Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABA
            <sub>A</sub>
            Receptors

Rye, David B.; Bliwise, Donald L.; Parker, Kathy P.; Trotti, Lynn Marie; Saini, Prabhjyot; Fairley, Jacqueline A.; Freeman, Amanda; García, Paul S.; Owens, Michael J.; Ritchie, James C.; Jenkins, Andrew

doi:10.1126/scitranslmed.3004685

Cited by 143 publications

(118 citation statements)

References 84 publications

(94 reference statements)

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“…Similarly, acute changes that occur with brain injury impact cellular functions and neural microstructure, potentially causing cell death and more persistent changes in brain function, including increased sleep drive [12]. Other hypothesized shared mechanisms between sleep disturbance and TBI of varying severity, including mTBI, include impaired neurotransmitter function [54,[110][111][112], cerebrovascular autoregulatory dysfunction [113,114], neuroinflammation [115], and dysregulation of circadian hormones [22,116,117]. In addition, interactions between mTBI and comorbid conditions such as PTSD [118], polytrauma, and chronic pain [119], have received increasing attention in the literature.…”

Section: What Are Potentially Unique Mechanisms For Sleep Disturbancementioning

confidence: 99%

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group

et al. 2016

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Disturbed sleep is one of the most common complaints following traumatic brain injury (TBI) and worsens morbidity and long-term sequelae. Further, sleep and TBI share neurophysiologic underpinnings with direct relevance to recovery from TBI. As such, disturbed sleep and clinical sleep disorders represent modifiable treatment targets to improve outcomes in TBI. This paper presents key findings from a national working group on sleep and TBI, with a specific focus on the testing and development of sleep-related therapeutic interventions for mild TBI (mTBI). First, mTBI and sleep physiology are briefly reviewed. Next, essential empirical and clinical questions and knowledge gaps are addressed. Finally, actionable recommendations are offered to guide active and efficient collaboration between academic, industry, and governmental stakeholders.

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Section: What Are Potentially Unique Mechanisms For Sleep Disturbancementioning

confidence: 99%

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group

et al. 2016

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“…34 Recent work suggests that somnolence in the CNS hypersomnias may derive from a gain in function in endogenous γ-aminobutyric acid (GABA) signaling mediated by a naturally occurring constituent of cerebrospinal fluid that allosterically modulates GABA A receptors. 35 Ultimately, the identification of biomarkers will improve diagnostic accuracy in these conditions. …”

Section: -32mentioning

confidence: 99%

Test-Retest Reliability of the Multiple Sleep Latency Test in Narcolepsy without Cataplexy and Idiopathic Hypersomnia

