Search

Objective/background: Extended-release, once-nightly sodium oxybate (ON-SXB) significantly improved narcolepsy symptoms in participants in the phase 3, randomized, double-blind, placebo-controlled REST-ON trial. This post hoc analysis of REST-ON data evaluated ON-SXB efficacy in participants with or without concomitant alerting agent use., Patients/methods: Participants with narcolepsy aged >16 years were randomized 1:1 to ON-SXB (week 1: 4.5 g, weeks 2-3: 6 g, weeks 4-8: 7.5 g, weeks 9-13: 9 g) or placebo. Primary endpoints in this post hoc analysis included change from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement (CGI-I) rating, and number of weekly cataplexy episodes. The secondary endpoints were change from baseline in the Epworth Sleepiness Scale (ESS) score and in objective and subjective disrupted nighttime sleep parameters. Post hoc analyses assessed participants with and without alerting agent use across 6-, 7.5-, and 9-g doses., Results: In the modified intent-to-treat population, 119 (63 %) were (ON-SXB, n = 66; placebo, n = 53) and 71 (37 %) were not (ON-SXB, n = 31; placebo, n = 40) taking alerting agents. Regardless of alerting agent use, treatment with ON-SXB resulted in significant improvements vs placebo (all doses, P < 0.05) for MWT, CGI-I, and number of weekly cataplexy episodes. Significant improvements in ESS (all doses, P < 0.05) with ON-SXB vs placebo were observed in the alerting agent use cohort. Directional improvements in ESS were reported with all doses in the no alerting agent use group., Conclusions: Regardless of concomitant alerting agent use, ON-SXB improved daytime and nighttime narcolepsy symptoms vs placebo., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YD is a consultant/advisory board member for Avadel Pharmaceuticals, Bioprojet, Harmony Biosciences, Idorsia, Jazz Pharmaceuticals, Centessa Pharmaceuticals, and Takeda Pharmaceutical Co. TR is a consultant for Avadel Pharmaceuticals, Eisai, Idorsia, Jazz Pharmaceuticals, Merck & Co., Orexo, and Takeda Pharmaceutical Co. RB is a shareholder in WaterMark Medical and Healthy Humming, LLC; serves on the board of directors for WaterMark Medical; is a consultant for Jazz Pharmaceuticals, Takeda Pharmaceutical Co., Avadel Pharmaceuticals, and Oventus; has received industry-funded research from Avadel Pharmaceuticals, BresoTec, Bayer, Idorsia, Suven Life Sciences Ltd., Jazz Pharmaceuticals, Balance, Vanda, Merck & Co., Eisai, Philips, FRESCA Medical, Takeda Pharmaceutical Co., LivaNova, Roche, and Sommetrics; and has served on speakers bureaus for Jazz Pharmaceuticals, Eisai, and Harmony Biosciences. MJT has served as a consultant or on advisory boards for Avadel Pharmaceuticals, Axsome Therapeutics, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences Ltd., and Takeda Pharmaceutical Co. AMM has served as a consultant, speaker, and/or on advisory boards for Avadel Pharmaceuticals, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Alkermes, and Takeda Pharmaceutical Co; has received grant funding from National Institutes of Health, UCB Pharmaceuticals, Jazz Pharmaceuticals, ResMed Foundation, Coverys Foundation, and Geisinger Health Plan; is the CEO of DAMM Good Sleep, LLC; and has served as an advisor for Neura Health. AR has received grant/research support from Jazz Pharmaceuticals, Suven, Inspire, Nyxoah, LivaNova, and Avadel Pharmaceuticals; is a speaker for Avadel Pharmaceuticals; is a consultant for Jazz Pharmaceuticals, Suven, Inspire, and Avadel Pharmaceuticals; and has served on speakers bureaus for Jazz Pharmaceuticals and Eisai. JG is an employee of Avadel Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Restless legs syndrome (RLS) has been associated with anxiety, depression, insomnia, lifestyle factors and infections. We aimed to study the prevalence of symptoms of RLS during the COVID-19 pandemic versus pre-pandemic. We hypothesized that pre-existing RLS symptoms worsened and pandemic-related factors may have triggered new symptoms of RLS., Methods: Adults (≥18 years) from fifteen countries across four continents participated in an online survey between May and August 2020. The harmonized questionnaire included a validated single question on RLS with response alternatives from 1 to 5 on a scale from never to every/almost every evening or night. Other measures were the Insomnia Severity Index (ISI), measures of symptoms of anxiety (GAD-2) and depression (PHQ-2), and questions on different pandemic-related factors., Results: Altogether, 17 846 subjects (63.8 % women) were included in the final analyses. The mean age was 41.4 years (SD 16.1). During the pandemic, symptoms of RLS (≥3 evenings/nights per week) were more common 9.1 % (95 % CI 8.7-10.1) compared to 5.4 % (95 % CI 4.9-6.0) before the pandemic (P < 0.0001). Alltogether 1.3 % (95 % CI 1.1-1.6) respondents had new-onset symptoms (≥3 evenings/nights per week). Moderate-severe insomnia was strongly associated with RLS symptoms. The occurrences of new-onset RLS symptoms were 5.6 % (95 % CI 0.9-13.0) for participants reporting COVID-19 and 1.1 % (95 % CI 0.7-1.5) for non-COVID-19 participants. In the fully adjusted logistic regression model, the occurrence of new-onset RLS symptoms was associated with younger age, social restrictions and insomnia severity. In a similar analysis, RLS symptoms (≥3 evenings/nights per week) were associated with lower education, financial hardship, sleep apnea symptoms, use of hypnotics, insomnia severity, symptoms of depression and possible post-traumatic stress disorder., Discussion: Our findings indicate that RLS symptoms were more common during the pandemic than before. Usually, the prevalence of RLS increases with age. However, during the pandemic, new-onset symptoms of RLS were more common in younger age groups. This may be due to the pandemic-related factors being more pronounced in the younger compared to the older. The association between insomnia, psychiatric symptoms and RLS warrants clinical attention., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Markku Partinen reports financial support was provided by Signe and Ane Gyllenberg Foundation. Other from Takeda, personal fees and other from