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Objective: Daridorexant is approved for the treatment of insomnia at two dose levels (25 and 50 mg). Dose-efficacy and -safety response relationships were evaluated using Phase 2 and 3 data., Methods: Data (N = 2153) from one Phase 2 (daridorexant 5, 10, 25, 50 mg, placebo once daily for 1 month) and two Phase 3 studies (daridorexant 10 and 25 or 25 and 50 mg, placebo once daily for 3 months) were pooled. Dose-response analyses at 1 month of double-blind treatment were performed using a linear regression and a two-stage meta-analysis approach. Efficacy endpoints were polysomnography-derived wake after sleep onset, latency to persistent sleep (LPS), self-reported total sleep time and the Insomnia Daytime Symptoms and Impacts Questionnaire total score (only Phase 3 data for the latter). Safety endpoints were the incidence of total adverse events (AEs) and AEs corresponding to somnolence/fatigue., Results: Dose-responses for all efficacy endpoints were significant in the observed dose range (both statistical approaches, p < 0.01). All dose-response relationships were linear except for LPS (two-stage meta-analysis) which showed a change in slope above 10 mg without reaching a plateau. No significant dose-response was observed for any AE (both approaches, p > 0.05). The incidence of AEs corresponding to somnolence/fatigue was low at all doses and, without linear assumption (two-stage meta-analysis) there was no dose-dependency (p = 0.369)., Conclusions: The data support the use of 50 mg as the preferred daridorexant dose in patients with insomnia disorder to provide the greatest opportunity for efficacy with no increased risk for AEs, including somnolence/fatigue, compared to lower doses., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report article publishing charges, statistical analysis, and writing assistance were provided by Idorsia Pharmaceuticals Ltd. Antonio Olivieri reports a relationship with Idorsia Pharmaceuticals Ltd that includes: employment and equity or stocks. Guy Braunstein reports a relationship with Idorsia Pharmaceuticals Ltd that includes: employment and equity or stocks. Pierre-Philippe Luyet reports a relationship with Idorsia Pharmaceuticals Ltd that includes: employment. Johann Laurent reports a relationship with Idorsia Pharmaceuticals Ltd that includes: employment. William V McCall reports a relationship with Idorsia Pharmaceuticals Ltd that includes: consulting or advisory. William V McCall reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. William V McCall reports a relationship with Carelon that includes: consulting or advisory. Claudio Bassetti reports a relationship with Bioproject that includes: consulting or advisory. Claudio Bassetti reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory. Claudio Bassetti reports a relationship with Jazz Pharmaceuticals Inc that includes: consulting or advisory. Claudio Bassetti reports a relationship with Idorsia Pharmaceuticals Ltd that includes: consulting or advisory. Jan Hedner reports a relationship with Somnomed that includes: funding grants. Jan Hedner reports a relationship with Desitin GmbH that includes: funding grants., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives/background: Narcolepsy type 1 (NT1) is an immune-mediated disorder characterized by excessive daytime sleepiness, cataplexy, low levels of hypocretin-1 in the cerebrospinal fluid, and a strong association with the HLA DQB1*06:02 allele. There is evidence for streptococcal infections as one pathogenic factor that may lead to NT1 as part of a multifactorial pathogenesis. Elevated titers of Antistreptolysin-O antibodies and increased inflammatory activity in response to streptococci antigens have been described in patients with NT1. Sydenham chorea (SC) results from a post-streptococcal autoimmune process targeting basal ganglia neurons. Despite this common trigger, SC has been interpreted as a misdiagnosis in a few described cases of patients who were first diagnosed with SC and later with NT1. Our goal was to analyze the association between SC and NT1., Patients/methods: We reviewed the literature and report three patients from three European sleep centers who were diagnosed with both SC and NT1 within a few months., Results: We describe the cases of one male (age 10) and two female (age 22 and 10) patients., Conclusions: We argue that in those cases both diagnoses are justified, unlike reports of previous cases in which SC was considered a misdiagnosis in patients with NT1. It remains, however, unclear if the conditions occur independently or if there is an overlap disorder- an SC-like subtype of narcolepsy with a particular sequence of symptoms. Further studies need to clarify the causality of the relationship and the pathophysiology of the reported rare association., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elena S. Wenz reports a relationship with University of Bern that includes: funding grants. Ulf Kallweit reports a relationship with Bioprojet, Jazz Pharmaceuticals, Takeda Pharmaceuticals that includes: consulting or advisory and speaking and lecture fees. Rolf Fronczek reports a relationship with Takeda Pharmaceuticals, Bioprojet that includes: consulting or advisory. Rolf Fronczek reports a relationship with Jazz Pharmaceuticals that includes: funding grants. Gert Jan Lammers reports a relationship with Bioprojet, Jazz Pharmaceuticals, Takeda Pharmaceuticals, NLS Pharmaceutics that includes: consulting or advisory and speaking and lecture fees., (Copyright © 2023. Published by Elsevier B.V.)

