Potential causes of IH

The Idiopathic Hypersomnia (IH) conundrum: more sleep is never enough and waking up is a constant struggle

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Could the quality of your patient's sleep play a role in their IH symptoms during the day?

For many living with IH, the long hours they sleep never seem to translate into the wakefulness they need. This conundrum means although patients are getting plenty of sleep, they may be left feeling¹:

Unrestored
Foggy and never fully awake
A continuous but often resistible urge to sleep

While the exact cause of IH is unknown, nighttime sleep dysfunction may be one contributor to the daytime symptoms in IH.²

IH patients: What's happening during their sleep?

A look at patients with IH vs healthy controls²

In a meta-analysis of the nocturnal sleep architecture of adult patients with IH, on average, several hallmarks differed from those of healthy controls*:

Nocturnal PSG Parameters in IH Patients vs Healthy Controls

Hedge's G^§

% of slow-wave sleep is decreased²:

This may partially explain the nonrestorative sleep experience by patients with IH

Sleep-onset latency is decreased²

Total sleep time is increased among patients with IH²

% of REM sleep is increased²

Sleep efficiency did not differ significantly between groups²

REM latency did not differ significantly between groups²

*Based on a systematic review that included 10 studies including nocturnal polysomnography data for IH and healthy controls. Meta-analysis compared standardized mean differences (Hedge's g) for total sleep time (TST), sleep-onset latency (SOL), sleep efficiency (SE), rapid eye movement (REM) sleep percentage, slow-wave sleep (SWS) percentage, and REM latency (REML). Moderator analyses were also conducted for variables with heterogeneity among studies for SOL, SE, and TST.²

^†10 studies met criteria for inclusion in meta-analysis.²

^‡9 studies with sufficient data for analysis of sleep efficiency were included in meta-analysis.²

^§Measure of effect size used for meta-analysis.²

In a separate study, high arousal indices were found among patients with IH relative to a control group^3II:

This may partially explain the nonrestorative sleep experienced by patients with IH³

^IIA study of a repository of deidentified sleep studies conducted at various sleep disorder clinics in the United States between 2005 and 2015, aggregating randomly selected records from each diagnostic group (narcolepsy, IH, and an age-matched snoring reference group) to evaluate the characteristics of the nocturnal PSG between groups.³

Several hypothesized physiological changes have been proposed as possible contributors to the pathophysiology of IH

GABAergic system dysfunction

One study found increased levels of a _A agonist in the of hypersomnolent patients⁴

Autonomic dysfunction

Dysfunction of the parasympathetic activity during wake and sleep, as well as altered autonomic response to arousals, were suggested in one study⁵
Another study showed autonomic symptoms were correlated with sleepiness⁶

Altered functional or regional connectivity of the brain

One study showed a greater volume and cortical thickness in the precuneus, proportional to sleepiness⁷
Another study found decreased cerebral blood flow in medial prefrontal cortex, posterior cingulate cortex, and putamen; as well as increased cerebral blood flow in the amygdala and temporo-occipital cortices⁸
A separate study demonstrated increased metabolism in anterior and middle cingulate cortices, the insula, and the right caudate nucleus⁹

Circadian system dysregulation

One study found prolonged circadian rhythm length, as well as delays in expression of melatonin and cortisol¹⁰
Another demonstrated changes in expression and dynamics of circadian clock genes¹¹

Dysfunction of energy metabolism

DQB1*06:02-negative essential hypersomnia was associated in one study with a single-nucleotide polymorphism, suggestive of dysfunction in energy metabolic pathways¹²

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References:

Arnulf I, Leu-Semenescu S, Dodet P. Precision medicine for idiopathic hypersomnia. Sleep Med Clin. 2019;14(3):333-350.
Plante DT. Nocturnal sleep architecture in idiopathic hypersomnia: a systematic review and meta-analysis. Sleep Med. 2018;45:17-24.
Cairns A, Bogan R. Comparison of the macro and microstructure of sleep in a sample of sleep clinic hypersomnia cases. Neurobiol Sleep Circadian Rhythms. 2019;6:62-69.
Rye DB, Bliwise DL, Parker K, et al. Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABA receptors. Sci Transl Med. 2012;4(161):161ra151.
Sforza E, Roche F, Barthélémy JC, Pichot V. Diurnal and nocturnal cardiovascular variability and heart rate arousal response in idiopathic hypersomnia. Sleep Med. 2016;24:131-136.
Miglis MG, Schneider L, Kim P, Cheung J, Trotti LM. Frequency and severity of autonomic symptoms in idiopathic hypersomnia. J Clin Sleep Med. 2020;16(5):749-756.
Pomares FB, Boucetta S, Lachapelle F, et al. Beyond sleepy: structural and functional changes of the default-mode network in idiopathic hypersomnia. Sleep. 2019;42(11):zsz156.
Boucetta S, Montplaisir J, Zadra A, et al. Altered regional cerebral blood flow in idiopathic hypersomnia. Sleep. 2017;40(10):zsx140.
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.
Materna L, Halfter H, Heidbreder A, et al. Idiopathic hypersomnia patients revealed longer circadian period length in peripheral skin fibroblasts. Front Neurol. 2018;9:424.
Lippert J, Halfter H, Heidbreder A, 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.
Miyagawa T, Khor SS, Toyoda H, et al. A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia. J Hum Genet. 2018;63(12):1259-1267.