinburgh, 4 Ridge Medical Centre, Bradford, 5 Burden Centre, Frenchay Hospital, Bristol, 6 National Hospital for Neurology and Neurosurgery, London, 7 Conquest Hospital, St Leonards-on-Sea, East Sussex, 8 Respiratory Support and Sleep Centre, Papworth Hospital, Cambridge, 9 University of Oxford, Oxford, 10 University of Bristol, Bristol, 11 Park Hospital and Radcliffe Infirmary, Oxford
Correspondence to: A Zeman az@skull.dcn.ed.ac.uk
Introduction
This paper is based on a literature search conducted to produce evidence based guidelines on the diagnosis and management of narcolepsy in adults and children.3 We searched Medline, Embase, the Cochrane Collaboration, and two specialist sleep literature resources for abstracts with the key word "narcolepsy." We read the full text of relevant papers and hand searched these for other relevant material. A multidisciplinary working party prepared the guidelines, and a group of 10 independent experts later reviewed them. These guidelines can be downloaded from the news section of www.sleeping.org.uk (accessed July 2004).
Clinical features of narcolepsy
The prevalence of narcolepsy with cataplexy in European populations has been estimated at 3-5 per 10 0006-8; this is approximately a quarter of the prevalence of multiple sclerosis in the United Kingdom. A recent study suggests that inclusion of patients without cataplexy would increase this estimate by around a third.8 The disorder most commonly starts in the teens or 20s, but it can present as early as 2 years of age or in middle age. Men and women are roughly equally affected. Family members are at an increased risk of the disorder, which occurs in 1-2% of first degree relatives, but a clear cut family history is unusual.9
Neurobiology of sleep and narcolepsy
The differential diagnosis of excessive daytime sleepiness occurring in isolation is wide.1 3 Narcolepsy is an important cause, although by no means the most common. Box 1 lists the main possibilities and diagnostic pointers. Excessive daytime sleepiness occurring in conjunction with unambiguous cataplexy is almost always due to narcolepsy. Very rarely, narcolepsy can be symptomatic of another underlying disorder of the central nervous system, usually a structural lesion involving the region of the hypothalamus. Additional symptoms and signs of endocrine or neurological disorder are likely to be present. Occasionally, epilepsy can be mistaken for narcolepsy, and factitious simulation of narcolepsy has been described.3 However, failure to recognise narcolepsy, with delayed diagnosis or misdiagnosis, is the more common error. Narcolepsy has been mistaken for epilepsy, chronic fatigue syndrome, and schizophrenia.3
Clinical assessment of excessive daytime sleepiness
General management
Narcolepsy is a lifelong condition with wide ranging implications. Relevant and accurate information should be made available to the patient, relatives, schools, employers, and medical professionals. Narcolepsy is compatible with success both at school and in the work-place, but schools should be encouraged to arrange appropriate schedules for children with narcolepsy, and career choices should take account of the possible hazards caused by excessive daytime sleepiness and cataplexy. The consensus is that regular nocturnal sleep habits and attention to sleep hygiene help to minimise excessive daytime sleepiness, and some evidence shows that planned naps can be used to optimise daytime performance.26 In the United Kingdom, people with narcolepsy are required by law to let the Driver and Vehicle Licensing Authority know about the diagnosis and are generally well advised to refrain from driving until the DVLA has reached a decision on their case. Holders of ordinary group 1 licences will be permitted to drive once "satisfactory control of symptoms" is achieved; people with narcolepsy are generally considered unfit to hold group 2 (heavy goods vehicle and bus) licences, although exceptions can be made.
Drug management
Sleepiness and cataplexy are the symptoms of narcolepsy that most often merit treatment with drugs. The decision to treat should always be guided by a discussion of the anticipated benefits and side effects with the patient.
