Publications by authors named "Yves Dauvilliers"

348 Publications

Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder.

J Parkinsons Dis 2021 Oct 19. Epub 2021 Oct 19.

Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.

Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy.

Objective: To examine the role of PSAP mutations in iRBD.

Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018).

Results: Two variants were stop mutations, p.Gln260Ter p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria was 98%or more.

Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.
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http://dx.doi.org/10.3233/JPD-212867DOI Listing
October 2021

Social Jetlag Changes During the COVID-19 Pandemic as a Predictor of Insomnia - A Multi-National Survey Study.

Nat Sci Sleep 2021 6;13:1711-1722. Epub 2021 Oct 6.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Purpose: Lifestyle and work habits have been drastically altered by restrictions due to the COVID-19 pandemic. Whether the associated changes in sleep timing modulate the risk of suffering from symptoms of insomnia, the most prevalent sleep disorder, is however incompletely understood. Here, we evaluate the association between the early pandemic-associated change in 1) the magnitude of social jetlag (SJL) - ie, the difference between sleep timing on working vs free days - and 2) symptoms of insomnia.

Patients And Methods: A total of 14,968 anonymous participants (mean age: 40 years; 64% females) responded to a standardized internet-based survey distributed across 14 countries. Using logistic multivariate regression, we examined the association between the degree of social jetlag and symptoms of insomnia, controlling for important confounders like social restriction extension, country specific COVID-19 severity and psychological distress, for example.

Results: In response to the pandemic, participants reported later sleep timing, especially during workdays. Most participants (46%) exhibited a reduction in their SJL, whereas 20% increased it; and 34% reported no change in SJL. Notably, we found that both increased and decreased SJL, as a result of the COVID-19 pandemic, were associated with later sleep midpoint (indicating a later chronotype) as well as more recurrent and moderate-to-severe symptoms of insomnia (about 23-54% higher odds ratio than subjects with unchanged SJL). Primarily those with reduced SJL shifted their bedtimes to a later timepoint, compared with those without changes in SJL.

Conclusion: Our findings offer important insights into how self-reported changes to the stability of sleep/wake timing, as reflected by changes in SJL, can be a critical marker of the risk of experiencing insomnia-related symptoms - even when individuals manage to reduce their social jetlag. These findings emphasize the clinical importance of analyzing sleep-wake regularity.
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http://dx.doi.org/10.2147/NSS.S327365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502537PMC
October 2021

Histamine in murine narcolepsy: What do genetic and immune models tell us?

Brain Pathol 2021 Oct 21:e13027. Epub 2021 Oct 21.

Sleep Team, Center for Research in Neuroscience of LYON, CNRS UMR5292, INSERM U1028, University of Lyon1, Bron, France.

An increased number of histaminergic neurons, identified by labeling histidine-decarboxylase (HDC) its synthesis enzyme, was unexpectedly found in patients with narcolepsy type 1 (NT1). In quest for enlightenment, we evaluate whether an increase in HDC cell number and expression level would be detected in mouse models of the disease, in order to provide proof of concepts reveling possible mechanisms of compensation for the loss of orexin neurons, and/or of induced expression as a consequence of local neuroinflammation, a state that likely accompanies NT1. To further explore the compensatory hypothesis, we also study the noradrenergic wake-promoting system. Immunohistochemistry for HDC, orexin, and melanin-concentrating hormone (MCH) was used to count neurons. Quantitative-PCR of HDC, orexin, MCH, and tyrosine-hydroxylase was performed to evaluate levels of mRNA expression in the hypothalamus or the dorsal pons. Both quantifications were achieved in genetic and neuroinflammatory models of narcolepsy with major orexin impairment, namely the orexin-deficient (Orex-KO) and orexin-hemagglutinin (Orex-HA) mice respectively. The number of HDC neurons and mRNA expression level were unchanged in Orex-KO mice compared to controls. Similarly, we found no change in tyrosine-hydroxylase mRNA expression in the dorsal pons between groups. Further, despite the presence of protracted local neuroinflammation as witnessed by the presence of reactive microglia, we found no change in the number of neurons nor the expression of HDC in Orex-HA mice compared to controls. Importantly, no correlation was found in all conditions between HDC and orexin. Our findings indicate that, in mice, the expression of histamine and noradrenalin, two wake-promoting systems, are not modulated by orexin level whether the lack of orexin is constitutive or induced at adult age, showing thus no compensation. They also show no recruitment of histamine by local neuroinflammation. Further studies will be needed to further define the role of histamine in the pathophysiology of NT1.
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http://dx.doi.org/10.1111/bpa.13027DOI Listing
October 2021

Idiopathic Hypersomnia Severity Scale to better quantify symptoms severity and their consequences in idiopathic hypersomnia.

