Narcolepsy, from Westphal to hypocretin

Clinical data Narcolepsy is a poorly known disease, though not exceptional, with a prevalence of 25 to 35 per 100 000 according to various surveys. Its onset can be anytime from childhood to the fifties with a peak in the second decade. It is characterized by two cardinal symptoms, irresistible sleep episodes and cataplexy or sudden loss of muscle tone triggered by emotional situations. The other symptoms, referred to as accessory due to their inconstancy, are hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. Its diagnosis relies on the identification of the cardinal symptoms. Laboratory tests are required to confirm the diagnosis before initiation of a life-long treatment. Theses test include: all-night and daytime polysomnography documenting sleep-onset REM periods, HLA typing, showing the association with HLA DQB1*0602, and, in unclear cases only, measurement of cerebro-spinal fluid (CSF) hypocretine-1 showing values below 110pg/ml, highly specific of narcolepsy with cataplexy. Pathophysiology owes a lot to the existence of a natural canine model, the narcoleptic dog. Irresistible sleep episodes and cataplexy exhibit different pharmacological control, the former depending on dopaminergic systems and the latter on noradrenergic systems. The most remarkable findings of the last twenty years are the close association with HLA DQB1*0602, the identification of a mutation of hypocretin receptor 2 in the narcoleptic dog and the absence of CSF hypocretin-1 in 90% of patients. An autoimmune mechanism is suggested but not evidenced. Three-fold treatment First line treatment of irresistible sleep episodes in modafinil, Cataplexy or tricyclic antidepressants or sodium oxybate, and disturbed nocturnal sleep by hypnotics or sodium oxybate. Current therapeutic research is oriented towards hypocretin agonists and immunosuppressors. (C) 2004, Masson, Paris.