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The Pathophysiology of Narcolepsy

In the majority of people with narcolepsy, loss of hypocretin leads to sleep-wake state instability.1-4

What Causes Narcolepsy?

In people with narcolepsy who experience cataplexy, the disorder is usually caused by the selective loss of hypocretin neurons (hypocretin deficiency).2,5 Patients with hypocretin deficiency are usually diagnosed with narcolepsy with cataplexy (narcolepsy type 1).2 The presence of cataplexy is generally thought to indicate more significant loss of hypocretin neurons.2,5,6

Genetic factors play a key role in the development of narcolepsy.5 Up to 98% of patients with narcolepsy have the human leukocyte antigen (HLA) gene variant HLA-DQB1*0602, compared with 12% to 38% of the general population.2,5 The loss of hypocretin neurons is likely triggered by an autoimmune response in genetically predisposed people.5,7

The underlying cause of narcolepsy without cataplexy (often called narcolepsy type 2) is often not known.2,5 However, 25% to 33% of patients with narcolepsy type 2 also have intermediate to undetectable cerebrospinal fluid (CSF) hypocretin levels.2,8 These individuals are more likely to develop cataplexy and subsequently be diagnosed with narcolepsy type 1.2,8

In narcolepsy, sleep-wake state instability is the result of insufficient activation of wake-promoting neurons, including histamine neurons.3-5,9

In most people with narcolepsy, lack of hypocretin leads to insufficient activation of histamine neurons and wake-promoting neurons outside of the hypothalamus, as well as insufficient inhibition of non-REM sleep- and REM sleep-promoting neurons.1,4,5,10 This process can lead to sleep-wake state instability.3,4 The transitions between wakefulness, non-REM sleep, and REM sleep become frequent and unpredictable, and the boundaries between them become unstable, allowing elements of one state to intrude into another.3,5,11-13 Watch to learn more about narcolepsy.

The Pathophysiology of Narcolepsy
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Narcolepsy is a disorder characterized by sleep-wake state instability.

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Signs and symptoms of sleep-wake state instability can manifest in a variety of ways.

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  1. Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep. 2002;25(2):197-202.
  2. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed.; 2014.
  3. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  4. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010;68(6):1023–1042
  5. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  6. Drakatos P, Leschziner G. Cataplexy with normal sleep studies and normal CSF hypocretin: an explanation? J Clin Sleep Med. 2016;12(3):449-450.
  7. Singh AK, Mahlios J, Mignot E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J Autoimmun. 2013;43:26-31.
  8. Andlauer O, Moore H, Hong SC, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep. 2012;35(9):1247-1255F.
  9. Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Y. Histamine: neural circuits and new medications. Sleep. 2019;42(1): doi: 10.1093/sleep/zsy183.
  10. Pillen S, Pizza F2, Dhondt K, Scammell TE, Overeem S. Cataplexy and its mimics: clinical recognition and management. Curr Treat Options Neurol. 2017;19(6):23.
  11. Broughton R, Valley V, Aguirre M, Roberts J, Suwalski W, Dunham W. Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy: a laboratory perspective. Sleep. 1986;9:205-215.
  12. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
  13. Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol. 2008;6(4):367-378.

Performance of routine tasks without awareness.

Sudden and brief loss of muscle strength or tone, often triggered by strong emotions. Narcolepsy with cataplexy is known as type 1 narcolepsy.

Complete collapse to the ground; all skeletal muscles are involved.

Only certain muscle groups are involved.

Biological clock mechanism that regulates the 24-hour cycle in the physiological processes of living beings. It is controlled in part by the SCN in the hypothalamus and is affected by the daily light-dark cycle.

Frequent inappropriate transitions between states of sleep and wakefulness.

The inability to stay awake and alert during the day.

A neurotransmitter that supports wakefulness. The TMN is the only source of histamine in the brain.

Vivid, realistic, and frightening dream-like events that occur when falling asleep.

Vivid, realistic, and frightening dream-like events that occur when falling asleep.

A neuropeptide that supports wakefulness and helps control non-REM sleep and REM sleep.

Primary brain region for regulating the timing of sleep-wake states.

Unintentionally falling asleep due to excessive daytime sleepiness.

Brief, unintentional lapses into sleep or loss of awareness.

A validated objective measure of the tendency to fall asleep in quiet situations.

A state of sleep when muscle tone is decreased. Deep stages help to restore the body.

Overnight study used to diagnose sleep disorders by monitoring sleep stages and cycles to detect disruptions of a normal sleep pattern.

Normally occurs at night and includes vivid dreams. Also known as “paradoxical sleep.”

Daytime and evening habits and routines to help improve nighttime sleep.

Brief loss of control of voluntary muscles with retained awareness at sleep-wake transitions.

Sleep-onset REM period.

People with type 1 narcolepsy have low levels of hypocretin.

Narcolepsy without cataplexy; the cause of type 2 narcolepsy is unknown.