![]() It increases during wakefulness and returns to lower levels during sleep. The hypocretin system acts in conjunction with histamine, which also has a pivotal role in the wake-promoting pathway in the brain by regulating the light/dark circadian cycle. 13, 14 Dogs that lack hcrtr2 receptors also have the canine form of narcolepsy with cataplexy and have decreased histamine and increased dopamine concentrations in the cortex and thalamus. 12 The absence of hcrtr2 receptors in mice results in cataplexy and disruption during wake compared to wild-type. 10, 11 Two receptors, hcrtr1 and hcrtr2, mediate the effects of hypocretin in mammals. There are only 10,000–20,000 neurons that produce hypocretin, and the selective loss of these neurons due to a presumed autoimmune etiology is implicated as the main cause of EDS and cataplexy in narcolepsy type 1. 9 Hypocretins also stimulate brain areas that inhibit REM sleep. ![]() Lateral hypothalamic neurons containing hypocretin-1 and −2, also known as orexin A and B, sustain wakefulness by activating wake-promoting neurons in other hypothalamic regions, including the tuberomammillary nucleus, and project both rostrally to the cortex, basal forebrain and thalamus and caudally to brainstem monoaminergic nuclei, most prominently the locus coeruleus. ![]() These originate from multiple nuclei that coordinate the release of wake-promoting neurotransmitters including norepinephrine, serotonin, dopamine, histamine and acetylcholine. Wakefulness is promoted by multiple interconnected brain circuits that control ascending arousal systems. The observation of onset during late adulthood may be confounded by delays in diagnosis. The onset of narcolepsy occurs most often between ten and 25 years of age but can occur as early as 5 years or after 40 years of age. Narcoleptic patients have a reduced quality of life, as the diagnosis affects many aspects of their day-to-day functioning, including work/school performance, social relationships and mental health. Depression, anxiety, and obesity also are frequently comorbid. Other sleep abnormalities are also common, including sleep-disordered breathing, periodic limb movements of sleep, and REM sleep behavior disorder. ![]() 4, 8 Patients with narcolepsy may enter rapid eye movement sleep (REM) earlier (<90 min) after nighttime sleep initiation and have sleep-onset REM periods that occur during daytime naps. 6, 7 Other symptoms common to both narcolepsy types 1 and 2 include fragmented, disrupted sleep, hypnogogic and hypnopompic hallucinations (vivid auditory or visual dreamlike perceptions at sleep onset or offset), automatic behaviors (activities performed without awareness) and sleep paralysis (temporary inability to move while falling asleep or awakening). 2 The prevalence of narcolepsy type 2 is not well studied, but estimated to be about 20–65 per 100,000 people. 3 Narcolepsy type 1 (often referred to as narcolepsy with cataplexy) is distinguished by either the presence of cataplexy or low CSF hypocretin-1 levels (=110 pg/mL) or unmeasured CSF hypocretin-1 levels. 1, 2 There are two types of narcolepsy, differentiated by the presence of cataplexy (recurrent brief episodes of sudden, usually symmetrical loss of muscle tone with retained consciousness precipitated by strong emotions) and cerebral spinal fluid (CSF) hypocretin-1 levels. Narcolepsy is a clinical syndrome marked by chronic, debilitating excessive daytime sleepiness (EDS) and the presence of arousal state instability where the thresholds between the various stages of sleep and wake are easily crossed.
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