J Clin Sleep Med 2021 Oct 4. Epub 2021 Oct 4.

CHU Montpellier, Hôpital Gui-de-Chauliac, Service de Neurologie, Unité du Sommeil, Centre National de Référence pour la Narcolepsie, Montpellier, France.

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: 226 (166 drug-free and 60 treated) patients with IH (cross-sectional sample) completed the 14-item IHSS to quantify the severity of the three 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 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 four clinically severity score levels. 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.
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http://dx.doi.org/10.5664/jcsm.9682DOI Listing
October 2021

How our Dreams Changed During the COVID-19 Pandemic: Effects and Correlates of Dream Recall Frequency - a Multinational Study on 19,355 Adults.

Nat Sci Sleep 2021 22;13:1573-1591. Epub 2021 Sep 22.

Institute for Consciousness and Dream Research, Vienna, Austria.

Objective: Many have reported odd dreams during the pandemic. Given that dreams are associated with mental health, understanding these changes could provide crucial information about wellbeing during the pandemic. This study explored associations between COVID-19 and dream recall frequency (DRF), and related social, health, and mental health factors.

Methods: We conducted a cross-sectional web survey of 19,355 individuals in 14 countries from May to July 2020. We collected data on COVID-19, mental health, sleep and DRF during the pandemic. We performed McNemar Tests to compare low (<3 nights per week) and high DRF (≥3 nights per week) before and during COVID-19 and to evaluate changes in sleep variables segmented by DRF. Chi-square tests were conducted to compare characteristics between low and high DRF. Logistic regression analyses were conducted to examine associations between various independent variables and DRF.

Results: Reports of high DRF during the pandemic were higher than before the pandemic (P<0.001). Female gender (aOR=1.25, 95% CI 1.10-1.41), nightmares (aOR=4.22, 95% CI 3.45-5.17), sleep talking (aOR= 2.36, 1.73-3.23), sleep maintenance problems (aOR=1.34, 95% CI 1.15-1.56), symptoms of REM sleep behavior disorder (RBD; aOR=1.24, 95% CI 1.09-1.41) and repeated disturbing thoughts (posttraumatic stress disorder (PTSD) symptoms) were associated with high DRF. Age group 55-64 years (aOR=0.69, 95% CI 0.58-0.83) reported less high DRF than younger participants. Unadjusted OR showed associations between depression, anxiety, and DRF; however, in adjusted regression depression (aOR= 0.71, 0.59-0.86) and anxiety (aOR=0.79, 95% CI 0.66-0.94) were negatively associated with high DRF.

Conclusion And Relevance: DRF was higher than pre-pandemic levels across four continents. DRF was associated with gender and parasomnias like nightmares and RBD symptoms, sleep maintenance problems, PTSD symptoms and negatively associated with depression and anxiety. The results implicate that COVID-19 is reflected in our dreams as an expression of the emotional intensity of the pandemic.
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http://dx.doi.org/10.2147/NSS.S324142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473566PMC
September 2021

A series of eight cases of sleep-related psychogenic dissociative disorders and proposed updated diagnostic criteria.

J Clin Sleep Med 2021 Sep 21. Epub 2021 Sep 21.

Minnesota Regional Sleep Disorders Center.

Study Objectives: To identify the most relevant clinical and video-polysomnographic (vPSG) characteristics of patients with sleep-related dissociative disorders (SRDDs) and to propose a framework for new diagnostic criteria.

Methods: We searched potential SRDD cases from the scientific literature and from a database of patients referred for clinical and vPSG assessment in a single sleep disorders center, for disruptive nocturnal behaviors (n=731). The most relevant clinical and neurophysiological characteristics of the cases were extracted and a descriptive analysis was performed.

Results: Twenty-six SRDD cases (8 new and 18 previously published cases) were reviewed. Almost all cases of SRDDs occurred in a context of past traumatic events or abuse and were associated with at least one comorbid psychiatric disorder. We highlighted four relevant clinical characteristics of SRDD useful for the differential diagnosis with parasomnias: episodes of long duration of more than one hour (90.9%), self-inflicted injuries (83.3%), occurrence while awake close to the bedtime (35.7%), and the presence of daytime dissociative symptoms (72.7%). The vPSG documented typical episodes of SRDD with prolonged wakefulness before, during, and after the event in 11/26 cases. New diagnostic criteria for SRDD were proposed, with three levels of certainty for the diagnosis based on clinical, vPSG and homemade video findings.

