Idiopathic hypersomnia (IH) is a rare neurological sleep disorder, characterized by excessive daytime sleepiness despite normal sleep duration, that can significantly impact patient\'s lives. The burden of IH goes beyond excessive daytime sleepiness, pervading all aspects of everyday life. Characteristic and burdensome symptoms of IH include sleep inertia/drunkenness, long sleep duration, and daytime cognitive dysfunction. This systematic review assessed current knowledge regarding IH diagnostic challenges and burden of illness. Literature searches for original epidemiological, clinical, humanistic, or economic research relevant to IH published between 2012 and 2022 in MEDLINE, Embase, Cochrane, gray literature (diagnostic criteria and treatment guidelines), conferences (2019-2022), and clinical trial databases yielded 97 articles. Findings indicate that IH remains a poorly defined diagnosis of exclusion that is difficult to distinguish from narcolepsy type 2 because of symptom overlap and inadequacies of objective testing. Consequently, individuals with IH endure diagnostic delays of up to 9 years. The economic burden of IH has not been characterized to any appreciable extent. Pharmacological treatment options can improve symptoms and functional status, but rarely restores normal levels of functioning. These findings highlight the need to reclassify central disorders of hypersomnolence. Further collaboration is now required between research groups to identify and validate objective markers to help redefine diagnostic criteria for IH. This would move IH into a position that could benefit from future targeted therapeutic interventions. The study was funded by Takeda Development Center Americas, Inc.

OBJECTIVE: The role of actigraphy in central disorders of hypersomnolence (CDH) is expanding but evidence of reliability with polysomnography (PSG) is scarce and provided only during nighttime. We explored the agreement between actigraphy and continuous 24-hour PSG at CDH diagnosis.
METHODS: Forty-four consecutive drug-naïve patients (28 narcolepsy, 16 idiopathic hypersomnia) underwent actigraphy during 24 hours of free-running PSG, during multiple sleep latency test (MSLT) and 13 of them also during maintenance of wakefulness test (MWT). Daytime and nighttime sleep features and MSLT and MWT mean sleep latencies (mSL) were estimated with the actigraphic algorithms by Cole-Kripke (CK) Sadeh, and University of California San Diego (UCSD). Agreement to corresponding PSG measures was assessed with Bland Altman plots.
RESULTS: Nighttime-total sleep time (TST) in narcolepsy was significantly underestimated with CK (bias 27.8 min, 95%CI 13.7-41.9) and Sadeh (bias 56.7 min, 95%CI 38.8/74.5). Daytime-TST was overestimated in IH and narcolepsy with all algorithms (CK: bias -42.2, 95%CI -67/-17.4; Sadeh: bias -30.2 min, 95%CI -52.7/-7.7; UCSD bias -86.9 min, 95%CI -118.2/-55.6). 24-hour-TST was overestimated by CK and UCSD in IH (CK: bias -58.5 min, 95%CI -105.5/-11.5; UCSD: bias -118.8 min, 95% CI -172.5/-65), and by UCSD in narcolepsy (bias -68.8 min, 95%CI -109.3/-38.2). In the entire cohort, actigraphy overestimated MSLT mSL but not MWT mSL.
CONCLUSIONS: Conventional actigraphic algorithms overestimate 24-hour TST in IH and underestimate nighttime TST in narcolepsy. These discrepancies call for cautious application of actigraphy in the diagnostic process of CDH and the development of new quantitative signal analysis approaches.

OBJECTIVE: The Multiple Sleep Latency Test (MSLT) is a key diagnostic component in the diagnosis of central disorders of hypersomnolence. Due to time constraints, it is common practice to wake patients at a standard time from overnight polysomnography (PSG) prior to the MSLT. This has the potential to influence MSLT results due to sleep deprivation. We describe the impact of allowing ad libitum sleep on the night prior to the MSLT in patients being assessed for hypersomnolence.
METHODS: 580 consecutive patients undergoing PSG/MSLT for assessment of hypersomnolence were analyzed: 290 either side of a change in laboratory protocol which allowed patients ad libitum sleep during the PSG, rather than being woken at a pre-specified time. Baseline characteristics, PSG and MSLT results were compared between the groups.
RESULTS: Groups were similar at baseline, other than there being more females in the ad libitum group. After adjusting for confounding variables, ad libitum patients had later sleep offset time (+58.7 minutes; p<0.001), longer PSG total sleep time (+47.8 minutes; p<0.001), longer MSLT mean sleep latency (+1.3 minutes; p=0.002) and 23% fewer MSLT with mean sleep latency less than 8 minutes (p=0.004) when compared with patients who were woken at a standard time.
CONCLUSIONS: The common practice of waking patients from their PSG at a standard time has the potential to curtail sleep and impact MSLT results by reducing mean sleep latency. Patients being assessed for hypersomnolence should be allowed ad libitum sleep during the PSG on the night prior to their MSLT.