Objective: In the absence of systematic and longitudinal data, this study prospectively assessed both frequency and evolution of sleep-wake disturbances (SWD) after stroke., Methods: In 437 consecutively recruited patients with ischemic stroke or transient ischemic attack (TIA), stroke characteristics and outcome were assessed within the 1 st week and 3.2 ± 0.3 years (M±SD) after the acute event. SWD were assessed by interview and questionnaires at 1 and 3 months as well as 1 and 2 years after the acute event. Sleep disordered breathing (SDB) was assessed by respirography in the acute phase and repeated in one fifth of the participants 3 months and 1 year later., Results: Patients (63.8% male, 87% ischemic stroke and mean age 65.1 ± 13.0 years) presented with mean NIHSS-score of 3.5 ± 4.5 at admission. In the acute phase, respiratory event index was >15/h in 34% and >30/h in 15% of patients. Over the entire observation period, the frequencies of excessive daytime sleepiness (EDS), fatigue and insomnia varied between 10-14%, 22-28% and 20-28%, respectively. Mean insomnia and EDS scores decreased from acute to chronic stroke, whereas restless legs syndrome (RLS) percentages (6-9%) and mean fatigue scores remained similar. Mean self-reported sleep duration was enhanced at acute stroke (month 1: 07:54 ± 01:27h) and decreased at chronic stage (year 2: 07:43 ± 01:20h)., Conclusions: This study documents a high frequency of SDB, insomnia, fatigue and a prolonged sleep duration after stroke/TIA, which can persist for years. Considering the negative effects of SWD on physical, brain and mental health these data suggest the need for a systematic assessment and management of post-stroke SWD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, neither financially nor non-financially., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Changes in sleep architecture following ischemic stroke have been poorly investigated. Our objective was to explore changes of sleep structure in patients with ischemic stroke or transient ischemic attack in order to verify a possible predictive value of sleep with respect to clinical outcome., Methods: Patients recruited in the prospective SAS-CARE study received two polysomnographies (PSG) in the acute and chronic phases after stroke/TIA. Sleep parameters were compared between the two time-points and matched with a non-stroke population randomly selected from the HypnoLaus cohort., Results: Of the 169 patients investigated with PSG in the acute phase, 104 were again studied 3 months after stroke symptom onset and compared with 162 controls. The acute phase of stroke/TIA was associated with sleep disruption, which significantly improved in the chronic phase, but remained worse than controls (total sleep time improve from 318.8 ± 90.8 to 348.4 ± 81.5 min, compared to 388.2 ± 71.3 in controls, sleep latency from 49.9 ± 58.4 to 27.9 min, compared to 20.2 ± 22 in controls, sleep efficiency from 58.2 ± 18.1% to 27.9 ± 36.4 min, compared to 83.4 ± 10.3% in controls, wakefulness after sleep onset percentage from 36.5 ± 17.3 to 29.3 ± 15.6, compared to 13.2 ± 9.2 in controls). The percentage of REM sleep was negatively associated with stroke severity, whereas stroke topography did not correlate with sleep parameters., Conclusions: This study confirmed a severe sleep disruption in the acute phase of stroke. Although a significant improvement of sleep quality was observed during the three months after stroke, sleep architecture did not normalize. In particular, sleep efficiency and REM sleep seem to be particularly affected by stroke in the acute phase, with a relative preservation of NREM sleep. We suggest that these sleep architecture changes represent a persistent marker of brain damage due to stroke. Further studies are needed to assess the relationship with stroke topographic and outcome., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Kleine-Levin syndrome (KLS) is a rare and debilitating disorder presenting with periodic hypersomnolence, cognitive, psychiatric and behavioral disturbances. In the absence of biomarkers it can be difficult to diagnose. Rare LMOD3 variants in a family and in seven sporadic cases with KLS have been described. Here we report a patient and her family with an unclassified, familial, periodic central disorder of hypersomnolence (CDH) in whom the presence of a LMOD3 gene variant was assessed., Case Description: The female patient presented since early adulthood with recurrent episodes of hypersomnolence. Over more than 20 years of follow-up the diagnoses of idiopathic hypersomnia, KLS and hypersomnia associated with a psychiatric condition were made. The family history is positive for periodic hypersomnolence and psychiatric conditions. The patient, her symptomatic mother and her asymptomatic sister carried a Proline for Histidine substitution at codon 552 of the LMOD3-gene. This variant was previously reported in two sporadic KLS patients and its frequency in the general population is below 0.02%., Discussion: We report the association of periodic hypersomnia with a polymorphism of the LMOD3-gene in a patient with atypical KLS and a positive family history. Further research is needed to assess the pathological and predictive value of LMOD3 variants in KLS., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Τhe association between Parkinson's disease (PD) and sleep apnea syndrome (SAS) is not fully elucidated and very few studies reported on SAS outcome after deep brain stimulation (DBS). Here, we compare the clinical profile of PD patients with and without SAS and assess, for the first time, the value of pre-DBS SAS as predictor of post-DBS outcome in PD., Methods: Fifty patients were grouped into PD with SAS (PD-SAS+,n = 22) and without (PD-SAS-,n = 28), based on the Apnea-Hypopnea-Index (AHI≥5) in polysomnography. We used novel multivariate statistical models to compare pre-DBS profiles and assess post-DBS motor, non-motor and quality of life (QoL) changes in both groups., Results: In the entire cohort, 44% of patients had at least mild SAS (AHI≥5), while 22% had at least moderate (AHI≥15). Mean AHI was 11/h (NREM-AHI = 10.2/h and REM-AHI = 13.5/h). The two groups had equal demographics and PD characteristics, and did not differ in respect to unified Parkinson's disease rating scale (UPDRS)-II OFF , Body-Mass-Index, polysomnographic features, RBD, depression, sleepiness and QoL scores. The PD-SAS+ group had significantly higher scores in UPDRS-III OFF (41.1 ± 17.7 vs. 30.9 ± 11.7,p < 0.05) compared to PD-SAS- group. The groups did not differ in respect to post-DBS change in UPDRS-II, UPDRS-III, Epworth sleepiness scale, Hamilton depression rating scale and PDQ39 scores. Positive airway pressure therapy had no impact on post-DBS outcome., Conclusions: In patients with PD and candidates for DBS, the presence of SAS is associated with increased motor signs, but not with a specific non-motor, QoL or sleep-wake profile. The presence of SAS prior to STN-DBS is not associated with worse outcome after surgery., (Copyright © 2021. Published by Elsevier B.V.)