Conclusions: More than thirty years after its formal identification, SRDD is not currently recognized as an official diagnostic entity. We better delineate the clinical and neurophysiological features of SRDD and propose a framework for its reinstatement in the next revisions of the sleep and psychiatric disorders classifications.
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http://dx.doi.org/10.5664/jcsm.9654DOI Listing
September 2021

Insomnia, anxiety, and depression during the COVID-19 pandemic: an international collaborative study.

Sleep Med 2021 Aug 4;87:38-45. Epub 2021 Aug 4.

Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Importance And Study Objective: The COVID-19 pandemic has produced unprecedented changes in social, work, and leisure activities, which all have had major impact on sleep and psychological well-being. This study documented the prevalence of clinical cases of insomnia, anxiety, and depression and selected risk factors (COVID-19, confinement, financial burden, social isolation) during the first wave of the pandemic in 13 countries throughout the world.

Design And Participants: International, multi-center, harmonized survey of 22 330 adults (mean age = 41.9 years old, range 18-95; 65.6% women) from the general population in 13 countries and four continents. Participants were invited to complete a standardized web-based survey about sleep and psychological symptoms during the first wave of the COVID-19 pandemic from May to August 2020.

Results: Clinical insomnia symptoms were reported by 36.7% (95% CI, 36.0-37.4) of respondents and 17.4% (95% CI, 16.9-17.9) met criteria for a probable insomnia disorder. There were 25.6% (95% CI, 25.0-26.2) with probable anxiety and 23.1% (95% CI, 22.5-23.6) with probable depression. Rates of insomnia symptoms (>40%) and insomnia disorder (>25%) were significantly higher in women, younger age groups, and in residents of Brazil, Canada, Norway, Poland, USA, and United Kingdom compared to residents from Asian countries (China and Japan, 8% for disorder and 22%-25% for symptoms) (all Ps < 0.01). Proportions of insomnia cases were significantly higher among participants who completed the survey earlier in the first wave of the pandemic relative to those who completed it later. Risks of insomnia were higher among participants who reported having had COVID-19, who reported greater financial burden, were in confinement for a period of four to five weeks, and living alone or with more than five people in same household. These associations remained significant after controlling for age, sex, and psychological symptoms.

Conclusion And Relevance: Insomnia, anxiety, and depression were very prevalent during the first wave of the COVID-19 pandemic. Public health prevention programs are needed to prevent chronicity and reduce long-term adverse outcomes associated with chronic insomnia and mental health problems.
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http://dx.doi.org/10.1016/j.sleep.2021.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425785PMC
August 2021

Disrupted nighttime sleep and sleep instability in narcolepsy.

J Clin Sleep Med 2021 Aug 31. Epub 2021 Aug 31.

National Reference Network for Narcolepsy, Sleep and Wake Disorders Centre, Department of Neurology, Gui de Chauliac Hospital, Montpellier, France.

Study Objectives: This review aimed to summarize current knowledge about disrupted nighttime sleep (DNS) and sleep instability in narcolepsy, including self-reported and objective assessments, potential causes of sleep instability, health consequences and functional burden, and management.

Methods: One hundred and two peer-reviewed publications from a PubMed search were included.

Results: DNS is a key symptom of narcolepsy but has received less attention than excessive daytime sleepiness (EDS) and cataplexy. There has been a lack of clarity regarding the definition of DNS, as many sleep-related symptoms and conditions disrupt sleep quality in narcolepsy (eg, hallucinations, sleep paralysis, rapid eye movement sleep behavior disorder, nightmares, restless legs syndrome/periodic leg movements, nocturnal eating, sleep apnea, depression, anxiety). In addition, the intrinsic sleep instability of narcolepsy results in frequent spontaneous wakings and sleep stage transitions, contributing to DNS. Sleep instability likely emerges in the setting of orexin insufficiency/deficiency, but its exact pathophysiology remains unknown. DNS impairs quality of life among people with narcolepsy, and more research is needed to determine its contributions to cardiovascular risk. Multimodal treatment is appropriate for DNS management, including behavioral therapies, counseling on sleep hygiene, and/or medication. There is strong evidence showing improvement of self-reported sleep quality and objective sleep stability measures with sodium oxybate, but rigorous clinical trials with other pharmacotherapies are needed. Treatment may be complicated by comorbidities, concomitant medications, and mood disorders.

