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International audience; 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.

International audience; 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.

International audience; Objectives: To 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.Methods: Two 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.Results: BDI-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.Conclusions: Depression, 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 Evaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB). Methods Adults aged 18–70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment. Results Efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (−0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (−1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%). Conclusions Efficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB. Clinical trial registration NCT03030599.

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.

Objective : Despite convincing evidence regarding the risk of highway accidents due to sleepiness at the wheel, highway drivers still drive while sleepy. Sleep disorders can affect driving skills, but the relative impact of sleep complaints among a large population of highway drivers is still unknown. Methods : Out of 37,648 questionnaires completed by frequent highway users (registered in an electronic payment system), we ran our analyses on 35,004 drivers who responded to all items. The questionnaire previously used in a telephone survey included socio-demographics, driving and sleep disorders items (Basic Nordic Sleep Questionnaire) and the Epworth Sleepiness Scale. Results : Of all drivers, 16.9% complained of at least one sleep disorder, 5.2% reported obstructive sleep apnea syndrome, 9.3% insomnia, and 0.1% narcolepsy and hypersomnia ; 8.9% of drivers reported experiencing at least once each month an episode of sleepiness at the wheel so severe they had to stop driving. One-third of the drivers (31.1%) reported near-miss accidents (50% being sleep-related), 2520 drivers (7.2%) reported a driving accident in the past year, and 146 (5.8%) of these driving accidents were sleep-related. The highest risk of accidents concerned patients suffering from narcolepsy and hypersomnia (odds ratio 3.16, p < .01) or multiple sleep disorders (odds ratio 1.46, p < .001). Other major risk factors were age [1830 years (OR 1.42, p < .001)] and being unmarried (OR 1.21-fold, p < .01). Conclusions : In regular highway drivers, sleepiness at the wheel or sleep disorders such as hypersomnia and narcolepsy are responsible for traffic accidents independent of age, sex, marital status or socioprofessional categories.

International audience; BACKGROUND: Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. METHODOLOGY: Serum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. PRINCIPAL FINDINGS: Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. CONCLUSION: Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation.