Update on narcolepsy.

The last two decades have seen an explosion in our understanding of the clinical nature of narcolepsy and its pathogenesis, fuelling new approaches to potentially effective treatments. It is now recognised that the full narcoleptic syndrome has significant adverse effects on sleep regulation across the full 24-h period and is often associated with clinical features outside the sleep-wake domain. The discovery that most narcoleptic subjects specifically lack a hypothalamic neuropeptide (hypocretin, also called orexin) was a truly original and landmark observation in 1999, greatly furthering our understanding both of the syndrome itself and sleep biology in general. An autoimmune pathophysiology has long been suggested by the tight association with specific histocompatibility antigens and very recently partly confirmed by detailed analysis of T-cell immunological function in affected subjects. Drug treatments remain symptomatic but may soon become more focussed by restoring central hypocretin signalling with replacement therapy. Potentially disease-modifying, immunological approaches have yet to be studied systematically, although the interval between disease onset and development of the full clinical syndrome may be longer than previously appreciated, affording a realistic window of opportunity for limiting neuronal damage in this disabling condition.