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Abstract Excessive daytime sleepiness (EDS) is highly prevalent in the general population; however little is known about its evolution and predictors. Our objectives were to document its natural history, provide estimates of its prevalence, incidence and persistence rates, and to identify predictors of increased daytime sleepiness (DS) in a longitudinal community study of 2157 adults over 5 years. Participants completed postal assessment at baseline and at each yearly follow-up. DS was evaluated by the Epworth Sleepiness scale (ESS). At baseline, 33% reported EDS (ESS > 10) with 33% of them reported persistent EDS. Of those without EDS at baseline, 28% developed incident EDS (15% were persistent) and 31% increased DS (augmentation ≥4-points between two consecutive evaluations). Younger age and depression were independent predictors of incident EDS and DS increase while lower coffee consumption, smoking, insomnia, tiredness and chronic pain were associated with incident EDS, and living alone with DS increase only. Persistent vs transient EDS or DS showed association with poor general health including metabolic diseases. Thus, sleepiness fluctuated over time and it was predicted by common lifestyle and psychological factors potentially modifiable. However, persistent sleepiness was associated with chronic medical diseases thus highlighting a homogeneous group at risk requiring a dedicated management.

Accurate measurement of habitual sleep duration (HSD) is crucial for understanding the relationship between sleep and health. This study aimed to assess the bias and agreement limits between two commonly used short HSD self-report methods, considering sleep quality (SQ) and social jetlag (SJL) as potential predictors of bias. Data from 10,268 participants in the International COVID Sleep Study-II (ICOSS-II) were used. Method-Self and Method-MCTQ were compared. Method-Self involved a single question about average nightly sleep duration (HSD self ), while Method-MCTQ estimated HSD from reported sleep times on workdays (HSD MCTQwork ) and free days (HSD MCTQfree ). Sleep quality was evaluated using a Likert scale and the Insomnia Severity Index (ISI) to explore its influence on estimation bias. HSD self was on average 42.41 ± 67.42 min lower than HSD MCTQweek , with an agreement range within ± 133 min. The bias and agreement range between methods increased with poorer SQ. HSD MCTQwork showed less bias and better agreement with HSD self compared to HSD MCTQfree . Sleep duration irregularity was - 43.35 ± 78.26 min on average. Subjective sleep quality predicted a significant proportion of variance in HSD self and estimation bias. The two methods showed very poor agreement and a significant systematic bias, both worsening with poorer SQ. Method-MCTQ considered sleep intervals without adjusting for SQ issues such as wakefulness after sleep onset but accounted for sleep irregularity and sleeping in on free days, while Method-Self reflected respondents' interpretation of their sleep, focusing on their sleep on workdays. Including an SQ-related question in surveys may help bidirectionally adjust the possible bias and enhance the accuracy of sleep-health studies., (© 2024. The Author(s).)

Parkinsonian patients often experience sleep/wake disturbances, which may appear at an early stage of the disease; however, these disturbances have not been fully described. To better understand the evolution of these disturbances with respect to disease progression, we aimed to characterize these clinical signs in a progressive nonhuman primate model of Parkinson's disease. Three adult macaques (Macaca fascicularis) were equipped with a polysomnographic telemetry system allowing the characterization of sleep/wake behavior via long-term neurophysiological recordings and underwent a modified multiple sleep latency test. Experiments were first performed in a healthy state and then during the progressive induction of a parkinsonian syndrome by intramuscular injections of low doses of MPTP. We observed an early onset of significant sleep/wake disturbances (i.e., before the appearance of motor symptoms). These disturbances resulted in (i) a disorganization of nighttime sleep with reduced deep sleep quality and (ii) an excessive daytime sleepiness characterized by sleep episodes occurring more rapidly in the morning and spreading through the middle of the day. The present study suggests that nighttime and daytime sleep/wake disturbances may appear early in the disease and should be considered in the development of biomarkers in further studies., (© 2022. The Author(s).)

The association between restless legs syndrome (RLS) and iron homeostasis remains unclear. We compared serum hepcidin and ferritin levels in patients with RLS and controls, and assessed their relationships with RLS phenotype, drug intake, and history of augmentation syndrome. 102 drug-free RLS patients (age 58.9 [24.5-77.2], 63 females) and 73 controls (age 56.8 [23.46-76.6], 45 females) underwent a polysomnography recording. Hepcidin levels were quantified by ELISA. 34 RLS patients had a second assessment after starting dopaminergic drugs. Ferritin level was low (< 50 µg/l) in 14.7% of patients and 25% of controls, with no between-group differences in the mean values. Hepcidin levels were higher in patients even after adjustment for confounding factors, and excluding participants with low ferritin levels. Ferritin and hepcidin levels were comparable before and after treatment, and between patients with (n = 17) and without history of augmentation. Ferritin and hepcidin levels correlated with age, body mass index, and periodic leg movements. Higher hepcidin levels were associated with older age, older age at RLS onset, less daytime sleepiness and familial RLS. In conclusion, serum hepcidin levels but not ferritin were higher in RLS patients regardless of treatment and history of augmentation. Serum hepcidin may be a more relevant biomarker of RLS than ferritin.

