“All of the sudden, I have this out of the blue urge to sleep.” – Scott
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Sleep-Wake State Instability
Narcolepsy is a disorder characterized by sleep-wake state instability.1

Narcolepsy Sleep-Wake Cycle
In narcolepsy, the sleep-wake cycle is unstable throughout a 24-hour period.3-6 Unstable wakefulness is reflected in an increased frequency of daytime naps.5,7 Rapid transitions to REM sleep during daytime naps are highly suggestive of narcolepsy.7,8 Narcolepsy is also characterized by disrupted nighttime sleep with frequent transitions between wakefulness, REM sleep, and stages of non-REM sleep.7,9
Sleep-wake instability in narcolepsy is characterized by unstable boundaries and frequent and unpredictable transitions between states.3,6,13
During the day, lack of hypocretin in narcolepsy leads to insufficient activation of histamine neurons and wake-promoting neurons outside the hypothalamus, intermittent activation of REM sleep-promoting neurons (REM at the Wrong Time™), and intermittent activation of non-REM sleep-promoting neurons (Non-REM at the Wrong Time™).6,8,14-16 This process causes sleep-wake state instability, which can manifest as unstable boundaries and frequent transitions between states of sleep and wakefulness.3,6,13 Non-REM sleep and elements of REM sleep can intrude into wakefulness and manifest as symptoms of narcolepsy, including excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis.6,8,15,16
Narcolepsy symptoms reflect the underlying sleep-wake state instability.
Histamine neurons help to promote and stabilize wakefulness.
- Ahmed I, Thorpy M. Clinical features, diagnosis and treatment of narcolepsy. Clin Chest Med. 2010;31(2):371-381.
- España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
- Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
- Rogers AE, Aldrich MS, Caruso CC. Patterns of sleep and wakefulness in treated narcoleptic subjects. Sleep. 1994;17(7):590-597.
- Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010;68(6):1023–1042
- Pizza F, Vandi S, Iloti M, et al. Nocturnal sleep dynamics identify narcolepsy type 1. Sleep. 2015;38(8):1277-1284.
- Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
- Roth T, Dauvilliers Y, Mignot E, et al. Disrupted nighttime sleep in narcolepsy. Sleep Med. 2013;9(9):955-965.
- 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.
- American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. 2014.
- Plazzi G, Serra L, Ferri R. Nocturnal aspects of narcolepsy with cataplexy. Sleep Med Rev. 2008;12(2):109-128.
- 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.
- 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.
- Bassetti C, Aldrich MS. Narcolepsy, idiopathic hypersomnia, and periodic hypersomnias. In. Culebras A, ed. Sleep disorders and neurological disease. Marcel Decker Inc;2000:323-354.
- 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.