Conclusions: DNS is a common symptom of narcolepsy deserving consideration in clinical care and future research.
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http://dx.doi.org/10.5664/jcsm.9638DOI Listing
August 2021

Sleep inertia measurement with the psychomotor vigilance task in idiopathic hypersomnia.

Sleep 2021 Aug 26. Epub 2021 Aug 26.

National Reference Centre for Orphan Diseases Narcolepsy Rare Hypersomnias, Sleep Unit, Department of Neurology, CHU Montpellier, Univ Montpellier, Montpellier, France.

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: Sixty-two (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 (7:00 PM, and 7:00, 7:30 and 11:00 AM) and three metrics were used: lapses, mean 1/Reaction Time (RT), 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 7:00 and 7:30AM, 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 7:00 and 7:30AM associated with severe sleep inertia and sleep drunkenness.

Conclusion: 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.
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http://dx.doi.org/10.1093/sleep/zsab220DOI Listing
August 2021

Evening-types show highest increase of sleep and mental health problems during the COVID-19 pandemic - Multinational study on 19,267 adults.

Sleep 2021 Aug 25. Epub 2021 Aug 25.

Department of Global Public Health and Primary Care, University of Bergen, and Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway.

Study Objectives: Individual circadian type is a ubiquitous trait defining sleep, with eveningness often associated with poorer sleep and mental health than morningness. However, it is unknown whether COVID-19 pandemic has differentially affected sleep and mental health depending on the circadian type. Here, the differences in sleep and mental health between circadian types are examined globally before and during the COVID-19 pandemic.

Methods: The sample collected between May and August 2020 across 12 countries/regions consisted of 19,267 adults with information on their circadian type. Statistical analyses were performed by using Complex Sample procedures, stratified by country and weighted by the number of inhabitants in the country/area of interest and by the relative number of responders in that country/area.

Results: Evening-types had poorer mental health, well-being, and quality of life or health than other circadian types during the pandemic. Sleep-wake schedules were delayed especially on working days, and evening-types reported an increase in sleep duration. Sleep problems increased in all circadian types, but especially among evening-types, moderated by financial suffering and confinement. Intermediate-types were less vulnerable to sleep changes, although morningness protected from most sleep problems. These findings were confirmed after adjusting for age, sex, duration of the confinement or socio-economic status during the pandemic.

Conclusions: These findings indicate an alarming increase in sleep and mental health problems, especially among evening-types as compared to other circadian types during the pandemic.
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http://dx.doi.org/10.1093/sleep/zsab216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499764PMC
August 2021

Once-Nightly Sodium Oxybate (FT218) Demonstrated Improvement of Symptoms in a Phase 3 Randomized Clinical Trial in Patients With Narcolepsy.

Sleep 2021 Aug 6. Epub 2021 Aug 6.

National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, Univ Montpellier, INM INSERM, Montpellier, France.

Study Objectives: To assess the efficacy and safety of FT218, a novel once-nightly formulation of sodium oxybate (ON-SXB), in patients with narcolepsy in the phase 3 REST-ON trial.

Methods: Narcolepsy patients aged ≥16 years were randomized 1:1 to uptitration of ON-SXB (4.5, 6, 7.5, and 9 g) or placebo. Three coprimary endpoints were change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression-Improvement rating, and weekly cataplexy attacks at 9, 7.5, and 6 g. Secondary endpoints included change from baseline on the Epworth Sleepiness Scale. Safety included adverse drug reactions and clinical laboratory assessments.

Results: In total, 222 patients were randomized; 212 received ≥1 dose of ON-SXB (n=107) or placebo (n=105). For the 3 coprimary endpoints and Epworth Sleepiness Scale, all 3 doses of ON-SXB demonstrated clinically meaningful, statistically significant improvement vs placebo (all P<0.001). For ON-SXB 9 g vs placebo, increase in mean sleep latency was 10.8 vs 4.7 min (LSMD [95% CI], 6.13 [3.52-8.75]), 72.0% vs 31.6% were rated much/very much improved on Clinical Global Impression-Improvement (OR [95% CI], 5.56 [2.76-11.23]), change in mean weekly number of cataplexy attacks was -11.5 vs -4.9 (LSMD [95% CI], -6.65 [-9.32 to -3.98]), and change in Epworth Sleepiness Scale was -6.5 and -2.7 (LSMD [95% CI], -6.52 [-5.47 to -2.26]). Common adverse reactions included nausea, vomiting, headache, dizziness, and enuresis.