Sleepiness—Excessive daytime sleepiness is reduced by amphetamine-like stimulants (usually dexamfetamine, which is licensed for this use, or methylphenidate) and the relatively recent "wake promoter" modafinil (also licensed for this use) (table). Little doubt exists about the efficacy of the amphetamine-like drugs, although the formal evidence base for their use is slim, reflecting the early date of their introduction.3 The use of modafinil is supported by up to date randomised controlled trials.3 27 Amphetamine-like drugs and modafinil have not been compared head to head in a randomised controlled trial, nor has combined use of the two classes of drug been formally studied. Advantages of amphetamine-like drugs include long experience, low cost, and possibly an action against cataplexy and higher efficacy; modafinil has the advantage that tolerance does not develop (which can occur with amphetamines) and possibly has a lower rate of side effects. Common side effects of amphetamine-like drugs include irritability and insomnia; modafinil may cause headache, nausea, and rhinitis and may interact with the oral contraceptive pill, necessitating a dose of at least 50 μg oestrogen.
Treatment of daytime sleepiness in narcolepsy
Box 4: Ongoing research
GHB UK study (further information from Adrian.Williams@gstt.sthames.nhs.uk)
Oxford study of psychosocial aspects of narcolepsy in childhood (data to be presented at ESRS meeting, Prague 2004)
Use of hypocretin in diagnosis
Development of hypocretin related drugs for use in treatment
Cataplexy—Cataplexy is reduced by antidepressant drugs, which suppress rapid eye movement sleep.3 Clomipramine at doses of 30-150 mg/day has been used most widely and is licensed for this indication (up to 75 mg/day), but evidence also exists that fluoxetine, other selective serotonin reuptake inhibitors, and the combined noradrenaline and serotonin reuptake inhibitor venlafaxine are effective.
Better treatments are needed for both excessive daytime sleepiness and cataplexy. The possible use of selegiline merits further study. A trial of gammahydroxybutyrate, which is now licensed in the United States for cataplexy, is under way in the United Kingdom. Hypocretin replacement may prove feasible in the future.
Additional educational resources
Websites
British Sleep Society (www.sleeping.org.uk)—the website of the main British organisation promoting clinical sleep research
Primary Care Sleep Group (www.primarycaresleep.com)—a website for primary care health professionals, providing information about sleep disorders
European Sleep Research Society (www.esrs.org)—the website of a major international sleep research organisation
Stanford Centre for Narcolepsy (www.med.stanford.edu/school/Psychiatry/narcolepsy)—a website providing information about narcolepsy and current research
Patient information resources
Narcolepsy Association UK (www.narcolepsy.org.uk)—website of the main British narcolepsy patient organisation
Narcolepsy Action for Positive Practical Solutions (www.napps.cwc.net)—website of an alternative patient support group
A patient's perspective
I have suffered from narcolepsy for 35 years. Onset was gradual, with attacks of cataplexy at the end of the week, perhaps when I relaxed. As these became more frequent, I began to experience frightening episodes of sleep paralysis on waking, terrifying hypnagogic hallucinations, and daytime sleepiness. Once the diagnosis was made, treatment proved highly effective, but when my medication became temporarily unavailable I was suspended from work as a surgeon for six months. I had to modify my lifestyle considerably after the diagnosis. My sleepiness worsens as the day progresses. Visits to the theatre, cinema, or even parents' evenings are impossible. Concentration on academic activities and boring meetings provokes sleep. Falling off one's chair is guaranteed to halt proceedings. Fortunately, I gained my academic qualifications before the onset of the condition.
Surprisingly, physical and practical work poses no problem: I have never had an attack when driving or operating, but 10 minutes after stopping such activity is a fraught period. My major problem now is cataplexy associated with emotion, usually laughter.
Close friends and relatives recognise prodromal signs of altered speech and convulsive jaw movements and support me if there is nothing convenient for me to lean on. Sleep paralysis and hallucinations have stopped with age.
Referral
Patients with suspected narcolepsy should be referred to a sleep disorders service, or its closest local equivalent, for diagnosis. Once the diagnosis is made, patients should have at least an annual review by a clinician who is knowledgeable about the disorder and its evolving treatment. The fascinating area of sleep disorders medicine needs considerable development in the United Kingdom. Box 4 shows areas of ongoing research.
We thank John Towers for his help, our colleagues for their comments, and Taylor Patten Communications for editorial support.
