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Narcolepsy

by Karl Doghramji, MD

Narcolepsy is characterized by chronic excessive daytime sleepiness, often with sudden loss of muscle tone (cataplexy). Other symptoms include sleep paralysis and hypnagogic and hypnopompic hallucinations. Diagnosis is by polysomnography and multiple sleep latency testing. Treatment is with modafinil, various stimulants, or Na oxybate for excessive daytime sleepiness and with certain antidepressants for associated symptoms.

The cause is unknown. In Europe, Japan, and the US, incidence is 0.2 to 1.6/1000. Narcolepsy is equally common in both sexes.

Narcolepsy is strongly associated with specific HLA haplotypes, and children of patients with narcolepsy have a 40-fold increased risk, suggesting a genetic cause. However, concordance in twins is low (25%), suggesting a prominent role for environmental factors, which often trigger the disorder. The neuropeptide hypocretin-1 is deficient in CSF of narcoleptic animals and most human patients, suggesting that the cause may be HLA-associated autoimmune destruction of hypocretin-containing neurons in the lateral hypothalamus.

Narcolepsy features dysregulation of the timing and control of REM sleep. Therefore, REM sleep intrudes into wakefulness and into the transition from wakefulness to sleep. Many symptoms of narcolepsy result from postural muscle paralysis and vivid dreaming, which characterize REM.

There are 2 types:

  • Type 1: Narcolepsy due to hypocretin deficiency and accompanied by cataplexy (momentary muscular weakness or paralysis evoked by sudden emotional reactions)

  • Type 2: Narcolepsy with normal hypocretin levels and without cataplexy

Symptoms and Signs

The main symptoms are

  • Excessive daytime sleepiness (EDS)

  • Cataplexy

  • Hypnagogic and hypnopompic hallucinations

  • Sleep paralysis

About 10% of patients have all 4 of these symptoms. Nocturnal sleep is often also disturbed, and some patients develop hypersomnia (prolonged sleep times).

Symptoms usually begin in adolescents or young adults without prior illness, although onset can be precipitated by an illness, a stressor, or a period of sleep deprivation. Once established, narcolepsy persists throughout life; life span is unaffected.

EDS: EDS can occur anytime. Sleep episodes vary from few to many per day, and each may last minutes or hours. Patients can resist the desire to sleep only temporarily but can be roused as readily as from normal sleep. Sleep tends to occur during monotonous conditions (eg, reading, watching television, attending meetings) but may also occur during complex tasks (eg, driving, speaking, writing, eating).

Patients may also experience sleep attacks—episodes of sleep that strike without warning. Patients may feel refreshed when they awaken yet fall asleep again in a few minutes.

Nighttime sleep may be unsatisfying and interrupted by vivid, frightening dreams.

Consequences include low productivity, breaches in interpersonal relationships, poor concentration, low motivation, depression, a dramatic reduction in quality of life, and potential for physical injury (particularly due to motor vehicle collisions).

Cataplexy: Momentary muscular weakness or paralysis occurs without loss of consciousness; it is evoked by sudden emotional reactions, such as mirth, anger, fear, joy, or, often, surprise.

Weakness may be confined to the limbs (eg, patients may drop the rod when a fish strikes their line) or may cause a limp fall during hearty laughter (as in “weak with laughter”) or sudden anger. Cataplexy can also affect other muscles: The jaw may droop, facial muscles may flicker, eyes may close, the head may nod, and speech may be slurred. These attacks resemble the loss of muscle tone that occurs during REM sleep.

Cataplexy occurs in about three fourths of patients.

Sleep paralysis: Patients are momentarily unable to move as they are just falling asleep or immediately after they awaken. These occasional episodes may be very frightening. They resemble the motor inhibition that accompanies REM sleep.

Sleep paralysis occurs in about one fourth of patients but also in some healthy children and, less commonly, in healthy adults.

Hypnagogic or hypnopompic hallucinations: Particularly vivid auditory or visual illusions or hallucinations may occur when just falling asleep (hypnagogic) or, less often, immediately after awakening (hypnopompic). They are difficult to distinguish from intense reverie and are somewhat similar to vivid dreams, which are normal in REM sleep.

Hypnagogic hallucinations occur in about one third of patients, are common among healthy young children, and occasionally occur in healthy adults.

Diagnosis

  • Polysomnography

  • Multiple sleep latency testing

A delay of 10 yr from onset to diagnosis is common.

A history of cataplexy strongly suggests narcolepsy in patients with EDS.

In patients with EDS, nocturnal polysomnography, followed by multiple sleep latency testing (MSLT), can confirm a diagnosis of narcolepsy when the findings include the following:

  • Sleep-onset REM episodes during at least 2 of 5 daytime nap opportunities or one during daytime nap opportunities plus one during the preceding nocturnal polysomnogram

  • Average sleep latency (time to fall asleep) of 8 min

  • No other diagnostic abnormalities on nocturnal polysomnography

Narcolepsy type 1 is diagnosed if patients also have cataplexy; type 2 is diagnosed if patients do not have cataplexy.

