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Excessive daytime sleepiness (EDS) is frequent among patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and can persist despite the optimal correction of respiratory events (apnea, hypopnea and respiratory efforts), using continuous positive airway pressure (CPAP) or mandibular advancement device. Symptoms like apathy and fatigue may be mistaken for EDS. In addition, EDS has multi-factorial origin, which makes its evaluation complex. The marketing authorization [Autorisation de Mise sur le Marché (AMM)] for two wake-promoting agents (solriamfetol and pitolisant) raises several practical issues for clinicians. This consensus paper presents recommendations of good clinical practice to identify and evaluate EDS in this context, and to manage and follow-up the patients. It was conducted under the mandate of the French Societies for sleep medicine and for pneumology [Société Française de Recherche et de Médecine du Sommeil (SFRMS) and Société de Pneumologie de Langue Française (SPLF)]. A management algorithm is suggested, as well as a list of conditions during which the patient should be referred to a sleep center or a sleep specialist. The benefit/risk balance of a wake-promoting drug in residual EDS in OSAHS patients must be regularly reevaluated, especially in elderly patients with increased cardiovascular and psychiatric disorders risks. This consensus is based on the scientific knowledge at the time of the publication and may be revised according to their evolution., Competing Interests: Declaration of competing interest Pr Andrejak has been a speaker at symposiums for Moderna, Chiesi, AstraZeneca et Insmed, unrelated to this subject. Pr Arnulf was a paid consultant for Idorsia Pharma in 2020 and unpaid for Takeda Pharma in 2022, unrelated to this subject. Dr Baillieul has been paid for work for Jazz Pharmaceuticals; clinical study investigator for Bioprojet; received support from Agiradom, Vitalaire and Bioprojet for participation in a congress. Dr Barateau was a consultant for Bioprojet, Takeda, Idorsia, and Jazz Pharmaceuticals between 2020 and 2022, and a speaker for Bioprojet, Jazz Pharmaceuticals and Idorsia. Dr Bequignon has been a consultant for Air Liquide Santé, GSK, Sanofi, paid talks for Bioprojet, Inspire, GSK, Sanofi, Amplifon. Pr Boutouyrie was a consultant for Bioprojet and Jazz-pharmaceutics in 2021 and 2022, related to this subject. Pr Dauvilliers has been consultant and speaker and has been invited to conferences by UCB Pharma, Jazz, Theranexus, Idorsia, Takeda, Avadel and Bioprojet. Pr Gagnadoux has worked as consultant for Air Liquide Santé, Asten santé, Bioprojet, Inspire, Sefam, Resmed; and as a paid speaker for Bioprojet, Cidelec, Inspire, Jazz Pharmaceuticals, Philips Respironics. Pr Geoffroy has been paid speaker for Biocodex, Bioprojet, Idorsia, Janssen-Cilag, Jazz pharmaceuticals, Lundbeck, MySom- meil, Withings; received fees as expert for Apneal, Biocodex, Dayvia, Idorsia, Janssen-Cilag, Jazz pharmaceuti- cals, Myndblue, Posos, ResilEyes, Withings; and is a member of the advisory boards of: Apneal, Idorsia, Mindblue, Mysommeil. Dr Jaffuel has been involved in clinical trials, scientific work, consulting, conferences, symposiums and other activities over the past 5 years for the following companies and organizations: ALK, AstraZeneca, Bohringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Sanofi; en rapport avec l'article, Adene, Bastide, Bioprojet, Jazz, Löwenstein, LVL, Nomics, Philips Respironics, Resmed, Sefam, Tali. Pr Micoulaud-Franchi has been a consultant for Gilead, Eisai et Bioprojet. Pr Monaca has been speaker for UCB Pharma, Jazz; consultant for Resmed, investigator for Jazz, Bioprojet, Theranexus. Pr Montani and Dr report no conflicts of interest. Dr Patout: research project funding: Fisher & Paykel, Resmed, Asten Santé - Consultant: Resmed, Philips Respironics, Asten Santé, GSK - Paid talks: Philips Respironics, Resmed, Elivie, SOS O2, Chiesi, Asten Santé, Air Liquide Medical Système, Antadir, Jazz Pharmaceutical, Lowenstein - Actions: Kernel Biomedical - Conference support: Asten Santé. Pr Pépin has received research funding from: Air Liquide Foundation, Agiradom, AstraZeneca, Fisher and Paykel, Mutualia, Philips, Resmed and Vitalaire; et a été consultant pour Agiradom, AstraZeneca, Boehringer Ingelheim, Jazz pharmaceutical, Night Balance, Philips, Resmed et Sefam. Pr Philip reports that he has been a consultant for Jazz Phar maceuticals and Bioprojet. Pr Tamisier has received payment for scientific communication from Resmed, Philips, Elivie and Agiradom, support for participating in a congress for Laboratoires Agiradom. RT received financing for research from Fondations Resmed APMC, Resmed, Philips, and Vitalaire, took part in scientific committees for Respicardia, Sorin et Jazz Pharmaceutical, Inspire and Resmed. Pr Trzepizur was invited to scientific congress by Asten and gave a paid talk for AstraZeneca., (Copyright © 2024 SPLF and Elsevier Masson SAS. All rights reserved.)

Many studies suggest a relationship between excessive daytime sleepiness (EDS) and dementia incidence, but the underlying mechanisms remain uncertain. The study aimed to investigate the role of cardiovascular burden in the relationship between EDS and dementia incidence over a 12-year follow-up in community-dwelling older adults. We performed analyses on 6171 subjects (aged ≥65 years) free of dementia and vascular disease at baseline. Participants self-reported EDS at baseline and an expert committee validated both prevalent and incident dementia. We defined cardiovascular burden by a low Cardiovascular Health score, constructed using the American Heart Association metrics, and incident vascular events. To explore the potential role of the cardiovascular burden in the relationship between EDS and dementia, we conducted mediation analyses with inverse odds ratio-weighted estimation, using multivariable-adjusted proportional hazard Cox and logistic regression models. Subjects with EDS had a higher risk of all-cause dementia (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.13-1.69) and dementia with vascular component (DVC) (HR 2.14, 95% CI 1.30-3.51), but not Alzheimer's disease (HR 1.18, 95% CI 0.93-1.51). Cardiovascular burden explained 5% (95% CI 4.1-5.2) and 11% (95% CI 9.7-11.3) of the relationship between EDS and all-cause dementia and DVC, respectively. These findings confirm that EDS may be implicated in the development of dementia and indicate a weaker than expected role of cardiovascular burden in the relationship between EDS and DVC., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