Conclusions: ON-SXB significantly improved narcolepsy symptoms; its safety profile was consistent with SXB. ON-SXB conferred efficacy with a clearly beneficial single nighttime dose.
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http://dx.doi.org/10.1093/sleep/zsab200DOI Listing
August 2021

Identifying the best biomarkers for α-synucleinopathies.

Authors:
Yves Dauvilliers

Lancet Neurol 2021 08;20(8):593-594

National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, Montpellier, France; Institute of Neuroscience Montpellier (INM), University of Montpellier, Inserm, Montpellier, France. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(21)00201-5DOI Listing
August 2021

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 2021 Jul 20. Epub 2021 Jul 20.

University of California, San Diego, CA.

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: NCT02348593; NCT02348606.
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http://dx.doi.org/10.5664/jcsm.9550DOI Listing
July 2021

Symptom network analysis of the sleep disorders diagnostic criteria based on the clinical text of the ICSD-3.

J Sleep Res 2021 Jul 16:e13435. Epub 2021 Jul 16.

University Sleep Clinic, Services of Functional Exploration of the Nervous System, University Hospital of Bordeaux, Bordeaux, France.

The third edition of the International Classification of Sleep Disorders (ICSD-3) is the authoritative clinical text for the diagnosis of sleep disorders. An important issue of sleep nosology is to better understand the relationship between symptoms found in conventional diagnostic manuals and to compare classifications. Nevertheless, to our knowledge, there is no specific exhaustive work on the general structure of the networks of symptoms of sleep disorders as described in diagnostic manuals. The general aim of the present study was to use symptom network analysis to explore the diagnostic criteria in the ICSD-3 manual. The ICSD-3 diagnostic criteria related to clinical manifestations were systematically identified, and the units of analysis (symptoms) were labelled from these clinical manifestation diagnostic criteria using three rules ("Conservation", "Splitting", "Lumping"). A total of 37 of the 43 main sleep disorders with 160 units of analysis from 114 clinical manifestations in the ICSD-3 were analysed. A symptom network representing all individual ICSD-3 criteria and connections between them was constructed graphically (network estimation), quantified with classical metrics (network inference with global and local measures) and tested for robustness. The global measure of the sleep symptoms network shows that it can be considered as a small world, suggesting a strong interconnection between symptoms in the ICSD-3. Local measures show the central role of three kinds of bridge sleep symptoms: daytime sleepiness, insomnia, and behaviour during sleep symptoms. Such a symptom network analysis of the ICSD-3 structure could provide a framework for better systematising and organising symptomatology in sleep medicine.
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http://dx.doi.org/10.1111/jsr.13435DOI Listing
July 2021

Self-perceived sleep during the Maintenance of Wakefulness Test: how does it predict accidental risk in patients with sleep disorders?

Sleep 2021 Jun 26. Epub 2021 Jun 26.

University of Bordeaux, Sleep, Addiction and Neuropsychiatry, USR, Bordeaux, France.

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: 192 patients suffering from OSAS, idiopathic hypersomnia, narcolepsy, restless leg syndrome or insufficient sleep syndrome were included. 165 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<.05). Multivariate logistic regression showed that patients with more than two misjudgments had a 2.52-fold (95% CI, 1.07-5.95, P<.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.
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http://dx.doi.org/10.1093/sleep/zsab159DOI Listing
June 2021

European guideline and expert statements on the management of narcolepsy in adults and children.

Eur J Neurol 2021 09 25;28(9):2815-2830. Epub 2021 Jun 25.

Sleep Wake Centre SEIN, Heemstede, The Netherlands.

Background And Aim: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children.

Methods: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.

Results: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions.

Conclusion: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.
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http://dx.doi.org/10.1111/ene.14888DOI Listing
September 2021

European guideline and expert statements on the management of narcolepsy in adults and children.

J Sleep Res 2021 Jun 25:e13387. Epub 2021 Jun 25.

Sleep Wake Centre SEIN, Heemstede, The Netherlands.

Background And Purpose: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children.

Methods: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.

Results: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions.

Conclusion: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.
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http://dx.doi.org/10.1111/jsr.13387DOI Listing
June 2021

Hypocretin/Orexin, Sleep and Alzheimer's Disease.

Authors:
Yves Dauvilliers

Front Neurol Neurosci 2021 28;45:139-149. Epub 2021 May 28.

