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Sleep-Wake State Instability in Narcolepsy

Loss of hypocretin neurons in narcolepsy leads to sleep-wake state instability.1

Narcolepsy circuit image
During the day, lack of hypocretin in narcolepsy leads to:
  • Insufficient activation of histamine neurons and wake-promoting neurons outside the hypothalamus2,3
  • Insufficient inhibition and intermittent activation of non-REM sleep–promoting neurons (Non-REM at the Wrong Time™)2,4
  • Insufficient inhibition and intermittent activation of REM sleep–promoting neurons (REM at the Wrong Time™)2,5,6
This process causes sleep-wake state instability, which manifests as:
  • Frequent and unpredictable transitions between sleep-wake states7,8
  • Unstable boundaries between sleep-wake states, which allows elements of one state to intrude into another7,9

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The Pathophysiology of Cataplexy

Cataplexy occurs when the muscle atonia associated with REM sleep intrudes into wakefulness during the day.3,11 Learn about the neuronal processes that allow strong emotions to trigger a loss of muscle tone in people living with narcolepsy.3,10

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Manifestations

Understand signs and symptoms that reflect underlying sleep-wake state instability.

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Histamine

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  1. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  2. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010;68(6):1023-1042.
  3. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  4. 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.
  5. 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.
  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. 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.
  8. Ahmed I, Thorpy M. Clinical features, diagnosis and treatment of narcolepsy. Clin Chest Med. 2010;31(2):371-381.
  9. 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.
  10. Szabo S, Thorpy M, Mayer G, Peever J, Kilduff T. Neurobiological and immunogenetic aspects of narcolepsy: implications of pharmacotherapy. Sleep Med Rev. 2019;43:23-36.
  11. Dauvilliers Y, Siegel J, Lopez R, Torontali Z, Peever J. Cataplexy – clinical aspects, pathophysiology and management strategy. Nat Rev Neurol. 2014;10(7):386-395.
  12. Meletti S, Vaudano AE, Pizza F, et al. The brain correlates of laugh and cataplexy in childhood narcolepsy. J Neurosci. 2015;35(33):11583-11594.
  13. Burgess C, Oishi Y, Mochizuki T, Peever J, Scammell T. Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci. 2013;33(23):9734-9742.
  14. Juvodden HT, Alnæs D, Lund MJ, et al. Hypocretin-deficient narcolepsy patients have abnormal brain activation during humor processing. Sleep. 2019;42(7):zsz082.

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; nearly 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 sometimes frightening dream-like events that occur when falling asleep.

Also known as orexin. 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 living 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 fast-frequency, desynchronized activity on 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.

An abnormal sleep phenomenon characterized by REM sleep occurrence within 15 minutes of sleep onset; may occur during nighttime sleep or daytime napping.

A group of neurons located in the hypothalamus that are essential for promoting non-REM sleep. These neurons project to all wake-promoting regions to inhibit wakefulness and promote non-REM sleep during the night.

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US-NAR-2300169/Nov 2023

US-NAR-2300169/Nov 2023