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Manifestations of Sleep-Wake State Instability

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

1 Sleep Wake Instability

Sleep-Wake State Instability Throughout the Day

People living with narcolepsy can experience multiple intrusions of non-REM sleep and REM sleep throughout the day.2,4-6 Gain more insight on the impact of ongoing sleep-wake state instability in narcolepsy.

In narcolepsy, the sleep-wake cycle is unstable throughout a 24-hour period.1,6,7

Unstable wakefulness is reflected in:

  • Increased frequency of daytime naps7,8
  • Rapid transitions to REM sleep during daytime naps8,9

Narcolepsy is also characterized by disrupted nighttime sleep with rapid onset of REM sleep and with frequent transitions between wakefulness, REM sleep, and stages of non-REM sleep.8,10

Narcolepsy Hypnogram Dekstop
Narcolepsy Hypnogram Mobile

Sleep-wake state instability can manifest as impaired alertness or lapses into sleep.2,6,11

EDS Character

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.2,5,9

  • Insufficient activation of wake-promoting neurons may lead to impaired alertness and neurocognitive functioning.1,2,9,12
  • 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.2,3,5
EDS Character
Cataplexy Character

Sleep-wake state instability can manifest as symptoms of REM sleep dysregulation.1,2,9

Cataplexy Character

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.2,9

In narcolepsy, unstable boundaries between REM sleep and wakefulness may allow elements of REM sleep to intrude into wakefulness.9,13

  • The muscle atonia characteristic of REM sleep can intrude into wakefulness, manifesting as symptoms such as cataplexy or sleep paralysis.2,9
  • The dreams of REM sleep can also intrude into wakefulness as hypnagogic hallucinations.2,14

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 night5,9
  • Vivid, frightening, or bizarre dreams15,16
  • Dreams during daytime naps17
  • Lack of muscle atonia during REM sleep16,18
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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. 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.
  4. 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.
  5. 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.
  6. 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.
  7. Rogers AE, Aldrich MS, Caruso CC. Patterns of sleep and wakefulness in treated narcoleptic subjects. Sleep. 1994;17(7):590-597.
  8. Pizza F, Vandi S, Iloti M, et al. Nocturnal sleep dynamics identify narcolepsy type 1. Sleep. 2015;38(8):1277-1284.
  9. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  10. Roth T, Dauvilliers Y, Mignot E, et al. Disrupted nighttime sleep in narcolepsy. J Clin Sleep Med. 2013;9(9):955-965.
  11. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
  12. Oken BS, Salinsky MC, Elsas SM. Vigilance, alertness, or sustained attention: physiological basis and measurement. Clin Neurophysiol. 2006;117(9):1885-1901.
  13. 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.
  14. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
  15. Pisko J, Pastorek L, Buskova J, Sonka K, Nevsimalova A. Nightmares in narcolepsy: underinvestigated symptom? Sleep Med. 2014;15(8):967-972.
  16. Thorpy MJ, Dauvilliers Y. Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med. 2015;16(1):9-18.
  17. 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.
  18. 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.

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.

Sleep-onset REM period.

The VLPO as well as the median preoptic nucleus (MnPO) are located in the hypothalamus and contain essential neurons for promoting non-REM sleep. These neurons project to all wake-promoting regions to inhibit wakefulness and promote non-REM sleep during the night.8,11 Neurons in the extended VLPO mediate the promotion of REM sleep by inhibiting certain wake-promoting neurons that suppress REM sleep.8