National Reference Centre for Orphan Diseases, Narcolepsy - Rare Hypersomnias, Sleep Unit, Department of Neurology, CHU Montpellier, University of Montpellier, Montpellier, France.

Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases. Recent findings suggest that sleep-wakefulness dysfunctions may predispose to neurodegenerative disorders such as Alzheimer's disease (AD), and vice versa. New theories on the link between sleep and β-amyloid and tau secretion, accumulation and clearance, and its interaction with hypocretins/orexins (key neuropeptides regulating wakefulness) suggest mechanistic ways to better understand the impact of sleep alterations in the pathogenesis of AD. Further studies should validate whether changes in circadian rhythm and sleep-wakefulness patterns could be used for early AD diagnosis and as prognostic markers for cognitive decline. Longitudinal studies are needed, not only to validate these biomarker interactions and to determine the cause-effect relationship and the role of sleep-wakefulness behavior in the regulation of amyloid plaque and neurofibrillary tangle formation, but also to identify the best sleep therapies and related preventive strategies for AD.
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http://dx.doi.org/10.1159/000514967DOI Listing
May 2021

Measurement of Narcolepsy Symptoms in School-Aged Children and Adolescents: The Pediatric Narcolepsy Severity Scale.

Neurology 2021 08 24;97(5):e476-e488. Epub 2021 May 24.

From the Sleep-Wake Disorders Unit (L.B., S.C., A.L.R., R.L., Y.D.), Department of Neurology, Gui-de-Chauliac Hospital; National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia, and Kleine-Levin Syndrome (L.B., S.C., A.L.R., R.L., C.P., Y.D.); INM (L.B., R.L., I.J., S.B., Y.D.), Université de Montpellier; Pediatric Sleep Centre (M.L.), Hospital Robert-Debré; and National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia, and Kleine-Levin Syndrome (M.L.), Paris, France.

Objective: We validated the Narcolepsy Severity Scale (NSS) in adults with narcolepsy type 1 (NT1) to quantify the severity, frequency, and consequences of the 5 key narcolepsy symptoms over the last month, and we now developed the Pediatric NSS (NSS-P); thus, the aims of this study were to assess NSS-P psychometric properties, validity, and reliability, and to evaluate its responsiveness to treatment in a well-characterized sample of children and adolescents with NT1.

Methods: The NSS was reformulated for children, and the item about driving was removed. The total score of the 14-item NSS-P ranges from 0 to 54, and higher scores reflect more severe disease. Children and adolescents (n = 209, 6-17 years of age) with NT1 diagnosed in 2 Reference Centers for Narcolepsy in France were consecutively asked to fill in the NSS-P. The scale was fully and correctly completed by 160 (10-18 years of age, 68 untreated). Moreover, 65 participants completed it twice (33 before/during treatment, and 32 under the same treatment). The NSS-P psychometric properties, score changes before/during treatment, and convergent validity with other clinical parameters were assessed.

Results: The NSS-P showed adequate psychometric properties with significant item-total score correlations. Factor analysis indicated a 4-factor solution with good reliability. The NSS-P score was lower in treated than untreated patients with a mean difference of 3.71 ± 1.45, with a minimum clinically important difference between untreated and treated patients in the longitudinal sample estimated at 4 points. Four severity levels were defined (mild, moderate, severe, very severe) with between-group differences related to treatment. The NSS-P total score was associated with self-reported sleepiness, insomnia, and depressive symptoms. Its temporal stability was satisfactory.

Discussion: We validated a brief instrument to assess NT1 symptom frequency, severity, and consequences in ≥10-year-old children and adolescents with 4 clinically relevant severity score ranges. This scale constitutes a relevant tool to improve and provide guidance for NT1 management in pediatric populations. The ease of administration, its good psychometric properties, and its sensitivity to detect symptom changes after treatment ensure future use of the NSS-P in clinical and research settings.
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http://dx.doi.org/10.1212/WNL.0000000000012272DOI Listing
August 2021

The association between high risk of sleep apnea, comorbidities, and risk of COVID-19: a population-based international harmonized study.

Sleep Breath 2021 06 28;25(2):849-860. Epub 2021 Apr 28.

Helsinki Sleep Clinic, Vitalmed Research Center, and Department of Neurosciences, Clinicum, University of Helsinki, Helsinki, Finland.

Purpose: Obstructive sleep apnea (OSA) may increase the risk of severe COVID-19; however, the level of potential modulation has not yet been established. The objective of the study was to determine the association between high risk of OSA, comorbidities, and increased risk for COVID-19, hospitalization, and intensive care unit (ICU) treatment.

