The inappropriate occurrence of rapid eye movement sleep in narcolepsy is not due to a defect in homeostatic regulation of rapid eye movement sleep.

Narcolepsy type 1 is a disabling disorder with four primary symptoms: excessive-daytime-sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. The later three symptoms together with a short rapid eye movement (REM) sleep latency have suggested impairment in REM sleep homeostatic regulation with an enhanced propensity for (i.e. tendency to enter) REM sleep. To test this hypothesis, we challenged REM sleep homeostatic regulation in a recognized model of narcolepsy, the orexin knock-out (Orex-KO) mice and their wild-type (WT) littermates. We first performed 48 hr of REM sleep deprivation using the classic small-platforms-over-water method. We found that narcoleptic mice are similarly REM sleep deprived to WT mice. Although they had shorter sleep latency, Orex-KO mice recovered similarly to WT during the following 10 hr of recovery. Interestingly, Orex-KO mice also had cataplexy episodes immediately after REM sleep deprivation, anticipating REM sleep rebound, at a time of day when cataplexy does not occur in baseline condition. We then evaluated REM sleep propensity using our new automated method of deprivation that performs a specific and efficient REM sleep deprivation. We showed that REM sleep propensity is similar during light phase in Orex-KO and WT mice. However, during the dark phase, REM sleep propensity was not suppressed in Orex-KO mice when hypocretin/orexin neuropeptides are normally released. Altogether our data suggest that in addition to the well-known wake-promoting role of hypocretin/orexin, these neuropeptides would also suppress REM sleep. Therefore, hypocretin/orexin deficiency would facilitate the occurrence of REM sleep at any time of day in an opportunistic manner as seen in human narcolepsy.

Restless legs syndrome is frequent in narcolepsy with cataplexy patients.

STUDY OBJECTIVES: To investigate the occurrence of restless legs syndrome (RLS) in narcolepsy with cataplexy (NC). DESIGN: A case-control study assessing the frequency of comorbidity of RLS and NC in three European sleep disorder centers. PATIENTS: Three sleep research centers recruited 184 NC patients and 235 age-matched controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: NC patients and controls underwent a face-to-face interview investigating demographics, medical and drug history, sleep habits, and sleep disorders, in particular RLS based on the 4 international criteria and on a frequency > or =2 times/week, with a detailed description of RLS symptoms when present. RLS was significantly more prevalent among NC patients (14.7%) than in controls (3.0%). The age at onset of RLS in NC patients fits with the age at onset in idiopathic RLS, and RLS appeared more than 10 years after NC onset. Unlike idiopathic RLS, RLS in NC subjects was not more prevalent in women and was less familial (15.4% of cases). Lastly, NC patients with RLS showed a moderate disease severity and an almost daily occurrence of symptoms, which were also diurnal in 35% of cases. Older age, higher blood ferritin levels, and sleep paralysis seem to have a predictive value for RLS in NC. The higher ferritin levels indicate that different pathophysiological mechanisms underlie secondary RLS associated with NC. CONCLUSIONS: This study highlights the association between RLS and NC. The nature of this association is still investigational, but it does indicate that RLS must be addressed in the evaluation and management of nocturnal sleep impairment in NC patients.