The mechanisms underlying the individual need for sleep are unclear. Sleep duration is indeed influenced by multiple factors, such as genetic background, circadian and homeostatic processes, environmental factors, and sometimes transient disturbances such as infections. In some cases, the need for sleep dramatically and chronically increases, inducing a daily-life disability. This "excessive need for sleep" (ENS) was recently proposed and defined in a European Position Paper as a dimension of the hypersomnolence spectrum, "hypersomnia" being the objectified complaint of ENS. The most severe form of ENS has been described in Idiopathic Hypersomnia, a rare neurological disorder, but this disabling symptom can be also found in other hypersomnolence conditions. Because ENS has been defined recently, it remains a symptom poorly investigated and understood. However, protocols of long-term polysomnography recordings have been reported by expert centers in the last decades and open the way to a better understanding of ENS through a neurophysiological approach. In this narrative review, we will 1) present data related to the physiological and pathological variability of sleep duration and their mechanisms, 2) describe the published long-term polysomnography recording protocols, and 3) describe current neurophysiological tools to study sleep microstructure and discuss perspectives for a better understanding of ENS., Competing Interests: Declaration of competing interest The authors report no financial or non-financial conflicts of interest in this work., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: In people with OSA, excessive daytime sleepiness is a prominent symptom and can persist despite adherence to CPAP, the first-line therapy for OSA. Pitolisant was effective in reducing daytime sleepiness in two 12-week randomized controlled trials (RCTs), one in patients adherent to CPAP (BF2.649 in Patients With OSA and Treated by CPAP But Still Complaining of EDS [HAROSA 1]) and the other in patients refusing or not tolerating CPAP (BF2.649 in Patients With OSA, Still Complaining of EDS and Refusing to be Treated by CPAP [HAROSA 2])., Research Question: Does the efficacy and safety of pitolisant persist when these patients take it long-term?, Study Design and Methods: All adults included in the HAROSA 1 and HAROSA 2 RCTs (both pitolisant and placebo arms) were offered pitolisant (up to 20 mg/d) after completion of the short-term double-anonymized phase (ie, from week 13) in an open-label cohort study. The primary efficacy outcome was the change in Epworth Sleepiness Scale score between baseline and week 52. Safety outcomes were treatment-emergent adverse event(s) (TEAE[s]), serious TEAEs, and special interest TEAEs., Results: Out of 512 adults included in the two RCTs, 376 completed the 1-year follow-up. The pooled mean difference in Epworth Sleepiness Scale score from baseline to 1 year for the intention-to-treat sample was -8.0 (95% CI, -8.3 to -7.5). The overall proportions of TEAEs, serious TEAEs, and TEAEs of special interest were 35.1%, 2.0%, and 11.1%, respectively, without any significant difference between patients in the initial pitolisant and placebo arms. No cardiovascular safety issues were reported., Interpretation: Pitolisant is effective in reducing daytime sleepiness over 1 year in adults with OSA, with or without CPAP treatment. Taken for 1 year, it has a good safety profile (including cardiovascular)., Trial Registration: ClinicalTrials.gov; Nos.: NCT01071876 and NCT01072968; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J.-L. P. reports administrative support and APC from Bioprojet during the conduct of the study; research grants from Agiradom, Air Liquide Foundation, Astra Zeneca, Bioprojet, Jazz Pharmaceuticals, Philips, Resmed, Sefam, and Vitalaire, outside the reported work; and honoraria or consultation fees from Agiradom, Somnomed, Bioprojet, ITAMAR, Jazz Pharmaceuticals, Philips, Resmed, and SEFAM, outside the reported work. C. C. is an employee of Bioprojet. Outside the reported work, J. V. has received institutional fees and educational grants from AirLiquide, AstraZen, Bekaert Deslee Academy, Bioprojet, Desitin, Ectosense, Epilog, Fisher & Paykel, Heinen & Löwenstein, Idorsia, Inspire, Jazz Pharmaceutics, Medidis, Mediq Tefa, OSG, Philips, ResMed, Sefam, SomnoMed, Total Care, UCB Pharma, Vivisol, and Westfalen Medical. Outside the reported work, R. T. reports research grants paid to his institution (Resmed, Inspire, BioProjet); personal lecture fees from Périmetres, Philips, Resmed, Jazz Pharmaceutical, and Bioprojet; and participation in advisory boards of Narval (Resmed), Bioprojet, and Idorsia. I. L. is an employee and shareholder of Bioprojet. Y. D. reports grants from Bioprojet, during the conduct of the study; and grants and/or consulting fees from UCB, JAZZ, Takeda, Theranexus, Harmony bioscience, Avadel, Paladin, and Idorsia, outside the submitted work. P. Lehert was a consultant statistician for Bioprojet during the conduct of the study; and is a consultant statistician for Merck, Sanofi, and Aguettant Pharma, outside the submitted work. None declared (V. A., J. H., and P. Lévy)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sleep disturbances after ischaemic stroke include alterations of sleep architecture, obstructive sleep apnea, restless legs syndrome, daytime sleepiness and insomnia. Our aim was to explore their impacts on functional outcomes at month 3 after stroke, and to assess the benefit of continuous positive airway pressure in patients with severe obstructive sleep apnea. Ninety patients with supra-tentorial ischaemic stroke underwent clinical screening for sleep disorders and polysomnography at day 15 ± 4 after stroke in a multisite study. Patients with severe obstructive apnea (apnea-hypopnea index ≥ 30 per hr) were randomized into two groups: continuous positive airway pressure-treated and sham (1:1 ratio). Functional independence was assessed with the Barthel Index at month 3 after stroke in function of apnea-hypopnea index severity and treatment group. Secondary objectives were disability (modified Rankin score) and National Institute of Health Stroke Scale according to apnea-hypopnea index. Sixty-one patients (71.8 years, 42.6% men) completed the study: 51 (83.6%) had obstructive apnea (21.3% severe apnea), 10 (16.7%) daytime sleepiness, 13 (24.1%) insomnia, 3 (5.7%) depression, and 20 (34.5%) restless legs syndrome. Barthel Index, modified Rankin score and Stroke Scale were similar at baseline and 3 months post-stroke in the different obstructive sleep apnea groups. Changes at 3 months in those three scores were similar in continuous positive airway pressure versus sham-continuous positive airway pressure patients. In patients with worse clinical outcomes at month 3, mean nocturnal oxygen saturation was lower whereas there was no association with apnea-hypopnea index. Poorer outcomes at 3 months were also associated with insomnia, restless legs syndrome, depressive symptoms, and decreased total sleep time and rapid eye movement sleep., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Study Objectives: Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2)., Methods: Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5 g, week 1; 6 g, weeks 2-3; 7.5 g, weeks 4-8; and 9 g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups., Results: The modified intent-to-treat population comprised 190 participants (NT1, n = 145; NT2, n = 45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, p < .001) and NT2 (6 and 9 g, p < .05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, p < .001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (p < .001), nocturnal arousals (p < .05), and ESS scores (p ≤ .001) were reported for NT1 with directional improvements for NT2., Conclusions: Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Study Objectives: To evaluate 6-month efficacy and safety of low-sodium oxybate in people with idiopathic hypersomnia during an open-label extension period (OLE) of a phase 3 clinical trial., Methods: Efficacy measures included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Patient Global Impression of Change (PGIc), Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). Treatment-emergent adverse events were collected throughout the OLE., Results: The OLE population included 106 participants. Most were female (71%) and White (83%), and the mean (SD) age was 41.0 (13.8) years. ESS scores decreased (improved) during the OLE (mean [SD], study baseline: 16.3 [2.8]; OLE week 2: 6.7 [4.7]; OLE end: 5.3 [3.7]), and IHSS total scores trended toward a decrease (study baseline: 32.6 [7.3]; OLE week 2: 16.2 [8.9]; OLE end: 14.8 [8.6]. Median (minimum, maximum) paired differences from OLE week 2 to OLE end were ESS, -1.0 (-20, 7; nominal P = .012); IHSS, -1.0 (-31, 19; nominal P = .086). The proportion of participants reporting PGIc ratings of "very much improved" increased from 36.7% at OLE week 2 to 53.8% at the OLE end. The FOSQ-10 and WPAI:SHP scores remained stable during OLE. The incidence of newly reported treatment-emergent adverse events decreased over the duration of the OLE., Conclusions: Efficacy and safety of low-sodium oxybate were maintained or improved during the 6-month OLE, supporting long-term treatment with low-sodium oxybate in adults with idiopathic hypersomnia., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) With an Open-label Safety Extension; URL: https://clinicaltrials.gov/study/NCT03533114; Identifier: NCT03533114 and Registry: EU Clinical Trials; Name: A Double-blind, Placebo-controlled, Randomized Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) with an Open-label Safety Extension; URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-001311-79/results; Identifier: 2018-001311-79., Citation: Morse AM, Dauvilliers Y, Arnulf I, et al. Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia. J Clin Sleep Med . 2023;19(10):1811-1822., (© 2023 American Academy of Sleep Medicine.)