BACKGROUND: Optimal measurement tools for problematic sleep inertia, common in some central disorders of hypersomnolence (CDH), have not yet been determined. We evaluated the performance of the Sleep Inertia Questionnaire (SIQ) in CDH, and how well it distinguished hypersomnolent groups from controls, and IH (idiopathic hypersomnia) from narcolepsy type 1 (NT1).
METHODS: This prospective, bi-centric study included 63 control, 84 IH, 16 NT1, 18 narcolepsy type 2 (NT2), and 88 subjective excessive daytime sleepiness (sEDS) participants, using ICSD-3 criteria. 126 (47.2 %) participants were on any medication at the time of SIQ completion. We assessed construct validity of SIQ scores, and sleep inertia duration (SID), and compared them across diagnoses, controlling for age and center. We derived cutpoints to distinguish hypersomnolent patients from controls and IH from NT1. Sensitivity analyses for depression, chronotype, and medication were performed.
RESULTS: The SIQ sum and composite score were significantly lower in controls than in other groups (p < 0.0001), demonstrating outstanding ability to distinguish patients from controls (AUCs 0.92), without differences among hypersomnolent groups. SID (AUC 0.76) was significantly shorter in controls than in all hypersomnolent groups except NT1, and was shorter in NT1 than in IH or sEDS. Optimal SIQ sum cutpoint was 42 (J = 0.71) for patients versus controls. Optimal SID cutpoint in distinguishing IH from NT1 was 25 min (J = 0.39).
CONCLUSIONS: The SIQ has excellent ability to distinguish hypersomnolent patients from healthy controls, after controlling for depression, eveningness, and medication. SID is best at distinguishing IH from NT1.

People with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH) often report cognitive impairment which can be quite burdensome but is rarely evaluated in routine clinical practice. In this systematic review and meta-analysis, we assessed the nature and magnitude of cognitive impairment in NT1, NT2, and IH in studies conducted from January 2000 to October 2022. We classified cognitive tests assessing memory, executive function, and attention by cognitive domain. Between-group differences were analyzed as standardized mean differences (Cohen\'s d), and Cohen\'s d for individual tests were integrated according to cognitive domain and clinical disease group. Eighty-seven studies were screened for inclusion; 39 satisfied inclusion criteria, yielding 73 comparisons (k): NT1, k = 60; NT2, k = 8; IH, k = 5. Attention showed large impairment in people with NT1 (d = -0.90) and IH (d = -0.97), and moderate impairment in NT2 (d = -0.60). Executive function was moderately impaired in NT1 (d = -0.30) and NT2 (d = -0.38), and memory showed small impairments in NT1 (d = -0.33). A secondary meta-analysis identified sustained attention as the most impaired domain in NT1, NT2, and IH (d ≈ -0.5 to -1). These meta-analyses confirm that cognitive impairments are present in NT1, NT2, and IH, and provide quantitative confirmation of reports of cognitive difficulties made by patients and clinicians. These findings provide a basis for the future design of studies to determine whether cognitive impairments can improve with pharmacologic and nonpharmacologic treatments for narcolepsy and IH.

This study aimed to progress the understanding of idiopathic hypersomnia (IH) by assessing the moderating influence of individual characteristics, such as age, sex, and body mass index (BMI) on sleep architecture. In this retrospective study, 76 IH participants (38.1 ± 11.3 years; 40 women) underwent a clinical interview, an in-laboratory polysomnography with a maximal 9-h time in bed and a multiple sleep latency test (MSLT). They were compared to 106 healthy controls (38.1 ± 14.1 years; 60 women). Multiple regressions were used to assess moderating influence of age, sex, and BMI on sleep variables. We used correlations to assess whether sleep variables were associated with Epworth Sleepiness Scale scores and mean sleep onset latency on the MSLT in IH participants. Compared to controls, IH participants had shorter sleep latency (p = 0.002), longer total sleep time (p < 0.001), more time spent in N2 sleep (p = 0.008), and showed trends for a higher sleep efficiency (p = 0.023) and more time spent in rapid eye movement (REM) sleep (p = 0.022). No significant moderating influence of age, sex, or BMI was found. More severe self-reported sleepiness in IH patients was correlated with shorter REM sleep latency and less N1 sleep in terms of proportion and duration (ps < 0.01). This study shows that, when compared to healthy controls, patients with IH had no anomalies in their sleep architecture that can explain their excessive daytime sleepiness. Moreover, there is no moderating influence of age, sex, and BMI, suggesting that the absence of major group differences is relatively robust.