Contributors: All authors contributed to the literature review and the writing of the guidelines on which this clinical review is based. AZ drafted this article, which was reviewed and edited by the guidelines working party. AZ is the guarantor.
Funding: The creation of the guidelines was funded by an unrestricted educational grant to Taylor Patten Communications by Cephalon UK, the manufacturers of modafinil.
Competing interests: Taylor Patten Communications paid travel expenses and honoraria to the working party members. ND received partial support for attendance at an international meeting on sleep apnoea from Cephalon and has had research on modafinil in sleep apnoea funded by Cephalon. JH has received travel grants from Cephalon. Cephalon has sponsored AM to attend conferences; he was runner-up in the Hospital Doctor sleep unit of the year award sponsored by Cephalon. IS has received travel grants and speakers' honoraria from Cephalon. SW received an honorarium from Cephalon for speaking to their sales force. Cephalon has supported ZZ to attend a sleep disorder conference and part funded a technician in her department to attend a conference. AZ is supported by the Health Foundation.
References
Guilleminault C, Brooks SN. Excessive daytime sleepiness. Brain 2001;124: 1482-91.
Stores G, Crawford C. Medical student education in sleep and its disorders. J R Coll Physicians Lond 1998;32: 149-53.
Britton T, Douglas N, Hansen A, Hicks J, Howard R, Meredith A, et al. Guidelines on the diagnosis and management of narcolepsy in adults and children. Ashtead: Taylor Patten Communications, 2002 (available at www.sleeping.org.uk or www.primarycaresleep.com).
Overeem S, Mignot E, van Dijk JG, Lammers GJ. Narcolepsy: clinical features, new pathophysiologic insights and future perspectives. J Clin Neurophysiol 2001;18: 78-105.
Daniels E, King MA, Smith IE, Shneerson JM. Health-related quality of life in narcolepsy. J Sleep Res 2001;10: 75-81.
Hublin C, Kaprio J, Partinen M, Koskenvuo M, Heikila K, Koskimies K, et al. The prevalence of narcolepsy: an epidemiological study of the Finnish twin cohort. Ann Neurol 1994;35: 709-16.
Ohayon MM, Priest RG, Caulet M, Guilleminault C. Hypnagogic and hypnopompic hallucinations: pathological phenomena? Br J Psychiatry 1996;169: 459-67.
Silber MH, Krahn LE, Pankratz VS. The epidemiology of narcolepsy in Olmstead County, Minnesota: a population-based study. Sleep 2002;25: 197-202.
Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50(suppl 1): 516-22.
Pace-Schott EF, Hobson JA. The neurobiology of sleep. Nat Rev Neurosci 2002;3: 591-605.
Hobson JA, Pace-Schott EF. The cognitive neuroscience of sleep. Nat Rev Neurosci 2002;3: 670-93.
Gelineau JBE. De la narcolepsie. Gazette des hopitaux de Paris 1880: 626-8, 635-7.
Rechtschaffen A, Wolpert E, Dement WC, Mitchell SA, Fisher C. Nocturnal sleep of narcoleptics. Electroencephalogr Clin Neurophysiol 1963;15: 599-609.
Juji T, Satake M, Honda Y, Doi Y. HLA antigens in Japanese patients with narcolepsy: all the patients were DR2 positive. Tissue Antigens 1984;24: 316-9.
Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep 1997;20: 1012-20.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behaviour. Cell 1998;92: 573-85.
De Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998;95: 322-7.
Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999;98: 365-76.
Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy . Lancet 2000;355: 39-40.
Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case of early onset narcolepsy and a generalised absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6: 991-7.
Thannickal TC, Moore RY, Nienhuls R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced numbers of hypocretin neurons in human narcolepsy. Neuron 2000;27: 469-74.
Scammell T. The neurobiology, diagnosis and treatment of narcolepsy. Ann Neurol 2003;53: 154-66.
Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59: 1553-62.
Johns MJ. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;6: 540-5.
Standard of Practice Committee, American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy. Sleep 2001;24: 451-66.
Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep 2001;24: 385-91.
US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology 2000;54: 1166-75.