Background: The COVID-19 pandemic and related restriction measures have affected our daily life, sleep, and circadian rhythms worldwide. Their effects on hypersomnolence and fatigue remain unclear., Methods: The International COVID-19 Sleep Study questionnaire which included items on hypersomnolence such as excessive daytime sleepiness (EDS), and excessive quantity of sleep (EQS), as well as sociodemographic factors, sleep patterns, psychological symptoms, and quality of life was distributed in 15 countries across the world from May to September in 2020., Results: Altogether responses from 18,785 survey participants (65% women, median age 39 years) were available for analysis. Only 2.8% reported having had COVID-19. Compared to before the pandemic, the prevalence of EDS, EQS, and fatigue increased from 17.9% to 25.5%, 1.6%-4.9%, and 19.4%-28.3% amid the pandemic, respectively. In univariate logistic regression models, reports of having a COVID-19 were associated with EQS (OR 5.3; 95%-CI 3.6-8.0), EDS (2.6; 2.0-3.4), and fatigue (2.8; 2.1-3.6). In adjusted multivariate logistic regression, sleep duration shorter than desired (3.9; 3.2-4.7), depressive symptoms (3.1; 2.7-3.5), use of hypnotics (2.3; 1.9-2.8), and having reported COVID-19 (1.9; 1.3-2.6) remained strong predictors of EDS. Similar associations emerged for fatigue. In the multivariate model, depressive symptoms (4.1; 3.6-4.6) and reports of having COVID-19 (2.0; 1.4-2.8) remained associated with EQS., Conclusions: A large increase in EDS, EQS, and fatigue occurred due to the COVID-19 pandemic, and especially in self-reported cases of COVID-19. These findings warrant a thorough understanding of their pathophysiology to target prevention and treatment strategies for long COVID condition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Idiopathic hypersomnia is a central hypersomnolence disorder of unknown origin characterized by excessive daytime sleepiness despite normal or long sleep time, and frequent severe sleep inertia. Management strategies have been largely derived from expert consensus, due to a lack of disease-specific assessments and reliance on case series and rare randomized controlled studies. Guidelines recommend treatment with off-label medications. Modafinil, which was approved for idiopathic hypersomnia until 2011 in Europe, is the most commonly used treatment and improved sleepiness in two recent randomized placebo-controlled trials. In 2021, low-sodium oxybate (LXB) was approved in the United States for idiopathic hypersomnia. In a placebo-controlled, double-blind, randomized withdrawal study, LXB reduced daytime sleepiness and sleep inertia, and improved daily functioning. Here, treatment options are reviewed considering the authors' professional experience, current guidelines, and the latest research developments. The choice of pharmacotherapy should be guided by symptom profile, age, comorbidities (eg, depressive symptoms, cardiovascular problems), and concomitant medications (eg, oral contraceptives). Nonpharmacologic approaches have a role in management. An instrument (idiopathic hypersomnia severity scale) has been validated in idiopathic hypersomnia specifically, opening a path to better assessment of symptoms, impact, and response to treatment. Continued research on idiopathic hypersomnia is needed to support treatment algorithms., Competing Interests: Declaration of competing interest Isabelle Arnulf has participated in advisory boards for UCB Pharma, Idorsia (2020), Ono Pharma (2019), and Roche Pharma (2019). Robert Thomas has patents and licenses for ECG-spectrogram, licensed to MyCardio, LLC through the Beth Israel Deaconess Medical Center, and for auto-CPAP algorithm, licensed by BIDMC to DeVilbiss-Drive; holds an unlicensed patent for a CO(2) device for central/complex sleep apnea; is a general sleep medicine consultant for GLG Councils and Guidepoint Global; and is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals. Asim Roy has received consultancy fees from Jazz Pharmaceuticals and Harmony Biosciences. Yves Dauvilliers is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, UCB Pharma, Avadel, Idorsia, Takeda, Harmony Biosciences, and Bioprojet., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Narcolepsy is a life-long disorder characterised by excessive daytime sleepiness and cataplexy, often arising in childhood or adolescence. Pitolisant, a selective histamine H3 receptor inverse agonist, has been approved in Europe and USA for adults with narcolepsy with or without cataplexy, with a favourable safety profile. This phase 3 study aimed to assess the safety and efficacy of pitolisant in children with narcolepsy with or without cataplexy., Methods: For this double-blind, randomised, placebo-controlled, multisite study, we recruited patients aged 6-17 years with narcolepsy with or without cataplexy in 11 sleep centres in five countries (Italy, France, Netherlands, Russia, and Finland). Participants were required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and to have not received psychostimulants for at least 14 days before enrolment; participants who needed anticataplectics (including sodium oxybate) were required to have been on a stable dose for at least 1 month. Participants were randomly assigned to treatment with pitolisant or placebo in a 2:1 ratio at the end of screening. Randomisation was stratified by study centre and treatment was allocated using an interactive web response system. After a 4-week screening period including a 2-week baseline period, patients entered in a 4-week individual up-titration scheme from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo; treatment was administered at a stable dose for 4 weeks, followed by a 1-week placebo period. For the primary analysis, we assessed pitolisant versus placebo using change in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of double-blind period in the full analysis set, defined as all randomly allocated patients who received at least one dose of treatment and who had at least one baseline UNS value. A decrease in the UNS total score reflects a reduction in both excessive daytime sleepiness and cataplexy. All adverse events were assessed in the safety population, defined as all participants who took at least one dose of study medication. An open-label follow-up is ongoing. This study is registered at ClinicalTrials.gov, NCT02611687., Findings: Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned (mean age 12·9 [SD 3·0] years, 61 [55%] male, and 90 [82%] with cataplexy; 72 assigned to pitolisant and 38 to placebo); 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. The mean adjusted difference in UNS total score from baseline to the end of the double-blind period was -6·3 (SE 1·1) in the pitolisant group and -2·6 (1·4) in the placebo group (least squares mean difference -3·7; 95% CI -6·4 to -1·0, p=0·007). Treatment-emergent adverse events were reported in 22 (31%) of 72 patients in the pitolisant group and 13 (34%) of 38 patients in the placebo group. The most frequently reported adverse events (affecting ≥5% of patients) in either group were headache (14 [19%] in the pitolisant group and three [8%] in the placebo group) and insomnia (five [7%] in the pitolisant group and one [3%] in the placebo group)., Interpretation: Pitolisant treatment resulted in an improvement in narcolepsy symptoms in children, although the UNS was not validated for use in children with narcolepsy when our study began. The safety profile was similar to that reported in adults but further studies are needed to confirm long-term safety., Funding: Bioprojet., Competing Interests: Declaration of interests YD reports grant and consultancy fees from Bioprojet, Idorsia, Avadel, Harmony Biosciences, Takeda, and Jazz Pharmaceuticals, during the conduct of the trials. GP reports grant and consultancy fees from Bioprojet, Idorsia, Takeda, Orexia, Fidia, and Jazz Pharmaceuticals. PF reports grant and consultancy fees from Bioprojet and Jazz Pharmaceuticals. ML reports consultancy fees from Bioprojet, and Jazz Pharmaceuticals. GJL reports grant and consultancy fees from Bioprojet and Jazz Pharmaceuticals. IJ, CC, JML, and JCS are employees of Bioprojet. MP and PL declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Central disorders of hypersomnolence include narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia and hypersomnia associated with medical or mental disorders. Treatment is both non-pharmacological and pharmacological, including wake enhancing drugs and stimulants. One of the first-line treatment (modafinil, MODIODAL®) was the subject of a health authority alert in 2019 concerning a risk of major congenital malformations when taken during organogenesis. Since this date, three epidemiological studies have presented contradictory results. Given their methodological weaknesses, it is not possible at this stage to confirm or deny such a risk for the embryo and its nature if there is one. In clinical practice, because of these uncertainties, it is preferable if possible to suspend the treatment of a pregnant woman during the first 10 weeks from last menstrual period (organogenesis). There is an unmet clinical need for research to clarify the potential teratogenic impact of modafinil., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Many people report suffering from post-acute sequelae of COVID-19 or "long-COVID", but there are still open questions on what actually constitutes long-COVID and how prevalent it is. The current definition of post-acute sequelae of COVID-19 is based on voting using the Delphi-method by the WHO post-COVID-19 working group. It emphasizes long-lasting fatigue, shortness of breath and cognitive dysfunction as the core symptoms of post-acute sequelae of COVID-19. In this international survey study consisting of 13,628 subjects aged 18-99 years from 16 countries of Asia, Europe, North America and South America (May-Dec 2021), we show that post-acute sequelae of COVID-19 symptoms were more prevalent amongst the more severe COVID-19 cases, i.e. those requiring hospitalisation for COVID-19. We also found that long-lasting sleep symptoms are at the core of post-acute sequelae of COVID-19 and associate with the COVID-19 severity when COVID-19 cases are compared with COVID-negative cases. Specifically, fatigue (61.3%), insomnia symptoms (49.6%) and excessive daytime sleepiness (35.8%) were highly prevalent amongst respondents reporting long-lasting symptoms after hospitalisation for COVID-19. Understanding the importance of sleep-related symptoms in post-acute sequelae of COVID-19 has a clinical relevance when diagnosing and treating long-COVID., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Sleepiness involves many dimensions that require investigation. Since sleepiness is often defined operationally, we exhaustively inventoried all the assessment tools designed to measure it in an umbrella review, without any preconceptions, i.e. a review of reviews. We included all reviews and systematic reviews related to sleepiness assessment tools published up to March 2021. Three investigators independently assessed the eligibility of studies for inclusion and identified 36 relevant reviews. In total, 99 tools were identified and classified into 8 categories. We classified them depending on their category, their publication year and the number of mentions in the 36 included reviews. The 6 most frequently cited were the Epworth sleepiness scale, the multiple sleep latency test, the maintenance of wakefulness test, the Stanford sleepiness scale, the Karolinska sleepiness scale, and the psychomotor vigilance task. Despite the limitation that we may have missed some recently developed tools, this historical perspective on sleepiness measurement is a first step toward a better delineation of the different dimensions underlying the constructs of sleepiness, and will serve as a basis for further discussion in the clinical and research sleep community., Competing Interests: Declaration of competing interest The author reports no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Study Objectives: To assess the performances of alternative measures of the multiple sleep latency test (MSLT) to identify hypocretin-deficiency in patients with a complaint of hypersomnolence, including patients with narcolepsy., Methods: MSLT parameters from 374 drug-free patients with hypersomnolence, with complete clinical and polysomnographic (PSG) assessment and cerebrospinal hypocretin-1 measurement were collected. Conventional (sleep latency, number of sleep onset REM-SOREM-periods) and alternative (sleep duration, REM sleep latency and duration, sleep stage transitions) MSLT measures were compared as function of hypocretin-1 levels (≤110 vs > 110 pg/mL). We performed receiver-operating characteristics analyses to determine the best thresholds of MSLT parameters to identify hypocretin-deficiency in the global population and in subgroups of patients with narcolepsy (i.e. typical cataplexy and/or positive PSG/MSLT criteria, n = 223)., Results: Patients with hypocretin-deficiency had shorter mean sleep and REM sleep latencies, longer mean sleep and REM sleep durations and more direct REM sleep transitions during the MSLT. The current standards of MSLT/PSG criteria identified hypocretin-deficient patients with a sensitivity of 0.87 and a specificity of 0.69, and 0.81/0.99 when combined with cataplexy. A mean REM sleep duration ≥ 4.1 min best identified hypocretin-deficiency in patients with hypersomnolence (AUC = 0.932, sensitivity 0.87, specificity 0.86) and ≥ 5.7 min in patients with narcolepsy (AUC = 0.832, sensitivity 0.77, specificity 0.82)., Conclusion: Compared to the current neurophysiological standard criteria, alternative MSLT parameters would better identify hypocretin-deficiency among patients with hypersomnolence and those with narcolepsy. We highlighted daytime REM sleep duration as a relevant neurophysiological biomarker of hypocretin-deficiency to be used in clinical and research settings., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: To explore the first coronavirus disease 2019 (COVID-19) lockdown effect on sleep symptoms in patients with narcolepsy, idiopathic hypersomnia (IH), and restless legs syndrome (RLS)., Methods: Between March and May 2020, a sample of adult patients regularly followed up in a Reference Hospital Sleep Unit (299 with narcolepsy, 260 with IH, and 254 with RLS) was offered an online survey assessing their sleep-wake habits, daily activities, medication intake, and validated scales: International RLS Study Group questionnaire, Narcolepsy Severity Scale (NSS), IH Severity Scale (IHSS), Epworth Sleepiness Scale (ESS), Insomnia Severity Index, Beck Depression Inventory-II, and European Quality of Life (QoL) scale. The survey was proposed once, and the questions were answered for the prelockdown (recall of the month before the confinement) and the lockdown (time of study) periods., Results: Overall, 331 patients completed the survey (response rate 40.7%): 102 with narcolepsy, 81 with IH, and 148 with RLS. All patients reported later bedtimes, with reduced differences for time in bed (TIB) and total sleep time (TST) over 24 hours between weekdays and weekends. Patients with narcolepsy spent more TIB and increased TST overnight, with more daytime napping. They had more awakenings, higher ESS scores, lower QoL, and no NSS changes. Patients with IH also increased their TIB, TST overnight and 24 hours on weekdays. Nocturnal sleep latency and the number of awakenings increased but with no change in ESS, QoL, and IHSS scores. Patients with RLS reported longer nocturnal sleep latency, more awakenings, more naps, decreased TIB, and TST overnight. RLS severity increased while QoL decreased. A significant portion of patients reported disease worsening during the lockdown (narcolepsy: 39.4%, IH: 43.6%, and RLS: 32.8%), and some patients stopped or lowered their medication (narcolepsy: 22.5%, IH: 28%, and RLS: 9.5%)., Discussion: During the lockdown, all patients reported later bedtimes; those with narcolepsy and IH extended their sleep duration unlike patients with RLS. These changes were often associated with negative consequences on QoL. In the current context of recurrent COVID-19 waves, the recent development of teleconsultations should enable physicians to monitor patients with chronic sleep disorders more closely and to recommend optimized sleep schedules and duration, in order to prevent psychological problems and improve their QoL., (© 2022 American Academy of Neurology.)

