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40 - Narcolepsy and REM sleep

from Section VI - Disturbance in the REM sleep-generating mechanism

Published online by Cambridge University Press:  07 September 2011

By
Seiji Nishino
Edited by
Birendra N. Mallick ,
S. R. Pandi-Perumal ,
Robert W. McCarley  and
Adrian R. Morrison
Seiji Nishino
Affiliation:
Stanford University School of Medicine
Birendra N. Mallick
Affiliation:
Jawaharlal Nehru University
S. R. Pandi-Perumal
Affiliation:
Somnogen Canada Inc, Toronto
Robert W. McCarley
Affiliation:
Harvard University, Massachusetts
Adrian R. Morrison
Affiliation:
University of Pennsylvania
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Summary

Summary

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, and/or other dissociated manifestations of rapid eye movement (REM) sleep (hypnagogic hallucinations and sleep paralysis).

The major pathophysiology of human narcolepsy has been recently elucidated based on the discovery of narcolepsy genes in animals. Using forward (i.e., positional cloning in canine narcolepsy) and reverse (i.e., mouse gene knock-out) genetics, the genes involved in the pathogenesis of narcolepsy (hypocretin/orexin ligand and its receptor) in animals have been identified. Hypocretins/orexins are novel hypothalamic neuropeptides also involved in various hypothalamic functions such as energy homeostasis and neuroendocrine functions. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in many narcolepsy–cataplexy cases.

After the discovery of sleep-onset REM periods (SOREMs) in narcolepsy, narcolepsy has often been referred as an “REM-sleep disorder.” REM sleep can intrude in active wake or at sleep onset, resulting in cataplexy, sleep paralysis, and hypnagogic hallucinations; these three symptoms are often categorized as “dissociated manifestations of REM sleep.” Although cataplexy and REM-sleep abnormalities are the hallmarks of narcolepsy and these symptoms differentiated narcolepsy from other types of hypersomnia, it is now conceived that impairments of hypocretin neurotransmission cause both the EDS (possibly due to the sleep–wake fragmentation) and REM-sleep abnormalities in narcolepsy; it is impossible to discuss these mechanisms independently.

While sleep paralysis and hypnagogic hallucinations exist in other sleep disorders (such as obstructive sleep apnea) and even in normal subjects, since cataplexy is tightly associated with hypocretin impairments, cataplexy is likely to be pathophysiologically distinct from other dissociated manifestations of REM sleep.

In this review, the clinical and pathophysiological aspects of sleep abnormalities in narcolepsy, with a special focus on those of REM sleep-related symptoms, are discussed.

Type
Chapter
Information
Rapid Eye Movement Sleep
Regulation and Function
 , pp. 403 - 416
Publisher: Cambridge University Press
Print publication year: 2011

