Narcolepsy

Narcolepsy is the most clearly understood of the central hypersomnia syndromes. It is characterized by profound EDS and is associated with cataplexy, sleep paralysis, hypnopompic or hypnagogic hallucinations, automatic behavior, and disrupted sleep. Narcolepsy is rare in all populations with reported prevalences ranging from 0.02% to 0.18% with lower prevalence in Israel and higher reported prevalence in Japan [1]. Symptoms usually arise in adolescence or young adulthood and rarely as early as age 5, although symptom onset can be delayed until the 6th or 7th decade of life.

Narcolepsy results from dysfunction within the hypothalamic hypocretin (orexin) system in both animal models and humans. While mice and canine models of narcolepsy are associated with hypocretin ligand knockout or receptor gene mutations [23,24], genetic abnormalities in the hypocretin system are extremely rare in humans. About 90% of patients with unequivocal narcolepsy with cataplexy have low or undetectable levels of hypocretin in their cerebrospinal fluid - a finding which is quite specific to narcolepsy [25,26]. Human leukocyte antigen (HLA) subtype DQB1*0602 has a strong, but non-specific association with narcolepsy with cataplexy. Nearly all patients with cataplexy have this subtype, while it is found in 12-38% of the general population, across various races. These and other immunological associations along with the age of onset and finding of postmortem destruction of hypothalamic hypocretin-producing cells have led to the theory that narcolepsy may arise from an autoimmune process.

The routine diagnosis of narcolepsy is based on a clinical history of excessive daytime sleepiness occurring almost daily for more than 3 months with a formal workup that excludes other potential etiologies for EDS and a mean sleep latency of less than 8 minutes with two or more sleep onset REM periods on the MSLT. Narcolepsy is categorized as either with cata-plexy or without cataplexy. Cataplexy is defined as a discrete episode of sudden and transient bilateral loss of voluntary muscle tone triggered by emotion [1].

Low CSF hypocretin is far more specific than the MSLT for the diagnosis of narcolepsy [27]. HLA subtyping is less invasive and more readily available, but grossly non-specific given the prevalence of this subtype in the general population. The clinical utility of HLA DQB1*0602 subtyping is limited to the fact that in the absence of cataplexy, a negative result very strongly suggests normal hypocretin function and obviates the need for CSF hypocretin evaluation. Currently these assays are not considered standard in the diagnosis of narcolepsy, but ongoing efforts are clarifying their potential clinical utility.

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