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Manifestations of Sleep-Wake State Instability in Narcolepsy

Signs and symptoms of narcolepsy reflect the underlying sleep-wake state instability.1-3

Wakefulness Rem Infographic

Narcolepsy causes frequent transitions and unstable boundaries between REM sleep and wakefulness.1-4

In narcolepsy, insufficient activation of certain neurons (e.g., histamine neurons, norepinephrine neurons) that normally inhibit REM sleep–promoting neurons leads to insufficient inhibition and intermittent activation of REM sleep–promoting neurons during the day.1,4-8 This can lead to abnormally rapid transitions into REM sleep and cause unstable boundaries between REM sleep and wakefulness, allowing elements of REM sleep to intrude into wakefulness.4,9

Narcolepsy significantly impairs the timing of REM sleep. REM sleep is more likely to occur at any time of day or night in people living with the disorder.4,10,11 This disordered regulation of REM sleep is reflected in shorter latencies to REM sleep after sleep onset, vivid dreams during daytime naps, and a greater propensity for sleep-onset REM periods (SOREMPs) ≤15 minutes after sleep onset during daytime naps (typically assessed by diagnostic MSLT) and at night (typically assessed by nighttime PSG).4,12,13

When elements of REM sleep intrude into wakefulness, symptoms of narcolepsy occur.4,14 Muscle atonia, characteristic of REM sleep, can intrude into wakefulness as symptoms such as cataplexy or sleep paralysis.4,6

Dreams, which are common during REM sleep, can also intrude as hypnagogic hallucinations or vivid dreams during naps.4,10,12

Signs and symptoms of REM sleep dysregulation can be very specific.14,15

Cataplexy and nocturnal SOREMPs on overnight PSG are very specific to narcolepsy, and are key criteria for making a narcolepsy diagnosis.14,15 Other signs and symptoms of potential REM sleep dysregulation should substantially raise the level of clinical suspicion for narcolepsy.14,15

  • Vivid dreams14-16
  • Hypnagogic hallucinations14-16
  • Sleep paralysis14-16
  • Dreaming during daytime naps14-16
  • Lack of muscle atonia during REM sleep14-16
NREM At The Wrong Time

Narcolepsy causes frequent transitions and unstable boundaries between non-REM sleep and wakefulness1,9,10

Insufficient activation of key wake-promoting neurons and insufficient inhibition of non-REM sleep–promoting neurons can cause manifestations of EDS.1,4,9,10,15,17 Insufficient activation of wake-promoting neurons may lead to impaired alertness and neurocognitive functioning,1,4,9,14,15 while insufficient inhibition of non-REM sleep–promoting neurons can lead to non-REM sleep intruding into wakefulness.1,4,9,10,17 EDS can present as an unrelenting pressure for sleep, automatic behavior, microsleep episodes, or unplanned sleep episodes.14,18

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

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Histamine neurons help to promote and stabilize wakefulness.

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  1. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  2. van der Heide A, Lammers GJ. Narcolepsy. In: Thorpy MJ, Billiard M, eds. Sleepiness: Causes, Consequences and Treatment. Cambridge: Cambridge University Press;2011:111-125.
  3. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010;68(6):1023–1042
  4. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  5. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241.
  6. Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53(2):154-166.
  7. 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.
  8. Burgess CR, Oishi Y, Mochizuki T, Peever JH, Scammell TE. Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci. 2013;33(23):9734-9742.
  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. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
  11. Plazzi G, Serra L, Ferri R. Nocturnal aspects of narcolepsy with cataplexy. Sleep Med Rev. 2008;12(2):109-128.
  12. Waihrich ES, Rodrigues RND, Silveira HA, et al. 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.
  13. Pizza F, Vandi S, Iloti M, et al. Nocturnal sleep dynamics identify narcolepsy type 1. Sleep. 2015;38(8):1277-1284.
  14. 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.
  15. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed.; 2014.
  16. Thorpy MJ, Dauvilliers Y. Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med. 2015;16(1):9-18.
  17. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
  18. Nishino S. Clinical and neurobiological aspects of narcolepsy. Sleep Med. 2007;8(4):373-399.

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.