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

Background and ObjectivesNarcolepsy type 1 (NT1) is an orphan brain disorder caused by the irreversible destruction of orexin neurons. Metabolic disturbances are common in patients with NT1 who have a body mass index (BMI) 10% to 20% higher than the general population, with one-third being obese (BMI >30 kg/m2). Besides the destruction of orexin neurons in NT1, the metabolic alterations in obese and nonobese patients with NT1 remain unknown. The aim of this study was to identify possible differences in plasma metabolic profiles between patients with NT1 and controls as a function of their BMI status.MethodsWe used a targeted liquid chromatography–mass spectrometry metabolomics approach to measure 141 circulating, low-molecular-weight metabolites in drug-free fasted plasma samples from 117 patients with NT1 (including 41 obese individuals) compared with 116 BMI-matched controls (including 57 obese individuals).ResultsCommon metabolites driving the difference between patients with NT1 and controls, regardless of BMI, were identified, namely sarcosine, glutamate, nonaylcarnitine (C9), 5 long-chain lysophosphatidylcholine acyls, 1 sphingolipid, 12 phosphatidylcholine diacyls, and 11 phosphatidylcholine acyl-akyls, all showing increased concentrations in NT1. Metabolite concentrations significantly affected by NT1 (n = 42) and BMI category (n = 40) showed little overlap (n = 5). Quantitative enrichment analysis revealed common metabolic pathways that were implicated in the NT1/control differences in both normal BMI and obese comparisons, namely glycine and serine, arachidonic acid, and tryptophan metabolism. The metabolites driving these differences were glutamate, sarcosine, and ornithine (glycine and serine metabolism); glutamate and PC aa C34:4 (arachidonic acid metabolism); and glutamate, serotonin, and tryptophan (tryptophan metabolism). Linear metabolite-endophenotype regression analyses highlight that as part of the NT1 metabolic phenotype, most of the relationships between the sleep parameters (i.e., slow-wave sleep duration, sleep latency, and periodic leg movement) and metabolite concentrations seen in the controls were lost.DiscussionThese results represent the most comprehensive metabolic profiling of patients with NT1 as a function of BMI and propose some metabolic diagnostic biomarkers for NT1, namely glutamate, sarcosine, serotonin, tryptophan, nonaylcarnitine, and some phosphatidylcholines. The metabolic pathways identified offer, if confirmed, possible targets for treatment of obesity in NT1.Classification of EvidenceThis study provides Class II evidence that a distinct metabolic profile can differentiate patients with NT1 from patients without the disorder.

Following severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine1,2, European health authorities have recommended that patients under the age of 55 who received one dose of ChAdOx1-S-nCoV-19 vaccine receive a second dose of Pfizer BNT162b2 vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here, we show that the heterologous ChAdOx1-S-nCoV-19/BNT162b2 combination confers better protection against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection than the homologous BNT162b2/BNT162b2 combination in a real-world observational study of healthcare workers (n=13121). To understand the underlying mechanism, we conducted a longitudinal survey of the anti-spike immunity conferred by each vaccine combination. Both combinations induced strong anti-spike antibody (Ab) responses but sera from heterologous vaccinated individuals displayed a stronger neutralizing activity, regardless of the SARS-CoV-2 variant. This enhanced neutralizing potential was correlated with increased frequencies of switched and activated memory B cells recognizing the SARS-CoV-2 Receptor Binding Domain (RBD). The ChAdOx1-S-nCoV-19 vaccine induced a weaker IgG response but a stronger T cell response than the BNT162b2 vaccine after the priming dose, which could explain the complementarity of both vaccines when used in combination. The heterologous vaccination regimen could therefore be particularly suitable for immune compromised individuals.

Despite progress in the prevention of pressure injuries (PIs), they remain a challenging public health problem because of their frequency and morbidity. Protection of the skin by multilayer silicone foam dressings may be an adjuvant measure to prevent PIs in high-risk patients. Despite the available clinical data and published recommendations on this measure, caregivers face difficulties in identifying patients who would benefit from this adjuvant measure. The objective of this work was to define the profiles of high-risk patients who would benefit optimally from this measure in combination with basic preventive procedures. This consensual expert opinion was drawn up using two methods: the Nominal Group Technique with eight medical and paramedical experts, and the Delphi process with 16 experts. The bases for this expert consensual opinion were a formal search and analysis of the published literature regarding evidence on the prevention of PIs using multilayer silicone foam dressings. The consensual expert opinion reported here addresses five proposals mostly intended to define patients who would benefit from the use of a multilayer silicone foam dressing (≥4 layers) to prevent PIs (sacrum and heels).

ObjectiveWe 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.MethodsThe 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.ResultsThe 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.DiscussionWe 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.

ObjectivesTo highlight the slow-wave sleep (SWS) fragmentation and validate the video-polysomnographic (vPSG) criteria and cutoffs for the diagnosis of disorders of arousal (DOA) in children, as already reported in adults.MethodsOne hundred children (66 boys, 11.0 ± 3.3 years) with frequent episodes of DOA and 50 nonparasomniac children (32 boys, 10.9 ± 3.9 years) underwent vPSG recording to quantify SWS characteristics (number of N3 sleep interruptions, fragmentation index, slow/mixed and fast arousal ratios, and indexes per hour) and associated behaviors. We compared SWS characteristics in the 2 groups and defined the optimal cutoff values for the diagnosis of DOA using receiver operating characteristic curves.ResultsPatients with DOA had higher amounts of N3 and REM sleep, number of N3 interruptions, SWS fragmentation, and slow/mixed arousal indexes than controls. The highest area under the curve (AUC) values were obtained for SWS fragmentation and slow/mixed arousal indexes with satisfactory classification performances (AUC 0.80, 95% confidence interval [CI] 0.73–0.87; AUC 0.82, 95% CI 0.75–0.89). SWS fragmentation index cutoff value of 4.1/h reached a sensitivity of 65.0% and a specificity of 84.0%. Slow/mixed arousal index cutoff of 3.8/h reached a sensitivity of 69.0% and a specificity of 82.0%. At least one parasomniac episode was recorded in 63.0% of patients and none of the controls. Combining behavioral component by vPSG increased sensitivity of both biomarkers to 83% and 89%, respectively.ConclusionsWe confirmed that SWS fragmentation and slow/mixed arousal indexes are 2 relevant biomarkers for the diagnosis of DOA in children, with different cutoffs obtained than those validated in adults.Classification of EvidenceThis study provides Class III evidence that SWS fragmentation and slow/mixed arousal indexes on vPSG accurately identify children with DOA.

