Is Idiopathic Hypersomnia a Circadian Rhythm Disorder?
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Purpose of Review
The pathophysiology of idiopathic hypersomnia remains unclear, but some of its clinical features suggest the possibility of circadian dysfunction. This review will provide an overview of recent studies of circadian biology that have begun to elucidate the potential role of circadian rhythm dysfunction in idiopathic hypersomnia.
Clinically, people with idiopathic hypersomnia tend to have both a late chronotype and prominent sleep inertia or sleep drunkenness. Melatonin and cortisol profiles in people with IH confirm this tendency toward phase delay. More recently, it has been suggested that the night phase as defined by melatonin profile or period length as defined by BMA1 in dermal fibroblasts may also be prolonged in people with IH. Additionally, amplitude of melatonin rhythm and circadian gene expression, particularly BMAL1, PER1, and PER2, may be impaired in this disease.
Clinical features, melatonin profiles, and circadian gene expression all suggest that abnormalities of the circadian system may be a contributor to the pathogenesis of IH.
KeywordsIdiopathic hypersomnia Circadian rhythm sleep-wake disorders Delayed sleep phase syndrome Circadian rhythm genetics Sleep inertia Sleep drunkenness
This was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K23 NS083748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Compliance with Ethical Standards
Conflict of Interest
Dr. Trotti reports fees to her institution from Jazz Pharmaceuticals, Balance Therapeutics, and Harmony Biosciences, outside this work. There are no financial or other conflicts of interest related to this article.
Human and Animal Rights Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 1.International classification of sleep disorders. 3rd ed. Darien, IL: American Acad. of Sleep Medicine.Google Scholar
- 5.Boucetta S, Montplaisir J, Zadra A, Lachapelle F, Soucy JP, Gravel P, et al. Altered regional cerebral blood flow in idiopathic hypersomnia. Sleep. 2017;40(10). https://doi.org/10.1093/sleep/zsx140.
- 6.Dauvilliers Y, Evangelista E, de Verbizier D, Barateau L, Peigneux P. [18F]Fludeoxyglucose-positron emission tomography evidence for cerebral hypermetabolism in the awake state in narcolepsy and idiopathic hypersomnia. Front Neurol. 2017;8:–350. https://doi.org/10.3389/fneur.2017.00350.
- 10.Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012;35:445–62. https://doi.org/10.1146/annurev-neuro-060909-153128.CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Pandi-Perumal SR, Smits M, Spence W, Srinivasan V, Cardinali DP, Lowe AD, et al. Dim light melatonin onset (DLMO): a tool for the analysis of circadian phase in human sleep and chronobiological disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31(1):1–11. https://doi.org/10.1016/j.pnpbp.2006.06.020.CrossRefGoogle Scholar
- 14.Billiard M, Merle C, Carlander B, Ondze B, Alvarez D, Besset A. Idiopathic hypersomnia. Psychiatry Clin Neurosci. 1998;52(2):125–9. https://doi.org/10.1111/j.1440-1819.1998.tb00987.x.CrossRefPubMedGoogle Scholar
- 16.Komada Y, Inoue Y, Mukai J, Shirakawa S, Takahashi K, Honda Y. Difference in the characteristics of subjective and objective sleepiness between narcolepsy and essential hypersomnia. Psychiatry Clin Neurosci. 2005;59(2):194–9. https://doi.org/10.1111/j.1440-1819.2005.01357.x.CrossRefPubMedGoogle Scholar
- 20.• Vernet C, Leu-Semenescu S, Buzare MA, Arnulf I. Subjective symptoms in idiopathic hypersomnia: beyond excessive sleepiness. J Sleep Res. 2010;19(4):525–34. https://doi.org/10.1111/j.1365-2869.2010.00824.xThis controlled cohort study reports subjective symptoms of idiopathic hypersomnia patients including the frequency of sleep drunkenness and chronotype HO scores.CrossRefPubMedGoogle Scholar
- 21.• Vernet C, Arnulf I. Idiopathic hypersomnia with and without long sleep time: a controlled series of 75 patients. Sleep. 2009;32(6):753–9. https://doi.org/10.1093/sleep/32.6.753This controlled prospective cohort study compares symptoms of IH patients with those of healthy controls including HO scores.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.•• Materna L, Halfter H, Heidbreder A, Boentert M, Lippert J, Koch R, et al. Idiopathic hypersomnia patients revealed longer circadian period length in peripheral skin fibroblasts. Front Neurol. 2018;9:424. https://doi.org/10.3389/fneur.2018.00424This study investigates the circadian period length in IH patients compared to healthy controls by using peripheral circadian clock cells.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.•• Trotti LM. Waking up is the hardest thing I do all day: sleep inertia and sleep drunkenness. Sleep Med Rev. 2017;35:76-84. Doi: https://doi.org/10.1016/j.smrv.2016.08.005. This review article reports alleviating and aggravating factors of both sleep inertia and sleep drunkenness. CrossRefGoogle Scholar
- 29.•• Nevsimalova S, Blazejova K, Illnerova H, Hajek I, Vankova J, Pretl M, et al. A contribution to pathophysiology of idiopathic hypersomnia. Suppl Clin Neurophysiol. 2000;53:366–70 This controlled cohort study provides evidence of delayed circadian phases in IH patients by examining salivary melatonin and cortisol levels.CrossRefGoogle Scholar
- 35.• Schirmacher AHH, Heidbreder A, Happe S, Kelsch R, Kuhlenbäumer G, Mayer G, et al. Sequence variants in circadian rhythmic genes in a cohort of patients suffering from hypersomnia of central origin. Biol Rhythm Res. 2011;42(5):407–16. https://doi.org/10.1080/09291016.2010.525382This candidate-gene associations study examines polymorphisms of circadian rhythmic genes in patients with EDS.CrossRefGoogle Scholar
- 36.•• Lippert J, Halfter H, Heidbreder A, Rohr D, Gess B, Boentert M, et al. Altered dynamics in the circadian oscillation of clock genes in dermal fibroblasts of patients suffering from idiopathic hypersomnia. PLoS One. 2014;9(1):e85255. https://doi.org/10.1371/journal.pone.0085255This cohort control study provides evidence of impaired gene expression of peripheral circadian clock genes in IH patients.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Moller-Levet CS, Archer SN, Bucca G, Laing EE, Slak A, Kabiljo R, et al. Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome. Proc Natl Acad Sci U S A. 2013;110(12):E1132–41. https://doi.org/10.1073/pnas.1217154110.CrossRefPubMedPubMedCentralGoogle Scholar