MSD, personal fees and other from Orion, personal fees and other from Umecrine, personal fees from Lundbeck, Other from Teva, outside the submitted work. Ilona Merikanto reports financial support was provided by Signe and Ane Gyllenberg Foundation. Courtney J. Bolstad reports financial support was provided by South Texas Veterans Healthcare System. Yuichi Inoue reports personal fees and other from Astellas Pharma, personal fees from Eisai, other from Idorsia Pharmaceuticals Japan, grants from Koike Medical, personal fees from Otsuka Pharmaceutical, grants from Philips Japan, outside the submitted work. Frances Chung – Dr. Chung reports grants from Ontario Ministry of Health Innovation Grant, grants from University Health NetworkFoundation, personal fees from Masimo Inc and Takeda Pharma, outside the submitted work; In addition, University Health Network has a patent STOP-Bang questionnaire pending. Thomas Penzel – Dr. Penzel reports personal fees from Jazz Pharmaceuticals, personal fees from Bayer Healthcare, personal fees from Neuwirth, personal fees from Löwenstein Medical, outside the submitted work; and Shareholder of The Siestagroup GmbH, Advanced Sleep Research GmbH, Nukute. Giuseppe Plazzi – Dr. Plazzi reports personal fees from UCB pharma, personal fees from Jazz pharmaceuticals, personal fees from Bioprojet, personal fees from Idorsia, personal fees from Takeda, outside the submitted work. YK Wing – personal fees from Eisai Co, Ltd, for delivering a lecture and sponsorship from Lundbeck HK Ltd and Aculys Pharma, Japan, outside the submitted work. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Many components of sleep are disrupted in patients with narcolepsy, including sleep quality, sleep architecture, and sleep stability (ie, frequent awakenings/arousals and frequent shifts from deeper to lighter stages of sleep). Sodium oxybate, dosed twice nightly, has historically been used to improve sleep, and subsequent daytime symptoms, in patients with narcolepsy. Recently, new formulations have been developed to address the high sodium content and twice-nightly dosing regimen of sodium oxybate: low-sodium oxybate and once-nightly sodium oxybate. To date, no head-to-head trials have been conducted to compare the effects of each oxybate product. This review aims to give an overview of the existing scientific literature regarding the impact of oxybate dose and regimen on sleep architecture and disrupted nighttime sleep in patients with narcolepsy. Evidence from 5 key clinical trials, as well as supporting evidence from additional studies, suggests that sodium oxybate, dosed once- and twice-nightly, is effective in improving sleep, measures of sleep architecture, and disrupted nighttime sleep in patients with narcolepsy. Direct comparison of available efficacy and safety data between oxybate products is complicated by differences in trial designs, outcomes assessed, and statistical analyses; future head-to-head trials are needed to better understand the advantage and disadvantages of each agent., Competing Interests: Declaration of competing interest T Roth has served as a consultant for Abbott, Acadia, Acogolix, Acorda, Actelion, Addrenex, Alchemer, Alza, Ancel, Arena, AstraZeneca, Aventis, AVER, Bayer, BMS, BTG, Cephalon, Cypress, Dove, Eisai, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Hypnion, Impax, Intec, Intra-Cellular, Jazz Pharmaceuticals, Johnson and Johnson, King, Lundbeck, McNeil, MediciNova, Merck, Neurim, Neurocrine, Neurogen, Novartis, Orexo, Organon, Otsuka, Prestwick, Proctor and Gamble, Pfizer, Purdue, Resteva, Roche, Sanofi, Schering Plough, Sepracor, Servier, Shire, Somaxon, Syrex, Takeda, TransOral, Yanda, VivoMetrics, Wyeth, Yamanouchi, and XenoPort. He has been a speakers bureau member for Purdue and Sepracor. He has received research support from Apnex, Aventis, Cephalon, GlaxoSmithKline, Merck, Neurocrine, Pfizer, Sanofi, Schering Plough, Sepracor, Somaxon, Syrex, Takeda, Transcept, Wyeth, and XenoPort. Y Dauvilliers is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, UCB Pharma, Avadel, Harmony Biosciences, Idorsia, Orexia, Takeda, Paladin, and Bioprojet. RK Bogan is a shareholder of Watermark Medical and Healthy Humming, LLC; serves on the board of directors for Watermark; is a medical consultant to Jazz Pharmaceuticals, Harmony Biosciences, Avadel Pharmaceuticals, Takeda, and Oventus; has conducted industry-funded research for Avadel, Axsome, Bresotec, Bayer, Idorsia, Suven, Jazz, Balance, NLS, Vanda, Merck, Eisai, Philips, Fresca, Takeda, LivaNova, Roche, Sanofi, Sommetrics, and Noctrix; and is on speakers bureaus for Jazz, Eisai, and Harmony. G Plazzi is a former consultant to Jazz Pharmaceuticals and has participated in advisory boards for UCB Pharma, Bioprojet, Idorsia, Jazz Pharmaceuticals, and Takeda. J Black is a part-time employee of Jazz Pharmaceuticals and shareholder of Jazz Pharmaceuticals, plc., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: There is evidence of a strong association between insomnia and COVID-19, yet few studies have examined the relationship between insomnia and long COVID. This study aimed to investigate whether COVID-19 patients with pre-pandemic insomnia have a greater risk of developing long COVID and whether long COVID is in turn associated with higher incident rates of insomnia symptoms after infection., Methods: Data were collected cross-sectionally (May-Dec 2021) as part of an international collaborative study involving participants from 16 countries. A total of 2311 participants (18-99 years old) with COVID-19 provided valid responses to a web-based survey about sleep, insomnia, and health-related variables. Log-binomial regression was used to assess bidirectional associations between insomnia and long COVID. Analyses were adjusted for age, sex, and health conditions, including sleep apnea, attention and memory problems, chronic fatigue, depression, and anxiety., Results: COVID-19 patients with pre-pandemic insomnia showed a higher risk of developing long COVID than those without pre-pandemic insomnia (70.8% vs 51.4%; adjusted relative risk [RR]: 1.33, 95% confidence interval [CI]: 1.07-1.65). Among COVID-19 cases without pre-pandemic