1 Western General Hospital, Edinburgh EH4 1PU, 2 King's College Hospital, London, 3 Royal Infirmary, Edinburgh, 4 Ridge Medical Centre, Bradford, 5 Burden Centre, Frenchay Hospital, Bristol, 6 National Hospital for Neurology and Neurosurgery, London, 7 Conquest Hospital, St Leonards-on-Sea, East Sussex, 8 Respiratory Support and Sleep Centre, Papworth Hospital, Cambridge, 9 University of Oxford, Oxford, 10 University of Bristol, Bristol, 11 Park Hospital and Radcliffe Infirmary, Oxford
Correspondence to: A Zeman az@skull.dcn.ed.ac.uk
Introduction
This paper is based on a literature search conducted to produce evidence based guidelines on the diagnosis and management of narcolepsy in adults and children.3 We searched Medline, Embase, the Cochrane Collaboration, and two specialist sleep literature resources for abstracts with the key word "narcolepsy." We read the full text of relevant papers and hand searched these for other relevant material. A multidisciplinary working party prepared the guidelines, and a group of 10 independent experts later reviewed them. These guidelines can be downloaded from the news section of www.sleeping.org.uk (accessed July 2004).
Clinical features of narcolepsy
The prevalence of narcolepsy with cataplexy in European populations has been estimated at 3-5 per 10 0006-8; this is approximately a quarter of the prevalence of multiple sclerosis in the United Kingdom. A recent study suggests that inclusion of patients without cataplexy would increase this estimate by around a third.8 The disorder most commonly starts in the teens or 20s, but it can present as early as 2 years of age or in middle age. Men and women are roughly equally affected. Family members are at an increased risk of the disorder, which occurs in 1-2% of first degree relatives, but a clear cut family history is unusual.9
Neurobiology of sleep and narcolepsy
The differential diagnosis of excessive daytime sleepiness occurring in isolation is wide.1 3 Narcolepsy is an important cause, although by no means the most common. Box 1 lists the main possibilities and diagnostic pointers. Excessive daytime sleepiness occurring in conjunction with unambiguous cataplexy is almost always due to narcolepsy. Very rarely, narcolepsy can be symptomatic of another underlying disorder of the central nervous system, usually a structural lesion involving the region of the hypothalamus. Additional symptoms and signs of endocrine or neurological disorder are likely to be present. Occasionally, epilepsy can be mistaken for narcolepsy, and factitious simulation of narcolepsy has been described.3 However, failure to recognise narcolepsy, with delayed diagnosis or misdiagnosis, is the more common error. Narcolepsy has been mistaken for epilepsy, chronic fatigue syndrome, and schizophrenia.3
Clinical assessment of excessive daytime sleepiness
General management
Narcolepsy is a lifelong condition with wide ranging implications. Relevant and accurate information should be made available to the patient, relatives, schools, employers, and medical professionals. Narcolepsy is compatible with success both at school and in the work-place, but schools should be encouraged to arrange appropriate schedules for children with narcolepsy, and career choices should take account of the possible hazards caused by excessive daytime sleepiness and cataplexy. The consensus is that regular nocturnal sleep habits and attention to sleep hygiene help to minimise excessive daytime sleepiness, and some evidence shows that planned naps can be used to optimise daytime performance.26 In the United Kingdom, people with narcolepsy are required by law to let the Driver and Vehicle Licensing Authority know about the diagnosis and are generally well advised to refrain from driving until the DVLA has reached a decision on their case. Holders of ordinary group 1 licences will be permitted to drive once "satisfactory control of symptoms" is achieved; people with narcolepsy are generally considered unfit to hold group 2 (heavy goods vehicle and bus) licences, although exceptions can be made.
Drug management
Sleepiness and cataplexy are the symptoms of narcolepsy that most often merit treatment with drugs. The decision to treat should always be guided by a discussion of the anticipated benefits and side effects with the patient.
