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, armodafinil, solriamfetol, pitolisant, or sodium oxybate for excessive daytime sleepiness and cataplexy.
(See also Approach to the Patient With a Sleep or Wakefulness Disorder.)
The cause of narcolepsy 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 human leukocyte antigen (HLA) haplotypes, but the cause is not thought to be genetic. 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 cerebrospinal fluid (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 rapid eye movement (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:
The Kleine-Levin syndrome, a very rare disorder in adolescent boys, resembles narcolepsy. The Kleine-Levin syndrome causes episodic hypersomnia (excessive daytime sleepiness) and hyperphagia. Etiology is unclear but may be an autoimmune response to an infection.
The main symptoms of narcolepsy are
About 10% of patients have all 5 of these symptoms.
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 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 with frequent arousals 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).
Momentary muscular weakness or paralysis occurs without loss of consciousness; it is evoked by sudden emotional reactions, such as laughter, 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. Vision may be blurred. These attacks resemble the loss of muscle tone that occurs during REM sleep.
Clinically significant cataplexy occurs in about 20% of patients.
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 25% of patients but also in some healthy children and, less commonly, in healthy adults.
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 30% of patients, are common among healthy young children, and occasionally occur in healthy adults.
Sleep is often also disturbed by increased arousals in patients with narcolepsy, possibly worsening EDS.
A delay of 10 years 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:
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. Hypersomnia also occurs in patients with meningoencephalitis due to African trypanosomiasis (sleeping sickness), which is transmitted by the tsetse fly.
Narcolepsy may not require treatment if patients have occasional episodes of sleep paralysis or hypnagogic and hypnopompic hallucinations, infrequent and partial cataplexy, and mild EDS. For others, wake-promoting drugs and anticataplectic drugs are used. Patients should also get enough sleep at night and take brief naps (< 30 minutes) at the same time every day (typically afternoon).
For type 1 narcolepsy, sodium oxybate or possibly pitolisant (although indicated for EDS, not cataplexy, it has a demonstrated effect for cataplexy) should be used for cataplexy, and if EDS persists, modafinil should be added.
For type 2 narcolepsy, modafinil should be first-line treatment, with solriamfetol as 2nd-line for EDS. Sodium oxybate or pitolisant can also be used to treat EDS.
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 orally is given in the morning. Dose is increased to 400 mg as needed. 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.
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. Modafinil should not be used during pregnancy because it may cause severe fetal congenital anomalies, including cardiac anomalies.
Armodafinil, the R-enantiomer of modafinil, has similar benefits and adverse effects but is longer-acting; dosage is 150 or 250 mg orally once in the morning.
Solriamfetol is a norepinephrine-dopamine reuptake inhibitor. It is indicated to treat EDS (but not cataplexy) in patients with narcolepsy or obstructive sleep apnea (OSA). The starting dose is 75 mg orally once a day, which can be doubled every 3 days to a maximum 150 mg once a day. Dose adjustment is required for patients with renal impairment, and solriamfetol should not be used in patients with end-stage renal disease. In clinical trials, solriamfetol was well-tolerated and significantly relieved symptoms of excessive sleepiness (documented by the Epworth Sleepiness Scale and maintenance of wakefulness testing) in adults with narcolepsy and in those with OSA and EDS. The most common adverse effects are insomnia, headache, nausea, decreased appetite, and diarrhea. There are no interactions with oral contraceptives.
Pitolisant is a histamine-3 receptor inverse agonist, which is indicated for treatment of EDS but not cataplexy in patients with narcolepsy, although studies have shown that it can decrease cataplexy. The dosage varies between 8.9 to 35.6 mg in the morning. Pitolisant is started at 8.9 mg orally once a day (taken on awakening), increased 17.8 mg once a day at week 2. The dose may be increased to a maximum of 35.6 mg once a day if needed. Dose adjustment is required for patients with renal or hepatic impairment, and pitolisant should not be used in patients with end-stage renal disease. Adverse effects include headache, irritability, anxiety, and nausea. It interacts with oral contraceptives, making them less effective.
Sodium oxybate can also be used to treat EDS and cataplexy; it is the drug of choice for cataplexy. A dose of 2.25 g orally is taken at bedtime while in bed, followed by the same dose 2.5 to 4 hours later. The maximum dose is 9 g a night. Adverse effects include headache, nausea, dizziness, nasopharyngitis, somnolence, vomiting, urinary incontinence, and sometimes sleepwalking. Sodium 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 be used cautiously in patients with untreated respiratory disorders and congestive heart failure (because of its high sodium load).
Tricyclic antidepressants (particularly clomipramine, imipramine, and protriptyline) and SSRIs (eg, venlafaxine, fluoxetine) have been used in the past to treat cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations; however, data about the effectiveness of these drugs are limited. These drugs should be used only if sodium oxybate is ineffective.
Methylphenidate or amphetamine derivatives can be used if patients do not respond to or cannot tolerate wake-promoting drugs. However, all stimulants should be considered 3rd- or 4th line after modafinil, armodafinil, solriamfetol, and pitolisant. Dosages are
Methylphenidate and amphetamine derivatives are available in long-acting preparations and therefore can be dosed once a day in many patients. However, these stimulants have significant adverse effects, including agitation, hypertension, tachycardia, myocardial infarction (secondary to vasoconstriction), changes in appetite, and mood changes (eg, manic reactions). Abuse potential is high.