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References

Aldrich, M. S., Chervin, R. D. & Malow, B. A. (1997) Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 20: –9.Google Scholar
Arii, J., Kanbayashi, T., Tanabe, Y. . (2004) CSF hypocretin-1 (orexin-A) levels in childhood narcolepsy and neurologic disorders. Neurology 63: –2.CrossRefGoogle ScholarPubMed
Beuckmann, C. T., Sinton, C. M., Williams, S. C. . (2004) Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat. J Neurosci 24: –77.CrossRefGoogle ScholarPubMed
Billiard, M., Besset, A. & Cadilhac, J. (1983) The clinical and polygraphic development of narcolepsy. In Sleep/Wake Disorders: Natural History, Epidemiology and Long-term Evolution, eds. C.Guilleminault, & Lugaresi, E.. New York: Raven Press.Google Scholar
Bishop, C., Rosenthal, L., Helmus, T., Roehrs, T. & Roth, T. (1996) The frequency of multiple sleep onset REM periods among subjects with no excessive daytime sleepiness. Sleep 19: –30.CrossRefGoogle ScholarPubMed
Bonakis, A., Howard, R. S. & Williams, A. (2008) Narcolepsy presenting as REM sleep behaviour disorder. Clin Neurol Neurosurg 110: –20.CrossRefGoogle ScholarPubMed
Bourgine, N., Claustrat, B., Besset, A. & Billiard, M. (1986) Melatonin plasma concentrations during day-time and night-time in narcoleptic subjects and controls. Sleep Res 15: .Google Scholar
Broughton, R., Dunham, W., Newman, J. . (1988) Ambulatory 24 hour sleep-wake monitoring in narcolepsy-cataplexy compared to matched control. Electroenceph Clin Neurophysiol 70: –81.CrossRefGoogle Scholar
Broughton, R., Krupa, S., Boucher, B., Rivers, M. & Mulligan, J. (1998) Impaired circadian waking arousal in narcolepsy-cataplexy. Sleep Res Online 1: –65.Google ScholarPubMed
Broughton, R., Valley, V., Aguirre, M. . (1986) Excessive daytime sleepiness and pathophysiology of narcolepsy-cataplexy: a laboratory perspective. Sleep 9: –15.CrossRefGoogle ScholarPubMed
Carskadon, M. A. & Dement, W. C. (1987) Daytime sleepiness: quantification of a Behavioral State. Neurosci Biobehav Rev 11: –17.CrossRefGoogle ScholarPubMed
Chemelli, R. M., Willie, J. T., Sinton, C. M. . (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: –51.CrossRefGoogle ScholarPubMed
Chou, T. C., Bjorkum, A. A., Gaus, S. E. . (2002) Afferents to the ventrolateral preoptic nucleus. J Neurosci 22: –90.CrossRefGoogle ScholarPubMed
Dantz, B., Edgar, D. M. & Dement, W. C. (1994) Circadian rhythms in narcolepsy: studies on a 90 minute day. Electroceph Clin Neurophy 90: –35.Google ScholarPubMed
Dauvilliers, Y., Rompre, S., Gagnon, J. F. . (2007) REM sleep characteristics in narcolepsy and REM sleep behavior disorder. Sleep 30: –9.CrossRefGoogle ScholarPubMed
Dement, W., Rechtschaffen, A. & Gulevich, G. (1966) The nature of the narcoleptic sleep attack. Neurology 16: –33.CrossRefGoogle ScholarPubMed
Dijk, D. J. & Czeisler, C. A. (1994) Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Lett 166: –8.CrossRefGoogle ScholarPubMed
Dijk, D. J. & Czeisler, C. A. (1995) Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 15: –38.CrossRefGoogle ScholarPubMed
Edgar, D. M., Dement, W. C. & Fuller, C. A. (1993) Effect of SCN-lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci 13: –79.CrossRefGoogle ScholarPubMed
Estabrooke, I. V., McCarthy, M. T., Ko, E. . (2001) Fos expression in orexin neurons varies with behavioral state. J Neurosci 21: –62.CrossRefGoogle ScholarPubMed
Ferrillo, F., Donadio, S., De Carli, F., Garbarino, S. & Nobili, L. (2007) A model-based approach to homeostatic and ultradian aspects of nocturnal sleep structure in narcolepsy. Sleep 30: –65.CrossRefGoogle ScholarPubMed
Fujiki, N., Yoshida, Y., Ripley, B. . (2001) Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. NeuroReport 12: –7.CrossRefGoogle ScholarPubMed