ObjectivesTo assess the frequency and determinants of depressive symptoms and suicidal thoughts in adults with narcolepsy type 1 (NT1) and controls, as well as the changes after NT1 management and the risk factors of major depressive episode (MDE) and suicide risk (SR) in NT1.MethodsTwo hundred ninety-seven patients with NT1 (age 39 ± 17 years, 172 drug-free) and 346 controls (age 38 ± 16 years) underwent a comprehensive clinical evaluation including the Beck Depression Inventory-II (BDI-II) self-questionnaire, with 1 item on suicidal thoughts. One hundred one drug-free patients with NT1 completed the BDI-II a second time during treatment. In 162 patients with NT1, the face-to-face Mini International Neuropsychiatric Interview was performed to formally diagnose current MDE and SR.ResultsBDI-II total scores were higher in patients with NT1 than controls and in untreated than treated patients. Patients with moderate to severe BDI-II scores (24.9%) were less educated, were more frequently obese, and had more severe narcolepsy symptoms, more autonomic dysfunctions, and poorer quality of life. Results were unchanged in models adjusted for NT1 medication intake. Suicidal thoughts were more frequent in untreated patients than controls (22.7% vs 12.4%). Patients with suicidal thoughts were more likely to be men and to have more severe narcolepsy symptoms. After narcolepsy management, BDI-II total score and suicidal thoughts decreased. MDE was diagnosed in 29 (18.1%) and SR in 27 (16.9%) patients.ConclusionsDepression, depressive symptoms, suicidal thoughts, and SR were frequent in patients with NT1, especially those without treatment, and were associated with NT1 severity. Depressive symptoms and suicidal thoughts improved after NT1 management.

STUDY OBJECTIVES: To identify the most relevant clinical and video-polysomnographic 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 video-polysomnographic 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 1 comorbid psychiatric disorder. We highlighted 4 relevant clinical characteristics of SRDD useful for the differential diagnosis with parasomnias: episodes of long duration of more than 1 hour (90.9%), self-inflicted injuries (83.3%), occurrence while awake close to bedtime (35.7%), and the presence of daytime dissociative symptoms (72.7%). The video-polysomnography 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 3 levels of certainty for the diagnosis based on clinical, video-polysomnographic, and homemade video findings. CONCLUSIONS: More than 30 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. CITATION: Lopez R, Lefevre L, Barateau L, Micoulaud-Franchi J-A, Dauvilliers Y, Schenck CH. A series of 8 cases of sleep-related psychogenic dissociative disorders and proposed updated diagnostic criteria. J Clin Sleep Med. 2022;18(2):563–573.

Purpose Deep learning methods (DLMs) have recently been proposed to generate pseudo-CT (pCT) for magnetic resonance imaging (MRI) based dose planning. This study aims to evaluate and compare DLMs (U-Net and generative adversarial network [GAN]) using various loss functions (L2, single-scale perceptual loss [PL], multiscale PL, weighted multiscale PL) and a patch-based method (PBM). Methods and Materials Thirty-nine patients received a volumetric modulated arc therapy for prostate cancer (78 Gy). T2-weighted MRIs were acquired in addition to planning CTs. The pCTs were generated from the MRIs using 7 configurations: 4 GANs (L2, single-scale PL, multiscale PL, weighted multiscale PL), 2 U-Net (L2 and single-scale PL), and the PBM. The imaging endpoints were mean absolute error and mean error, in Hounsfield units, between the reference CT (CTref) and the pCT. Dose uncertainties were quantified as mean absolute differences between the dose volume histograms (DVHs) calculated from the CTref and pCT obtained by each method. Three-dimensional gamma indexes were analyzed. Results Considering the image uncertainties in the whole pelvis, GAN L2 and U-Net L2 showed the lowest mean absolute error (≤34.4 Hounsfield units). The mean errors were not different than 0 (P ≤ .05). The PBM provided the highest uncertainties. Very few DVH points differed when comparing GAN L2 or U-Net L2 DVHs and CTref DVHs (P ≤ .05). Their dose uncertainties were ≤0.6% for the prostate planning target Volume V95%, ≤0.5% for the rectum V70Gy, and ≤0.1% for the bladder V50Gy. The PBM, U-Net PL, and GAN PL presented the highest systematic dose uncertainties. The gamma pass rates were >99% for all DLMs. The mean calculation time to generate 1 pCT was 15 s for the DLMs and 62 min for the PBM. Conclusions Generating pCT for MRI dose planning with DLMs and PBM provided low-dose uncertainties. In particular, the GAN L2 and U-Net L2 provided the lowest dose uncertainties together with a low computation time.

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

Adaptive radiotherapy (ART) is a complexe image-guided radiotherapy modality that comprises multiple planning to account for anatomical variations occurring during irradiation. Schematically, two strategies of RTA can be distinguished and combined according to tumor locations. One or more replanning can be proposed to correct systematic variations such as tumor shrinkage. A library of treatment plans with day-to-day plan selection from cone-beam CT imaging can also be proposed to correct random variations such as uterine motion or bladder/rectum volume changes. Because of strong anatomical variations occurring during irradiation, RTA appears therefore particularly justified in head and neck, lung, bladder, cervical and rectum and pancreas tumors, and to a lesser extent for prostate tumors and other digestive tumors. For these tumor locations, ART provides a fairly clear dosimetric benefit but a clinical benefit not yet formally demonstrated. ART cannot be proposed in a routine practice but must be evaluated medico-economically in the context of prospective trials. A rigorous quality control must be associated.

