Chapter 028. Sleep Disorders (Part 11)

Source: Modified from TA Roth, L Merlotti in SA Burton et al (eds), Narcolepsy 3rd International Symposium: Selected Symposium Proceedings, Chicago, Matrix Communications, 1989.Narcolepsy affects about 1 in 4000 people in the United States and appears to have a genetic basis. Recently, several convergent lines of evidence suggest that the hypothalamic neuropeptide hypocretin (orexin) is involved in the pathogenesis of narcolepsy: (1) a mutation in the hypocretin receptor 2 gene has been associated with canine narcolepsy; (2) hypocretin "knockout" mice that are genetically unable to produce this neuropeptide exhibit behavioral and electrophysiologic features resembling human narcolepsy; and (3) cerebrospinal...
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Chapter 028. Sleep Disorders (Part 11) Chapter 028. Sleep Disorders (Part 11) Source: Modified from TA Roth, L Merlotti in SA Burton et al (eds),Narcolepsy 3rd International Symposium: Selected Symposium Proceedings,Chicago, Matrix Communications, 1989. Narcolepsy affects about 1 in 4000 people in the United States and appearsto have a genetic basis. Recently, several convergent lines of evidence suggest thatthe hypothalamic neuropeptide hypocretin (orexin) is involved in the pathogenesisof narcolepsy: (1) a mutation in the hypocretin receptor 2 gene has been associatedwith canine narcolepsy; (2) hypocretin knockout mice that are genetically unableto produce this neuropeptide exhibit behavioral and electrophysiologic featuresresembling human narcolepsy; and (3) cerebrospinal fluid levels of hypocretin arereduced in most patients who have narcolepsy with cataplexy. The inheritancepattern of narcolepsy in humans is more complex than in the canine model.However, almost all narcoleptics with cataplexy are positive for HLADQB1*0602 (Chap. 309), suggesting that an autoimmune process may beresponsible. Diagnosis The diagnostic criteria continue to be a matter of debate. Certainly,objective verification of excessive daytime somnolence, typically with MSLTmean sleep latencies history of automatic behavior during wakefulness (a trancelike state duringwhich simple motor behaviors persist) is not specific for narcolepsy and servesprincipally to corroborate the presence of daytime somnolence. Narcolepsy: Treatment The treatment of narcolepsy is symptomatic. Somnolence is treated withwake-promoting therapeutics. Modafinil is now the drug of choice, principallybecause it is associated with fewer side effects than older stimulants and has a longhalf-life; 200–400 mg is given as a single daily dose. Older drugs such asmethylphenidate (10 mg bid to 20 mg qid) or dextroamphetamine (10 mg bid) arestill used as alternatives, particularly in refractory patients. These lattermedications are now available in slow-release formulations, extending theirduration of action and allowing once daily dosing. Treatment of the REM-related phenomena cataplexy, hypnogogichallucinations, and sleep paralysis requires the potent REM sleep suppressionproduced by antidepressant medications. The tricyclic antidepressants [e.g.,protriptyline (10–40 mg/d) and clomipramine (25–50 mg/d)] and the selectiveserotonin reuptake inhibitors (SSRIs) [e.g., fluoxetine (10–20 mg/d)] arecommonly used for this purpose. Efficacy of the antidepressants is limited largelyby anticholinergic side effects (tricyclics) and by sleep disturbance and sexualdysfunction (SSRIs). Alternately, gamma hydroxybutyrate (GHB), given at bedtime, and 4 h later, is effective in reducing daytime cataplectic episodes. Adequatenocturnal sleep time and planned daytime naps (when possible) are importantpreventative measures. Sleep Apnea Syndromes Respiratory dysfunction during sleep is a common, serious cause ofexcessive daytime somnolence as well as of disturbed nocturnal sleep. Anestimated 2–5 million individuals in the United States have a reduction orcessation of breathing for 10–150 s, from thirty to several hundred times everynight during sleep. These episodes may be due to either an occlusion of the airway(obstructive sleep apnea), absence of respiratory effort (central sleep apnea), or acombination of these factors (mixed sleep apnea) (Fig. 28-3). Failure to recognizeand treat these conditions appropriately may lead to impairment of daytimealertness, increased risk of sleep-related motor vehicle accidents, hypertension andother serious cardiovascular complications, and increased mortality. Sleep apnea isparticularly prevalent in overweight men and in the elderly, yet it is estimated toremain undiagnosed in 80–90% of affected individuals. This is unfortunate sinceeffective treatments are available. Readers are referred to Chap. 259 for acomprehensive review of the diagnosis and treatment of patients with theseconditions.