insomnia, the rates of incident insomnia symptoms after infection were 24.1% for short COVID cases and 60.6% for long COVID cases (p < .001). Compared with short COVID cases, long COVID cases were associated with an increased risk of developing insomnia symptoms (adjusted RR: 2.00; 95% CI: 1.50-2.66)., Conclusions: The findings support a bidirectional relationship between insomnia and long COVID. These findings highlight the importance of addressing sleep and insomnia in the prevention and management of long COVID., Competing Interests: Declaration of competing interest Authors declare none., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Background: The COVID-19 pandemic and related restriction measures have affected our daily life, sleep, and circadian rhythms worldwide. Their effects on hypersomnolence and fatigue remain unclear., Methods: The International COVID-19 Sleep Study questionnaire which included items on hypersomnolence such as excessive daytime sleepiness (EDS), and excessive quantity of sleep (EQS), as well as sociodemographic factors, sleep patterns, psychological symptoms, and quality of life was distributed in 15 countries across the world from May to September in 2020., Results: Altogether responses from 18,785 survey participants (65% women, median age 39 years) were available for analysis. Only 2.8% reported having had COVID-19. Compared to before the pandemic, the prevalence of EDS, EQS, and fatigue increased from 17.9% to 25.5%, 1.6%-4.9%, and 19.4%-28.3% amid the pandemic, respectively. In univariate logistic regression models, reports of having a COVID-19 were associated with EQS (OR 5.3; 95%-CI 3.6-8.0), EDS (2.6; 2.0-3.4), and fatigue (2.8; 2.1-3.6). In adjusted multivariate logistic regression, sleep duration shorter than desired (3.9; 3.2-4.7), depressive symptoms (3.1; 2.7-3.5), use of hypnotics (2.3; 1.9-2.8), and having reported COVID-19 (1.9; 1.3-2.6) remained strong predictors of EDS. Similar associations emerged for fatigue. In the multivariate model, depressive symptoms (4.1; 3.6-4.6) and reports of having COVID-19 (2.0; 1.4-2.8) remained associated with EQS., Conclusions: A large increase in EDS, EQS, and fatigue occurred due to the COVID-19 pandemic, and especially in self-reported cases of COVID-19. These findings warrant a thorough understanding of their pathophysiology to target prevention and treatment strategies for long COVID condition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 <19 min had a 5.5- (CI 95%[2.2; 13.8], p = 0.003) fold increase in this risk, compared to the referent group (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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Obstructive sleep apnea (OSA) is a high prevalent disorder with severe consequences including sleepiness, metabolic, and cardiovascular disorders. The aim of this study was to assess the effect of an individualized exercise-training (IET) program with educational sessions vs educational sessions alone on severity markers of OSA over an eight-week duration., Methods: This was a randomised, controlled, parallel-design study. In sum, 64 patients with moderate-to-severe OSA (apnea-hypopnea index AHI 15-45/hour), low physical activity level (Voorrips<9), body-mass index (BMI) <40 kg/m 2 were included in intervention group (IG) or control group (CG), and 54 patients finished the study. All underwent polysomnography (PSG), multiple sleep latency test (MSLT), constant workload exercise test, blood samples and fulfilled questionnaires twice. The primary endpoint was the change in apnea-hypopnea (AHI) at eight weeks from baseline. Main secondary endpoints were daytime sleepiness assessed by questionnaire and objective tests., Results: No significant between-group differences were found for changes in AHI. A reduction in AHI was found in IG only (p = 0.005). Compared to CG, exercise training leads to a greater decrease in AHI during REM sleep (p = 0.0004), with a significant increase in mean daytime sleep latency (p = 0.02). Between-group differences were significant for weight reduction, severity of fatigue, insomnia and depressive symptoms with trend for sleepiness symptoms., Conclusions: In adult patients with moderate-to-severe OSA, IET did not decrease AHI compared to the control group but improved markers of severity of OSA, in particular AHI in rapid eye movement (REM) sleep and objective daytime sleepiness. Adding personalized exercise training to the management of patients with OSA should be considered. CLINICALTRIALS., Gov Identifier: NCT01256307., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Solriamfetol (formerly JZP-110), a dopamine/norepinephrine reuptake inhibitor, is approved in the US to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy (75-150 mg/d) or obstructive sleep apnea (37.5-150 mg/d). In a randomized, double-blind, placebo-controlled trial in participants with narcolepsy, effects of solriamfetol on functional status, health-related quality of life (HRQoL), and work productivity were evaluated., Methods: Participants with narcolepsy (N = 239) were randomized to solriamfetol 75, 150, or 300 mg, or placebo for 12 weeks. Outcome measures included the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10), 36-Item Short Form Health Survey version 2 (SF-36v2), and Work Productivity and Activity Impairment questionnaire for Specific Health Problem (WPAI:SHP). A mixed-effects model with repeated measures was used for comparisons vs placebo., Results: At week 12, solriamfetol increased FOSQ-10 total score, with greatest mean difference from placebo (95% CI) at 300 mg (1.45 [0.31, 2.59]). On SF-36v2, improvements vs placebo were observed in physical component summary scores (300 mg: 2.22 [0.04, 4.41]) and subscales of role physical, general health, and vitality. On WPAI:SHP, solriamfetol 150 mg reduced overall work impairment vs placebo (-15.5 [-29.52, -1.47]), and 150 and 300 mg reduced activity impairment vs placebo (-10.05 [-19.48, -0.62] and -13.49 [-23.19, -3.78], respectively). Most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. Common TEAEs were headache, nausea, decreased appetite, nasopharyngitis, dry mouth, and anxiety., Conclusions: