International Classification of Sleep Disorders-Third Edition

Sateia, Michael J.

doi:10.1378/chest.14-0970

Cited by 2,293 publications

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“…According to the clinical definition by the International Classification of Sleep Disorders-Third Edition, two types of narcoleptic disorders are categorized (7). Narcolepsy type 1 is characterized by the existence of cataplexy and low levels of orexin-A in cerebrospinal fluid (CSF) (8)(9)(10).…”

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Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

Irukayama-Tomobe

Ogawa

Tominaga

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

107

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Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexindeficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists. neuropeptides produced by neurons exclusively localized to the lateral hypothalamus that act on two G protein-coupled receptors termed OX1R and OX2R (1). Orexin-producing neurons send axons diffusely through the central nervous system, with especially dense innervations to several nuclei involved in sleep/wakefulness regulation (2, 3). Because orexins have been implicated in the maintenance of wakefulness, many groups are trying to develop nonpeptidic orexin receptor antagonists aiming at new medication for insomnia. Recently, suvorexant, a dual orexin receptor antagonist, was clinically approved in Japan and the United States (4, 5).A crucial role of the orexin system in the regulation of sleep/ wakefulness was initially uncovered by the discovery that OX2R-deficient dogs (6) and prepro-orexin knockout (Hcrt −/− , abbreviated as OXKO) mice (2) exhibited symptoms resembling human narcolepsy-cataplexy. According to the clinical definition by the International Classification of Sleep Disorders-Third Edition, two types of narcoleptic disorders are categorized (7). Narcolepsy type 1 is characterized by the existence of cataplexy and low levels of orexin-A in cerebrospinal fluid (CSF) (8-10). However, patients with narcolepsy type 2 show no cataplexy and normal orexin-A levels in CSF. Narcolepsy-cataplexy, or narcolepsy type 1 (11), is characterized by a marked instability of sleep/ wake state transitions, resulting in nonrapid eye movement (NREM) sleep-related symptoms (e.g., excessive daytime sleepiness, "sleep attacks," and fragmented nighttime sleep), and rapid eye movement (REM) sleep-related symptoms (e.g., cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations). In polysomnography, narcolepsy-cataplexy patients show markedly reduced daytime sleep latency, and sleep-onset REM periods (SOREMs). Currently available treatments for narcolepsyca...

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confidence: 99%

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

Irukayama-Tomobe

Ogawa

Tominaga

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

107

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“…Narcolepsy can be primary or secondary, and two forms of primary narcolepsy are described 2. Type 1 primary narcolepsy is caused by selective loss of hypothalamic neurons that produce the neuropeptide hypocretin (also called orexin), resulting in low levels of hypocretin in the CSF 5. These neurons are located in the ventral lateral hypothalamic nucleus in dogs and have extensive connections throughout the central nervous system (CNS) that promote wakefulness and muscle tone in response to the release of hypocretin 6.…”

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confidence: 99%

“…In type 2 primary narcolepsy, cataplexy is not a component, and CSF hypocretin levels are normal. The cause of type 2 primary narcolepsy is not known 5. The underlying etiology of both types of primary narcolepsy is thought to be multifactorial, with genetics playing a role in each 10…”

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confidence: 99%

Pituitary Macrotumor Causing Narcolepsy‐Cataplexy in a Dachshund

Schmid

Hodshon

Olin

et al. 2017

Veterinary Internal Medicne

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Familial narcolepsy secondary to breed‐specific mutations in the hypocretin receptor 2 gene and sporadic narcolepsy associated with hypocretin ligand deficiencies occur in dogs. In this report, a pituitary mass is described as a unique cause of narcolepsy‐cataplexy in a dog. A 6‐year‐old male neutered Dachshund had presented for acute onset of feeding‐induced cataplexy and was found to have a pituitary macrotumor on magnetic resonance imaging (MRI). Cerebral spinal fluid hypocretin‐1 levels were normal, indicating that tumor effect on the ventral lateral nucleus of the hypothalamus was not the cause of the dog's narcolepsy‐cataplexy. The dog was also negative for the hypocretin receptor 2 gene mutation associated with narcolepsy in Dachshunds, ruling out familial narcolepsy. The Dachshund underwent stereotactic radiotherapy (SRT), which resulted in reduction in the mass and coincident resolution of the cataplectic attacks. Nine months after SRT, the dog developed clinical hyperadrenocorticism, which was successfully managed with trilostane. These findings suggest that disruptions in downstream signaling of hypocretin secondary to an intracranial mass effect might result in narcolepsy‐cataplexy in dogs and that brain MRI should be strongly considered in sporadic cases of narcolepsy‐cataplexy.

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“…Periodische Beinbewegungen im Schlaf ("periodic leg movements in sleep", PLMS), früher auch als "nächtlicher Myoklonus" bezeichnet, sind durch wiederholte Beinbewegungen in kurzem Zeitabstand charakterisiert [14]. Füh-ren diese Bewegungen zu Schlaflosigkeit (Insomnie) oder erhöhtem Schlafdruck (Hypersomnie), die nicht durch andere Ursachen erklärt werden kann, so liegt eine "periodic limb movement disorder" (PLMD) vor.…”

Section: Medizinisches Problemunclassified