Excessive daytime sleepiness (EDS) is a public health issue. However, it remains largely undervalued, scarcely diagnosed, and poorly supported. Variations in the definition of EDS and limitations in clinical assessment lead to difficulties in its epidemiological study, but the relevance of this symptom from a socioeconomic perspective is inarguable. EDS might be a consequence of several behavioural issues leading to insufficient or disrupted sleep, as well as a consequence of sleep disorders including sleep apnoea syndrome, circadian disorders, central hypersomnolence disorders (narcolepsy and idiopathic hypersomnia), other medical or psychiatric conditions, or medications. Furthermore, EDS can have implications for health as it is thought to act as a risk factor for other conditions, such as cardiovascular and neurodegenerative disorders. Because of the heterogeneous causes of EDS and the complexity of its pathophysiology, management will largely depend on the cause, with the final aim of making treatment specific to the individual using precision medicine and personalised medicine., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Study Objectives: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls., Methods: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs., Results: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 × 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.0006) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases., Conclusions: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Recent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed, and the question arises of whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see whether data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers., Methods: We used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups., Results: We included 1,078 unmedicated adolescents and adults. Seven clusters were identified, of which 4 clusters included predominantly individuals with cataplexy. The 2 most distinct clusters consisted of 158 and 157 patients, were dominated by those without cataplexy, and among other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening, and weekend-week sleep length difference. Patients formally diagnosed as having narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these 2 clusters., Discussion: Using a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of sleep-onset REM periods in diagnostic criteria for people without cataplexy and provide promising new variables for reliable diagnostic categories that better resemble different patient phenotypes. Cluster-guided classification will result in a more solid hypersomnolence classification system that is less vulnerable to instability of single features., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Lower-sodium oxybate (LXB) is an oxybate medication with the same active moiety as sodium oxybate (SXB) and a unique composition of cations, resulting in 92% less sodium. LXB was shown to improve cataplexy and excessive daytime sleepiness in people with narcolepsy in a placebo-controlled, double-blind, randomized withdrawal study (NCT03030599). Additional analyses of data from this study were conducted to explore the effects of LXB on cataplexy, including the clinical course and feasibility of transition from other anticataplectics to LXB monotherapy., Objective: The aim of these analyses was to evaluate cataplexy frequency during initiation/optimization of LXB and taper/discontinuation of prior antidepressant/anticataplectic medications., Methods: Eligible participants (adults aged 18-70 years with narcolepsy with cataplexy) entered the study taking SXB only (group A), SXB + other anticataplectics (group B), or anticataplectic medication other than SXB (group C), or were cataplexy-treatment naive (group D). LXB was initiated/optimized during a 12-week, open-label, optimized treatment and titration period (OLOTTP). Other anticataplectics were tapered/discontinued during weeks 3-10 of OLOTTP. A 2-week stable-dose period (SDP; during which participants took a stable dose of open-label LXB) and 2-week double-blind randomized withdrawal period (during which participants were randomized to continue LXB treatment or switch to placebo) followed OLOTTP. Treatment-emergent adverse events (TEAEs) were recorded throughout the duration of the study., Results: At the beginning of OLOTTP, median weekly cataplexy attacks were lower in participants taking SXB at study entry (SXB only [2.00]; SXB + other anticataplectics [0.58]) versus participants who were taking other anticataplectics (3.50) or were anticataplectic naive (5.83). Median weekly cataplexy attacks decreased during weeks 1-2 of OLOTTP in all groups. Increased cataplexy frequency was observed in participants tapering/discontinuing other anticataplectics during weeks 3-10 and was more prominent in participants taking other anticataplectics alone compared with those taking SXB plus other anticataplectics. Cataplexy frequency decreased throughout initiation/optimization in anticataplectic-naive participants. Median number of cataplexy-free days/week at the end of SDP (study week 14) was similar in all groups (6.0, 6.1, 6.0, and 6.2 in groups A, B, C, and D, respectively). During OLOTTP and SDP, TEAEs of worsening cataplexy were reported in 0%, 47.8%, 16.7%, and 2.2% of participants in groups A, B, C, and D, respectively; most TEAEs of worsening cataplexy were reported during tapering/discontinuation of other anticataplectics., Conclusions: LXB monotherapy was effective in reducing cataplexy and increasing cataplexy-free days. These results illustrate the feasibility of switching from SXB to LXB while tapering/discontinuing other anticataplectics., Trial Registration: A Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy; https://clinicaltrials.gov/ct2/show/NCT03030599 ; clinicaltrials.gov identifier: NCT03030599., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Study Objectives: To assess the frequency, determinants, and clinical impact of clinical rapid eye movement (REM) and non-REM (NREM) parasomnias in adult patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia compared with healthy controls., Methods: Familial and past and current personal parasomnias were assessed by questionnaire and medical interviews in 710 patients (220 NT1, 199 NT2, and 221 idiopathic hypersomnia) and 595 healthy controls., Results: Except for sleep-related eating disorder, current NREM parasomnias were rare in all patient groups and controls. Sleep-related eating disorder was more frequent in NT1 patients (7.9% vs 1.8% in NT2 patients, 2.1% in patients with idiopathic hypersomnia, and 1% in controls) and associated with disrupted nighttime sleep (odds ratio = 3.9) and nocturnal eating in full awareness (odds ratio = 6.9) but not with sex. Clinical REM sleep behavior disorder was more frequent in NT1 patients (41.4%, half being violent) than in NT2 patients (13.2%) and affected men more often than women (odds ratio = 2.4). It was associated with disrupted nighttime sleep, depressive symptoms, and antidepressant use. Frequent (> 1/week) nightmares were reported by 39% of patients with NT1, 29% with NT2, and 27.8% with idiopathic hypersomnia (vs 8.3% in controls) and were associated with depressive symptoms in narcolepsy. No parasomnia (except sleep-related hallucinations) worsened daytime sleepiness., Conclusions: In patients with central disorders of hypersomnolence, comorbid NREM parasomnias (except for sleep-related eating disorder) are rare and do not worsen sleepiness. In contrast, REM parasomnias are prevalent (especially in NT1) and are associated with male sex, disrupted nighttime sleep, depressive symptoms, and antidepressant use., Citation: Leu-Semenescu S, Maranci J-B, Lopez R, et al. Comorbid parasomnias in narcolepsy and idiopathic hypersomnia: more REM than NREM parasomnias. J Clin Sleep Med . 2022;18(5):1355-1364., (© 2022 American Academy of Sleep Medicine.)

Daytime sleepiness and fatigue are prominent symptoms of myotonic dystrophy type 1 (DM1) that can be amenable to treatment in the context of randomized controlled trials. No study has yet documented whether self-reported measures of daytime sleepiness and fatigue can detect change over time and the meaning of this change. The aim was to explore indicators of responsiveness to change and interpretability for the Daytime Sleepiness Scale and the Fatigue Severity Scale in 115 DM1 prospectively followed patients. Results suggest that these two self-reported questionnaires are sufficiently sensitive to detect changes beyond expected measurement error over time in this population.