The maintenance of wakefulness test does not help with diagnosis but does help monitor treatment efficacy.

Other disorders that can cause chronic EDS are usually suggested by the history and physical examination; brain imaging and blood and urine tests can confirm the diagnosis. These disorders include space-occupying lesions affecting the hypothalamus or upper brain stem, increased intracranial pressure, and certain forms of encephalitis. Hypothyroidism, hyperglycemia, hypoglycemia, anemia, uremia, hypercapnia, hypercalcemia, hepatic failure, and seizure disorders can also cause EDS with or without hypersomnia. Acute, relatively brief EDS and hypersomnia commonly accompany acute systemic disorders such as influenza.

The Kleine-Levin syndrome, a very rare disorder in adolescent boys, causes episodic hypersomnia and hyperphagia. Etiology is unclear but may be an autoimmune response to an infection.

Treatment

  • Modafinil

  • Methylphenidate and its derivatives, amphetamine derivatives, or Na oxybate

  • Certain REM-suppressant antidepressants

Some patients who have occasional episodes of sleep paralysis or hypnagogic and hypnopompic hallucinations, infrequent and partial cataplexy, and mild EDS need no treatment. For others, stimulant drugs and anticataplectic drugs are used. Patients should also get enough sleep at night and take brief naps (< 30 min) at the same time every day (typically afternoon).

Modafinil, a long-acting wake-promoting drug, can help patients with mild to moderate EDS. The mechanism of action is unclear. Typically, modafinil 100 to 200 mg po is given in the morning. Dose is increased to 400 mg as needed. Doses > 400 mg have not been shown to be more effective. If effects do not last into the evening, a small 2nd dose (eg, 100 mg) at noon or 1 pm may be used, although this dose sometimes interferes with nocturnal sleep. Alternatively, a short-acting form of methylphenidate can be added in the afternoon on a regular or as-needed basis.

Adverse effects of modafinil include nausea and headache, which are mitigated by lower initial doses and slower titration. Modafinil can lower the effectiveness of oral contraceptives and has abuse potential, although it is low. Rarely, serious rashes and Stevens-Johnson syndrome have developed in patients taking modafinil. If serious reactions develop, the drug should be stopped permanently.

Armodafinil, the R -enantiomer of modafinil, has similar benefits and adverse effects; dosage is 150 or 250 mg po once in the morning.

Methylphenidate or amphetamine derivatives are usually used instead of or with modafinil if patients do not respond to modafinil. Methylphenidate 5 mg po bid to 20 mg po tid is especially useful for immediate management because modafinil’s onset is delayed. Methamphetamine 5 to 20 mg po bid or dextroamphetamine 5 mg po bid to 20 mg po tid may be used; all are available in long-acting preparations and therefore can be dosed once/day in many patients. They can also be used on an as-needed basis for patients already taking modafinil because their onset is rapid and duration is relatively short. Adverse effects include agitation, hypertension, tachycardia, and mood changes (eg, manic reactions); abuse potential is high.

Pemoline, although less addictive than amphetamines, is not recommended because it may be hepatotoxic and liver enzymes must be monitored every 2 wk.

Na oxybate can also be used to treat EDS and cataplexy. A dose of 2.25 g po is taken at bedtime while in bed, followed by the same dose 2.5 to 4 h later. The maximum dose is 9 g/night. Adverse effects include headache, nausea, dizziness, nasopharyngitis, somnolence, vomiting, urinary incontinence, and sometimes sleepwalking. Na oxybate is a schedule III drug and has potential for abuse and dependence. It is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency and should not be used in patients with untreated respiratory disorders.

Tricyclic antidepressants (particularly clomipramine, imipramine, and protriptyline) and SSRIs (eg, venlafaxine, fluoxetine) are useful in treating cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations. Clomipramine 25 to 150 mg po once/day in the morning seems to be the most potent anticataplectic but should be taken only during the day to reduce nocturnal arousal.

Key Points

  • Narcolepsy may be caused by autoimmune destruction of hypocretin-containing neurons in the lateral hypothalamus in genetically at-risk patients.

  • The main symptoms are excessive daytime sleepiness (EDS), cataplexy, hypnagogic and hypnopompic hallucinations, and sleep paralysis.

  • Confirm the diagnosis by polysomnography and multiple sleep latency testing.

  • EDS usually responds to modafinil (sometimes used with methylphenidate, an amphetamine derivative) or to Na oxybate.

  • Tricyclic antidepressants and SSRIs may be useful for cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • PROVIGIL
  • ANAFRANIL
  • DESOXYN
  • DEXEDRINE
  • PROZAC, SARAFEM
  • EFFEXOR XR
  • TOFRANIL
  • VIVACTIL
  • NUVIGIL
  • CONCERTA, RITALIN

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