Hypersomnia spectrum disorders are underdiagnosed and poorly treated due to their heterogeneity and absence of biomarkers. The electroretinography has been proposed as a proxy of central dysfunction and has proved to be valuable to differentiate certain psychiatric disorders. Hypersomnolence is a shared core feature in central hypersomnia and psychiatric disorders. We therefore aimed to identify biomarkers by studying the electroretinography profile in patients with narcolepsy type 1, idiopathic hypersomnia and in controls. Cone, rod and retinal ganglion cells electrical activity were recorded with flash-electroretinography in non-dilated eye of 31 patients with idiopathic hypersomnia (women 84%, 26.6 ± 5.9 years), 19 patients with narcolepsy type 1 (women 63%, 36.6 ± 12.7 years) and 43 controls (women 58%, 30.6 ± 9.3 years). Reduced cone a-wave amplitude (p = 0.039) and prolonged cone (p = 0.022) and rod b-wave (p = 0.009) latencies were observed in patients with narcolepsy type 1 as compared with controls, while prolonged photopic negative response-wave latency (retinal ganglion cells activity) was observed in patients with idiopathic hypersomnia as compared with controls (p = 0.033). The rod and cone b-wave latency clearly distinguished narcolepsy type 1 from idiopathic hypersomnia and controls (area under the curve > 0.70), and the photopic negative response-wave latency distinguished idiopathic hypersomnia and narcolepsy type 1 from controls with an area under the curve > 0.68. This first original study shows electroretinography anomalies observed in patients with hypersomnia. Narcolepsy type 1 is associated with impaired cone and rod responses, whereas idiopathic hypersomnia is associated with impaired retinal ganglion cells response, suggesting different phototransduction alterations in both hypersomnias. Although these results need to be confirmed with a larger sample size, the electroretinography may be a promising tool for clinicians to differentiate hypersomnia subtypes.

Idiopathic hypersomnia(IH) is a chronic central disorders of hypersomnolence that manifests as excessive daytime sleepiness occurring despite normal or prolonged sleep time. Due to the individual heterogeneity of disease, the high overlap of clinical, poor repeatability of polysomnography monitoring results and the lack of clear disease biomarkers, clinical diagnosis and differential diagnosis are still difficult. This article summarizes the update of diagnostic criteria, clinical manifestations, diagnosis and treatment strategies of IH, in order to receive attention, increase the recognition rate of clinical diagnosis, reduce the misdiagnosis rate and missed diagnosis rate.
特发性过度睡眠（IH）是一种慢性中枢性嗜睡疾病，主要表现为尽管睡眠时间正常或延长，但白天仍会出现过度嗜睡。由于疾病个体异质性、临床症状重叠性高、多导睡眠监测结果重复性差及缺乏明确生物标志物，造成诊断与鉴别诊断困难。本文总结IH的诊断标准更新、临床表现、诊断及治疗策略更新，以期能够得到重视，增加临床诊断识别率、减少误诊率及漏诊率。.

OBJECTIVE: Idiopathic hypersomnia (IH) is characterized by excessive sleepiness during the day, prolonged sleep at night, and difficulty waking up. The true prevalence of IH is uncertain. ICSD provides criteria for diagnosing IH; however, the definition has evolved. Managing IH involves using pharmacologic and non-pharmacologic approaches, although the most effective strategies are still unclear. The objective of this scoping review was to identify the extent, range, and nature of the available evidence, identify research gaps, and discuss the implications for clinical practice and policy.
METHODS: To conduct this review, a comprehensive search was conducted across scientific databases, without any restrictions on the date or study type. Eligible studies examined the effectiveness of pharmacologic and non-pharmacologic treatments for IH and reported the outcomes of these interventions. Data from the studies were screened, analyzed, and synthesized to provide an overview of the available literature landscape.
RESULTS: 51 studies were included in this review, which used various methods and interventions. Pharmacological treatments, particularly modafinil, have been frequently studied and have yielded positive results. There is also emerging evidence for alternative medications such as low-sodium oxybate and pitolisant. Non-pharmacological approaches, such as CBT-H and tDCS have also shown promise in managing IH.
CONCLUSIONS: This review highlights the complexity of managing IH management and emphasizes the need for personalized multidisciplinary approaches. Pharmacological interventions are important in managing IH and can be complemented by non-medication strategies. Larger-scale studies are necessary to advance our understanding of IH and to improve treatment outcomes.

Patients with idiopathic hypersomnia frequently report having unrefreshing naps. However, whether they have abnormal sleep architecture during naps that may explain their unrefreshing aspect is unknown. We compared sleep architecture during short daytime naps in patients with idiopathic hypersomnia reporting unrefreshing and refreshing naps. One-hundred and thirty-four patients tested with one-night polysomnography, followed by an adapted version of the Multiple Sleep Latency Test with four naps, were included. They were asked about the refreshing aspect of their habitual naps during a clinical interview. They were classified as having objective (Multiple Sleep Latency Test ≤ 8 min) or subjective idiopathic hypersomnia (Multiple Sleep Latency Test > 8 min), and as presenting refreshing or unrefreshing naps. We tested Group differences (refreshing versus unrefreshing naps) on nap sleep architecture in the whole sample and for subjective and objective idiopathic hypersomnia subgroups separately using ANCOVAs. No Group effects were observed in the Multiple Sleep Latency Test architecture in the whole sample and in objective and subjective idiopathic hypersomnia subgroups. This study provides preliminary evidence that reporting unrefreshing naps is not associated with clinically significant findings in Multiple Sleep Latency Test sleep architecture in patients with idiopathic hypersomnia. Given that naps taken by patients with idiopathic hypersomnia are typically long, future studies should investigate longer daytime sleep episodes.