Purpose Methods have been recently developed to generate pseudo–computed tomography (pCT) for dose calculation in magnetic resonance imaging (MRI)–only radiation therapy. This study aimed to propose an original nonlocal mean patch-based method (PBM) and to compare this PBM to an atlas-based method (ABM) and to a bulk density method (BDM) for prostate MRI-only radiation therapy. Materials and Methods Thirty-nine patients received a volumetric modulated arc therapy for prostate cancer. In addition to the planning computed tomography (CT) scans, T2-weighted MRI scans were acquired. pCTs were generated from MRIs using 3 methods: an original nonlocal mean PBM, ABM, and BDM. The PBM was performed using feature extraction and approximate nearest neighbor search in a training cohort. The PBM accuracy was evaluated in a validation cohort by using imaging and dosimetric endpoints. Imaging endpoints included mean absolute error and mean error between Hounsfield units of the pCT and the reference CT (CTref). Dosimetric endpoints were based on dose-volume histograms calculated from the CTref and the pCTs for various volumes of interest and on 3-dimensional gamma analyses. The PBM uncertainties were compared with those of the ABM and BDM. Results The mean absolute error and mean error obtained from the PBM were 41.1 and –1.1 Hounsfield units. The PBM dose-volume histogram differences were 0.7% for prostate planning target volume V95%, 0.5% for rectum V70Gy, and 0.2% for bladder V50Gy. Compared with ABM and BDM, PBM provided significantly lower dose uncertainties for the prostate planning target volume (70-78 Gy), the rectum (8.5-29 Gy, 40-48 Gy, and 61-73 Gy), and the bladder (12-78 Gy). The PBM mean gamma pass rate (99.5%) was significantly higher than that of ABM (94.9%) or BDM (96.1%). Conclusions The proposed PBM provides low uncertainties with dose planned on CTref. These uncertainties were smaller than those of ABM and BDM and are unlikely to be clinically significant.

OBJECTIVE To determine whether brain amyloid burden in elderly patients with narcolepsy type 1 (NT1) is lower than in controls, and to assess in patients with NT1 the relationships between amyloid burden, cerebral spinal fluid (CSF) markers of Alzheimer disease (AD), CSF orexin-A, and cognitive profile. METHODS Cognitive and 18 F-florbetapir positron emission tomography (PET) data were compared in patients with NT1 aged ≥ 65 years (n = 23) and in age- and sex-matched controls free of clinical dementia selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 69) and the Multi-Domain Intervention Alzheimer's Prevention Trial (MAPT-18F AV45-PET; n = 23) cohorts. The standardized uptake values (SUVs) of the cortical retention index for 6 regions of interest were computed and averaged to create a mean SUV ratio normalized to 3 subcortical reference regions (cerebellum, pons, and a composite region). A cortical/cerebellum SUV ratio ≥ 1.17 defined positive PET amyloid. RESULTS Lower cortical amyloid burden was observed in the NT1 than in the ADNI and MAPT-AV45 groups (mean cortical/cerebellum SUV ratios = 0.95 ± 0.15, 1.11 ± 0.18 [p

International audience; Several approaches have been proposed to generate pseudo computed tomography (pCT) from MR images for radiotherapy dose calculation. Quantification of errors in pCT has been reported using global scores disregarding spatial heterogeneity. The aim of this work was to propose a population voxel-based workflow allowing the local assessment of errors in the generation of pCTs from MRI. For the voxel-wise analysis to be anatomically meaningful, a robust customized inter-patient non-rigid registration method brought the population images to the same coordinate system. To illustrate the use of this methodology, four pCT generation methods were compared: atlas-based, patch-based, and two deep learning methods. Considering global and local scores, deep learning appeared widely superior. Main source of errors were found in the cortical bones. The proposed workflow paves the way for quality control procedures within the clinical workflow. © 2021 IEEE.

International audience; 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.

International audience; PURPOSE: In radiotherapy, MRI is used for target volume and organs-at-risk delineation for its superior soft-tissue contrast as compared to CT imaging. However, MRI does not provide the electron density of tissue necessary for dose calculation. Several methods of synthetic-CT (sCT) generation from MRI data have been developed for radiotherapy dose calculation. This work reviewed deep learning (DL) sCT generation methods and their associated image and dose evaluation, in the context of MRI-based dose calculation. METHODS: We searched the PubMed and ScienceDirect electronic databases from January 2010 to March 2021. For each paper, several items were screened and compiled in figures and tables. RESULTS: This review included 57 studies. The DL methods were either generator-only based (45% of the reviewed studies), or generative adversarial network (GAN) architecture and its variants (55% of the reviewed studies). The brain and pelvis were the most commonly investigated anatomical localizations (39% and 28% of the reviewed studies, respectively), and more rarely, the head-and-neck (HandN) (15%), abdomen (10%), liver (5%) or breast (3%). All the studies performed an image evaluation of sCTs with a diversity of metrics, with only 36 studies performing dosimetric evaluations of sCT. CONCLUSIONS: The median mean absolute errors were around 76 HU for the brain and HandN sCTs and 40 HU for the pelvis sCTs. For the brain, the mean dose difference between the sCT and the reference CT was

Study Objectives Sleep-related head jerks (SRHJ) are often considered as a physiological motor phenomenon, occurring mainly during rapid eye movement (REM) sleep. Their clinical relevance and links with other sleep parameters are unclear. We characterized the clinical and polysomnographic features of patients with excessive SRHJ and compare them with healthy controls and patients with isolated REM sleep behavior disorder (iRBD). Methods A total of 30 patients (19 males, 27.5 y.o., 16.0–51.0) with a REM-HJ index >30/h were identified over a period of 5 years. All had a video-polysomnographic (PSG) recording to characterize the SRHJ, to assess associations with other sleep parameters and to quantify phasic and tonic electromyographic activity during REM sleep, compared with 30 healthy controls and 30 patients with iRBD. Results Five among the 30 patients had a primary complaint of involuntary nighttime head movements associated with sleepiness or non-restorative sleep. The mean REM-HJ index was 57.22/h ± 24.42, a nonperiodic pattern, stable across the sleep cycles, and with a low between-test variability (for the nine patients with two PSG assessments in untreated condition). REM-HJs were often associated with arousals (65.2%) and leg movements (38.1%) and less with respiratory events (9.6%), without association with increased phasic and tonic electromyographic activities. SRHJ were also found in 36.7% of controls and 56.7% of iRBD patients, but with a lower index in REM sleep (0.79/h ± 1.59 and 2.76/h ± 4.57). Conclusions Although SRHJ are frequent in the general population and with uncertain clinical significance, rare severe symptomatic forms should be individualized and eventually be categorized as a new sleep-related movement disorder, distinct from RBD and periodic leg movements.