Sleepiness—Excessive daytime sleepiness is reduced by amphetamine-like stimulants (usually dexamfetamine, which is licensed for this use, or methylphenidate) and the relatively recent "wake promoter" modafinil (also licensed for this use) (table). Little doubt exists about the efficacy of the amphetamine-like drugs, although the formal evidence base for their use is slim, reflecting the early date of their introduction.3 The use of modafinil is supported by up to date randomised controlled trials.3 27 Amphetamine-like drugs and modafinil have not been compared head to head in a randomised controlled trial, nor has combined use of the two classes of drug been formally studied. Advantages of amphetamine-like drugs include long experience, low cost, and possibly an action against cataplexy and higher efficacy; modafinil has the advantage that tolerance does not develop (which can occur with amphetamines) and possibly has a lower rate of side effects. Common side effects of amphetamine-like drugs include irritability and insomnia; modafinil may cause headache, nausea, and rhinitis and may interact with the oral contraceptive pill, necessitating a dose of at least 50 μg oestrogen.
Treatment of daytime sleepiness in narcolepsy
Box 4: Ongoing research
GHB UK study (further information from Adrian.Williams@gstt.sthames.nhs.uk)
Oxford study of psychosocial aspects of narcolepsy in childhood (data to be presented at ESRS meeting, Prague 2004)
Use of hypocretin in diagnosis
Development of hypocretin related drugs for use in treatment
Cataplexy—Cataplexy is reduced by antidepressant drugs, which suppress rapid eye movement sleep.3 Clomipramine at doses of 30-150 mg/day has been used most widely and is licensed for this indication (up to 75 mg/day), but evidence also exists that fluoxetine, other selective serotonin reuptake inhibitors, and the combined noradrenaline and serotonin reuptake inhibitor venlafaxine are effective.
Better treatments are needed for both excessive daytime sleepiness and cataplexy. The possible use of selegiline merits further study. A trial of gammahydroxybutyrate, which is now licensed in the United States for cataplexy, is under way in the United Kingdom. Hypocretin replacement may prove feasible in the future.
Additional educational resources
Websites
British Sleep Society (www.sleeping.org.uk)—the website of the main British organisation promoting clinical sleep research
Primary Care Sleep Group (www.primarycaresleep.com)—a website for primary care health professionals, providing information about sleep disorders
European Sleep Research Society (www.esrs.org)—the website of a major international sleep research organisation
Stanford Centre for Narcolepsy (www.med.stanford.edu/school/Psychiatry/narcolepsy)—a website providing information about narcolepsy and current research
Patient information resources
Narcolepsy Association UK (www.narcolepsy.org.uk)—website of the main British narcolepsy patient organisation
Narcolepsy Action for Positive Practical Solutions (www.napps.cwc.net)—website of an alternative patient support group
A patient's perspective
I have suffered from narcolepsy for 35 years. Onset was gradual, with attacks of cataplexy at the end of the week, perhaps when I relaxed. As these became more frequent, I began to experience frightening episodes of sleep paralysis on waking, terrifying hypnagogic hallucinations, and daytime sleepiness. Once the diagnosis was made, treatment proved highly effective, but when my medication became temporarily unavailable I was suspended from work as a surgeon for six months. I had to modify my lifestyle considerably after the diagnosis. My sleepiness worsens as the day progresses. Visits to the theatre, cinema, or even parents' evenings are impossible. Concentration on academic activities and boring meetings provokes sleep. Falling off one's chair is guaranteed to halt proceedings. Fortunately, I gained my academic qualifications before the onset of the condition.
Surprisingly, physical and practical work poses no problem: I have never had an attack when driving or operating, but 10 minutes after stopping such activity is a fraught period. My major problem now is cataplexy associated with emotion, usually laughter.
Close friends and relatives recognise prodromal signs of altered speech and convulsive jaw movements and support me if there is nothing convenient for me to lean on. Sleep paralysis and hallucinations have stopped with age.
Referral
Patients with suspected narcolepsy should be referred to a sleep disorders service, or its closest local equivalent, for diagnosis. Once the diagnosis is made, patients should have at least an annual review by a clinician who is knowledgeable about the disorder and its evolving treatment. The fascinating area of sleep disorders medicine needs considerable development in the United Kingdom. Box 4 shows areas of ongoing research.
We thank John Towers for his help, our colleagues for their comments, and Taylor Patten Communications for editorial support.
