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International audience; Recent evidence suggests that people with schizophrenia are at high risk for severe COVID-19 and should be prioritized for vaccination. However, impaired decision-making capacities could negatively affect the uptake of COVID-19 vaccination in this population. Capacity to consent to COVID-19 vaccination was assessed in 80 outpatients with schizophrenia. Using the MacArthur Competence Assessment Tool for Treatment, 56.3% of the sample were classified as having diminished capacity to consent to the vaccination. Diminished capacity to consent to COVID-19 vaccination was associated with lower vaccination rates, poorer cognition and higher level of psychotic symptoms. Developing interventions for enhancing informed consent for vaccination is urgent within this population.

Background Fatigue is a well-known common clinical feature of numerous chronic diseases including various forms of cancer, neurological disorders such as multiple sclerosis, and psychiatric disorders. A significant proportion of people with schizophrenia (30–60%) reportedly experience fatigue, which impacts negatively on participation in various activities, including work, study, leisure, and social pursuits. Causes of fatigue in schizophrenia are poorly understood and there are no established treatments. Several evidence-based interventions for fatigue syndrome including psychoeducation, cognitive behavioral therapy, and graded exercise therapy have been shown to be effective in other medical conditions and could be adapted to address fatigue in schizophrenia patients. As there are no psychosocial or pharmacological interventions with proved efficacy for fatigue in schizophrenia, there is an urgent need for the development of strategies to improve fatigue management in schizophrenia. The aim of this project is to evaluate in a single blind randomized clinical trial the efficacy of a cognitive-behavioral therapy (CBT) intervention compared to treatment as usual (TAU) on fatigue as the main outcome in schizophrenia patients. Clinical symptoms, physical functioning, major cognitive functions, quality of life and functioning, treatment dosage, daily motor activity, biological markers with inflammatory markers are also considered as secondary outcomes. Methods/design Two hundred patients meeting the inclusion criteria will be randomized to either of the study arms (intervention or TAU). The ENERGY intervention will be delivered according to a standardized treatment manual comprising six modules addressing fatigue and sleep over 14 individual therapy sessions. The treatment encompasses core CBT principles of psycho-education, behavioral activation, behavioral experiments, cognitive restructuring, problem-solving, and relapse prevention. Sessions will follow the traditional CBT structure of agenda setting, review of homework tasks, and introduction of a new concept/technique with collaborative discussions on how to implement such strategies in the participant’s day-to-day environment. Our primary endpoint will be the severity of fatigue assessed at baseline and at the 9-month follow-up using the “Multidimensional Fatigue Inventory” (MFI). Discussion The trial will provide the first test of CBT intervention for fatigue for patients with schizophrenia. This study will also test to what extent the treatment can be implemented in everyday practice. Trial registration ClinicalTrials.govNCT04332601. Registered on 10 April 2020.

International audience; Attention Deficit/Hyperactivity Disorder (ADHD) often persists into adulthood. However, few screening tools have been adaptedto assess adult ADHD using the DSM-5 criteria. This study assessed the diagnostic accuracy of a French version of the ADHDSelf-Report Screening for DSM-5 (ASRS-5). This multicentric cross-sectional study included 557 participants: 309 adult ADHDoutpatients without bipolar disorder (BD)/borderline personality disorder (BPD) (n = 236) or with BD/BPD (n = 36) and 285adults without ADHD who were either healthy volunteers (n = 248) or outpatients with BD or BPD (n = 37). Measures includedADHD diagnosis and the ASRS-5. The ASRS-5 was a good predictor of ADHD diagnosis (cut-off score ! 13/24: sensitivity =84.3%, specificity = 91.9%) in the sample of adult outpatients without comorbid disorders/healthy controls. Performances werelower with this cut-off score in some subgroups, notably low-severity ADHD symptomatology (sensitivity = 63.5%) and participantswith BD or BPD (sensitivity = 91.7%, specificity = 54.1%). The French ASRS-5 had acceptable screening properties,even if its performance varied according to clinical variables. Further evidence is needed for patients with comorbid disordershaving overlapping symptoms.

Background: Patients with schizophrenia (SZP) have been reported to exhibit impairments in reward-based decision-making, but results are heterogeneous with multiple potential confounds such as age, intelligence level, clinical symptoms or medication, making it difficult to evaluate the robustness of these impairments.\ud \ud \ud Methods: We conducted a meta-analysis of studies comparing the performance of SZP and healthy controls (HC) in the Iowa Gambling Task (IGT) as well as comprehensive analyses based on subject-level data (n = 303 SZP, n = 188 HC) to investigate reward-based decision-making in SZP. To quantify differences in the influence of individual deck features (immediate gain, gain frequency, net loss) between SZP and HC, we additionally employed a least-squares model.\ud \ud Results: SZP showed statistically significant suboptimal decisions as indicated by disadvantageous deck choices (d from 0.51 to −0.62) and lower net scores (d from −0.35 to −1.03) in a meta-analysis of k = 29 samples (n = 1127 SZP, n = 1149 HC) and these results were confirmed in a complementary subject-level analysis. Moreover, decision-making in SZP was characterized by a relative overweighting of immediate gain and net losses and an underweighting of gain frequency. Moderator analyses revealed that in part, decision-making in the IGT was moderated by intelligence level, medication and general symptom scores.\ud \ud Conclusion: Our results indicate robust impairments in reward-based decision-making in SZP and suggest that decreased cognitive resources, such as working memory, may contribute to these alterations.