Primary Sjögren’s syndrome (pSS) is an autoimmune disease, associated with a high risk of lymphoma. Mounting evidence suggests that cardiovascular morbidity and mortality are higher in patients with pSS, although data are heterogeneous. The aim of this study was to assess whether pSS patients are at higher risk of hospitalisation for cardiovascular events (CVEs), venous thromboembolic events (VTEs), pulmonary hypertension (PH), and sleep apnoea syndrome (SAS). Through a nationwide population-based retrospective study using the French health insurance database, we selected new-onset pSS in-patients hospitalised between 2011 and 2018. We compared the incidence of CVEs (ischemic heart diseases (IHDs), strokes, and heart failure), SAS, VTEs, and PH with an age- and sex-matched (1:10) hospitalised control group. The calculations of adjusted hazard ratios (aHR) included available confounding factors. We studied 25,661 patients hospitalised for pSS compared with 252,543 matched patients. The incidence of hospitalisation for IHD, SAS, and PH was significantly higher in pSS patients (aHR: 1.20 (1.06–1.34), p = 0.003, aHR: 1.97 (1.70–2.28), p &lt, 0.001, and aHR: 3.32 (2.10–5.25), 0.001, respectively), whereas the incidence of stroke, heart failure, and VTE was the same between groups. Further prospective studies are needed to confirm these results and to explore the pathophysiological mechanisms involved.

The destruction of orexin/hypocretin neurons results in the sleep disorder narcolepsy type 1 (NT1). Formerly known as narcolepsy with cataplexy, the major clinical features of NT1 are excessive daytime sleepiness (EDS), cataplexy, and other rapid eye movement (REM) sleep phenomena (e.g., sleep paralysis and sleep-related hallucinations). Orexin neurons are located exclusively in the lateral hypothalamus, but project widely through the brain, and especially in hypothalamic and brainstem structures that play a central role in autonomic and cardiovascular regulation. This chapter focuses on the pathophysiological mechanisms underlying dysautonomia in narcolepsy, related to orexin deficiency, and the clinical aspects of autonomic impairment in narcolepsy. A general overview of dysautonomia in other central hypersomnolence disorders (narcolepsy type 2, idiopathic hypersomnia, and Kleine-Levin syndrome) is provided, with clinical implications discussed.

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

International audience; Objective: The objective of this study was to assess the rotigotine effect on the nocturnal blood pressure (BP) dip by 24-hour ambulatory BP monitoring and on endothelial function in patients with restless legs syndrome (RLS) compared with placebo.Methods: In this double-blind, placebo-controlled trial, 76 adult patients with moderate to severe RLS and periodic legs movements in sleep index ≥10/hour were randomized to rotigotine at optimal dose of 3 mg per day or placebo for 6 weeks. A total of 6 patients had a major protocol deviation. Polysomnography, ambulatory BP monitoring, and endothelial function were assessed at baseline and end point. The primary outcome was the between-group difference in the percentage of BP nondipper profiles at end point. The main secondary outcomes were the mean BP dip, periodic legs movements in sleep index, and endothelial function.Results: Of the 70 patients (age, 59.4 ± 11.40; 43 women) randomized to rotigotine (n = 34) and placebo (n = 36), 66 (33 rotigotine, 33 placebo) completed the study. The percentage of BP nondippers at end point was higher in the placebo than in the rotigotine group (systolic BP, 72.22% vs 47.06%; diastolic BP, 47.22% vs 20.59%; P < 0.05). Mean BP dip at end point was higher in the rotigotine than in the placebo group (systolic BP, 11.24 ± 6.15 vs 6.12 ± 7.98; diastolic BP, 15.12 ± 7.09 vs 9.36 ± 10.23; P < 0.05). Endothelial function was comparable between the groups. No significant safety concerns were reported with similar incidences of adverse events between groups.Conclusion: Rotigotine increased the percentage of BP dipper profiles and the BP dip in patients with RLS. Future studies should assess whether this change is associated with a reduction in the long-term cardiovascular risk in RLS. © 2020 International Parkinson and Movement Disorder Society.

Objective Deep-tendon reflexes are abolished during generalized cataplexy, but whether this is the case in partial cataplexy currently remains unknown. Partial cataplexy may mimic other neurologic/psychiatric phenomena, and knowledge of the reflexes status may provide information for differential diagnosis. We assessed whether deep-tendon reflexes are persistent during partial cataplexy. Methods Five drug-free patients with typical diagnoses of narcolepsy and clear-cut partial cataplexy were diagnosed in Reference Narcolepsy Centers in France and Italy. Biceps and patellar reflexes were elicited by physicians in charge and video-documented during cataplexy. Reflexes were assessed several times for each patient in different conditions and for various localizations of cataplexy. Results The absence of tendon reflexes and complete loss of muscle tone during generalized cataplexy was confirmed, but the persistence of those reflexes during several partial cataplectic attacks at different ages, gender, localization of cataplexy (upper limbs, face) and reflexes (biceps, patellar) in drug-naive or withdrawal conditions was documented. Conclusion The persistence of tendon reflexes during several partial cataplexy episodes contrasts with their absence during generalized cataplexy. This discovery has clinical implications: the persistence of tendon reflexes does not rule out cataplexy diagnosis for partial attacks, whereas their transient abolishment or persistence during generalized attacks indicates cataplexy or pseudocataplexy, respectively.

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 rapideye-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 EU-NN database is financed by the EU-NN. The EU-NN has received financial support from UCB Pharma Brussels for developing the EU-NN database.

International audience; Adaptive radiotherapy (ART) corresponds to various replanning strategies aiming to correct for anatomical variations occurring during the course of radiotherapy. The goal of the article was to report the rational, feasibility and benefit of using PET and/or MRI to guide this ART strategy in various tumor localizations. The anatomical modifications defined by scanner taking into account tumour mobility and volume variation are not always sufficient to optimise treatment. The contribution of functional imaging by PET or the precision of soft tissue by MRI makes it possible to consider optimized ART. Today, the most important data for both PET and MRI are for lung, head and neck, cervical and prostate cancers. PET and MRI guided ART appears feasible and safe, however in a very limited clinical experience. Phase I/II studies should be therefore performed, before proposing cost-effectiveness comparisons in randomized trials and before using the approach in routine practice.

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.

Study Objectives Rhythmic movements (RMs) during sleep are frequent and often considered as benign in children. Disabling forms are diagnosed as RM disorder and may persist in adulthood. Whether RMs severely impact sleep architecture in patients with RM disorder remain unclear. We performed a case–control study to characterize the clinical and polysomnographic patterns of children and adults with a diagnosis of RM disorder in comparison to controls, and to assess the associations between the RMs and the sleep architecture. Methods All consecutive patients (n = 50; 27 children, 35 males) with RM disorder from a single sleep clinic (from 2006 to 2019) underwent a comprehensive clinical evaluation and a polysomnographic recording in comparison to 75 controls (42 children and 53 males). Results About 82% of children and adult patients had a complaint of disturbed nighttime sleep. Comorbid neurodevelopmental, affective or sleep disorders were found in 92% of patients. While RM sequences defined by video polysomnographic criteria were observed in 82% of patients (in wakefulness and in all sleep stages), no similar sequences were observed in controls. Patients had altered sleep continuity, with low sleep efficiency, increased wake time after sleep onset, and frequent periodic leg movements and apnea events. The severity of RMs was associated with disrupted nighttime sleep, even after controlling for comorbid motor and respiratory events. Conclusions RM disorder is a rare, highly comorbid and disabling condition both in children and adults with frequent disturbed nighttime sleep that may contribute to the burden of the disease.