Solriamfetol improved measures of functional status, HRQoL, and work productivity, particularly at the 150- and 300-mg doses. Most TEAEs were mild to moderate., Trial Registration: ClinicalTrials.gov identifier NCT02348593, EudraCT number 2014-005487-15., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Study Objectives: To assess the relationship between real and simulated driving performance and the objective level of alertness as measured by the Maintenance of Wakefulness Test (MWT) in patients suffering from narcolepsy or idiopathic hypersomnia., Methods: Twenty-seven patients (10 patients with narcolepsy, type 1 (n = 7) and type 2 (n = 3), and 17 patients with idiopathic hypersomnia, mean age = 33.8 ± 11.1 years, range = 18-65 y; four males) were recruited in a randomized, crossover, double-blind placebo-controlled trial, and compared to 27 matched healthy controls. Patients were randomly assigned to receive modafinil (400 mg) or placebo before the driving test (2 h of real and 2 h of simulated highway driving for each patient). Standard deviation of lateral position (SDLP) of the vehicle in real and simulated driving and mean sleep latency in a 4 × 40 min MWT were assessed., Results: Untreated patients presented shorter sleep latencies on the MWT (20.8 (IQ range 16.1-32.9) vs. 34.9 min (IQ range 28.1-40.0)) and worse simulated driving performance (P < 0.001) than treated patients. Nevertheless, treated patients still exhibited shorter mean sleep latencies on the MWT than controls (34.9 (IQ range 28.1-40.0) vs. 40 min (IQ range 37.1-40.0), P < 0.05), but driving performance was identical in both groups. The SDLP of the vehicle in real driving conditions and the MWT score correlated with the SDLP in simulated driving (respectively, r = 0.34, P < 0.05 and r = -0.56, P < 0.001)., Conclusions: In patients with narcolepsy/idiopathic hypersomnia, simulated driving and MWT explore different dimensions of fitness-to-drive and could be used complementarily to better evaluate sleep-related driving impairment., (Copyright © 2018. Published by Elsevier B.V.)

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., (Copyright © 2018. Published by Elsevier B.V.)

Objective: To assess the effects of three narcolepsy treatment modalities on sleep stage shifts associated with disrupted nighttime sleep (DNS) using data from a clinical trial., Methods: Polysomnograms were reviewed from 155 patients (who had these data available at baseline and 8 weeks) of the 278 patients who were randomized to placebo, 9-g sodium oxybate (SXB)/nightly, 200-600 mg/d modafinil, or SXB + modafinil. Major outcomes of these post hoc analyses, analyzed using analysis of covariance, were change from baseline in number of shifts from Stages N2/3/rapid eye movement (REM) to Stage N1/Wake, and from Stage N1/Wake to REM. Sleep quality was evaluated using the sleep-quality question from the Pittsburgh Sleep Quality Index., Results: SXB alone or in combination with modafinil significantly decreased the number of shifts from Stage N2/3/REM to Stage N1/Wake (p < 0.01); least-squares mean change in number of shifts from baseline was -0.6, -16.5, 1.8, and -13.7 in the placebo, SXB, modafinil and SXB + modafinil groups, respectively. A similar pattern was observed for changes in shifts from REM to Stage N1/Wake and from Stage N1/Wake to REM. Relative to placebo, sleep quality significantly improved with SXB and SXB + modafinil (p ≤ 0.05) but not with modafinil alone., Conclusion: These results show that SXB with and without modafinil significantly consolidated sleep and improved patient-reported sleep quality relative to placebo. In contrast, no such effects were observed with modafinil alone, suggesting a specific effect of SXB on DNS in addition to its effect on daytime sleepiness. CLINICALTRIALS., Gov Identifier: NCT00066170., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The temporal association between sudden infant death syndrome (SIDS) and sleep suggests that the arousability from sleep provides a protective mechanism for survival. Recently, the hypocretin system, which promotes wakefulness, has been implicated in SIDS, since it has been reported that SIDS victims have fewer hypocretin neurons than infants who have died from other causes. To understand the role of hypocretin in SIDS, it is essential to better understand how this system matures. The present study compared cerebrospinal fluid (CSF) hypocretin in children aged 2-6 months, which is the age of peak incidence for SIDS, to both younger and older children., Method: Hypocretin levels were measured in CSF samples from 101 children who underwent a clinically relevant lumbar puncture. Children were separated into five age groups: 0-2 months, 2-6 months, 1-5 years, 5-10 years, and 10-18 years., Results: Hypocretin levels were not significantly different between 1-5 years, 5-10 years, and 10-18 years. Therefore, these three groups were pooled into a single one (1-18 years) for further analysis. Between the 0-2 month, 2-6 month, and 1-18 year groups, a significant difference in CSF hypocretin levels existed (p = 0.001). Simple comparisons showed that CSF hypocretin levels in the 2-6 month age group were significantly lower than hypocretin levels in both the 0-2 month and 1-18 year group (p < 0.001 and p = 0.008, respectively), but not significantly between 0-2 month and 1-18 year children., Conclusions: The CSF hypocretin levels were lower at the age of peak incidence for SIDS. This could underlie an increased vulnerability to SIDS at this specific age., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: Narcolepsy type 1 (NT1) is considered to be an immune-mediated disease in which environmental factors, such as vitamin D, might play a major role. The association between NT1 and vitamin D deficiency has previously been reported. The aim of this case-control study was to reassess vitamin D levels in a large clinic-based adult and paediatric population of patients with NT1 by considering several potential confounding factors., Methods: The serum level of 25-hydroxyvitamin D (25OHD) was measured in 174 Caucasian patients with NT1 and 174 controls. Demographic and clinical features, body mass index (BMI), Pandemrix® vaccination, age, and season at the time of blood sampling were recorded. Between-group comparisons were made using univariate and multivariate logistic regression analyses. When appropriate, interaction terms were tested using the Wald Chi-squared test., Results: Age, BMI, and season of blood sampling were different between groups. Conversely, the 25OHD level and fraction of subjects with vitamin D deficiency (serum level <75 nmol/L: 46.6% of patients vs 48.3% of controls; <50 nmol/L: 20.7% vs 17.2%) did not differ between patients with NT1 and controls. Overall, vitamin D deficiency was more frequent in men, obese subjects, and in samples collected in winter, without any association with NT1. In the patients group, no significant association was found between vitamin D deficiency, NT1 duration and severity, treatment, and Pandemrix® vaccination., Conclusions: Vitamin D levels were not associated with NT1 in a large case-control population when potential demographic and clinical confounding factors were taken into account., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To measure CSF biomarkers of hypothalamic dysfunction in patients with typical Kleine-Levin syndrome (KLS) during symptomatic and asymptomatic periods., Patients/methods: Two patients with typical KLS were admitted during symptomatic and asymptomatic periods to a research Sleep Disorders Center. Cerebrospinalfluid (CSF) hypocretin-1, histamine (HA), and its major metabolite tele-methylhistamine (t-MHA) levels were measured in two KLS patients in and out of episode., Results: CSF biomarkers of hypothalamic dysfunction measured in two KLS patients in and out of episode revealed low hypocretin levels (within the narcolepsy-cataplexy range) during a hypersomnia episode in the more severe patient, and a 42% decrease (although within normal range) in the second patient. CSF HA and t-MHA measurements in and out of episode revealed a two-fold in-episode decrease in HA in the more severe patient, with no significant change for the second patient, nor for t-MHA levels., Conclusion: We reported reversible changes in CSF hypothalamic biomarkers in a typical patient with KLS that reinforces the hypothesis that in some patients KLS episodes may be caused by recurrent functional alterations of the hypothalamus., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Despite published treatment recommendations and the availability of approved and off-label pharmacologic therapies for narcolepsy, the clinical management of this incurable, chronic neurologic disorder remains challenging. While treatment is generally symptomatically driven, decisions regarding which drug(s) to use need to take into account a variety of factors that may affect adherence, efficacy, and tolerability. Type 1 narcolepsy (predominantly excessive daytime sleepiness with cataplexy) or type 2 narcolepsy (excessive daytime sleepiness without cataplexy) may drive treatment decisions, with consideration given either to a single drug that targets multiple symptoms or to multiple drugs that each treat a specific symptom. Other drug-related characteristics that affect drug choice are dosing regimens, tolerability, and potential drug-drug interactions. Additionally, the patient should be an active participant in treatment decisions, and the main symptomatic complaints, treatment goals, psychosocial setting, and use of lifestyle substances (ie, alcohol, nicotine, caffeine, and cannabis) need to be discussed with respect to treatment decisions. Although there is a lack of narcolepsy-specific instruments for monitoring therapeutic effects, clinically relevant subjective and objective measures of daytime sleepiness (eg, Epworth Sleepiness Scale and Maintenance of Wakefulness Test) can be used to provide guidance on whether treatment goals are being met. These considerations are discussed with the objective of providing clinically relevant recommendations for making treatment decisions that can enhance the effective management of patients with narcolepsy., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To analyze the acute effects of sodium oxybate (SO) on polysomnographic night-time recordings (PSG) and multiple sleep latency test (MSLT) on patients with narcolepsy with cataplexy (NC)., Methods: Sixteen NC adult patients were recruited, together with 16 normal controls. Two consecutive PSG followed by two MSLT sessions were carried out, before and during the first night of SO assumption, respectively., Results: The administration of SO was followed by a significant decrease in number of stage shifts and awakenings, wakefulness after sleep onset, and percentage of sleep stage 1. Sleep efficiency and slow wave sleep percentage increased. REM latency decreased significantly from 73 to 12 min. Cyclic alternating pattern (CAP) rate remained unchanged but the percentage of CAP A3 subtypes decreased. The number of CAP A3 subtypes per hour of NREM sleep decreased significantly, whereas that of A1 remained unchanged. The duration of A1 and A3 subtypes was slightly increased. Chin muscle tone was not modified by SO as well as periodic leg movements during sleep, but their periodicity index decreased, becoming similar to that of controls. MSLT sleep latency also significantly improved after SO intake., Conclusions: The administration of SO in NC patients is followed by immediate important and complex effects on PSG parameters and MSLT, including an evident (over)increase in slow wave sleep, which does not display a physiological microstructure, a moderate decrease in periodic and isolated LMs, possibly mediated by a disinhibited dopaminergic neuronal activity, and an improvement on daytime mean sleep latency at the MSLT., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Exercise training may improve components of metabolic syndrome and obstructive sleep apnea syndrome (OSAS). The objective of our pilot randomized controlled study was to determine the benefits of a short intensive inpatient individualized exercise training (IET) program in sedentary untreated OSAS patients., Methods: Twenty-two sedentary patients with moderate to severe OSAS were randomly assigned either to one-month education