(See also Approach to the Patient With a Sleep or Wakefulness Disorder.)
The cause of narcolepsy is unknown. In Europe, Japan, and the United States, incidence is 0.2 to 1.6/1000 (1). Narcolepsy is equally common in both sexes.
There are 2 types (type 2 narcolepsy is more common than type 1)(2) :
Type 1: Narcolepsy due to hypocretin deficiency and accompanied by cataplexy (momentary muscular weakness or paralysis evoked by sudden emotional reactions), sleep paralysis, and hypnagogic hallucinations
Type 2: Narcolepsy with normal hypocretin levels and without cataplexy; primarily EDS
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 (approximately 25% in type 1 narcolepsy [3]), 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 human patients with type 1 narcolepsy, 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 patients with type 1 narcolepsy result from postural muscle paralysis and vivid dreaming, which characterize REM.
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.
References
1. Longstreth WT Jr, Koepsell TD, Ton TG, et al: The epidemiology of narcolepsy. Sleep 30(1):13-26, 2007. doi: 10.1093/sleep/30.1.13
2. Ohayon MM, Duhoux S, Grieco J, et al: Prevalence and incidence of narcolepsy symptoms in the US general population. Sleep Medicine: X 6(10095):2590-1427, 2023. oi.org/10.1016/j.sleepx.2023.100095
3. Miyagawa T, Tokunaga K: Genetics of narcolepsy. Hum Genome Var 6:4, 2019. doi: 10.1038/s41439-018-0033-7, 2019. doi: 10.1038/s41439-018-0033-7
Symptoms and Signs of Narcolepsy
The main symptoms of narcolepsy are
Excessive daytime sleepiness (EDS)
Cataplexy
Hypnagogic and hypnopompic hallucinations
Sleep paralysis
Disturbed nocturnal sleep (due to increased arousals)
Up to 15% of patients have all 5 of these symptoms (1).
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.
Excessive daytime sleepiness
EDS is the primary symptom in patients with both type 1 and 2 narcolepsy and 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).
Cataplexy
Momentary episodes of muscular weakness or paralysis occur without loss of consciousness and usually last < 2 minutes; they are 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, knees may buckle 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 a fifth of patients and only in patients with type 1 narcolepsy.
Sleep paralysis
Patients are momentarily unable to move as they are just falling asleep or immediately after they awaken. These 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 (1). Among patients with narcolepsy, sleep paralysis affects primarily those with type 1.
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 daydreaming and are somewhat similar to vivid dreams, which are normal in REM sleep.
Hypnagogic hallucinations occur in about 30 to 60% of patients, are common among healthy young children, and occasionally occur in healthy adults (1). Among patients with narcolepsy, it affects primarily those with type 1.
Disturbed nocturnal sleep
Sleep is often also disturbed by increased arousals in patients with narcolepsy, potentially worsening EDS. Sleep disturbance occurs in patients with both type 1 and 2 narcolepsy.
Symptoms and signs reference
1. Drakatos P, Leschiziner GD: Update on hypersomnias of central origin. Curr Opin Pulm Med 20(6):572-580, 2014. doi: 10.1097/MCP.0000000000000098
Diagnosis of Narcolepsy
Polysomnography
Multiple sleep latency testing
A delay of 10 years from onset of symptoms to diagnosis of narcolepsy is common.
A history of cataplexy strongly suggests type 1 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 minutes
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. EDS occurs in patients with narcolepsy type 1 or type 2.
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.
Treatment of Narcolepsy
Oxybates
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). Patients with cataplexy should avoid precipitating factors (eg, laughter, anger, fear)(1).
For type 1 narcolepsy,
For type 2 narcolepsy,
pm may be used, although this dose sometimes interferes with nocturnal sleep.
, the R
Oxybate, available in 3 formulations (a high-sodium formulation dosed twice a night, a high-sodium formulation dosed once a night, and a low-sodium formulation dosed twice a night), can also be used to treat EDS and cataplexy. It is taken at bedtime while in bed, followed by the same dose 2.5 to 4 hours later (if a twice-a-night formulation is being used). Adverse effects include headache, nausea, dizziness, nasopharyngitis, somnolence, vomiting, urinary incontinence, and sometimes sleepwalking. Oxybates are schedule III drugs and have the potential for abuse and dependence. They are contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. Oxybates should be used cautiously in patients with untreated respiratory disorders, hypertension, or heart failure.
Tricyclic antidepressantsSSRIs
or
Treatment reference
1. Maski K, Trotti LM, Kotagal S, et al: Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 17(9):1881-1893, 2021. doi: 10.5664/jcsm.9328
Key Points
Narcolepsy may be caused by autoimmune destruction of hypocretin-containing neurons in the lateral hypothalamus.
The main symptoms are excessive daytime sleepiness (EDS), cataplexy, hypnagogic and hypnopompic hallucinations, sleep paralysis, and disturbed nocturnal sleep.
Confirm the diagnosis by polysomnography and multiple sleep latency testing.