Objectives To investigate whether cerebrospinal fluid (CSF) and serum ferritin levels differ between patients with narcolepsy type 1 (NT1) comorbid with restless legs syndrome (RLS) or periodic leg movements during sleep (PLMS), and patients with NT1 or controls without comorbid RLS or PLMS. Methods Sixty‐six drug‐free patients with NT1 (44 males, age 38.5 years [14–81]) were enrolled, including 20 with RLS, 18 with PLMS index ≥15/h (six with both RLS and PLMS). Thirty‐eight drug‐free patients (12 males, age 22.5 years [12–61]) referred for sleepiness complaint, but without central hypersomnia, RLS, PLMS were included as controls. Clinical, electrophysiological and biological (CSF/serum ferritin, orexin [ORX]) data were quantified. Results NT1 patients with and without RLS did not differ for age, gender, and body mass index (BMI). No between‐group differences were found for CSF ferritin, ORX, and serum ferritin levels. No CSF ferritin, ORX, and serum ferritin level differences were found between NT1 patients with and without PLMS, or with RLS or PLMS versus not. CSF‐ferritin levels were not different between NT1 and controls in adjusted analyses. CSF‐ferritin levels in the whole population correlated positively with age, serum‐ferritin, BMI, negatively with ORX, but not with PLMS index. In NT1, CSF‐ferritin levels correlated with age and serum‐ferritin but not with PLMS. Conclusion The absence of CSF ferritin deficiency in NT1 with comorbid RLS or PLMS indicates normal brain iron levels in that condition. This result suggests that the frequent association between RLS, PLMS, and NT1 is not based on alterations in brain iron metabolism, a pathophysiological mechanism involved in primary RLS.

International audience; Purpose - To guide parotid gland (PG) sparing at the dose planning step, a specific model based on overlap between PTV and organ at risk (Moore et al.) was developed and evaluated for VMAT in head-and-neck (H&N) cancer radiotherapy. Materials and methods - One hundred and sixty patients treated for locally advanced H&N cancer were included. A model optimization was first performed (20 patients) before a model evaluation (110 patients). Thirty cases were planned with and without the model to quantify the PG dose sparing. The inter-operator variability was evaluated on one case, planned by 12 operators with and without the model. The endpoints were PG mean dose (D), PTV homogeneity and number of monitor units (MU). Results - The PG D predicted by the model was reached in 89% of cases. Using the model significantly reduced the PG D: -6.1±4.3Gy. Plans with the model showed lower PTV dose homogeneity and more MUs (+10.5% on average). For the inter-operator variability, PG dose volume histograms without the optimized model were significantly different compared to those with the model; the D standard deviation for the ipsilateral PG decreased from 2.2Gy to 1.2Gy. For the contralateral PG, this value decreased from 2.9Gy to 0.8Gy. Conclusion - During the H&N inverse planning, the optimized model guides to the lowest PG achievable mean dose, allowing a significant PG mean dose reduction of -6.1Gy. Integrating this method at the treatment-planning step significantly reduced the inter-patient and inter-operator variabilities.

Study Objectives To define clinically relevant Narcolepsy Severity Scale (NSS) score ranges, confirm its main performances and sensitivity to medications, and determine whether items need to be weighted. Methods One hundred and forty-three consecutive untreated and 238 treated adults with narcolepsy type 1 (NT1) completed the NSS, a 15-item self-administered questionnaire (score: 0–57) that assesses the severity and consequences of the five major narcolepsy symptoms such as daytime sleepiness, cataplexy, hallucinations, sleep paralysis, and disturbed nighttime sleep (DNS). They also completed the Epworth Sleepiness scale (ESS; daytime sleepiness), Beck Depression Inventory (BDI; depressive symptoms), and EQ5D (quality of life). Results The mean symptom number (4.3 vs 3.5), NSS total score (33.3 ± 9.4 vs 24.3 ± 10.2), and number of narcolepsy symptoms (five symptoms: 53.1% vs 24.8%; four symptoms: 26.6% vs 22.7%; three symptoms: 15.4% vs 32.4%; two symptoms: 4.9% vs 20.2%) were significantly different between untreated and treated patients (p < 0.0001). DNS was often the third symptom (95.5 per cent). The symptom number was associated with diagnosis delay, age at onset, and ESS and BDI scores. Comparisons with ESS, BDI and EQ5D showed that NSS item weighting was not necessary to highlight between-group differences. Four NSS severity levels were defined (mild, moderate, severe, and very severe) with between-group differences related to treatment. The probability of having ESS ≥ 16, BDI ≥ 20, and EQ-5D < 60 increased with the severity level. Conclusion NSS is valid, reliable, and responsive to treatment in patients with NT1, with four clinically relevant severity score ranges provided. NSS has adequate clinimetric properties for broadening its use for both clinic and research.

Increased incidence rates of narcolepsy type 1 (NT1) after the 2009-2010 H1N1 influenza pandemic (pH1N1) have been reported world-wide. While some European countries found an association between the NT1 increase and H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus rather than Pandemrix to be linked with the increase of new NT1 cases. We analyzed the number of de-novo NT1 cases in the last two decades until 2016 using the European Narcolepsy Network (EU-NN) database. Using robust data-driven modelling approaches we confirmed the peak of NT1 incidence in 2009-2010 pH1N1 and identified a new peak in 2013 that is age-specific for children/adolescents. Most of these de-novo cases showed a subacute disease onset consistent with an immune-mediated type of narcolepsy, which is most likely not related to Pandemrix vaccination that was used in 2009-2010, but may have been triggered by some new epidemiological event in Europe. Our finding of an unexpected peak in de-novo children narcolepsy in 2013 provides a unique opportunity to develop new hypotheses, such as considering other (influenza) viruses to further investigate the pathophysiology of immune-mediated narcolepsy.