Fukuda, K., Miyasita, A., Inugami, M. & Ishihara, K. (1987) High prevalence of isolated sleep paralysis: Kanashibari phenomenon in Japan. Sleep 10: –86.CrossRefGoogle ScholarPubMed
Gallopin, T., Fort, P., Eggermann, E., . (2000) Identification of sleep-promoting neurons in vitro. Nature 404 : –5.CrossRefGoogle ScholarPubMed
Gélineau, J. B. E. (1880) De la narcolepsie. Gazette des hôpitaux 53 : –8.Google Scholar
Guilleminault, C. (1976) Cataplexy. In Narcolepsy (Advances in Sleep Research Vol. 3). pp. 125–43.Google Scholar
Guilleminault, C., Wilson, R. A. & Dement, W. C. (1974) A study on cataplexy. Arch Neurol 31: –61.CrossRefGoogle ScholarPubMed
Hagan, J. J., Leslie, R. A., Patel, S. . (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci U S A 96: –16.CrossRefGoogle ScholarPubMed
Hara, J., Beuckmann, C. T., Nambu, T. . (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30: –54.CrossRefGoogle ScholarPubMed
Hishikawa, Y. (1976) Sleep paralysis. In Narcolepsy, eds. Guilleminault, C. & Passpouant, P.. New York: Spectrum.Google Scholar
Hishikawa, Y., Wakamatsu, H., Furuya, E. . (1976) Sleep satiation in narcoleptic patients. Electroencephalogr Clin Neurophysiol 41: –18.CrossRefGoogle ScholarPubMed
Hobson, J. A., McCarley, R. W. & Wyzinski, P. W. (1975) Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science 189: –8.CrossRefGoogle ScholarPubMed
Honda, Y. (1988) Clinical features of narcolepsy. In HLA in Narcolepsy, eds. Y. Honda, & T. Juji, . Berlin: Springer-Verlag.CrossRefGoogle Scholar
ICSD-2 (ed.) (2005) ICSD-2-International Classification of Sleep Disorders, 2nd edn. . Westchester, Illinois: American Academy of Sleep Medicine.Google Scholar
Kaitin, K. I., Kilduff, T. S. & Dement, W. C. (1986) Evidence for excessive sleepiness in canine narcoleptics. Electroencephalogr Clin Neurophysiol 64: –54.CrossRefGoogle ScholarPubMed
Kanbayashi, T., Shimohata, T., Nakashima, I. . (2009) Symptomatic narcolepsy in MS and NMO patients; new neurochemical and immunological implications. Arch Neurol 66: –6CrossRefGoogle Scholar
Khatami, R., Landolt, H. P., Achermann, P. . (2008) Challenging sleep homeostasis in narcolepsy-cataplexy: implications for non-REM and REM sleep regulation. Sleep 31: –67.CrossRefGoogle ScholarPubMed
Khatami, R., Landolt, H. P., Achermann, P. . (2007) Insufficient non-REM sleep intensity in narcolepsy-cataplexy. Sleep 30: –9.CrossRefGoogle ScholarPubMed
Lavie, P. (1991) REM periodicity under ultrashort sleep/wake cycle in narcoleptic patients. Can J Psychol 45: –93.CrossRefGoogle ScholarPubMed
Lee, M. G., Hassani, O. K. & Jones, B. E. (2005) Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 25: –20.CrossRefGoogle ScholarPubMed
Mayer, G., Hellmann, F., Leonhard, E. & Meier-Ewert, K. (1997) Circadian temperature and activity rhythms in unmedicated narcoleptic patients. Pharmacol Biochem Behav 58: –402.CrossRefGoogle ScholarPubMed
Mayer, G., Pollmächer, T., Meier-Ewert, K. & Schulz, H. (1993) Zur Einschätzung des Behinderungsgrades bei Narkolepsie. Gesundh-Wes 55: –42.Google Scholar
Mignot, E., Lammers, G. J., Ripley, B., . (2002) The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 59: –62.CrossRefGoogle Scholar
Mileykovskiy, B. Y., Kiyashchenko, L. I. & Siegel, J. M. (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46: –98.CrossRefGoogle ScholarPubMed
Montplaisir, J., Billard, M., Takahashi, S. . (1978) Twenty-four-hour recording in REM-narcoleptics with special reference to nocturnal sleep disruption. Biol Psych 13: –89.Google ScholarPubMed
Moscovitch, A., Partinen, M. & Guilleminault, C. (1993) The positive diagnosis of narcolepsy and narcolepsy’s borderland. Neurology 43: –60.CrossRefGoogle ScholarPubMed
