Hypocretin/orexin and sleep: implications for the pathophysiology and diagnosis of narcolepsy

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy. The discovery that the majority of human patients lack the hypothalamic neuropeptide hypocretin-1 has initiated a large body of new research.

Several studies on cerebrospinal fluid hypocretin-1 levels in narcolepsy and in various other sleep disorders have shown that hypocretin deficiency is both highly sensitive and specific for narcolepsy/cataplexy. Importantly, 15% of narcoleptic patients show low hypocretin levels, despite a negative multiple sleep latency test. Besides regulating sleep, the hypocretin system is involved in the regulation of energy balance, autonomic function and several neuroendocrine ensembles. Consequently, up to one-third of patients are obese (body mass index > 30). Furthermore, serum leptin levels are decreased in both nonoverweight and obese patients. The new rodent models for narcolepsy may aid in the further characterization of these endocrinological abnormalities. Finally, there is increasing insight into the physiological role of the hypocretin system in the regulation of sleep and wakefulness.

Hypocretin measurements may now be applied as a new diagnostic tool, providing the results are interpreted within the clinical context. In the clinical care of narcoleptic patients, attention should be paid to the obesity that frequently accompanies the disorder. In the future, hypocretin agonists may become available. Further characterization of animal models for narcolepsy will undoubtedly increase our insight into the pathophysiology of the disorder.