International audience; Purpose Anatomical variations occur during head and neck (HandN) radiotherapy treatment. kV cone-beam computed tomography (CBCT) images can be used for daily dose monitoring to assess dose variations owing to anatomic changes. Deep learning methods (DLMs) have recently been proposed to generate pseudo-CT (pCT) from CBCT to perform dose calculation. This study aims to evaluate the accuracy of a DLM and to compare this method with three existing methods of dose calculation from CBCT in HandN cancer radiotherapy. Methods Forty-four patients received VMAT for HandN cancer (70-63-56 Gy). For each patient, reference CT (Bigbore, Philips) and CBCT images (XVI, Elekta) were acquired. The DLM was based on a generative adversarial network. The three compared methods were (a) a method using a density to Hounsfield Unit (HU) relation from phantom CBCT image (HU-D curve method), (b) a water-air-bone density assignment method (DAM), and iii) a method using deformable image registration (DIR). The imaging endpoints were the mean absolute error (MAE) and mean error (ME) of HU from pCT and reference CT (CTref). The dosimetric endpoints were dose discrepancies and 3D gamma analyses (local, 2%/2 mm, 30% dose threshold). Dose discrepancies were defined as the mean absolute differences between DVHs calculated from the CT(ref)and pCT of each method. Results In the entire body, the MAEs and MEs of the DLM, HU-D curve method, DAM, and DIR method were 82.4 and 17.1 HU, 266.6 and 208.9 HU, 113.2 and 14.2 HU, and 95.5 and -36.6 HU, respectively. The MAE obtained using the DLM differed significantly from those of other methods (Wilcoxon,P

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

International audience; Background: Despite cognitive-behavioral therapy for insomnia (CBT-I) being the recommended treatment for insomnia disorder, its access remains very limited. Automated Internet-delivered CBT-I (eCBT-I) is an emerging cost-effective strategy for adults with insomnia, however no such program is currently available in French Language. We evaluated a French-speaking, eCBT-I intervention to improve insomnia disorder in comparison to minimal psychoeducation therapy (mPT). Methods: Forty-six adults with insomnia disorder were randomly allocated to eCBT-I or mPT. The eCBT-I program consisted of seven sessions that delivered the typical components of CBT-I during 12 weeks. The mPT provided structured and non-tailored information about sleep and insomnia during a 1 h session. Insomnia severity Index (ISI, primary outcome), measures of fatigue, sleepiness, anxiety, depressive symptoms and quality of life were collected at baseline and endpoint. Electronic sleep diaries were completed over 2 week periods pre- and post-intervention. Results: Compared to mPT, eCBT-I resulted in greater decrease in ISI scores between baseline and endpoint. Sleep diaries parameters improved in both groups, with a greater improvement in the eCBT-I group. Patients allocated to eCBT-I group also improved depressive, fatigue, anxiety symptoms, and quality of life. Among patients with CNS-active drug at baseline, 91.7% reduced or stopped their hypnotic medication, and 16.7% in the mPT group. Conclusions: The present eCBT-I program seems feasible, acceptable and effective in reducing insomnia severity and insomnia-related functional outcomes in this small clinically-derived population. Given the high prevalence of insomnia, our data are supportive of the use of such program as an effective alternative to treat insomnia in daily clinical practice in French speaking countries.

In external beam radiotherapy, the dose planning is currently based on computed tomography (CT) images. A relation between Hounsfield numbers and electron densities (or mass densities) is necessary for dose calculation taking heterogeneities into account. In image-guided radiotherapy process, the cone beam CT is classically used for tissue visualization and registration. Cone beam CT for dose calculation is also attractive in dose reporting/monitoring perspectives and particularly in a context of dose-guided adaptive radiotherapy. The accuracy of cone beam CT-based dose calculation is limited by image characteristics such as quality, Hounsfield numbers consistency and restrictive sizes of volume acquisition. The analysis of the literature identifies three kinds of strategies for cone beam CT-based dose calculation: establishment of Hounsfield numbers versus densities curves, density override to regions of interest, and deformable registration between CT and cone beam CT images. Literature results show that discrepancies between the reference CT-based dose calculation and the cone beam CT-based dose calculation are often lower than 3%, regardless of the method. However, they can also reach 10% with unsuitable method. Even if the accuracy of the cone beam CT-based dose calculation is independent of the method, some strategies are promising but need improvements in the automating process for a routine implementation.

Objective To assess the diagnostic value of extended sleep duration on a controlled 32-hour bed rest protocol in idiopathic hypersomnia (IH). Methods One hundred sixteen patients with high suspicion of IH (37 clear-cut IH according to multiple sleep latency test criteria and 79 probable IH), 32 with hypersomnolence associated with a comorbid disorder (non-IH), and 21 controls underwent polysomnography, modified sleep latency tests, and a 32-hour bed rest protocol. Receiver operating characteristic curves were used to find optimal total sleep time (TST) cutoff values on various periods that discriminate patients from controls. Results TST was longer in patients with clear-cut IH than other groups (probable IH, non-IH, and controls) and in patients with probable IH than non-IH and controls. The TST cutoff best discriminating clear-cut IH and controls was 19 hours for the 32-hour recording (sensitivity = 91.9%, specificity = 85.7%) and 12 hours (100%, 85.7%) for the first 24 hours. The 19-hour cutoff displayed a specificity and sensitivity of 91.9% and 81.2% between IH and non-IH patients. Patients with IH above the 19-hour cutoff were overweight, had more sleep inertia, and had higher TST on all periods compared to patients below 19 hours, whereas no differences were found for the 12-hour cutoff. An inverse correlation was found between the mean sleep latency and TST during 32-hour recording in IH patients. Interpretation In standardized and controlled stringent conditions, the optimal cutoff best discriminating patients from controls was 19 hours over 32 hours, allowing a clear-cut phenotypical characterization of major interest for research purposes. Sleepier patients on the multiple sleep latency test were also the more severe in terms of extended sleep. Ann Neurol 2018;83:235-247.