Study Objectives: To assess the responsiveness of the Idiopathic Hypersomnia Severity Scale (IHSS) to medications and estimate the minimum clinically important difference, to report clinically relevant score ranges, and to confirm its psychometric properties and whether items need to be weighted in drug-free and treated patients with idiopathic hypersomnia (IH)., Methods: Two-hundred twenty-six (166 drug-free and 60 treated) patients with IH (cross-sectional sample) completed the 14-item IHSS to quantify the severity of the 3 major IH symptoms (excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia) and consequences; 77 untreated patients were evaluated again after treatment (longitudinal sample). Patients filled in the Epworth Sleepiness Scale, Beck Depression Inventory II, and European Quality of Life questionnaires., Results: The IHSS confirmed adequate psychometric properties with a factor analysis indicating a 3-component solution. IHSS total score was lower in treated than untreated patients, with a mean difference of 4-5 points in the cross-sectional and longitudinal samples. Distribution-based methods were used to estimate that 4 points represented the minimum clinically important difference. Four severity levels were defined with between-group differences related to treatment. The probability of having severe sleepiness, depressive symptoms, and low quality of life increased with the severity level. Our results showed that IHSS item-weighting was not necessary., Conclusions: The IHSS is a valid and reliable tool to quantify IH symptoms, with 4 severity score levels of clinical importance. The IHSS has adequate psychometric properties and can detect symptom changes after treatment. These findings should stimulate its use in clinical settings and in research studies., Citation: Rassu AL, Evangelista E, Barateau L, et al. Idiopathic Hypersomnia Severity Scale to better quantify symptoms severity and their consequences in idiopathic hypersomnia. J Clin Sleep Med . 2022;18(2):617-629., (© 2022 American Academy of Sleep Medicine.)

Background: Excessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide., Objective: The aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS., Methods: The method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score., Results: Both doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: -1.4 [-2.49; -0.31], P = 0.012) but did not change significantly with the 200/18 dosage., Conclusions: THN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Sleep disturbances are common in elderly and occur frequently in dementia. The impact of excessive daytime sleepiness (EDS), insomnia complaints, sleep quality, and hypnotics on the risk of all-cause dementia, Alzheimer disease (AD), and dementia with vascular component (DVC) remains unclear, as does the association between sleep profile and plasma β-amyloid levels., Methods: Analyses were carried out on 6851 participants aged 65 years and over randomly recruited from three French cities and free of dementia at baseline. A structured interview and self-questionnaire assessed sleep complaints (EDS, insomnia complaints, sleep quality) and medications at baseline. Incident cases of dementia were diagnosed systematically over a 12-year period. Multivariate Cox models were used to estimate the risk of dementia associated with the sleep complaints considered individually and globally. Plasma β-amyloid levels were measured by an xMAP-based assay technology in 984 subjects., Results: After adjustment for socio-demographic characteristics, lifestyle, APOE-ε4, cardiovascular factors, and depressive status, EDS had a higher risk of all-cause dementia (HR = 1.21; 95%CI = [1.01-1.46]) and DVC (HR = 1.58; 95%CI = [1.07-2.32]) but not AD. Persistent use of hypnotics increased the risk for all-cause dementia, specifically AD (HR = 1.28; 95%CI = [1.04-1.58]), but not DVC. No association was found for insomnia complaints and sleep quality taken as individual factors or combined with EDS on the risk of dementia. No association was found between β-amyloid, sleep complaints, and incident dementia., Conclusions: The results suggest a deleterious role of EDS and hypnotics on dementia. Further studies are required to elucidate the mechanisms involved in these associations and whether its management can prevent the risk of dementia., (© 2022. The Author(s).)

Study Objectives: Sleep inertia is a frequent and disabling symptom in idiopathic hypersomnia (IH), but poorly defined and without objective measures. The study objective was to determine whether the psychomotor vigilance task (PVT) can reliably measure sleep inertia in patients with IH or other sleep disorders (non-IH)., Methods: A total of 62 (51 women, mean age: 27.7 ± 9.2) patients with IH and 140 (71 women, age: 33.3 ± 12.1) with non-IH (narcolepsy = 29, non-specified hypersomnolence [NSH] = 47, obstructive sleep apnea = 39, insomnia = 25) were included. Sleep inertia and sleep drunkenness in the last month (M-sleep inertia) and on PVT day (D-sleep inertia) were assessed with three items of the Idiopathic Hypersomnia Severity Scale (IHSS), in drug-free conditions. The PVT was performed four times (07:00 pm, 07:00 am, 07:30 am, and 11:00 am) and three metrics were used: lapses, mean 1/reaction time (RT), and slowest 10% 1/RT., Results: Sleep inertia was more frequent in patients with IH than non-IH (56.5% and 43.6% with severe sleep inertia in the past month, including 24% and 12% with sleep drunkenness). Lapse number increase and slowest 10% 1/RT decrease, particularly at 07:00 am and 07:30 am, were proportional with M-sleep inertia severity, but regardless of sleep drunkenness and sleep disorders. Similar results were obtained when PVT results were compared in patients with/without D-sleep inertia, with the largest increase of the lapse number at 07:00 am and 07:30 am associated with severe sleep inertia and sleep drunkenness., Conclusions: PVT is a reliable and objective measure of sleep inertia that might be useful for its characterization, management, and follow-up in patients with IH., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Idiopathic hypersomnia is a central hypersomnolence disorder mainly characterised by excessive daytime sleepiness, with prolonged night-time sleep and pronounced sleep inertia. Until August, 2021, no medication had regulatory approval for the treatment of idiopathic hypersomnia. This study aimed to evaluate the safety and efficacy of lower-sodium oxybate in idiopathic hypersomnia., Methods: This was a phase 3, multicentre (50 specialist sleep centres; six EU countries and the USA), placebo-controlled, double-blind, randomised withdrawal study. Participants (aged 18-75 years) with idiopathic hypersomnia (meeting criteria from the International Classification of Sleep Disorders, 2nd or 3rd editions) began lower-sodium oxybate treatment (oral solution once or twice nightly) in an open-label titration and optimisation period (10-14 weeks), followed by a 2-week, open-label, stable-dose period. After these open-label periods, participants were randomised (1:1) by means of an interactive web recognition system, stratified by participants' baseline medication use, to either placebo or lower-sodium oxybate (individually optimised dose; range 2·5-9·0 g/night) during a 2-week, double-blind, randomised withdrawal period. To maintain masking of treatment assignment, placebo and lower-sodium oxybate oral solutions were matched in volume, appearance, and taste. During the double-blind, randomised withdrawal period, participants and investigators were unaware of treatment assignments. The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score from the end of the stable-dose period to the end of the double-blind, randomised withdrawal period, which was assessed in the modified intention-to-treat population (defined as all participants who were randomly assigned, took at least one dose of study medication during the double blind, randomised withdrawal period, and had at least one set of post-randomisation assessments for the primary or key secondary endpoints). Adverse events were assessed in the safety population (defined as all participants who took at least one dose of study medication). This study is registered at ClinicalTrials.gov, NCT03533114, and at EU Clinical Trials, 2018-001311-79, and is complete., Findings: Between Nov 27, 2018, and March 6, 2020, 154 participants were enrolled and comprised the safety population. ESS scores decreased from a mean of 15·7 (SD 3·8) at baseline to 6·1 (4·0) by the end of the stable-dose period. After the open-label periods, 115 participants were randomly assigned either placebo (n=59) or lower-sodium oxybate (n=56) and comprised the modified intention-to-treat population. During the double-blind, randomised withdrawal period, ESS scores increased (worsened) in participants randomly assigned to placebo but remained stable in those assigned to lower-sodium oxybate (least squares mean difference -6·5; 95% CI -8·0 to -5·0; p<0·0001). Treatment-emergent adverse events included nausea (34 [22%] of 154), headache (27 [18%] of 154), dizziness (19 [12%] of 154), anxiety (17 [11%] 154), and vomiting (17 [11%] 154). No deaths were reported during the study., Interpretation: Lower-sodium oxybate treatment resulted in a clinically meaningful improvement in idiopathic hypersomnia symptoms, with an overall safety profile consistent with that reported for narcolepsy. Lower-sodium oxybate was approved in August, 2021, by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults., Funding: Jazz Pharmaceuticals., Competing Interests: Declaration of interests YD is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, UCB Pharma, Avadel, Idorsia, Takeda, Theranexus, and Bioprojet. IA has participated in an advisory board for Idorsia. NF-S has received research grants or contracts from Jazz Pharmaceuticals, Suven, and Takeda; served on an advisory committee for Jazz Pharmaceuticals; received support for attending meetings or travel from Jazz Pharmaceuticals; and participated in clinical trials supported by Jazz Pharmaceuticals, Suven, and Takeda. AMM has received research funding from the National Institutes of Health, Geisinger Health Plan, and the Klarman Foundation; has been a site investigator for Avadel Pharmaceuticals and Jazz Pharmaceuticals; has served on an advisory board/speakers bureau for Jazz Pharmaceuticals; has received payment or honoraria from Harmony Biosciences; and has served on an AASM public advocacy committee. KŠ has served on the speakers’ bureau for Sanofi, Angelini, and Stada and as a consultant for AOP Orphan; participated in advisory boards for UCB and in clinical trials for Jazz Pharmaceuticals, Flamel-Avadel, and Luitpold Pharmaceuticals; and received funding from the Ministry of Health, Czech Republic, and the Michael J Fox Foundation. MJT has received research or grant support and consultancy fees from Jazz Pharmaceuticals, Harmony Biosciences, Balance Therapeutics, Axsome Therapeutics, and Avadel Pharmaceuticals; and has participated in data safety monitoring or advisory boards for Axsome, Balance Therapeutics, Eisai Pharmaceuticals, Flamel–Avadel, Harmony Biosciences, LLC, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, Takeda Pharmaceutical, and XW Pharma. EM has received research support from Apple, Jazz Pharmaceuticals, Merck, Takeda, and Huami; is a consultant for Dreem, Alerion, Orexia, and Inexia; and is on the speakers’ bureau for Vox Media. PC, AS, and FS are full-time employees of Jazz Pharmaceuticals who, in the course of this employment, have received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals. RP and DC are former full-time employees of Jazz Pharmaceuticals who, in the course of this employment, received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals. JB is a part-time employee of Jazz Pharmaceuticals and shareholder of Jazz Pharmaceuticals. RKB has served on the speakers’ bureau and participated in advisory boards for Jazz Pharmaceuticals; has received consulting fees from Jazz Pharmaceuticals and Harmony Biosciences; and has received payment or honoraria from Eisai., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Study Objectives: This post hoc analysis characterized the weekly incidence and overall duration of common early-onset, treatment-emergent adverse events (TEAEs) during solriamfetol treatment., Methods: Participants (obstructive sleep apnea [OSA], n = 474; narcolepsy, n = 236) were randomized to 12 weeks of placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg. For common early-onset TEAEs (those occurring in ≥ 5% of participants in any solriamfetol dose group and with a higher incidence than that observed in placebo-treated participants during week 1), the incidence of new occurrence or change in severity over time was calculated for each subsequent study week. Data were analyzed separately for each study and summarized by placebo and combined solriamfetol groups., Results: Common early-onset TEAEs (at doses ≤ 150 mg; ie, approved doses) included headache (OSA, 5.1%; narcolepsy, 8.5%), nausea (OSA, 2.5%; narcolepsy, 4.2%), decreased appetite (OSA, 4.2%; narcolepsy, 5.9%), as well as anxiety (2.1%), insomnia (1.3%), and feeling jittery (3.0%) in OSA and dry mouth (4.2%) in narcolepsy. Incidence of common early-onset TEAEs was highest at week 1 and decreased over time. In OSA at doses ≤ 150 mg, headache, nausea, and feeling jittery had median durations ≤ 8 days, whereas decreased appetite, anxiety, and insomnia had longer durations. In narcolepsy at doses ≤ 150 mg, headache and nausea had median durations ≤ 8 days, whereas decreased appetite and dry mouth had longer durations. Most TEAEs were mild to moderate in severity., Conclusions: Common early-onset TEAEs with solriamfetol are limited in duration, with the majority subsiding during the first week of treatment., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in Narcolepsy; URL: https://clinicaltrials.gov/ct2/show/NCT02348593; Identifier: NCT02348593; and Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in OSA; URL: https://clinicaltrials.gov/ct2/show/NCT02348606; Identifier: NCT02348606., Citation: Rosenberg R, Thorpy MJ, Dauvilliers Y, et al. Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy. J Clin Sleep Med . 2022;18(1):235-244., (© 2022 American Academy of Sleep Medicine.)

