We used the term “narcolepsy” for PubMed searches, including articles in all languages. Articles published between 2001 and 2006 (although key articles were included irrespective of publication date), systematic review articles, meta-analyses, and evidence-based guidelines were preferentially selected. As well as this material, this Seminar is based on consultation with experts in the area of narcolepsy, and on feedback from reviewers.
SeminarNarcolepsy with cataplexy
Section snippets
Epidemiology
From investigations in California in the early 1970s,18 the prevalence of narcolepsy with cataplexy was estimated at between 0·05% and 0·067% in the USA. In a study of a cohort of 8000 twins from Finland, 0·026% reported daily sleep attacks and at least one episode of muscular weakness per week.7 Similar results were reported with different methods in more recent studies in Europe,8 Hong Kong,9 and MN, USA.10 The US study also reported an incidence of 0·74 per 100 000 inhabitants per year. The
Excessive daytime sleepiness
In most cases, daytime sleepiness is the first symptom to appear. It is also the most severe symptom and the most frequent cause for consultation.3, 4, 21 Daytime sleepiness occurs daily, recurring typically every 2 h, although this can vary widely. Sleepiness is exacerbated when the patient is physically inactive. The sleep episodes have several characteristics: (1) they are often irresistible, despite the individual making desperate efforts to fight the urge to sleep; (2) they are usually
Diagnostic criteria
The diagnosis of narcolepsy with cataplexy is based on excessive daytime sleepiness (occurring almost daily for at least 3 months) and on a history of cataplexy (panel 1).1 Since individuals rarely go into cataplexy in the presence of the clinician, the doctor should refer the patient to a specialist sleep centre to confirm the clinical diagnosis with night-time polysomnography followed by a daytime multiple sleep latency test (MSLT). The aim of the polysomnography is to eliminate other causes
Differential diagnosis
Narcolepsy with cataplexy can be confused with other forms of hypersomnolence, such as narcolepsy without cataplexy, sleep apnoea syndrome, idiopathic hypersomnia, recurrent hypersomnia, hypersomnia associated with depression, and chronic sleep deprivation.2, 3, 47, 48
Sleep apnoea syndrome (defined by more than five apnoea or hypopnoea events per hour of sleep) occurs in 24% of men and 9% of women in the general population, and is associated with daytime sleepiness in 4% of men and 2% of women.
Canine model of narcolepsy
A natural canine narcolepsy model was identified in 1973. Narcoleptic dogs have cataplexy (mainly elicited by the presentation of food), sleepiness, and have SOREMPs. The disease is transmitted as a recessive autosomal trait with complete penetrance in Doberman Pinschers and Labrador Retrievers,59 whereas it is polygenic and determined by environmental factors (sporadic narcolepsy) in Poodles, Beagles, and other breeds. We discovered in 1999 a mutation in the gene coding for the hypocretin type
Studies in human beings
After the discovery of the hypocretin 2 receptor gene mutation in narcoleptic dogs, the hypocretin system was also studied in human narcolepsy. The systematic screening of mutations in the hypocretin system was undertaken in patients with cataplexy and SOREMPs, both with and without a family history of narcolepsy, with or without HLA DQB1*0602. So far, we have identified only one patient with a mutation in hypocretin-related genes. This patient was atypical, with unusually early onset of
Disease management
Major advances in the treatment of daytime sleepiness and cataplexy have been made in the past few years. Because narcolepsy has no cure, its management relies on symptomatic therapies. These include stimulants (mostly dopaminergic) for daytime sleepiness and sleep attacks, antidepressants (mostly noradrenergic) for cataplexy and other REM-associated symptoms, and hypnotics for disturbed night-time sleep.2, 3, 4, 28, 103, 104 In 2006, a single drug named sodium oxybate was effective in
Future directions
Current research in the area aims to develop new treatments (panel 2),126 and to better understand the physiological role of hypocretin. The cause of hypocretin cell loss is the major unresolved issue in the area. Although an autoimmune cause is likely, a focal inflammatory process targeting hypocretin neurons is so far unproven. Other mechanisms, for example a viral infection or spontaneous neurodegenerative process are also possible. 10% of narcoleptic patients with cataplexy and most
Conclusion
Major advances in the past decade have led to improved symptomatic therapies and a better understanding of the pathophysiology of narcolepsy with cataplexy. Although the HLA DQB1*0602 remains the only established genetic risk factor, future approaches could focus on identifying new genetic susceptibility factors and environmental factors that lead to hypocretin neuronal degeneration. This might in turn lead to an understanding of the cause of hypocretin cell death. A better understanding of the
Search strategy and selection criteria
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