Objective To assess video-polysomnographic (vPSG) criteria and their cutoff values for the diagnosis of disorders of arousal (DOAs; sleepwalking, sleep terror). Methods One hundred sixty adult patients with DOAs and 50 sex- and age-matched healthy participants underwent a clinical evaluation and vPSG assessment to quantify slow wave sleep (SWS) interruptions (SWS fragmentation index, slow/mixed and fast arousal ratios, and indexes per hour) and the associated behaviors. First, a case-control analysis was performed in 100 patients and the 50 controls to define the optimal cutoff values using receiver operating characteristic curves. Their sensitivity was then assessed in the other 60 patients with DOAs. Results The SWS fragmentation index and the mixed, slow, and slow/mixed arousal indexes and ratios were higher in patients with DOAs than controls. The highest area under the curve (AUC) values were obtained for the SWS fragmentation and slow/mixed arousal indexes (AUC = 0.88 and 0.90, respectively). The SWS fragmentation index cutoff value of 6.8/h reached a sensitivity of 79% and a specificity of 82%. The slow/mixed arousal index had a sensitivity of 94% for the 2.5/h cutoff, and 100% specificity for 6/h. Both parameters showed good interrater agreement, and their sensitivities were confirmed in the second group of patients. Combining electroencephalographic parameters and video-based behavioral analyses increased the correct classification rate up to 91.3%. Interpretation Frequent slow/mixed arousals in SWS and complex behaviors during vPSG are strongly associated with DOAs, and could be promising biomarkers for the diagnosis of non-rapid eye movement parasomnias. Ann Neurol 2018;83:341-351.

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

Summary Introduction The aim of this study was to describe the implementation of interactive telemedicine in nursing homes (NHs) and to describe geriatric assessment performed during these acts. Patients and methods The design of the study was a retrospective descriptive study based on acts of interactive telemedicine in a total of 39 NHs located in the departments of Gironde and Dordogne, France. A total of 304 nursing home residents who benefited from interactive telemedicine acts because of complex situations such as behavioral disturbance related to dementia, chronic wounds, psychiatric disorders, chronic spasticity, or palliative care were included in this study. The following variables were collected: mean age, ADL (Katz) score, MMSE score, CIRS-G score, number of drugs intake per day, rate of avoided specialists request (consultation, planned or unplanned hospitalization) and rate of treatment optimizations during telemedicine. Data were analyzed with the statistical software SPSS 23. Results A total of 500 interactive telemedicine acts were analyzed and concerned: behavioral disturbance related to dementia (28.4%), complex chronic wounds (27.8%), dermatological pathologies (9.2%), psychiatric disorders (19.0%), situations of chronic spasticity (10%) and complex palliative care situations (2.8%). Interactive telemedicine avoided transfer to hospital in 378 (75.6%) cases [specialized consultations ( n = 264, 52.8%); programmed hospitalizations (day hospital and hospitalization, n = 110, 22.0%), and emergency admission ( n = 4, 0.8%)]. Inappropriate prescriptions were corrected in 351 cases (70.2%). Discussion and conclusion Telemedicine should be a relevant option to avoid and decrease return trips to the hospital for nursing home residents. These preliminary results also showed that beyond the reason for telemedicine, interactive telemedicine acts make it possible to carry out a global geriatric evaluation.

National audience; Intensity modulated radiotherapy combined with image guided radiotherapy has led to increase the precision of external beam radiotherapy. However, intra or inter-fraction anatomical variations are frequent during the treatment course and can cause under-dosing of the target volume and/or over-dosing of the organs at risk. Several adaptive radiotherapy (ART) strategies can be defined to compensate these anatomical variations. The purpose of this article is to provide an overview of available ART strategies: offline, online, hybrid (library of treatment plans) or in real-time, while considering the arrival of MR-Linac devices in radiotherapy departments. The tools required to these ART strategies such as auto-segmentation, deformable image registration, calculation of the daily dose or dose accumulation, are also described. Implementing an ART strategy requires a rigorous quality assurance process, at each stage and on the entire workflow, as well as prior organization and training from of all the trades. A strong multidisciplinary involvement is finally required in order to ensure ART treatments.

Objective To investigate the relationship between sensory discomfort/motor component and cardiovascular autonomic response by continuous beat-to-beat blood pressure monitoring (CBPM) during the suggested immobilization test (SIT) in patients with restless legs syndrome (RLS). Methods Thirty-two drug-free patients with primary RLS (10 men; mean age 60.29 ± 10.81 years) and 17 healthy controls (2 men; mean age 58.82 ± 11.86 years) underwent a 1-hour SIT starting at 8 pm with concomitant CBPM to measure the heart rate (HR) and systolic/diastolic blood pressure (SBP, DBP). In all subjects, the presence of sensory discomfort and motor component during the SIT (S-SIT+ and M-SIT+, respectively) was quantified. Mixed regression models were used to compare the SBP, DBP, and HR profiles during the SIT by taking into account the repeated measures (6 time periods of 10 minutes). Results In patients with S-SIT+ (n = 17), SBP (p < 0.0001), DBP (p = 0.0007), and HR (p = 0.03) increased during the SIT compared with other patients and controls. Seventeen patients had M-SIT+ (none among healthy controls). Classifying patients in 4 groups in function of the presence/absence of the SIT sensory and motor components revealed that SDB and DBP increased throughout the SIT in patients with S-SIT+, independently of the motor component (p < 0.0001 and p = 0.0008 for SBD; p < 0.0001 and p = 0.01 for DBP in the S-SIT+/M-SIT− and S-SIT+/M-SIT+ groups, respectively). Conclusion During the SIT, BP concomitantly increased only in patients with RLS and sensory discomfort, with or without motor component. This highlights the link between evening sensory RLS symptoms, autonomic activation, and potential long-term cardiovascular consequences.

Study Objectives(1) To compare the presence of autonomic symptoms using the validated SCOPA-AUT questionnaire in untreated patients with narcolepsy type 1 (NT1) to healthy controls, (2) to study the determinants of a high total SCOPA-AUT score in NT1, and (3) to evaluate the effect of drug intake on SCOPA-AUT results in NT1.MethodsThe SCOPA-AUT questionnaire that evaluates gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual dysfunction was completed by 92 consecutive drug-free adult NT1 patients (59 men, 39.1 ± 15.6 years old) and 109 healthy controls (63 men, 42.6 ± 18.2 years old). A subgroup of 59 NT1 patients completed the questionnaire a second time, under medication (delay between two evaluations: 1.28 ± 1.14 years).ResultsCompared to controls, NT1 patients were more frequently obese, had more dyslipidemia, with no difference for age and gender. The SCOPA-AUT score of NT1 was higher than in controls in crude and adjusted models. Patients experienced more problems than controls in all subdomains. A higher score in NT1 was associated with older age, longer disease duration, altered quality of life and more depressive symptoms, but not with orexin levels and disease severity. Among patients evaluated twice, the SCOPA-AUT score total did not differ according to treatment status, neither did each subdomain.ConclusionWe captured a frequent and large spectrum of clinical autonomic dysfunction in NT1, with impairment in all SCOPA-AUT domains, without key impact of medication intake. This assessment may allow physicians to screen and treat various symptoms, often not spontaneously reported but associated with poor quality of life.