Hypothalamic orexin neurons are involved in various physiological functions, including thermoregulation. The orexinergic system has been considered as a potent mediator of the exercise response. The present study describes how the antagonization of the orexinergic system by a dual orexin receptor antagonist (DORA) modifies the thermoregulatory process during exercise. Core Body Temperature (CBT) and Spontaneous Locomotor Activity (SLA) of 12 male Wistar rats were recorded after either oral administration of DORA (30 mg/kg or 60 mg/kg) or placebo solution, both at rest and in exercise conditions with treadmill running. DORA ingestion decreased SLA for 8 hours (p < 0.001) and CBT for 4 hours (p < 0.01). CBT (°C) response was independent of SLA. The CBT level decreased from the beginning to the end of exercise when orexin receptors were antagonized, with a dose-dependent response (39.09 ± 0.36 and 38.88 ± 0.28 for 30 and 60 mg/kg; p < 0.001) compared to placebo (39.29 ± 0.31; p < 0.001). CBT increased during exercise was also blunted after DORA administration, but without dose effects of DORA. In conclusion, our results favor the role of orexin in the thermoregulation under stress related to exercise conditions.

Restless legs syndrome (RLS) is frequently comorbid with hypertension and cardiovascular diseases; however this relationship and underlying mechanisms remain controversial. After clinical evaluation, 84 drug-free patients with primary RLS (53 women; mean age 55.1 ± 12.3 years) and 76 controls (47 women; mean age 52.2 ± 15.3 years) underwent 24-hour ambulatory blood pressure (BP) and polysomnographic monitoring, and peripheral arterial tonometry to assess endothelial function for 61 patients and 69 controls. Hypertension was diagnosed in 11.9% of patients with RLS based on office measurement, and in 46.4% on the 24 h recording, with nighttime hypertension, two times more frequent than daytime hypertension. Periodic limb movement during sleep (PLMS), markers of sleep fragmentation, and systolic and mean BP non-dipping profile were more frequent among patients. BP non-dipping status was associated with older age, later RLS onset and diagnosis, RLS severity and higher sleep fragmentation. The mean 24-hour, daytime and nighttime BP values, the frequency of hypertension and the endothelial function were comparable between groups. However, both systolic and diastolic BP trajectories over a 24-hour period differed between groups. In conclusion, patients with RLS exhibit a 24-hour BP deregulation with increased frequency of systolic non-dipping profiles that could worsen the risk for CVD morbidity and mortality.

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

The pathophysiology of rapid eye movement sleep behavior disorder (RBD) associated with narcolepsy type 1 (NT1) is still poorly understood, potentially distinct from idiopathic RBD (iRBD), but may share affected common pathways. We investigated whether MIBG cardiac uptake differs between iRBD and NT1 comorbid with RBD. Thirty-four patients with NT1-RBD and 15 patients with iRBD underwent MIBG cardiac scintigraphy. MIBG uptake was measured by calculating the early and delayed heart to mediastinum (H/M) ratios. A delayed H/M ratio lower than 1.46 was considered abnormal based on a population of 78 subjects without neurological or cardiac diseases. Patients with iRBD were older, had an older RBD onset age and higher REM sleep phasic and tonic muscular activities than NT1-RBD. Lower delayed and early H/M ratios were associated with iRBD, but not with NT1-RBD, in crude and adjusted associations. The delayed H/M ratio differed between iRBD and controls, after adjustment, but not between patients with NT1-RBD and controls. In conclusion, the MIBG cardiac uptake difference between NT1-RBD and iRBD supports the hypothesis of different processes involved in RBD pathogenesis, providing for the first time a cardiac biomarker to differentiate those disorders.

Obstructive sleep apnea (OSA) occurs when the upper airway narrows or collapses due to the loss of upper airway muscle activation at sleep onset. This study investigated the effectiveness of triggered kinesthetic stimulation in patients with OSA. This proof-of-concept, open-label, multicenter prospective study was conducted on 24 patients with severe OSA. During a one night evaluation, kinesthetic stimulation was intermittently delivered in 30 minute periods. The duration of apneas and hypopneas during Stim on and Stim off periods were compared. Five hospital-based university centers in France participated. Sleep studies were evaluated by a single scorer at a core laboratory (CHU Grenoble). Results show that during the Stim on phases, statistically significant decreases in durations of apneas and hypopneas were observed in 56% and 46% of patients, respectively. Overall, 75% of patients showed an improvement in apneas or hypopneas durations. The mean reduction in durations for patients with a significant decrease was 4.86 seconds for apneas and 6.00 seconds for hypopneas. This proof of concept study is the first to identify kinesthetic stimulation as a potentially effective therapy for OSA. These data justify evaluation in a controlled study.

