Cerebrospinal Fluid Hypocretin 1 Deficiency, Overweight, and Metabolic Dysregulation in Patients with Narcolepsy

Narcolepsy is a lifelong disorder which usually starts between the age of 10 and 30 years, disturbing the regulation of sleep and wakefulness. The disease affects approximately 0.02% to 0.05% of the European population.1–4 It is characterized by sleep attacks and excessive daytime sleepiness, cataplexy (attacks of muscle weakness/paralysis caused by laughter or sudden emotions), sleep paralysis, and hypnagogic hallucinations, as well as reduced sleep quality and other accessory symptoms. The diagnostic criteria were specified and revised in 2005 and include narcolepsy with cataplexy, narcolepsy without cataplexy, and narcolepsy secondary to medical conditions.5 Hypocretin is produced in the lateral parafornical area of hypothalamus and has properties as neuroexcitatory transmitters promoting wakefulness and motor activity.6,7 Studies have demonstrated very low or unmeasurable CSF hypocretin in 70% to 90% of patients with narcolepsy with typical cataplexy and loss of hypocretin producing neurons.8–12 In rodents, hypocretins have been suggested to stimulate food seeking behavior, indicating possible participation in complex homeostatic mechanisms regulated via hypothalamus, in addition to their major effect on wakefulness.13,14 Several studies have reported increased BMI and increased risk of type 2 diabetes in patients with narcolepsy, but the underlying pathophysiological mechanisms are still unclear.15–19 Based on animal experiments and clinical reports, a possible association between food intake, energy balance, and the functions of hypocretin has been advocated.13–15,19–21 BRIEF SUMMARY Current Knowledge/Study Rationale: Several studies of patients with narcolepsy have reported increased BMI, which has been tentatively attributed to an effect of hypocretin-1 deficiency. To clarify whether increased BMI in narcolepsy is related to hypocretin-1 deficiency, this study compares BMI and leptin values of narcolepsy/cataplexy patients with normal CSF hypocretin-1 concentration to patients with low hypocretin values. Study Impact: The study concludes with a moderate tendency to overweight and obesity in narcolepsy with cataplexy which is independent of CSF hypocretin levels, but may be connected to the narcoleptic condition by other mechanisms. Previous studies have not compared the tendency to overweight in patients with narcolepsy and hypocretin deficiency to patients with narcolepsy and normal CSF hypocretin levels, to clarify the possible role of hypocretin deficiency in the development of obesity in narcolepsy. The present exploratory study was initiated to elucidate the possible association between overweight, metabolic parameters, and CSF hypocretin deficiency in a population of well characterized Norwegian patients with narcolepsy with and without hypocretin deficiency, compared to patients with idiopathic hypersomnia and controls.