Study Objectives: To determine whether the feeling of having slept or not during the Maintenance of Wakefulness Test (MWT) is associated with the occurrence of self-reported sleep-related traffic near misses and accidents in patients with sleep disorders., Methods: This study was conducted in patients hospitalized in a French sleep center to perform a 4 × 40 min MWT. Relationship between mean sleep latency on the MWT, feeling of having slept or not during MWT trials and sleep-related near misses and accidents reported during the past year was analyzed., Results: One hundred and ninety-two patients suffering from OSAS, idiopathic hypersomnia, narcolepsy, restless leg syndrome or insufficient sleep syndrome were included. One hundred and sixty-five patients presented no or one misjudgment of feeling of having slept during MWT trials while 27 presented more than two misjudgments. Almost half of the latter (48.1%) reported a sleepiness-related traffic near miss or accident in the past year versus only one third (27.9%) for the former (p < 0.05). Multivariate logistic regression showed that patients with more than two misjudgments had a 2.52-fold (95% CI, 1.07-5.95, p < 0.05) increase in the risk of reporting a sleepiness-related near miss/accident., Conclusions: Misjudgment in self-perceived sleep during the MWT is associated with the occurrence of self-reported sleepiness-related traffic near misses and accidents in the past year in patients suffering from sleep disorders. Asking about the perception of the occurrence of sleep during the MWT could be used to improve driving risk assessment in addition to sleep latencies., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Narcolepsy type 1 (NT1) is a lifelong disorder of sleep-wake dysregulation defined by clinical symptoms, neurophysiological findings, and low hypocretin levels. Besides a role in sleep, hypocretins are also involved in regulation of heart rate and blood pressure. This literature review examines data on the autonomic effects of hypocretin deficiency and evidence about how narcolepsy is associated with multiple cardiovascular risk factors and comorbidities, including cardiovascular disease. An important impact in NT1 is lack of nocturnal blood pressure dipping, which has been associated with mortality in the general population. Hypertension is also prevalent in NT1. Furthermore, disrupted nighttime sleep and excessive daytime sleepiness, which are characteristic of narcolepsy, may increase cardiovascular risk. Patients with narcolepsy also often present with other comorbidities (eg, obesity, diabetes, depression, other sleep disorders) that may contribute to increased cardiovascular risk. Management of multimorbidity in patients with narcolepsy should include regular assessment of cardiovascular health (including ambulatory blood pressure monitoring), mitigation of cardiovascular risk factors (eg, cessation of smoking and other lifestyle changes, sleep hygiene, and pharmacotherapy), and prescription of a regimen of narcolepsy medications that balances symptomatic benefits with cardiovascular safety., Competing Interests: Conflicts of interest PJ Jennum has participated in advisory boards for UCB Europe, Bioprojet, and Jazz Pharmaceuticals. G Plazzi is a consultant and has participated in advisory boards for UCB Pharma, Bioprojet, Idorsia, Jazz Pharmaceuticals, and Takeda. A Silvani reports no conflicts of interest. LA Surkin has participated in advisory boards for Jazz Pharmaceuticals. Y Dauvilliers is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, UCB Pharma, Flamel Technologies, Idorsia, Theranexus, and Bioprojet., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Study Objectives: Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin (ORX) neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear. The neurobiology underlying sleepiness in other central hypersomnolence disorders, narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH), is currently unknown., Methods: Eleven biogenic amines including the monoaminergic neurotransmitters and their metabolites and five trace amines were measured in the cerebrospinal fluid (CSF) of 94 drug-free subjects evaluated at the French National Reference Center for Narcolepsy: 39 NT1(orexin-deficient) patients, 31 patients with objective sleepiness non orexin-deficient (NT2 and IH), and 24 patients without objective sleepiness., Results: Three trace amines were undetectable in the sample: tryptamine, octopamine, and 3-iodothyronamine. No significant differences were found among the three groups for quantified monoamines and their metabolites in crude and adjusted models; however, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels tended to increase in NT1 compared to other patients after adjustment. Most of the biomarkers were not associated with ORX-A levels, clinical or neurophysiological parameters, but a few biomarkers (e.g. 3-methoxy-4-hydroxyphenylglycol and norepinephrine) correlated with daytime sleepiness and high rapid eye movement (REM) sleep propensity., Conclusions: We found no striking differences among CSF monoamines, their metabolites and trace amine levels, and few associations between them and key clinical or neurophysiological parameters in NT1, NT2/IH, and patients without objective sleepiness. Although mostly negative, these findings are a significant contribution to our understanding of the neurobiology of hypersomnolence in these disorders that remain mysterious and deserve further exploration., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Objectives: Hypersomnolence, defined by excessive daytime sleepiness (EDS) or excessive quantity of sleep (EQS), has been associated with increased morbidity. The aim of this study was to determine the clinical and polysomnographic characteristics associated with EQS and EDS assessed objectively during extended polysomnography recording., Methods: A total of 266 drug-free subjects (201 women; mean age: 26.5 years [16.08; 60.87]) underwent 32-h bed-rest polysomnography recording preceded by polysomnography and modified multiple sleep latency test (mMSLT). Participants were categorized according to their total sleep time (bed-rest TST ≥19 h, hypersomnia), objective EDS (mean sleep latency on MSLT ≤8 min), and self-reported EDS (Epworth sleepiness scale score >10) and EQS (≥9 h/24 h per week)., Results: Subjects with hypersomnia were often younger, with normal sleep architecture, high nighttime sleep efficiency, and severe objective EDS. No association with sex, body mass index, Epworth sleepiness scale, EQS, and depressive symptoms was detected. Subjects with objective EDS had less EQS, higher sleep efficiency, and increased hypersomnia. Discrepancies were observed between objective and self-reported measures of sleep duration and EDS. Finally, 71 subjects were identified who had objective hypersomnia and/or EDS, no medical and psychiatric conditions and normal polysomnography parameters, and therefore met the stringent criteria of idiopathic hypersomnia, an orphan disorder., Conclusions: Sleep duration and EDS should be quantified using self-reported and objective measures in a controlled procedure to differentiate long sleepers, patients with hypersomnia, and patients with idiopathic hypersomnia. This will help to better understand their biology, to identify specific biomarkers, and to assess related health outcomes., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Background: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects., Research Question: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS?, Study Design and Methods: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to-treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety., Results: Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS ≤ 10 or change in ESS ≥ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported., Interpretation: Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity., Trial Registry: ClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu., (Copyright © 2020. Published by Elsevier Inc.)

