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Pathophysiology

Narcolepsy Is Characterized by Sleep-Wake State Instability1

During the day, unstable wakefulness can occur as excessive daytime sleepiness (EDS) and cataplexy,1,2 the two most common symptoms of narcolepsy3,4

Loss of hypocretin neurons in narcolepsy ultimately leads to sleep-wake state instability1,5

  • During the day, unstable wakefulness can occur due to:
    • - Reduced or inconsistent activation of histamine and other wake-promoting neurons1,5
    • - Periodic activation of REM sleep–promoting neurons and non-REM sleep–promoting neurons1,9,10

Loss of hypocretin neurons causes narcolepsy in most patients3,7,8

  • About 95% of patients with narcolepsy with cataplexy (narcolepsy type 1) are estimated to have low levels of hypocretin3,*
  • 24% of patients with narcolepsy without cataplexy (narcolepsy type 2) are estimated to have low levels of hypocretin† and are more likely to develop cataplexy11

*Low levels of cerebrospinal fluid (CSF) hypocretin were defined as <110 pg/mL.3

†Low levels of CSF hypocretin were defined as ≤110 pg/mL.3


See how EDS and cataplexy can vary»View complementary roles of hypocretin and histamine»

References

  1. Saper CB, Fuller PM, Pederson NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010;68(6):1023-1042.
  2. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  3. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed, text revision. American Academy of Sleep Medicine; 2023.
  4. Ahmed I, Thorpy M. Clinical features, diagnosis and treatment of narcolepsy. Clin Chest Med. 2010;31(2):371-381.
  5. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  6. 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.
  7. Thorpy MJ. Recently approved and upcoming treatments for narcolepsy. CNS Drugs. 2020;34(1):9-27.
  8. Ruoff C, Rye D. The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality. Curr Med Res Opin. 2016;32(10):1611-1622.
  9. Kumar S, Haritha S. Etiopathogenesis and neurobiology of narcolepsy: a review. J Clin Diagn Res. 2014;8(2):190-195.
  10. Overeem S, Reading P, Bassetti CL. Narcolepsy. Sleep Med Clin. 2012;7(2):263-281.
  11. Andlauer O, Moore H, Hong S-C, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep. 2012;35(9):1247-1255.