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The Pathophysiology of Narcolepsy

In the majority of people with narcolepsy, loss of hypocretin leads to sleep-wake state instability.1-3

Most People With Narcolepsy Have Low CSF Hypocretin Levels1

In people with narcolepsy who experience cataplexy (often called narcolepsy type 1), the disorder is usually caused by the selective loss of hypocretin neurons in the hypothalamus.1

The underlying cause of narcolepsy without cataplexy (often called narcolepsy type 2) is often not known.1

However, 25% to 33% of patients with narcolepsy type 2 also have intermediate to undetectable cerebrospinal fluid (CSF) hypocretin levels. These individuals are more likely to develop cataplexy and subsequently be diagnosed with narcolepsy type 1.1,7 The presence of cataplexy is generally thought to indicate more significant loss of hypocretin neurons.1,8,9


The loss of hypocretin neurons is likely triggered by an autoimmune response in genetically predisposed people.8,10

  • Genetic factors play a key role in the development of narcolepsy.8 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.1,8
  • In a recent study that analyzed blood samples from individuals with narcolepsy, autoreactive CD4+ memory T cells that target self-antigens expressed by hypocretin neurons were detected in all participants in the study, regardless of the hypocretin deficiency or the presence of HLA subtype DQB1*0602. Hypocretin-specific CD8+ T cells were also detected in some participants in the study.11


Loss of Hypocretin Neurons in Narcolepsy Leads to Sleep-Wake State Instability2


During the day, lack of hypocretin in narcolepsy leads to:

  • Insufficient activation of histamine neurons and wake-promoting neurons outside the hypothalamus3,8
  • Insufficient inhibition and intermittent activation of non-REM sleep–promoting neurons (Non-REM at the Wrong Time™)3,12
  • Insufficient inhibition and intermittent activation of REM sleep–promoting neurons (REM at the Wrong Time™)3,13,14

This process causes sleep-wake state instability, which manifests as:

  • Frequent and unpredictable transitions between sleep-wake states4,5
  • Unstable boundaries between sleep-wake states, which allows elements of one state to intrude into another4,6

Signs and Symptoms of Narcolepsy Reflect the Underlying Sleep-Wake State Instability2-4

Sleep-wake state instability can manifest as impaired alertness or lapses into sleep.1,3,4

In narcolepsy, manifestations of excessive daytime sleepiness can occur due to insufficient activation of key wake-promoting neurons and insufficient inhibition of non-REM sleep–promoting neurons.3,8,13

  • Insufficient activation of wake-promoting neurons may lead to impaired alertness and neurocognitive functioning2,3,8,15
  • Insufficient inhibition of non-REM sleep–promoting neurons can allow non-REM sleep to intrude into wakefulness as microsleep episodes or unintended lapses into sleep.3,12,13


Boundaries img 01

Sleep-wake state instability can manifest as symptoms of REM sleep dysregulation.2,3,8

Boundaries img 02

Insufficient inhibition and intermittent activation of REM sleep–promoting neurons can lead to disordered regulation of REM sleep, which may manifest as symptoms such as cataplexy, hypnagogic hallucinations, and sleep paralysis.3,8

In narcolepsy, unstable boundaries between REM sleep and wakefulness may allow elements of REM sleep to intrude into wakefulness.6,8

  • The muscle atonia characteristic of REM sleep can intrude into wakefulness, manifesting as symptoms such as cataplexy or sleep paralysis.3,8
  • The dreams of REM sleep can also intrude into wakefulness as hypnagogic hallucinations.3,16


Other potential signs and symptoms of REM sleep dysregulation in narcolepsy include:

  • Abnormally rapid transitions to REM sleep (i.e., sleep-onset REM periods [SOREMPs]) during daytime naps or at night8,13
  • Vivid, frightening, or bizarre dreams17,18
  • Dreams during daytime naps19
  • Lack of muscle atonia during REM sleep18,20

A study in patients with narcolepsy has shown that the degree of REM sleep dysregulation is correlated with EDS severity.21

  • Patients with more frequent SOREMPs on MSLT had significantly shorter mean sleep latencies.