Study Objective: To determine whether the objective level of alertness measured by the Maintenance of Wakefulness Test (MWT) is associated with the occurrence of self-reported sleepiness-related traffic near misses and accidents related to sleepiness in patients with sleep disorders., Methods: This case-control study was conducted over a three-year period in four French sleep centers during a 4∗40 min MWT in patients driving more than 5000 Km/year. Relationship between mean sleep latency on the MWT (MWT latency) and age, sex, driving, sleepiness-related near misses and accidents reported during the previous year, and sleep disorder characteristics was analyzed., Results: Of 377 patients suffering from OSAS, idiopathic hypersomnia, narcolepsy, restless leg syndrome or insufficient sleep syndrome, 176 were included. 74 cases reported an accident or near miss related to sleepiness at the wheel in the past year, and 102 reported no accident/near miss (control patients). Thirty-one (37.8 %) cases and 9 (8.8 %) controls reported being sleepy at the wheel more than once a week (p < 0.0001). After adjusted regression analyses, patients with MWT latency between 19 and 33 minutes had a 3.2- (CI 95%[1.5; 6.8], p < 0.0001) fold increase in risk of reporting a near miss/ accident and patients with MWT latency <19 min had a 5.5- (CI 95%[2.2; 13.8], p = 0.003) fold increase in this risk, compared to the referent group (MWT latency>33 min)., Conclusions: MWT latency is associated with self-reported, sleepiness-related near misses and accidents related to sleepiness in the past year in patients routinely investigated in sleep clinics. The MWT could be used to assess driving risk together with clinical interviews assessing sleepiness at the wheel., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To evaluate the associations between CSF orexin-A (ORX) levels and markers of nocturnal sleep stability, assessed by polysomnography., Methods: Nocturnal polysomnography data and ORX levels of 300 drug-free participants (55% men, 29.9±15.5 years, ORX level 155.1±153.7 pg/mL) with hypersomnolence were collected. Several markers of nocturnal sleep stability were analyzed: sleep and wake bouts and sleep/wake transitions. Groups were categorized according to ORX levels, in 2 categories (deficient ≤110; >110), in tertiles (≤26, 26-254, >254), and compared using logistic regression models. Results were adjusted for age, sex, and body mass index., Results: We found higher number of wake bouts (43 vs 25, p < 0.0001), sleep bouts (43 vs 25.5, p < 0.0001), and index of sleep bouts/hour of sleep time, but lower index of wake bouts/hour of wake time (41.4 vs 50.6, p < 0.0001), in patients with ORX deficiency. The percentage of wake bouts <30 seconds was lower (51.3% vs 60.8%, p < 0.001) and of wake bouts ≥1 minutes 30 seconds higher (7.7% vs 6.7%, p = 0.02) when ORX deficient. The percentage of sleep bouts ≤14 minutes was higher (2-5 minutes: 23.7% vs 16.1%, p < 0.0001), and of long sleep bouts lower (>32 minutes 30 seconds: 7.3% vs 18.3%, p < 0.0001), when ORX deficient. These findings were confirmed when groups were categorized according to ORX tertiles, with a dose-response effect of ORX levels in post hoc comparisons, and in adjusted models., Interpretation: This study shows an association between ORX levels and nocturnal sleep stabilization in patients with hypersomnolence. Sleep and wake bouts are reliable markers of nighttime sleep stability that correlate with CSF ORX levels in a dose-dependent manner., (© 2020 American Academy of Neurology.)

The aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on central disorders of hypersomnolence. The ultimate goal for a sleep disorders classification is to be based on the underlying neurobiological causes of the disorders with clear implication for treatment or, ideally, prevention and or healing. The current ICSD classification, published in 2014, inevitably has important shortcomings, largely reflecting the lack of knowledge about the precise neurobiological mechanisms underlying the majority of sleep disorders we currently delineate. Despite a clear rationale for the present structure, there remain important limitations that make it difficult to apply in routine clinical practice. Moreover, there are indications that the current structure may even prevent us from gaining relevant new knowledge to better understand certain sleep disorders and their neurobiological causes. We suggest the creation of a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence; containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity and sensitivity in the diagnostic context. We propose and define three diagnostic categories (with levels of certainty): 1/"Narcolepsy" 2/"Idiopathic hypersomnia", 3/"Idiopathic excessive sleepiness" (with subtypes)., Competing Interests: Conflict of Interest The authors do not have any conflicts of interest to disclose., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, improved wakefulness and reduced excessive daytime sleepiness (EDS) in studies of participants with narcolepsy with and without cataplexy., Objective: Prespecified subgroup analyses of data from a 12-week randomized, double-blind, placebo-controlled, phase III trial of solriamfetol for EDS in narcolepsy evaluated the efficacy and safety of solriamfetol by cataplexy status., Methods: Participants with narcolepsy received solriamfetol (75, 150, or 300 mg/day) or placebo and were stratified by cataplexy status. Coprimary endpoints were change from baseline on Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS); Patient Global Impression of Change (PGI-C) was the key secondary endpoint. Change in frequency of cataplexy attacks was evaluated in participants reporting cataplexy at baseline. Safety was evaluated. No adjustments were made for multiple comparisons; therefore p values are nominal., Results: There were 117 participants in the cataplexy subgroup and 114 in the non-cataplexy subgroup. At week 12, least-squares (LS) mean (95% confidence interval [CI]) differences from placebo on change from baseline in MWT for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were 1.6 (- 3.6 to 6.9), 6.1 (0.7-11.4), and 8.9 (3.5-14.2) minutes, respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup were 3.4 (- 1.9 to 8.7), 9.1 (3.8-14.3), and 11.2 (5.8-16.6) minutes, respectively (p < 0.001; 150 and 300 mg). At week 12, LS mean (95% CI) differences from placebo on ESS change from baseline for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were - 1.3 (- 3.9 to 1.3), - 3.7 (- 6.4 to - 1.1), and - 4.5 (- 7.1 to - 1.9), respectively (p < 0.01; 150 and 300 mg), and in the non-cataplexy subgroup were - 3.0 (- 5.6 to - 0.4), - 3.7 (- 6.3 to - 1.2), and - 4.9 (- 7.6 to - 2.2), respectively (p < 0.05; all doses). For PGI-C at week 12, the mean percentage difference from placebo (95% CI) for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup was 10% (- 15 to 35), 33% (9-57), and 39% (16-61), respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup was 48% (25-70), 44% (21-67), and 52% (30-73), respectively (p < 0.001; all doses), with somewhat differential treatment effects for 75 mg by cataplexy status. No changes in the number of cataplexy attacks were observed for solriamfetol compared with placebo (mean ± standard deviation changes: - 3.6 ± 13.3 [combined solriamfetol] and - 3.5 ± 9.8 [placebo]). Common adverse events (headache, nausea, decreased appetite, and nasopharyngitis) were similar between cataplexy subgroups., Conclusions: These data strongly indicate that solriamfetol was effective in treating EDS in participants with narcolepsy with or without cataplexy, as indicated by robust effects on MWT, ESS, and PGI-C. The safety profile was similar regardless of cataplexy status., Trial Registration and Date: ClinicalTrials.gov NCT02348593. 28 January 2015.

Objective: Obstructive sleep apnea (OSA) is a high prevalent disorder with severe consequences including sleepiness, metabolic, and cardiovascular disorders. The aim of this study was to assess the effect of an individualized exercise-training (IET) program with educational sessions vs educational sessions alone on severity markers of OSA over an eight-week duration., Methods: This was a randomised, controlled, parallel-design study. In sum, 64 patients with moderate-to-severe OSA (apnea-hypopnea index AHI 15-45/hour), low physical activity level (Voorrips<9), body-mass index (BMI) <40 kg/m 2 were included in intervention group (IG) or control group (CG), and 54 patients finished the study. All underwent polysomnography (PSG), multiple sleep latency test (MSLT), constant workload exercise test, blood samples and fulfilled questionnaires twice. The primary endpoint was the change in apnea-hypopnea (AHI) at eight weeks from baseline. Main secondary endpoints were daytime sleepiness assessed by questionnaire and objective tests., Results: No significant between-group differences were found for changes in AHI. A reduction in AHI was found in IG only (p = 0.005). Compared to CG, exercise training leads to a greater decrease in AHI during REM sleep (p = 0.0004), with a significant increase in mean daytime sleep latency (p = 0.02). Between-group differences were significant for weight reduction, severity of fatigue, insomnia and depressive symptoms with trend for sleepiness symptoms., Conclusions: In adult patients with moderate-to-severe OSA, IET did not decrease AHI compared to the control group but improved markers of severity of OSA, in particular AHI in rapid eye movement (REM) sleep and objective daytime sleepiness. Adding personalized exercise training to the management of patients with OSA should be considered. CLINICALTRIALS., Gov Identifier: NCT01256307., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome. Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment. Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire. Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P  < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns. Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