ObjectiveTo validate the Idiopathic Hypersomnia Severity Scale (IIHSS), a self-report measure of hypersomnolence symptoms, consequences, and responsiveness to treatment.MethodsThe 14-item IHSS (developed and validated by sleep experts with patients' feedback) was filled in by 218 participants (2.3% missing data). Among the 210 participants who fully completed the IHSS, there were 57 untreated and 43 treated patients with idiopathic hypersomnia (IH) aged 16 years or older, 37 untreated patients with narcolepsy type 1 (NT1), and 73 controls without sleepiness. IHSS psychometric properties, discriminant diagnostic validity, and score changes with treatment were assessed.ResultsThe IHSS showed good internal consistency and content validity. Factor analysis indicated a 2-component solution with good reliability expressed by satisfactory Cronbach α values. IHSS scores were reproducible without changes in the test–retest evaluation (13 treated and 14 untreated patients). Convergent validity analysis showed that IHSS score was correlated with daytime sleepiness, depressive symptoms, and quality of life in patients with IH. The IHSS score was lower in treated than untreated patients (5–8 unit difference, without ceiling effect). The cutoff value for discriminating between untreated and treated patients was 26/50 (sensitivity 55.8%, specificity 78.9%). IHSS scores were higher in drug-free IH patients than NT1 and controls. The best cutoff value to differentiate between untreated IH patients and controls was 22 (sensitivity 91.1%, specificity 94.5%), and 29 with NT1.ConclusionsThe IHSS is a reliable and valid clinical tool for the quantification of IH symptoms and consequences that might be useful for patient identification, follow-up, and management.

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

To compare cardiac sympathetic adrenergic nerve activity in patients with narcolepsy type 1 (NT1) and controls usingFifty-six NT1 patients and 91 controls without neurological diseases underwent a cardiac scintigraphy. MIBG uptake was quantified by delayed heart/mediastinum (H/M) ratio. Clinical, neurophysiological and biological determinants of a low H/M were assessed in NT1.MIBG uptake did not differ between NT1 and controls in crude and adjusted associations. Five patients had low MIBG uptake (1.42, first decile of controls), often with advanced age, cardiovascular (CV) diseases, stimulants intake, and REM sleep behavior disorder. Patients with H/M1.62 (lowest tertile) were older, with higher BMI, microarousal index and CV comorbidities. A three-fold increase of phasic/tonic REM sleep motor activities was found in those patients, confirmed in a subanalysis of 40 drug-free patients. No association was found with CSF hypocretin levels.A direct measure of the heart adrenergic nerve activity revealed no sympathetic denervation in NT1.Our results indicate normal cardiac sympathetic innervation in NT1. However, few patients with low MIBG uptake also presented CV comorbidities and REM sleep motor deregulation, potentially at high CV risk, requiring a careful follow-up.

International audience; Narcolepsy type 1 (NT1) is a chronic orphan disorder, caused by the selective and irreversible loss of hypocretin/orexin (ORX) neurons, by a probable autoimmune process. Little is known about NT2 etiology and prevalence, sharing with NT1 excessive daytime sleepiness (EDS) and dysregulation of rapid eye movement (REM) sleep, but without cataplexy and loss of ORX neurons. Despite major advances in our understanding of the neurobiological basis of NT1, management remains nowadays only symptomatic. The main and most disabling symptom, EDS, is managed with psychostimulants, as modafinil/armodafinil, methylphenidate, or amphetamines as a third-line therapy. Narcolepsy is an active area for drug development, and new wake-promoting agents have been developed over the past years. Pitolisant, a selective histamine H3 receptor inverse agonist, has been recently approved to treat patients with NT1 and NT2. Solriamfetol, a phenylalanine derivative with dopaminergic and noradrenergic activity will be soon a new therapeutic option to treat EDS in NT1 and NT2. Sodium oxybate, used for decades in adult patients with narcolepsy, was recently shown to be effective and safe in childhood narcolepsy. The discovery of ORX deficiency in NT1 opened new therapeutic options oriented towards ORX-based therapies, especially nonpeptide ORX receptor agonists that are currently under development. In addition, immune-based therapies administered as early as possible after disease onset could theoretically slow down or stop the destruction of ORX neurons in some selected patients. Further well-designed controlled trials are required to determine if they could really impact on the natural history of the disease. Given the different clinical, biological and genetic profiles, narcolepsy may provide a nice example for developing personalized medicine in orphan diseases, that could ultimately aid in similar research and clinical efforts for other conditions.

Introduction The orexin (ORX)/hypocretin system stabilizes sleep-wake regulation by sustaining long periods of wakefulness in humans and animals. We aimed to evaluate the relationships between cerebrospinal fluid (CSF) ORX levels and markers of nocturnal sleep stability assessed by polysomnography (PSG) in humans. Methods Nocturnal PSG data and CSF ORX levels of 300 drug-free subjects (55% men, 29.9±15.5 years old, mean ORX levels 155.1±153.7 pg/mL) with a complaint of hypersomnolence were collected in the National Reference Center for Narcolepsy, France. Several markers of nocturnal sleep stability were analyzed: wake (WB), sleep bouts (SB), and sleep/wake transitions. Groups were categorized according to ORX levels: two categories (≤110, >110 pg/mL, the current established threshold of ORX-deficiency), and tertiles (≤26,]26;254], >254 pg/mL); and were compared using logistic regression models. Results were adjusted for age, gender and body mass index. Results ORX-deficient subjects had more WB, SB, and sleep-wake transitions than the others. The WB duration was longer and the SB duration shorter in ORX-deficient category. The proportion of the shortest WB (30 sec) was lower in the ORX-deficient category whereas the proportion of WB above 1 min 30 sec was higher. The proportion of SB ≤ 14min was higher among ORX-deficient patients, with opposite results for longer SB. Subsequent analyses performed in the population categorized according to tertiles of CSF ORX-A confirmed all these findings, with a strong dose-response effect of ORX levels in post-hoc comparisons. All results remained highly significant in adjusted statistical models. Conclusion This study provides a strong evidence of the direct effect of ORX on nocturnal sleep stabilization in humans. WB and SB are reliable markers of nighttime sleep stability, strongly correlated to CSF ORX-A levels in a dose dependent way. These PSG biomarkers are promising to be applied in clinical and research settings. Support none