activity sessions (n=11; control group) or to inpatient rehabilitation program (n=11), including IET, education activities sessions, and dietary management. Full polysomnography (PSG), OSLER (Oxford Sleep Resistance test), body composition, anthropometric measurements, metabolic syndrome components, and questionnaires were performed at baseline and at study end point., Results: No changes occurred in the control group in all variables. Compared to controls, participants randomized to the IET group presented a significant decrease in apnea-hypopnea index (AHI) (40.6±19.4 vs. 28.0±19.3; P<0.001), oxygen desaturation index (ODI), and arousal index, which occurred in conjunction with significant decrease in body mass index (BMI), neck circumference, fat mass, fasting glucose, and diastolic blood pressure. Increased sleep latency was found in participants in the IET group with altered values at baseline., Conclusions: IET reduced OSAS severity with improvement of metabolic syndrome components with concomitant loss in body fat in sedentary adults. If confirmed on a larger scale, a comprehensive rehabilitation program could constitute an additional or alternative treatment for moderate to severe OSAS patients., (Copyright © 2014. Published by Elsevier B.V.)

Objectives: We aimed to evaluate depressive feelings and their correlations in children and adolescents with narcolepsy collected in national reference centers for narcolepsy., Methods: We compared clinical and sleep characteristics of patients with and without depressive symptoms evaluated on the Children's Depression Inventory (CDI)., Results: Our study sample included 88 children (44 boys; 44 de novo patients) with a mean age of 11.9 ± 3.1 years at diagnosis (37.5% were aged ⩽ 10 years). Obesity was found in 59% of the sample and cataplexy was present in 80.7%. The DQB1*0602 allele was positive in 93.5% of our sample. There were 25% of children who had clinically depressive feelings (CDI>16), especially girls older than the age of 10 years. Bivariate associations indicated that depressive feelings were associated with fatigue (48%), hyperactivity (31%), insomnia (16%), and excessive daytime sleepiness (EDS) (14-24%). In the multivariate model adjusted for gender and age, only fatigue explained the variability of the depression score., Conclusion: In our large cohort, high levels of depressive symptoms essentially expressed by fatigue affected 25% of children with narcolepsy. The girls older than 10 years of age were especially vulnerable. The similar prevalence of depressive feelings in treated vs never-treated patients suggests a specific need for diagnosing and managing this symptom in young patients with narcolepsy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: Sleepwalkers often complain of excessive daytime somnolence (EDS). Our retrospective study aimed to document the presence of EDS in a substantial sample of sleepwalkers and to explore the contribution of other sleep disorders, nocturnal sleep disruption, and sleep depth to the alteration of their daytime vigilance., Methods: Seventy adult sleepwalkers and 70 control subjects completed the Epworth Sleepiness Scale (ESS). Sleepwalkers also were studied for one night in the sleep laboratory. We compared the sleep profiles of 32 somnolent vs 38 nonsomnolent sleepwalkers and investigated the relationship between ESS scores and sleep-related variables., Results: No differences were found in polysomnographic (PSG) parameters. Slow-wave activity (SWA) also was similar in the two subgroups. Sleepwalkers' ESS scores were not correlated with their body mass index (BMI) or periodic limb movements during sleep (PLMS) index, but they tended to be negatively correlated with indices of respiratory events., Conclusions: The EDS reported by adult sleepwalkers does not appear to be explained by the presence of concomitant sleep disorders or PSG signs of nocturnal sleep disruption. These results raise the possibility that EDS is part of the sleepwalking phenotype and that it is linked to its underlying pathophysiology., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Narcolepsy is a rare disabling hypersomnia disorder that may include cataplexy, sleep paralysis, hypnagogic hallucinations, and sleep-onset rapid eye movement (REM) periods, but also disrupted nighttime sleep by nocturnal awakenings, and REM sleep behavior disorder (RBD). RBD is characterized by dream-enacting behavior and impaired motor inhibition during REM sleep (REM sleep without atonia, RSWA). RBD is commonly associated with neurodegenerative disorders including Parkinsonisms, but is also reported in narcolepsy in up to 60% of patients. RBD in patients with narcolepsy is, however, a distinct phenotype with respect to other RBD patients and characterized also by absence of gender predominance, elementary rather than complex movements, less violent behavior and earlier age at onset of motor events, and strong association to narcolepsy with cataplexy/hypocretin deficiency. Patients with narcolepsy often present dissociated sleep features including RSWA, increased density of phasic chin EMG and frequent shift from REM to NREM sleep, with or without associated clinical RBD. Most patients with narcolepsy with cataplexy lack the hypocretin neurons in the lateral hypothalamus. Tonic and phasic motor activities in REM sleep and dream-enacting behavior are mostly reported in presence of cataplexy. Narcolepsy without cataplexy is a condition rarely associated with hypocretin deficiency. We proposed that hypocretin neurons are centrally involved in motor control during wakefulness and sleep in humans, and that hypocretin deficiency causes a functional defect in the motor control involved in the development of cataplexy during wakefulness and RBD/RSWA/phasic motor activity during REM sleep., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder., Methods: The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria., Results: 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features., Conclusions: In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objectives: We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD., Methods: The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA])., Results: Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies., Conclusions: The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The management of pregnancy in patients with narcolepsy poses many questions regarding therapy, including the risk to the mother and fetus related to the disease, potential risks at the time of conception, the risk to both the mother and the fetus of the medications used to treat narcolepsy, and the risk to the infant from medications that might be secreted in breast milk. There are no detailed practice parameters on the treatment of narcolepsy patients during pregnancy. We surveyed narcolepsy specialists from around the world to determine their clinical approach to the management of patients with narcolepsy at the time of conception, during pregnancy and while breastfeeding., Methods: Survey invitations were sent via e-mail to 75 clinicians worldwide between 2/2011 and 3/2011 with 34 responses (USA, n=10; Brazil, n=3; Czech Republic, n=2; France, n=2; Italy; n=2; Netherlands, n=2; Canada, n=1; Denmark, n=1; Finland, n=1; Germany, n=1; Japan, n=1; Spain, n=1; unknown n=7). Responders who completed the survey had 20 years (median range, 5-35) of experience in sleep medicine practice with a median number of five narcolepsy patients seen per week. The number of pregnant narcoleptic patients followed per physician was five (median range 1-40)., Results: The survey results indicated that the management of patients with narcolepsy varies greatly from clinician to clinician and from country to country. The majority of the clinicians stopped the narcolepsy medications at the time of conception, during pregnancy, and during breastfeeding some reduced the dose and others did not change the dosage, depending on the particular medication., Conclusions: The findings from our survey and literature review suggest that the perceived risks of narcolepsy medication during pregnancy to the mother and the fetus usually are overestimated, as the risk for teratogenic effects from narcolepsy medications in therapeutic doses is essentially nonexistent. However, the potential for rare complications during pregnancy and congenital abnormalities cannot be excluded. Most narcolepsy patients have vaginal delivery without complications. In rare cases patients had cataplexy that interfered with delivery, but if caesarian is required there appears to be no increased anaesthetic or surgical risks. Further prospective information for the appropriate treatment of narcolepsy patients during pregnancy is needed., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: Mazindol is a tricyclic, anorectic, non-amphetamine stimulant used in narcolepsy and obesity since 1970. This study aimed to evaluate the long-term benefit/risk ratio in drug-resistant hypersomniacs and cataplexy sufferers., Methods: By retrospective analysis of the patients' files in the hospitals of Paris-Salpêtrière (n=91), Montpellier (n=40) and Lyon (n=8), the benefit (Epworth Sleepiness Score (ESS), cataplexy frequency, authorization renewal) and tolerance (side-effects, vital signs, electrocardiogram and cardiac echography) of mazindol were assessed., Results: The 139 patients (45% men) aged 36±15years (range: 9-74) suffered narcolepsy (n=94, 66% with cataplexy), idiopathic (n=37) and symptomatic hypersomnia (n=8) refractory to modafinil, methylphenidate and sodium oxybate. Under mazindol (3.4±1.3mg/day, 1-6mg) for an average of 30months, the ESS decreased from 17.7±3.5 to 12.8±5.1, with an average fall of -4.6±4.7 (p<0.0001) and the frequency of cataplexy fell from 4.6±3.1 to 2±2.8 episodes per week. The cataplexy was eliminated in 14.5% of patients, improved in 27.5%, and unchanged in 29% (missing data in 29%). The treatment was maintained long term in 83 (60%) patients, and stopped because of a lack of efficacy (22%) and/or secondary effects (9%). There was no pulmonary hypertension in the 45 patients who underwent a cardiac echography. The most common adverse effects were dry mouth (13%), palpitations (10%, including one with ventricular hyperexcitability), anorexia (6%), nervousness (6%) and headaches (6%)., Conclusion: Mazindol has a long-term, favorable benefit/risk ratio in 60% of drug-resistant hypersomniacs, including a clear benefit on cataplexy., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To investigate in narcolepsy with cataplexy (NC) patients of working age (18-65 years) the influence of age at onset, age at diagnosis and clinical features on socio-occupational conditions, disease-related economic burden, and quality of life., Methods: One hundred consecutive patients underwent a semistructured interview on socio-occupational aspects, NC-related direct and indirect costs, and NC history. Questionnaires were used to evaluate excessive daytime sleepiness, cataplexy, depressive symptoms, and quality of life., Results: NC patients (51 males, mean age 37±11.5 years) had educational and occupational levels similar to those of the Italian population of the same age range, but married less often, especially if NC onset occurred at a young age. Total annual NC-related costs were €9814 ± 10,372 per patient. Multivariate analyses showed that patients with NC onset before the age of 30 years had a higher educational level, married less frequently, and were less frequently unemployed or inactive (retired, housewife). Patients diagnosed before the age of 30 years were less frequently unemployed or inactive, had fewer work changes, and had a better general health perception. Irresistible sleepiness was associated with work absences and higher indirect costs. Depressive symptoms were strongly associated with lower quality-of-life scores., Conclusions: NC age at onset and at diagnosis modulates the disease-related burden. A diagnosis at a young age could improve patients' occupational prognosis, and their general health perception., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Narcolepsy with cataplexy (NC) is a disabling disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations, due to a deficient hypocretin/orexin neurotransmission. Melanin concentrating hormone (MCH) neurons involved in the homeostatic