Chapter 028. Sleep Disorders (Part 11) ppt

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 fluid levels of hypocretin are
reduced in most patients who have narcolepsy with cataplexy. The inheritance
pattern of narcolepsy in humans is more complex than in the canine model.
However, almost all narcoleptics with cataplexy are positive for HLA
DQB1*0602 (Chap. 309), suggesting that an autoimmune process may be
responsible.
Diagnosis
The diagnostic criteria continue to be a matter of debate. Certainly,
objective verification of excessive daytime somnolence, typically with MSLT
mean sleep latencies <8 min, is an essential if nonspecific diagnostic feature.
Other conditions that cause excessive sleepiness, such as sleep apnea or chronic
sleep deprivation, must be rigorously excluded. The other objective diagnostic
feature of narcolepsy is the presence of REM sleep in at least two of the naps
during the MSLT. Abnormal regulation of REM sleep is also manifested by the
appearance of REM sleep immediately or within minutes after sleep onset in 50%
of narcoleptic patients, a rarity in unaffected individuals maintaining a
conventional sleep-wake schedule. The REM-related symptoms of the classic
narcolepsy tetrad are variably present. There is increasing evidence that
narcoleptics with cataplexy (one-half to two-thirds of patients) may represent a

more homogeneous group than those without this symptom. However, a history of
cataplexy can be difficult to establish reliably. Hypnogogic and hypnopompic
hallucinations and sleep paralysis are often found in nonnarcoleptic individuals
and may be present in only one-half of narcoleptics. Nocturnal sleep disruption is
commonly observed in narcolepsy but is also a nonspecific symptom. Similarly, a
history of "automatic behavior" during wakefulness (a trancelike state during
which simple motor behaviors persist) is not specific for narcolepsy and serves
principally to corroborate the presence of daytime somnolence.
Narcolepsy: Treatment
The treatment of narcolepsy is symptomatic. Somnolence is treated with
wake-promoting therapeutics. Modafinil is now the drug of choice, principally
because it is associated with fewer side effects than older stimulants and has a long
half-life; 200–400 mg is given as a single daily dose. Older drugs such as
methylphenidate (10 mg bid to 20 mg qid) or dextroamphetamine (10 mg bid) are
still used as alternatives, particularly in refractory patients. These latter
medications are now available in slow-release formulations, extending their
duration of action and allowing once daily dosing.
Treatment of the REM-related phenomena cataplexy, hypnogogic
hallucinations, and sleep paralysis requires the potent REM sleep suppression
produced by antidepressant medications. The tricyclic antidepressants [e.g.,
protriptyline (10–40 mg/d) and clomipramine (25–50 mg/d)] and the selective
serotonin reuptake inhibitors (SSRIs) [e.g., fluoxetine (10–20 mg/d)] are
commonly used for this purpose. Efficacy of the antidepressants is limited largely
by anticholinergic side effects (tricyclics) and by sleep disturbance and sexual
dysfunction (SSRIs). Alternately, gamma hydroxybutyrate (GHB), given at bed
time, and 4 h later, is effective in reducing daytime cataplectic episodes. Adequate
nocturnal sleep time and planned daytime naps (when possible) are important
preventative measures.
Sleep Apnea Syndromes
Respiratory dysfunction during sleep is a common, serious cause of

excessive daytime somnolence as well as of disturbed nocturnal sleep. An
estimated 2–5 million individuals in the United States have a reduction or
cessation of breathing for 10–150 s, from thirty to several hundred times every
night 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 a
combination of these factors (mixed sleep apnea) (Fig. 28-3). Failure to recognize
and treat these conditions appropriately may lead to impairment of daytime
alertness, increased risk of sleep-related motor vehicle accidents, hypertension and
other serious cardiovascular complications, and increased mortality. Sleep apnea is
particularly prevalent in overweight men and in the elderly, yet it is estimated to
remain undiagnosed in 80–90% of affected individuals. This is unfortunate since
effective treatments are available. Readers are referred to Chap. 259 for a
comprehensive review of the diagnosis and treatment of patients with these
conditions.