Methods: We conducted a cross-sectional population-based web survey in adults in 14 countries/regions. The survey included sociodemographic variables and comorbidities. Participants were asked questions about COVID-19, hospitalization, and ICU treatment. Standardized questionnaire (STOP questionnaire for high risk of OSA) was included. Multivariable logistic regression was conducted adjusting for various factors.

Results: Out of 26,539 respondents, 20,598 (35.4% male) completed the survey. Mean age and BMI of participants were 41.5 ± 16.0 years and 24.0 ± 5.0 kg/m, respectively. The prevalence of physician-diagnosed OSA was 4.1% and high risk of OSA was 9.5%. We found that high risk of OSA (adjusted odds ratio (aOR) 1.72, 95% confidence interval (CI): 1.20, 2.47) and diabetes (aOR 2.07, 95% CI: 1.23, 3.48) were associated with reporting of a COVID-19 diagnosis. High risk for OSA (aOR 2.11, 95% CI: 1.10-4.01), being male (aOR: 2.82, 95% CI: 1.55-5.12), having diabetes (aOR: 3.93, 95% CI: 1.70-9.12), and having depression (aOR: 2.33, 95% CI: 1.15-4.77) were associated with increased risk of hospitalization or ICU treatment.

Conclusions: Participants at high risk of OSA had increased odds of having COVID-19 and were two times more likely to be hospitalized or treated in ICU.
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http://dx.doi.org/10.1007/s11325-021-02373-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079162PMC
June 2021

Responsiveness of Daytime Sleepiness and Fatigue Scales in Myotonic Dystrophy Type 1.

Can J Neurol Sci 2021 Apr 20:1-4. Epub 2021 Apr 20.

Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.

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.
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http://dx.doi.org/10.1017/cjn.2021.77DOI Listing
April 2021

2018 worldwide survey of health-care providers caring for patients with narcolepsy: WSS narcolepsy task force.

Sleep Med 2021 06 15;82:23-28. Epub 2021 Mar 15.

National Reference Network for Narcolepsy, Sleep-Wake Disorders Unit, Department of Neurology, Gui-de- Chauliac Hospital, CHU Montpellier, Univ Montpellier, Institute of Neuroscience INM INSERM, Montpellier, France.

Background: There are limited data available on regional differences in the diagnosis and management of narcolepsy. In order to better understand worldwide trends in clinical assessment and management of narcolepsy, a survey of health-care providers was conducted by the World Sleep Society Narcolepsy task force.

Methods: A total of 146 surveys that included items on the diagnosis and management of narcolepsy were completed by practitioners representing 37 countries.

Results: Most of the participants were from Europe, North America, Oceania, Asia and Latin America. A consistent approach to applying the diagnostic criteria of Narcolepsy was documented with the exception of measurement of CSF hypocretin-1, which has limited availability. While the majority of practitioners (58%) reported not using the test, 1% indicated always evaluating CSF hypocretin-1 levels. There was much variability in the availability of currently recommended medications such as sodium oxybate and pitolisant; modafinil and antidepressants were the most commonly used medications. Amphetamines were unavailable in some countries.

Conclusion: The results of the study highlight clinical and therapeutic realities confronted by worldwide physicians in the management of narcolepsy. While the diagnostic criteria of narcolepsy rely in part on the quantification of CSF hypocretin-1, few physicians reported having incorporated this test into their routine assessment of the condition. Regional differences in the management of narcolepsy appeared to be related to geographic availability and expense of the therapeutic agents.
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http://dx.doi.org/10.1016/j.sleep.2021.03.014DOI Listing
June 2021

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.

Ann Neurol 2021 07 7;90(1):62-75. Epub 2021 May 7.

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

Objective: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD).

Methods: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria.

Results: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups.

Interpretation: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.
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http://dx.doi.org/10.1002/ana.26085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252762PMC
July 2021

Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the gene loci.

Proc Natl Acad Sci U S A 2021 03;118(12)

Histocompatibility Department, Blood Center of the Community of Madrid, 28032 Madrid, Spain.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, = 8.6 × 10) within the 3'region of gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo = 0.15; < 2.0 × 10 at = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the polymorphisms in conjunction with reported birth difficulties may predispose to KLS.
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http://dx.doi.org/10.1073/pnas.2005753118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999876PMC
March 2021

A systematic analysis of ICSD-3 diagnostic criteria and proposal for further structured iteration.

