Narcolepsy is a lifelong neurological disorder of rapid eye movement (REM) sleep in which the affected individual has attacks of irresistible daytime sleepiness, cataplexy (sudden muscle weakness in response to emotional triggers like surprise, laughter, fright, or anger), hypnagogic hallucinations (vivid and often terrifying dreams at sleep onset), and sleep paralysis (a momentary inability to move as one is drifting off to sleep). Cataplexy, hypnagogic hallucinations, and sleep paralysis are all manifestations of intrusion of REM sleep onto wakefulness. The entire constellation of symptoms may not be present initially, but appears gradually over a period of 5 to 10 years. Daytime sleepiness and cataplexy are the two most reliable features of narcolepsy. The daytime sleepiness frequently leads to automatic behavior of which the subject is unaware, impairment of memory, concentration, and executive function as well as mood swings. Nighttime sleep is also disturbed, with frequent awakenings, with or without associated periodic limb movements in sleep.
The incidence of narcolepsy in United States is 1.37 per 100,000 persons per year (1.72 for men and 1.05 for women). It is highest in the second decade, followed by a gradual decline thereafter. The prevalence rate is approximately 56 persons per 100,000 persons (Silber, Krahn, Olson, & Pankrantz, 2002). A meta-analysis of 235 subjects derived from three studies found that 34% of all subjects had onset of symptoms prior to age 15, 16% prior to age 10, and 4.5% prior to age 5 (Challamel et al., 1994). Patients frequently report a lag of 5 to 10 years between the onset of clinical symptoms and establishment of the definitive diagnosis, suggesting insufficient awareness of the disorder among health professionals.
Narcolepsy has been described in miniature horses, Brahmin bulls, quarter horses, and about 15 breeds of dogs. Canine narcolepsy has autosomal recessive inheritance, and is related to a deficiency of hypocretin 2 receptors. On the other hand, the murine model of narcolepsy is associated with deficiency of the hypocretin (orexin) ligand. Hypocretin is a peptide that is elaborated in dorsomedial and dorsolateral areas of the hypothalamus. Hypocretin-containing neurons have widespread projections to the fore-brain and brain stem. Activation of hypocretin projections leads to up-regulation of arousal mechanisms, increased muscle tone, muscle activity, and metabolic rate.
Human narcolepsy-cataplexy is associated with a marked deficiency hypocretin-1 in the cerebrospinal fluid. In contrast to the autosomal recessive transmission of canine narcolepsy, the pathogenesis of human narcolepsy is more complex, and appears to be related to an interplay between genetic and environmental factors. The histocom-patibility antigen DQB1*0602 is present in 90 to 95% of patients with narcolepsy, in contrast to a 25 to 30% prevalence in the general population. Genetic susceptibility per se is, however, insufficient to trigger symptoms, as evidenced by the fact that monozygotic twins may be discordant for the disorder. Environmental stresses like head trauma, systemic infection, or surgery precede the development of clinical symptoms in two thirds of subjects, thus supporting a "two-hit" hypothesis. Rare instances of secondary narcolepsy following encephalitis, hypothalamic tumors, central nervous system lymphoma, and vascular malformations also suggest a contribution from acquired factors. It is presumed that low central nervous system levels of hypocretin-1 decrease noradrenergic activity and also lead to disinhibition of the brain stem cholinergic systems, thus triggering both sleepiness and cataplexy.
The diagnosis of narcolepsy is established on the basis of the narcoleptic tetrad (overwhelming sleepiness, cata-plexy, hypnagogic hallucinations, sleep paralysis), combined with characteristic findings on the nocturnal poly-somnogram and the multiple sleep latency test (MSLT). The nocturnal polysomnogram is a procedure in which the activity of multiple bodily functions, such as the electroencephalogram (EEG), eye movements, chin and leg electro-myogram (EMG), airflow, thoracic and abdominal respiratory effort, electrocardiogram, and oxygen saturation, are recorded simultaneously on a strip of moving graph paper or a computer system. The test helps exclude disorders such as obstructive sleep apnea and periodic limb movement disorder which may also impair daytime alertness and mimic narcolepsy. On the morning following the nocturnal poly-somnogram, the patient undergoes the MSLT, during which four 20-minute nap opportunities are provided at two hourly intervals in a darkened, quiet room (e.g., at 1000, 1200, 1400, and 1600 hours). The speed with which the subject falls asleep is measured using the EEG, chin EMG, and eye movement recordings. The time between "lights out" and sleep onset is termed the sleep latency. The mean sleep latency is calculated by adding the sleep latencies of individual naps and dividing by the total number of naps. The
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mean sleep latency is markedly shortened to less than 5 minutes in subjects with narcolepsy, as compared to normal values in the 14 to 20 minute range in unaffected controls. Furthermore, unaffected individuals show a transition from wakefulness into REM sleep, while patients with narcolepsy tend to shift from wakefulness directly into REM sleep.
The differential diagnosis of narcolepsy includes insufficient sleep, abnormal sleep hygiene, circadian rhythm disorders like the delayed sleep phase syndrome, the upper airway resistance syndrome, idiopathic hypersomnia, depression, periodic hypersomnia, and abuse of hypnotic/ sedative drugs (prescription or over-the-counter).
Narcolepsy requires lifelong treatment. Daytime sleepiness is countered with stimulants like methylphenidate or dextroamphetamine. The side effects include anorexia, nervousness, tics, and insomnia. Modafinil (Provigil), a drug with an unspecified mode of action, is also effective in enhancing alertness and improving psychomotor performance. Gamma hydroxybutyrate also holds promise as an agent for both enhancing alertness and reducing cataplexy. Because cholin-ergic pathways in the brain stem mediate cataplexy, drugs such as clomimipramine and protryptiline with anticholin-ergic properties have been used to treat cataplexy. Replacement therapy with hypocretin analogues holds some long-term promise. One to three planned naps per day, each lasting 25 to 30 minutes, are also helpful in enhancing alertness. Supportive psychotherapy and fluoxetine may be needed if the patient develops emotional or behavioral problems.
Because of the increased risk of accidents from sleepiness, patients with narcolepsy should be cautioned against driving and should not work close to sharp, moving machinery. The Narcolepsy Network, Inc. (http://www.narcolepsy network.org) is a helpful nonprofit patient support organization.
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