Contributors: All authors contributed to the literature review and the writing of the guidelines on which this clinical review is based. AZ drafted this article, which was reviewed and edited by the guidelines working party. AZ is the guarantor.
Funding: The creation of the guidelines was funded by an unrestricted educational grant to Taylor Patten Communications by Cephalon UK, the manufacturers of modafinil.
Competing interests: Taylor Patten Communications paid travel expenses and honoraria to the working party members. ND received partial support for attendance at an international meeting on sleep apnoea from Cephalon and has had research on modafinil in sleep apnoea funded by Cephalon. JH has received travel grants from Cephalon. Cephalon has sponsored AM to attend conferences; he was runner-up in the Hospital Doctor sleep unit of the year award sponsored by Cephalon. IS has received travel grants and speakers' honoraria from Cephalon. SW received an honorarium from Cephalon for speaking to their sales force. Cephalon has supported ZZ to attend a sleep disorder conference and part funded a technician in her department to attend a conference. AZ is supported by the Health Foundation.
References
Guilleminault C, Brooks SN. Excessive daytime sleepiness. Brain 2001;124: 1482-91.
Stores G, Crawford C. Medical student education in sleep and its disorders. J R Coll Physicians Lond 1998;32: 149-53.
Britton T, Douglas N, Hansen A, Hicks J, Howard R, Meredith A, et al. Guidelines on the diagnosis and management of narcolepsy in adults and children. Ashtead: Taylor Patten Communications, 2002 (available at www.sleeping.org.uk or www.primarycaresleep.com).
Overeem S, Mignot E, van Dijk JG, Lammers GJ. Narcolepsy: clinical features, new pathophysiologic insights and future perspectives. J Clin Neurophysiol 2001;18: 78-105.
Daniels E, King MA, Smith IE, Shneerson JM. Health-related quality of life in narcolepsy. J Sleep Res 2001;10: 75-81.
Hublin C, Kaprio J, Partinen M, Koskenvuo M, Heikila K, Koskimies K, et al. The prevalence of narcolepsy: an epidemiological study of the Finnish twin cohort. Ann Neurol 1994;35: 709-16.
Ohayon MM, Priest RG, Caulet M, Guilleminault C. Hypnagogic and hypnopompic hallucinations: pathological phenomena? Br J Psychiatry 1996;169: 459-67.
Silber MH, Krahn LE, Pankratz VS. The epidemiology of narcolepsy in Olmstead County, Minnesota: a population-based study. Sleep 2002;25: 197-202.
Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50(suppl 1): 516-22.
Pace-Schott EF, Hobson JA. The neurobiology of sleep. Nat Rev Neurosci 2002;3: 591-605.
Hobson JA, Pace-Schott EF. The cognitive neuroscience of sleep. Nat Rev Neurosci 2002;3: 670-93.
Gelineau JBE. De la narcolepsie. Gazette des hopitaux de Paris 1880: 626-8, 635-7.
Rechtschaffen A, Wolpert E, Dement WC, Mitchell SA, Fisher C. Nocturnal sleep of narcoleptics. Electroencephalogr Clin Neurophysiol 1963;15: 599-609.
Juji T, Satake M, Honda Y, Doi Y. HLA antigens in Japanese patients with narcolepsy: all the patients were DR2 positive. Tissue Antigens 1984;24: 316-9.
Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep 1997;20: 1012-20.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behaviour. Cell 1998;92: 573-85.
De Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998;95: 322-7.
Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999;98: 365-76.
Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy . Lancet 2000;355: 39-40.
Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case of early onset narcolepsy and a generalised absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6: 991-7.
Thannickal TC, Moore RY, Nienhuls R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced numbers of hypocretin neurons in human narcolepsy. Neuron 2000;27: 469-74.
Scammell T. The neurobiology, diagnosis and treatment of narcolepsy. Ann Neurol 2003;53: 154-66.
Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59: 1553-62.
Johns MJ. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;6: 540-5.
Standard of Practice Committee, American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy. Sleep 2001;24: 451-66.
Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep 2001;24: 385-91.
US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology 2000;54: 1166-75.