Excessive daytime sleepiness (EDS) is highly prevalent in the general population; however little is known about its evolution and predictors. Our objectives were to document its natural history, provide estimates of its prevalence, incidence and persistence rates, and to identify predictors of increased daytime sleepiness (DS) in a longitudinal community study of 2157 adults over 5 years. Participants completed postal assessment at baseline and at each yearly follow-up. DS was evaluated by the Epworth Sleepiness scale (ESS). At baseline, 33% reported EDS (ESS > 10) with 33% of them reported persistent EDS. Of those without EDS at baseline, 28% developed incident EDS (15% were persistent) and 31% increased DS (augmentation ≥4-points between two consecutive evaluations). Younger age and depression were independent predictors of incident EDS and DS increase while lower coffee consumption, smoking, insomnia, tiredness and chronic pain were associated with incident EDS, and living alone with DS increase only. Persistent vs transient EDS or DS showed association with poor general health including metabolic diseases. Thus, sleepiness fluctuated over time and it was predicted by common lifestyle and psychological factors potentially modifiable. However, persistent sleepiness was associated with chronic medical diseases thus highlighting a homogeneous group at risk requiring a dedicated management.

Restless Legs Syndrome (RLS) is a genetically complex neurological disorder in which overlapping genetic risk factors may contribute to the diversity and heterogeneity of the symptoms. The main goal of the study was to investigate, through analysis of heart rate variability (HRV), whether in RLS patients the MEIS1 polymorphism at risk influences the sympathovagal regulation in different sleep stages. Sixty-four RLS patients with periodic leg movement index above 15 per hour, and 38 controls underwent one night of video-polysomnographic recording. HRV in the frequency- and time- domains was analyzed during nighttime sleep. All RLS patients were genotyped, and homozygotes for rs2300478 in the MEIS1 locus were used for further analysis. Comparison of the sympathovagal pattern of RLS patients to control subjects did not show significant differences after adjustments for confounding factors in frequency-domain analyses, but showed an increased variability during N2 and N3 stages in time-domain analyses in RLS patients. Sorting of RLS patients according to MEIS1 polymorphism reconfirmed the association between MEIS1 and PLMS, and showed a significant increased sympathovagal balance during N3 stage in those homozygotes for the risk allele. RLS patients should be considered differently depending on MEIS1 genotype, some being potentially at risk for cardiovascular disorders.

I(125) radioimmunoassay (RIA) is currently the standard technique for quantifying cerebrospinal fluid (CSF) orexin-A/hypocretin-1, a biomarker used to diagnose narcolepsy type 1. However, orexin-A RIA is liable to undergo cross-reactions with matrix constituents generating interference, high variability between batches, low precision and accuracy, and requires special radioactivity precautions. Here we developed the first quantitative mass spectrometry assay of orexin-A based on a multiple reaction monitoring (MRM) approach. This method was tested in keeping with the Clinical and Laboratory Standards Institute (CLSI) guidelines and its clinical relevance was confirmed by comparing patients with narcolepsy type 1 versus patients with other neurological conditions. The results obtained using MRM and RIA methods were highly correlated, and Bland-Altman analysis established their interchangeability. However, the MRM values had a wider distribution and were 2.5 time lower than the RIA findings. In conclusion, this method of assay provides a useful alternative to RIA to quantify orexin-A, and may well replace it not only in narcolepsy type 1, but also in the increasing number of pathologies in which the quantification of this analyte is relevant.

Frequency and mechanisms underlying the association between narcolepsy type 1 (NT1) and psychosis remain unclear with potential role for a common immune pathway. We estimated the frequency of psychosis and its characteristics in NT1 at two European sleep centers (France, n = 381; Spain, n = 161) and measured IgG autoantibodies that recognize the GluN1 subunit of the NMDAR in 9 patients with NT1 with psychosis, and 25 NT1 patients without psychosis. Ten NT1 patients (6 in France, 4 in Spain) were diagnosed with comorbid psychosis, a frequency of 1.8%. One patient reported psychotic symptoms few months before narcolepsy onset, two patients few months after onset, and one patient one year after onset but after modafinil introduction. The six remaining patients reported long delays between NT1 and psychosis onset. Half the patients, mostly male adults, reported onset or worsening of psychotic symptoms after medication. We found no IgG antibodies to NR1/NR2B heteromers of the NMDARs in patients with NT1 with or without psychosis. To conclude, psychosis is rare in NT1, with limited evidence for a key impact of stimulants, and no association with anti-NMDAR antibodies. However, dramatic NT1 and schizophrenia exists especially in early onset NT1, which may lead to inappropriate diagnosis and management.

The evolutionary reasons for sleep remain controversial. The immune theory of sleep suggests that sleep is essential to the immune system, allowing organisms to allocate more energy to their immunity. This hypothesis was tested by exploring the links between excessive daytime sleepiness (EDS) and vulnerability to infectious diseases in a large (n = 9294) cohort of elderly individuals, with information on socio-demographics, daily habits, and medical characteristics. At the two-year and four-year follow-ups, we obtained individual data from the national healthcare insurance about all medications prescribed to the participants between 2001 and 2003 (n = 2865). We found an independent positive association between EDS and the consumption of some anti-pathogen drugs. This relationship was mostly explained by fungal and parasitic infections rather than by viral and bacterial ones. These results, although based on correlations, are consistent with the idea that EDS as a proxy of altered sleep quality/quantity may affect the efficiency of the immune system, and hence vulnerability to infections.