Narcolepsy

Basics

Lifelong neurologic disorder that often initially manifests in childhood or adolescence and can cause significant functional impairment and disability
Excessive daytime sleepiness (EDS) and inappropriate transitions from wakefulness into rapid eye movement (REM) sleep
Narcolepsy may occur with or without cataplexy.
Other associated features include hypnagogic hallucinations, sleep paralysis, and nighttime sleep fragmentation.

Narcolepsy is not preventable.
Narcolepsy is underrecognized, especially in children.
Physicians should screen for sleep dysfunction and excessive sleepiness as part of anticipatory guidance.

Prevalence in the United States is reported to range from 25 to 50 per 100,000; prevalence may be higher in the Japanese population.
An estimated 200,000 Americans have narcolepsy, but fewer than 50,000 of these individuals have been diagnosed with the disorder.
Approximately half of patients with narcolepsy have symptoms before age 15 years and <10% with symptoms <age 5 years, but often, diagnosis may lag 10 to 15 years after onset of symptoms.
Cataplexy is present in 50–70% of adult patients and perhaps at least as many pediatric patients but may be initially sporadic or difficult to identify.

1st-degree relatives of patients with narcolepsy with cataplexy have a 1–2% risk (which is 10- to 40-fold more than the general population) of developing narcolepsy.
Both genetic and environmental factors may be involved in the development of narcolepsy.
There is an association between narcolepsy with cataplexy and human leukocyte antigens (HLAs) subtypes, specifically DQB1*0602 in 85–95% and DR2 antigens. About 40% of cases of narcolepsy without cataplexy are also DQB1*0602 positive.
Increased risk of narcolepsy after H1N1 vaccination or infection has been a topic of interest.

Hypocretin (also known as orexin) is a neuropeptide produced by neurons in the perifornical area of the lateral hypothalamus that is supplied to several areas of the brain that promote wakefulness. It may also inhibit REM sleep. It mediates appetite.
To better reflect pathophysiology, the American Academy of Sleep Medicine has categorized narcolepsy into type 1 and type 2.
- Type 1 involves hypocretin deficiency, such as would be detected in cerebrospinal fluid (CSF) via lumbar puncture or manifested clinically by the presence of cataplexy.
- Type 2 does not involve hypocretin deficiency, and in the absence of CSF testing would be the presumptive diagnosis for a patient who had not manifested cataplexy.
- Onset of cataplexy would herald a change in diagnosis from type 2 to type 1.
Narcolepsy type 1 is caused by selective loss of the hypocretin-producing neurons in the hypothalamic region.
The association between narcolepsy and specific HLA antigens has suggested autoimmune pathogenesis; however, this has yet to be definitively established.

Secondary narcolepsy may be seen with CNS trauma, strokes, brain tumors, and demyelinating diseases, particularly involving the lateral and posterior hypothalamus, midbrain, and the pons.
Genetic syndromes associated with secondary narcolepsy include:
- Prader-Willi syndrome
- Myotonic dystrophy
- Niemann-Pick type C

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