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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

Understanding the pathophysiology of narcolepsy infographicUnderstanding the pathophysiology of narcolepsy infographic
Histamine and orexin neurons in the hypothalamusHistamine and orexin neurons in the hypothalamus

Hypothalamic neurons play a role in regulating the sleep-wake cycle9

Orexin (hypocretin) and histamine neurons both originate in the hypothalamus10,11

  • Studies show that orexin and histamine play complementary roles in promoting and stabilizing wakefulness2,10-13
See how EDS and cataplexy can vary»

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. 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. Ono D, Yamanaka A. Hypothalamic regulation of the sleep/wake cycle. Neurosci Res. 2017;118:74-81.
  10. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
  11. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241.
  12. 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
  13. Anaclet C, Parmentier R, Ouk K, et al. Orexin/hypocretin and histamine: distinct roles in the control of wakefulness demonstrated using knock-out mouse models. J Neurosci. 2009;29(46):14423-14438.