regulation of REM sleep are intact. We hypothesized that an increased release of MCH in NC would be partly responsible for the abnormal REM sleep manifestations., Methods: Twenty-two untreated patients affected with central hypersomnia were included: 14 NC, six idiopathic hypersomnia with long sleep time, and two post-traumatic hypersomnia. Fourteen neurological patients without any sleep disorders were included as controls. Using radioimmunoassays, we measured hypocretin-1 and MCH levels in cerebrospinal fluid (CSF)., Results: The MCH level was slightly but significantly lower in patients with hypersomnia (98 ± 32 pg/ml) compared to controls (118 ± 20 pg/ml). After exclusion of patients affected with post-traumatic hypersomnia the difference became non-significant. We also failed to find any association between MCH level and hypocretin level, the severity of daytime sleepiness, the number of SOREMPs, the frequency of cataplexy, and the presence of hypnagogic hallucinations or sleep paralysis., Conclusion: This study reports the first measurement of MCH in CSF using radioimmunoassay technology. It appears to be a non-informative tool to differentiate etiologies of central hypersomnia with or without REM sleep dysregulation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Narcolepsy with cataplexy (NC) is caused by the loss of hypocretin neurons. Recent studies highlighted the roles for hypocretins in the modulation of nociceptive transmission. The aims of the present multicenter case-control study were to look at the frequency of pain in NC and to study the determinants and impact of pain on narcolepsy symptoms and quality of life (QoL)., Methods: Sixty-seven adult patients with NC, together with their physician, partner/friend, and sex- and age-matched normal controls underwent a face-to-face interview and completed questionnaires on the presence and frequency of pain, narcolepsy symptoms and QoL (Short-Form 36-item score, Functional Outcomes of Sleep Questionnaire, Medical Outcomes Study, Fatigue Severity Scale, and Beck Depression Inventory)., Results: One-third (32.8%) of NC patients experienced pain at least monthly, with a significantly higher frequency and impact than controls (17.9%) and independent of the patients' narcolepsy medication. The reporting of pain was well matched between patients and partners/friends but significant differences were observed between patients and physicians, with physicians significantly underestimating its frequency and impact. The location of chronic pain varies within subjects with differences between NC and controls. We pinpointed that sleep quantity and depression were determinants for pain, and chronic pain had significant impact on sleep quantity, depression and QoL in NC., Conclusion: We report, for the first time, evidence that chronic pain is significantly more common and disabling in NC compared to the general population. The findings call for improved attention to assessment and treatment of pain in the follow-up of NC., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The benefit/risk ratio of modafinil was recently re-evaluated by the European Medicines Agency and was shown to be negative for idiopathic hypersomnia (IH) because of insufficient data., Objective: To evaluate the benefit/risk ratio of modafinil in idiopathic hypersomnia (with and without long sleep time) vs. narcolepsy/cataplexy., Subjects and Methods: The benefit (Epworth sleepiness score, ESS; visual analog scale, patient and clinician opinions) and risks (habituation, adverse effects) of modafinil were studied in a consecutive clinical cohort of 104 IH patients (59 with long sleep time) and 126 patients with narcolepsy/cataplexy., Results: Modafinil was the first line treatment in 96-99% of patients. It produced a similar ESS change in IH patients and in narcolepsy patients (-2.6±5.1 vs. -3±5.1) and a similar benefit as estimated by the patients (6.9±2.7 vs. 6.5±2.5 on a visual analog scale) and clinicians. The ESS change was lower in IH patients with long sleep time than in those without. Sudden loss of efficacy and habituation were rare in both groups. Patients with IH reported similar but more frequent adverse effects with modafinil than narcolepsy patients: nervousness (14%), palpitations (13%), and headache (11%)., Conclusion: Modafinil has an excellent benefit/risk ratio in idiopathic hypersomnia, with or without long sleep time, similar to its effect on narcolepsy/cataplexy., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Narcolepsy-cataplexy (NC) is caused by the loss of hypocretin neurons. Several lines of evidence suggest a role for hypocretin in olfactory function. Recent data have documented that NC is associated with olfactory dysfunction but smell testing has been performed only in small studies., Methods: One hundred thirty NC patients were recruited from two sleep disorders centers in France and Italy. They were compared to 129 age- and gender-matched healthy controls on two well standardized olfactory tests: the Sniffin' Sticks (France) and Brief Smell Identification (Italy) tests. Olfactory dysfunction was defined as a score below the tenth centile on each smell test., Results: Altogether, olfactory deficit was higher in NC compared to controls (23.8% vs. 13.9%, p=0.042, OR: 1.93 CI 95%, 1.01-3.66); olfactory identification deficit was found in 35.8% of NC compared to 13.9% of controls in Italy (p=0.03), and in 11.2% vs. 8.2% in France (NS). Using the Sniffin' Sticks (France) we noted significant lower discrimination and global olfactory performance in NC compared to controls. Based on standardized criteria for Sniffin' Sticks, none of the NC patients or controls presented anosmia or severe hyposmia, but 6.4% of the NC patients had moderate hyposmia and 22.2% mild, in contrast to 6.4% of controls with only mild hyposmia. Finally except tobacco smoking, clinical potential factors including age at onset and severity of the condition did not modify olfactory performances in the whole population., Conclusion: Our study is the largest investigation of olfactory performance in NC showing that the disease perse is associated with mild/moderate dysfunction in a quarter of patients.