Sleep Med Rev 2021 Aug 26;58:101439. Epub 2021 Jan 26.

Sleep Clinic, University Hospital of Bordeaux, 33 076 Bordeaux, France; USR CNRS 3413 SANPSY, University Hospital of Bordeaux, 33 076 Bordeaux, France. Electronic address:

The main objective of this theoretical review is to systematically analyze the type of International Classification of Sleep Disorders-3 (ICSD-3) diagnostic criteria by labeling each of them in order to propose an overview of the way in which the diagnostic criteria are organized. Labeling of diagnostic criteria using a rigorous iterative process of "aggregation" and "generalization" was conducted and inter-rater reliability calculation (Cohen's Kappa with three raters) was calculated. 241 criteria from 43 main sleep disorders of the ICSD-3 were labeled into nine types (Clinical manifestation 86.0% of sleep disorders, Objective markers 53.5%, Distress 30.2%, Disability 30.2%, Duration 30.2%, Frequency 58.1%, Age in 18.6%, Exclusion condition 81.4% and Associated condition 34.8%), with a high inter-rater reliability (Cohen's Kappa = 0.85). This analysis assumes that the structuring of the ICSD-3 diagnostic criteria is based on the Harmful Dysfunction Analysis (HDA). Some criteria correspond to the dysfunction part of the HDA while others refer to the harmful part. However, the approach does not seem to be homogeneous across the nosological classification. The use of a structured definition of sleep disorder and a framework to organize the ICSD diagnostic criteria is discussed with regard to the reliability and validity of criteria for diagnosing sleep disorders.
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http://dx.doi.org/10.1016/j.smrv.2021.101439DOI Listing
August 2021

Cardiovascular disorders in narcolepsy: Review of associations and determinants.

Sleep Med Rev 2021 Aug 23;58:101440. Epub 2021 Jan 23.

Sleep and Wake Disorders Centre, Department of Neurology, Gui de Chauliac Hospital, Montpellier, France; University of Montpellier, INSERM U1061, Montpellier, France.

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.
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http://dx.doi.org/10.1016/j.smrv.2021.101440DOI Listing
August 2021

Systematic assessment of autonomic symptoms in restless legs syndrome.

Sleep Med 2021 04 18;80:30-38. Epub 2021 Jan 18.

Sleep-Wake Disorders Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, France; National Reference Network for Narcolepsy, CHU Montpellier, France; Institute for Neurosciences of Montpellier INM, Univ Montpellier, INSERM, Montpellier, France. Electronic address:

Objectives: To compare the clinical features of autonomic dysfunction using the SCOPA-AUT questionnaire in untreated patients with restless legs syndrome (RLS) with controls, to identify factors associated with more severe autonomic symptoms, and to assess the effect of medication in patients.

Methods: The SCOPA-AUT questionnaire that evaluates cardiovascular, gastrointestinal, urinary, thermoregulatory, pupillomotor, and sexual dysfunctions was completed by 409 consecutive untreated patients with RLS (54.1 ± 14.5 y.o; 265 women) and 331 controls (59.0 ± 17.0; 161 women). Clinical and polysomnographic data were assessed in all patients. A subgroup of 57 patients were evaluated a second time after treatment (mostly dopaminergic agonist) after an interval of 0.88 ± 1.42 year.

Results: Compared to controls, untreated patients with RLS were younger, more often women, obese, with increased cardiovascular diseases (CVD). The SCOPA-AUT total score was higher in patients than controls in unadjusted and adjusted models. Patients had more autonomic symptoms in all subdomains of the scale (except for sexual dysfunction in men). These results were confirmed in a subgroup of 259 cases and age-sex-matched controls. Female gender, obesity, RLS severity, diabetes mellitus, CVD, sleepiness, insomnia and depressive symptoms but neither periodic legs movements during sleep (PLMS) nor objective sleep parameters were associated with high scores. Despite RLS and PLMS improvement, medication did not change total and subdomain scores.

Conclusions: Patients with RLS have frequent and large spectrum of autonomic symptoms, without effect of PLMS, sleep fragmentation and medication. These results suggest a global autonomic dysfunction in RLS that should be assessed more systematically in severe patients.
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http://dx.doi.org/10.1016/j.sleep.2021.01.017DOI Listing
April 2021

Cerebrospinal fluid monoamine levels in central disorders of hypersomnolence.

Sleep 2021 07;44(7)

Sleep-Wake Disorders Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France.

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.
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http://dx.doi.org/10.1093/sleep/zsab012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271127PMC
July 2021
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