Mosko, S. S., Shampain, D. S. & Sassin, J. F. (1984) Nocturnal REM latency and sleep disturbance in narcolepsy. Sleep 7: –25.CrossRefGoogle ScholarPubMed
Nevsimalova, S., Prihodova, I., Kemlink, D., Lin, L. & Mignot, E. (2007) REM behavior disorder (RBD) can be one of the first symptoms of childhood narcolepsy. Sleep Med 8: –6.CrossRefGoogle ScholarPubMed
Nishino, S. & Mignot, E. (1997) Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol 52: –78.CrossRefGoogle ScholarPubMed
Nishino, S. and Kanbayashi, T. (2005) Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/ovexin system. Sleep Med Rev 9: –310.CrossRefGoogle ScholarPubMed
Nishino, S., Arrigoni, J., Valtier, D. . (1991) Dopamine D2 mechanisms in canine narcolepsy. J Neurosci 11: –71.CrossRefGoogle ScholarPubMed
Nishino, S., Riehl, J., Hong, J. . (2000a) Is narcolepsy REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans. Neurosci Res 38: –46.CrossRefGoogle ScholarPubMed
Nishino, S., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. (2000b) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355: –40.CrossRefGoogle ScholarPubMed
Nishino, S., Bliesath, J., Honda, K. & Mignot, E. (2004) The occurrence of cataplexy in relation to proceeding REM sleep. Sleep 27: .Google Scholar
Okura, M., Fujiki, N., Ripley, B. . (2001) Narcoleptic canines display periodic leg movements during sleep. Psychiatry Clin Neurosci 55: –4.CrossRefGoogle ScholarPubMed
Okura, M., Riehl, J., Mignot, E. & Nishino, S. (2000) Sulpiride, a D2/D3 blocker, reduces cataplexy but not REM sleep in canine narcolepsy. Neuropsychopharmacology 23: –38.CrossRefGoogle Scholar
Peyron, C., Tighe, D. K., van den Pol, A. N. . (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18 : –10015.CrossRefGoogle ScholarPubMed
Peyron, C., Faraco, J., Rogers, W. . (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6: –7.CrossRefGoogle Scholar
Ribstein, M. (1976) Hypnagogic hallucinations. In Narcolepsy, eds C. Guilleminault, W. C. Dement & Passouant, P.. New York: Spectrum.Google Scholar
Rosenthal, C. (1939) Uber das aufreten von halluzinatorisch-kataplektischem angstsyndrom, wachanfallen und ahnlichen storungen bei schizophrenen. Mschr Psychiat 102: .Google Scholar
Saper, C. B., Chou, T. C. & Scammell, T. E. (2001) The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 24: –31.CrossRefGoogle ScholarPubMed
Tafti, M., Rondouin, G., Basset, A. & Billiard, M. (1992) Sleep deprivation in narcoleptic subjects: effect on sleep stages and EEG power density. Electroencephalogr Clin Neurophysiol 83: –49.CrossRefGoogle ScholarPubMed
Takahashi, Y. & Jimbo, M. (1963) Polygraphic study of narcoleptic syndrome, with special reference to hypnagogic hallucinations and cataplexy. Folia Psychiatr Neurol Jpn Suppl. 7: –7.Google Scholar
Vogel, G. (1960) Studies in psychophysiology of dreams III. The dream of narcolepsy. Arch Gen Psychiatry 3: –8.CrossRefGoogle ScholarPubMed
Yoshida, K., McCormack, S., Espana, R. A., Crocker, A. & Scammell, T. E. (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494: –61.CrossRefGoogle ScholarPubMed
Yoshida, Y., Fujiki, N., Nakajima, T. . (2001) Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light–dark cycle and sleep–wake activities. Eur J Neurosci 14: –81.CrossRefGoogle ScholarPubMed
Zeitzer, J. M., Buckmaster, C. L., Lyons, D. M. & Mignot, E. (2004) Locomotor-dependent and -independent components to hypocretin-1 (orexin A) regulation in sleep-wake consolidating monkeys. J Physiol 557: –53.CrossRefGoogle ScholarPubMed
Zhang, S., Zeitzer, J. M., Yoshida, Y. . (2004) Lesions of the suprachiasmatic nucleus eliminate the daily rhythm of hypocretin-1 release. Sleep 27: –27.CrossRefGoogle ScholarPubMed

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