Trotti

Staab²,

Rye³

2013

Journal of Clinical Sleep Medicine

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169

107

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conducted within three weeks of each other.11 Inter-test intervals are generally much longer in clinical practice, and in that case the stability of MSLT features has not been established. We therefore evaluated the test-retest reliability of the MSLT in a clinic population of patients with narcolepsy without cataplexy and idiopathic hypersomnia. METHODS Patient SelectionPatients with a clinical syndrome consistent with a CNS hypersomnia (i.e., reports of problematic, excessive daytime sleepiness persisting ≥ 3 months despite adequate or supra-normal habitual sleep durations, not explained by other causes of daytime sleepiness) who had undergone 2 MSLTs were identiStudy Objectives: Differentiation of narcolepsy without cataplexy from idiopathic hypersomnia relies entirely upon the multiple sleep latency test (MSLT). However, the test-retest reliability for these central nervous system hypersomnias has never been determined. Methods: Patients with narcolepsy without cataplexy, idiopathic hypersomnia, and physiologic hypersomnia who underwent two diagnostic multiple sleep latency tests were identifi ed retrospectively. Correlations between the mean sleep latencies on the two studies were evaluated, and we probed for demographic and clinical features associated with reproducibility versus change in diagnosis. Results: Thirty-six patients (58% women, mean age 34 years) were included. Inter-test interval was 4.2 ± 3.8 years (range 2.5 months to 16.9 years). Mean sleep latencies on the fi rst and second tests were 5.5 (± 3.7 SD) and 7.3 (± 3.9) minutes, respectively, with no signifi cant correlation (r = 0.17, p = 0.31). A change in diagnosis occurred in 53% of patients, and was accounted for by a difference in the mean sleep latency (N = 15, 42%) or the number of sleep onset REM periods (N = 11, 31%). The only feature predictive of a diagnosis change was a history of hypnagogic or hypnopompic hallucinations. Conclusions S C I E N T I F I C I N V E S T I G A T I O N ST he central nervous system (CNS) hypersomnias manifest as excessive daytime sleepiness with or without prolonged nocturnal sleep in the absence of demonstrable nocturnal sleep pathology or insuffi cient sleep. They include the entities of narcolepsy with and without cataplexy and idiopathic hypersomnia. Narcolepsy with cataplexy is a chronic disease characterized by short latencies to both sleep and REM sleep on daytime nap opportunities during the multiple sleep latency test (MSLT) and is caused by immunogenetically mediated loss of hypocretin.1 Cataplexy is a clinical feature highly specifi c to hypocretin-defi cient narcolepsy, although is not always evident near the onset of sleepiness. The remaining CNS hypersomnias begin at a similar age, are much less likely to be associated with hypocretin defi ciency, 1-4 and lack a pathognomonic sign or symptom. 5,6 They have many features in common, including hallucinations and sleep paralysis, 1,4 unrefreshing naps, 7,8 sleep drunkenness, 1,7,8 and prolonged nocturnal sleep. [8][9][10] Therefore, differenti...

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“…Th e eff ect on GABA A receptors could be reversed in vitro with fl umazenil, a negative allosteric modulator of GABA A receptors, and IV fl umazenil improved subjective sleepiness and measured vigilance in patients. 9 Case reports of two patients treated successfully with sublingual/transdermal 9 or subcutaneous 91 fl umazenil over weeks to years further support the hypothesis that abnormal GABA A receptor activity may be contributing to sleepiness, but further work is needed to establish the possible role of the GABA system in hypersomnolence.…”

Section: Epidemiologymentioning

confidence: 98%

Central Disorders of Hypersomnolence

Khan¹,

Trotti²

2015

Chest

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The central disorders of hypersomnolence are characterized by severe daytime sleepiness, which is present despite normal quality and timing of nocturnal sleep. Recent reclassifi cation distinguishes three main subtypes: narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia (IH), which are the focus of this review. Narcolepsy type 1 results from loss of hypothalamic hypocretin neurons, while the pathophysiology underlying narcolepsy type 2 and IH remains to be fully elucidated. Treatment of all three disorders focuses on the management of sleepiness, with additional treatment of cataplexy in those patients with narcolepsy type 1.Sleepiness can be treated with modafi nil/armodafi nil or sympathomimetic CNS stimulants, which have been shown to be benefi cial in randomized controlled trials of narcolepsy and, quite recently, IH. In those patients with narcolepsy type 1, sodium oxybate is eff ective for the treatment of both sleepiness and cataplexy. Despite these treatments, there remains a subset of hypersomnolent patients with persistent sleepiness, in whom alternate therapies are

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Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABA _A Receptors

Cited by 143 publications

References 84 publications

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group

Test-Retest Reliability of the Multiple Sleep Latency Test in Narcolepsy without Cataplexy and Idiopathic Hypersomnia

Central Disorders of Hypersomnolence

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Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABA A Receptors

Cited by 143 publications

References 84 publications

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group

Test-Retest Reliability of the Multiple Sleep Latency Test in Narcolepsy without Cataplexy and Idiopathic Hypersomnia

Central Disorders of Hypersomnolence

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Product

Resources

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Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABA _A Receptors