The frequency of SOREMPs on MSLT may help indicate clinical symptom severity in patients complaining of EDS.21


In narcolepsy, the sleep-wake cycle is unstable throughout a 24-hour period.2,4,22

Unstable wakefulness is reflected in:

  • Increased frequency of daytime naps22,23
  • Rapid transitions to REM sleep during daytime naps8,23

Narcolepsy is also characterized by disrupted nighttime sleep with frequent transitions between wakefulness, REM sleep, and stages of non-REM sleep.23,24

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  1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
  2. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  3. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010;68(6):1023–1042
  4. van der Heide A, Lammers GJ. Narcolepsy. In: Thorpy MJ, Billiard M, eds. Sleepiness: Causes, Consequences and Treatment. Cambridge, UK: Cambridge University Press; 2011:111-125.
  5. Ahmed I, Thorpy M. Clinical features, diagnosis and treatment of narcolepsy. Clin Chest Med. 2010;31(2):371-381.
  6. 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.
  7. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  8. Andlauer O, Moore H, Hong SC, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep. 2012;35(9):1247-1255.
  9. Drakatos P, Leschziner G. Cataplexy with normal sleep studies and normal CSF hypocretin: an explanation? J Clin Sleep Med. 2016;12(3):449-450.
  10. Singh AK, Mahlios J, Mignot E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J Autoimmun. 2013;43:26-31.
  11. Latorre D, Kallweit U, Armentani E, et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature. 2018;562(7725):63-68.
  12. Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE. Behavioral state instability in orexin knock-out mice. J Neurosci. 2004;24(28):6291-6300.
  13. Pillen S, Pizza F, Dhondt K, Scammell TE, Overeem S. Cataplexy and its mimics: clinical recognition and management. Curr Treat Options Neurol. 2017;19(6):23.
  14. Bassetti C, Aldrich MS. Narcolepsy, idiopathic hypersomnia, and periodic hypersomnias. In: Culebras A, ed. Sleep Disorders and Neurological Disease. New York, NY: Marcel Dekker; 2000:323-354.
  15. Oken BS, Salinsky MC, Elsas SM. Vigilance, alertness, or sustained attention: physiological basis and measurement. Clin Neurophysiol. 2006;117(9):1885-1901.
  16. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
  17. Pisko J, Pastorek L, Buskova J, Sonka K, Nevsimalova A. Nightmares in narcolepsy: underinvestigated symptom? Sleep Med. 2014;15(8):967-972.
  18. Thorpy MJ, Dauvilliers Y. Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med. 2015;16(1):9-18.
  19. Waihrich ES, Rodrigues RN, Silveira HA, Fróes Fda F, Rocha GH. Comparative analysis of multiple sleep latency tests (MSLT) parameters and occurrence of dreaming in patients with daytime sleepiness of narcoleptic and non-narcoleptic origin. Arq Neuropsiquiatr. 2006;64(4):958-962.
  20. Thorpy M, Morse AM. Reducing the clinical and socioeconomic burden of narcolepsy by earlier diagnosis and effective treatment. Sleep Med Clin. 2017;12(1):61-71.
  21. Jeong JH, Kim J-Y, Yoo BE, et al. The correlation between clinical variables and sleep onset rapid eye movement period frequencies in narcoleptic patients. Sleep Med Res. 2010;1(1):15-19.
  22. Rogers AE, Aldrich MS, Caruso CC. Patterns of sleep and wakefulness in treated narcoleptic subjects. Sleep. 1994;17(7):590-597.
  23. Pizza F, Vandi S, Iloti M, et al. Nocturnal sleep dynamics identify narcolepsy type 1. Sleep. 2015;38(8):1277-1284.
  24. Roth T, Dauvilliers Y, Mignot E, et al. Disrupted nighttime sleep in narcolepsy. J Clin Sleep Med. 2013;9(9):955-965.

Performance of routine tasks without awareness.

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

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 awakenings and inappropriate transitions between states of sleep and wakefulness during nighttime sleep.

The inability to stay awake and alert during the day.

A neurotransmitter in the brain that supports wakefulness.

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

A neuropeptide that supports wakefulness and helps suppress 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. Also known as “sleep attacks.”

Brief, unintentional lapses into sleep, or loss of awareness.

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

People with narcolepsy type 1 have low levels of hypocretin.

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

A state of sleep characterized by slower-frequency, more synchronized neuronal activity and decreased muscle tone. Deep stages help to restore the body.

A multiparameter test that monitors physiologic signals during sleep; used as a diagnostic tool in sleep medicine.

A state of sleep characterized by low-amplitude, fast-frequency EEG, vivid dreams, and loss of muscle tone. Normally occurs 60-90 minutes after sleep onset. Also known as “paradoxical sleep.”

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

Sleep-onset REM period.