Study Objectives: To document the rates of persistent, remitted, and intermittent excessive daytime sleepiness (EDS) in a longitudinal 5-year community study of adults and to assess how changes in risk factors over time can predict improvement of daytime sleepiness (DS)., Methods: Participants were recruited in 2007-2008 as part of a population-based epidemiological study implemented in Canada. They completed postal assessments at baseline and at each yearly follow-up. An Epworth Sleepiness Scale total score >10 indicated clinically significant EDS; a 4-point reduction between two consecutive evaluations defined DS improvement. Socio-demographic, lifestyle, health characteristics, and sleep-related measures (e.g. insomnia symptoms, sleep duration, sleep medication) were self-reported at each time point. Cox proportional-hazard models were used to predict EDS and DS remissions over 5 years., Results: Among the 2167 participants, 33% (n = 714) met criteria for EDS at baseline, of whom 33% had persistent EDS, 44% intermittent EDS, and 23% remitted EDS over the follow-up. Furthermore, 61.4% of 2167 initial participants had stable DS, 27.1% sustained DS improvement and 8.5% transient improvement over the follow-up. The main predictors of EDS remission or DS improvement were normal weight, taking less hypnotics, having hypertension, increased nighttime sleep duration, and decreased insomnia, and depressive symptoms., Conclusions: EDS waxes and wanes over time with frequent periods of remission and is influenced by behavioral characteristics and changes in psychological, metabolic, and nighttime sleep patterns. Targeting these predictors in future interventions is crucial to reduce DS in the general adult population., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Objective: To assess the relationship between excessive daytime sleepiness (EDS), inattention, and hyperactivity/impulsivity in adults with ADHD and central hypersomnia. Method: Drug-free adult patients with ADHD ( n = 100) or hypersomnia ( n = 100) were evaluated using a structured clinical interview and self-report questionnaires on ADHD symptoms and EDS. Results: In all, 61% of patients with hypersomnia had clinically significant ADHD symptoms with 25% having an ADHD diagnosis (with both childhood and adulthood ADHD symptoms) and 36% ADHD-like symptoms, without history of childhood ADHD. EDS was reported in 47% of patients with ADHD, among whom 22% had a hypersomnolence disorder. Conclusion: We confirmed the high frequency of ADHD and ADHD-like symptoms in central hypersomnia, and of EDS and hypersomnolence in ADHD in adults. The nature of the link between EDS, inattention, and hyperactivity appears to be complex that may involve either a cause-effect relationship or intrinsic features of a similar neurodevelopmental dysfunction.

Objective: Daytime sleepiness and fatigue are prominent symptoms of myotonic dystrophy type I (DM1) that exact a heavy toll on patients' quality of life, but information is scarce on their predictive factors. This study aimed to determine factors that may influence levels of daytime sleepiness and fatigue in a large cohort of DM1 patients followed for 9 years., Methods: This study included 115 patients with DM1 at baseline (Time 1, T1) and at Time 2 (T2) who were questioned for daytime sleepiness, fatigue, history of depression, psychological distress, pain, hypothyroidism, and sleep habits. Also, their muscular impairment and intellectual quotient were evaluated. Regression models were used to identify correlates of daytime sleepiness and fatigue while controlling for time effect., Results: Both daytime sleepiness and fatigue increased between T1 and T2, but their rate of change are higher when CTG repeat number is higher (p < 0.05). Also, higher psychological distress level is associated with higher daytime sleepiness and fatigue levels both at T1 and T2 (p < 0.01). Moreover, patients with a history of depression report higher daytime sleepiness levels both at T1 and T2 (p < 0.05). In addition, patients with higher fatigue levels both at T1 and T2 have more severe muscular impairment (p < 0.01) and report a longer habitual sleep duration (p < 0.05). Finally, a higher BMI and a history of hypothyroidism predict higher daytime sleepiness levels at T2 (p < 0.05)., Conclusion: This study identified potentially modifiable risk factors of future daytime sleepiness and fatigue in DM1 patients, including BMI, psychological distress, hypothyroidism, and sleep habits.

Central nervous system hypersomnias (narcolepsy type 1 and type 2, idiopathic hypersomnia, and Kleine-Levin syndrome) are orphan sleep disorders in which the predominant symptom is excessive daytime sleepiness. The evaluation of sleepiness requires rigorous clinical and neurophysiologic approaches that may include the Epworth Sleepiness Scale, multiple sleep latency tests, and the maintenance of wakefulness test. However, to date, no gold standard measurement of excessive sleepiness exists, and there are no quantifiable biologic markers. The main pathophysiologic feature of central hypersomnias is thought to reflect a deficiency of arousal systems, rather than an overactivity of sleep systems or an imbalance between those systems. Impaired neurotransmission of hypocretin/orexin (neuropeptides of the lateral hypothalamus) is involved in the neurobiology of narcolepsy with cataplexy (NT1). NT1 is a well-characterized disorder, due to the destruction of hypocretin/orexin neurons by a probable autoimmune process. The biologic hallmarks of the other central hypersomnias remain unknown, and neurophysiologic biomarkers are still of major importance for the diagnosis and characterization of those disorders., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Study Objectives: To assess the test-retest reliability of the polysomnography-multiple sleep latency test (PSG-MSLT) diagnostic classification and measures and to study the determinants of its variability in patients with narcolepsy type 1 (NT1) or with noncataplectic central disorders of hypersomnolence (NCHS): type 2 (NT2), idiopathic hypersomnia (IH), and unspecified hypersomnolence (unspecified excessive daytime sleepiness [UnsEDS])., Methods: PSG-MSLT in drug-free conditions was administered twice (median interval of 1.9 years) in 22 patients with NT1 (10 males, median age 31.2 years) and 75 patients with NCHS (32 males, median age 25.7 years)., Results: At the first PSG-MSLT, patients with NCHS were classified as having NT2 (22.7%), IH (26.7%), or UnsEDS (50.6%). A positive PSG-MSLT was confirmed in 72.7% of NT1. The classification consistency at retesting was significantly lower for the NT2 (47.1%), IH (25.0%), and UnsEDS (42.1%) categories than NT1 (81.3%). The between-test mean sleep latency (MSL) variability was significantly different in NT1 and NCHS, with higher changes in NT2 and lower in NT1. A longer test-retest interval was associated with improved MSL and MSLT normalization. Between-test variations in SOREMP number were associated with changes in nocturnal REM sleep parameters and MSL. No association was found with the clinical decision to repeat the evaluation or the disease clinical course., Conclusion: The PSG-MSLT measures and classification are not stable in patients with NCHS, with frequent diagnostic changes, particularly for NT2 and IH, compared with NT1. MSLT needs to be repeated at regular intervals to confirm a stable hypersomnia and provide an accurate diagnosis of NT2 and IH., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Recent population-based longitudinal studies concluded that most adults with attention deficit/hyperactivity disorder (ADHD) symptoms would not have a childhood history of ADHD, leading to the concept of adult-onset ADHD. In a large, well-characterized clinical population of 446 adults with a primary complaint of ADHD, we reported a low frequency of adult-onset ADHD (6.9%), being a primary isolated condition in 2.8%. They had less severe symptoms and tendencies for higher hypersomnolence disorder comorbidity than patients with typical childhood-onset ADHD. Our findings reinforce the requirement to exclude other disorders that might overlap with ADHD or mimic ADHD symptoms in adulthood onset patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Hypersomnolence is a clinically defined syndrome characterized by the association of prolonged nocturnal sleep, impaired arousal quality, and sleep inertia. Hypersomnolence is the major feature of central hypersomnias and is frequently reported in various mood disorders, such as major depressive disorder, bipolar disorder, or seasonal affective disorder. Assessment of hypersomnolence is challenging in depressed patients, with objective tests often in the normal range despite a high level of sleepiness complaint. On the other hand, many patients with central hypersomnias reported depressive symptoms. The self-assessment of mood symptoms in patients with central hypersomnias may overdiagnose depression with an overlap between both conditions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose of Review: This article focuses on the clinical presentation, pathophysiology, diagnosis, differential diagnosis, and management of narcolepsy type 1 and narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, and other central disorders of hypersomnolence, as defined in the International Classification of Sleep Disorders, Third Edition (ICSD-3)., Recent Findings: In ICSD-3, the names of some central disorders of hypersomnolence have been changed: narcolepsy with cataplexy and narcolepsy without cataplexy have been renamed narcolepsy type 1 and narcolepsy type 2, respectively. A low level of hypocretin-1/orexin-A in the CSF is now theoretically sufficient to diagnose narcolepsy type 1, as it is a highly specific and sensitive biomarker. Conversely, other central hypersomnias are less well-defined disorders with variability in the phenotype, and few reliable biomarkers have been discovered so far. The epidemiologic observation that influenza A (H1N1) infection and vaccination are potential triggering factors of narcolepsy type 1 (discovered during the 2009 H1N1 pandemic) has increased interest in this rare disease, and progress is being made to better understand the process (highly suspected to be autoimmune) responsible for the destruction of hypocretin neurons. Treatment of narcolepsy remains largely symptomatic, usually initially with modafinil or armodafinil or with higher-potency stimulants such as methylphenidate or amphetamines. Several newer wake-promoting agents and psychostimulants have also been developed, including sodium oxybate, which has a role in the treatment of cataplexy and as an adjunctive wake-promoting agent, and pitolisant, a selective histamine H3 receptor inverse agonist that is currently only available in Europe., Summary: Although far less common than many other sleep disorders, central hypersomnias are among the most severe and disabling diseases in the field of sleep medicine, and their early recognition is of major importance for patients, especially children, to maximize their quality of life and functioning in activities of daily living.