Hypocretin Status in Neurological Disorders in Relation to Excessive Sleepiness and Cataplexy

Abstract

A tight association (90–95%) between human narcolepsy-cataplexy and hypocretin orexin deficiency has recently been revealed (1–8). Hypocretins are hypothalamic neuropeptides involved in various fundamental hypothalamic functions including sleep-wake control, energy homeostasis, and autonomic and neuroendocrine functions (9–11). Hypocretin-containing neurons are located exclusively in the lateral hypothalamic area (LHA). Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations (HH), and sleep paralysis (SP) (i.e., the narcolepsy tetrad) (5,12). Since hypocretin deficiency in narcolepsy is also tightly associated with human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602) positivity, an acquired cell loss of hypocretin-containing neurons along with the autoimmune process is suggested in so-called idiopathic cases of narcolepsy (4,5). The term idiopathic narcolepsy has been used for cases of narcolepsy unassociated with apparent radiographical or clinical evidence of brain pathology apart from sleep-related abnormalities. Hypocretin deficiency in the brain can be determined clinically via cerebrospinal fluid (CSF) hypocretin-1 measures; CSF hypocretin-1 levels in healthy subjects are above 200 pg/mL regardless of gender, age (from neonatal to the 70s), and time of CSF collection (2,4,12). Owing to the specificity and sensitivity of low CSF hypocretin-1 levels (<110pg/mL or one-third of the mean normal value), narcolepsy-cataplexy is high among various sleep disorders (5,13,14), CSF hypocretin measures will be included in the diagnostic criteria for narcolepsy-cataplexy in the second revision of the International Classification of Sleep Disorders (ICSD).KeywordsHuman Leukocyte AntigenMyotonic DystrophyAcute Disseminate EncephalomyelitisMultiple SclerosisSleep ParalysisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.