A multiple sleep latency test (MSLT) with occurrence of sleep onset REM periods (SOREMP) is considered one of the central diagnostic criteria for narcolepsy according to the International Classification of Sleep Disorders, but its sensitivity and specificity have been questioned. This study aims to describe MSLT and polysomnography (PSG) findings, including frequency and distribution of SOREMP during the day, in a large cohort of patients with central disorders of hypersomnolence (CDH). We retrospectively analyzed electrophysiological data from MSLT and PSG in 370 consecutive patients with narcolepsy type 1 (NT1, n = 97), type 2 (NT2, n = 31), idiopathic hypersomnia (IH, n = 48), nonorganic hypersomnia (NOH, n = 116) and insufficient sleep syndrome (ISS, n = 78). NT1 and NT2 patients had a significantly shorter mean Sleep Latency (mSL) and REM-Latency (REML) in MSLT and PSG. SOREMP occurred more frequently in narcoleptic vs. non-narcoleptic patients in MSLT and PSG. Occurrence of 3 or more SOREMP in MSLT and a SOREMP in PSG had a very high specificity and positive predictive value (98%/96% and 100% respectively), however relatively low sensitivity (65% and 45% respectively). NT1 more than NT2 patients have shorter mSL and more frequent SOREMP in MSLT and shorter SL as well as REML during nocturnal PSG. Increasing numbers of SOREMP in MSLT and especially SOREMP during PSG increase specificity on the expense of sensitivity in diagnosing narcolepsy. Therefore, frequency of SOREMP in MSLT naps and PSG can help to discriminate but not clearly separate narcoleptic from non-narcoleptic patients., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

REM-sleep behavior disorder (RBD) is a parasomnia and a common sleep disorder in Parkinson's disease (PD). While deep brain stimulation (DBS) is an established treatment for advanced PD with beneficial effects on cardinal PD motor symptoms, the data on the impact of DBS on RBD are limited and often controversial. We reviewed published articles that reported on RBD in the context of DBS surgery via systematic PubMed search. We identified 75 studies and included 12 studies, involving a total of 320 subjects, in our review. Results in respect to EMG activity outcome after subthalamic stimulation are inconsistent. We found no study that reported on RBD outcome after pallidal DBS and no DBS study quantified complex behavior during REM sleep. We also added data on RBD outcome after subthalamic (N = 4 patients) or pallidal (N = 3 patients) DBS from patients with PD with RBD, obtained as part of a prospective DBS study in our centre. Our case series showed an increase of complex behavior during REM (CB-REM) after surgery, independent of DBS target. Conversely, we found a trend towards increasing REM sleep without atonia (RSWA) in subthalamic-stimulated patients and a trend towards decreased RSWA in pallidal stimulated patients. We conclude that CB-REM and RSWA might represent two distinct elements in RBD and should be assessed separately, especially in studies that report on RBD outcome after treatment interventions. Further, larger, prospective, controlled studies in different DBS targets, reporting separately on the different RBD modalities, are needed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Narcolepsy with cataplexy (NT1) is a chronic hypothalamic disorder with a presumed immune-mediated etiology leading to a loss of hypocretin neurons. Previous studies reported conflicting results in terms of presence of auto-antibodies involved in narcolepsy pathophysiology. A total of 86 patients with primary/idiopathic narcolepsy (74 NT1, 12 NT2) and 23 control patients with excessive daytime sleepiness due to other causes were tested for the presence of a wide range of anti-neuronal antibodies in both serum and cerebrospinal fluid (CSF). Anti-neuronal antibodies were rarely found in patients with narcolepsy (n = 2) and in controls (n = 1). Our results are in line with previous reports. We can therefore support the current evidence, that conventional anti-neuronal antibodies are not routinely detected during the workup of NT1 and other CDH patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)