Background In spite of their extensive use, the ecological relevance of tasks dedicated to assessing real-world decision-making in a laboratory setting remains unclear. Objectives Our study aimed to evaluate the relationship between decision-making and behavioral competency and awareness of limitations. Methods A total of 20 patients with Alzheimer's disease (AD), 20 with amnestic mild cognitive impairment (aMCI) and 20 healthy controls (HC) were assessed for decision-making using the Iowa Gambling Task (IGT). Behavioral competency was evaluated by the Patient Competency Rating Scale (PCRS), which requires each participant and a relative to answer the same 30 questions on participant's competency and to rate each item, while awareness of limitations was evaluated by subtracting the self-rated score from the relative-rated score. Results Using the median-split approach, the proportion of disadvantageous decision-makers was higher in both the MCI and AD groups than in HC (P = 0.02 and P = 0.03, respectively), with no differences between clinical groups. The percentage of participants with poorer behavioral competency was also higher in the MCI and AD than in the HC (self-rated: P = 0.025 and P = 0.01, respectively; relative-rated: P = 0.008 and P = 0.008, respectively), again with no differences between MCI and AD. All groups were comparable in awareness. For all participants, disadvantageous decision-making was associated with both reduced behavioral competency and poor awareness of limitations (OR: 3.47, P = 0.03 and OR: 5.4, P = 0.004, respectively). Conclusion Our findings support the ecological relevance of the IGT. Behavioral competency integrity and awareness of limitations are both associated with advantageous decision-making profiles.

Summary Insomnia disorder is frequent in the population, yet there is no French screening instrument available that is based on the updated DSM-5 criteria. We evaluated the validity and reliability of the French version of an insomnia screening instrument based on DSM-5 criteria, the Sleep Condition Indicator, in a population-based sample of adults. A total of 366 community-dwelling participants completed a face-to-face clinical interview to determine insomnia disorder against DSM-5 criteria and several questionnaires including the French Sleep Condition Indicator version. Three-hundred and twenty-nine participants completed the Sleep Condition Indicator again after 1 month. Statistical analyses were performed to determine the reliability, construct validity, divergent validity and temporal stability of the French translation of the Sleep Condition Indicator. In addition, an explanatory factor analysis was performed to assess the underlying structure. The internal consistency (α = 0.87) and temporal stability (r = 0.86, P

IF 3.326; International audience; Kabuki syndrome (KS-OMIM 147920) is a rare developmental disease characterized by the association of multiple congenital anomalies and intellectual disability. This study aimed to investigate intellectual performance in children with KS and link the performance to several clinical features and molecular data. We recruited 31 children with KMT2D mutations who were 6 to 16 years old. They all completed the Weschler Intelligence Scale for Children, fourth edition. We calculated all indexes: the Full Scale Intellectual Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptive Reasoning Index (PRI), Processing Speed Index (PSI), and Working Memory Index (WMI). In addition, molecular data and several clinical symptoms were studied. FSIQ and VCI scores were 10 points lower for patients with a truncating mutation than other types of mutations. In addition, scores for FSIQ, VCI and PRI were lower for children with visual impairment than normal vision. We also identified a discrepancy in indexes characterized by high WMI and VCI and low PRI and PSI. We emphasize the importance of early identification and intensive care of visual disorders in patients with KS and recommend individual assessment of intellectual profile.

International audience; Objective We previously developed normative data for a French version of the Hayling Sentence Completion Test (f-HSCT) for adults and elderly people. The present study aimed to evaluate the clinical utility of the f-HSCT norms in two clinical populations in which inhibition dysfunction has been largely documented, i.e., Parkinson's disease (PD) and schizophrenia. Method Eighty-five non-demented patients with idiopathic PD and 64 out-patients with schizophrenia completed the automatic and inhibition conditions of the f-HSCT. Time latencies and errors raw data of each patient were compared to the norms previously developed by the authors. Results In the automatic condition, errors were rare in both clinical groups and time latencies on this condition felt within the normative data range. Compared with the standardized norms, 46% of patients with PD and 61% of patients with schizophrenia had a deviant performance (i.e., borderline or deficit) for the inhibition error score. The proportion of patients with a deviant performance on the inhibition response time score was similar in both clinical samples (respectively, 25% and 23%). Finally, slightly more than half of patients with PD and more than two-thirds of patients with schizophrenia had a deviant performance on at least one of the f-HSCT inhibition measures. Conclusions Our results suggest that the f-HSCT has a strong potential for characterizing inhibition of prepotent responses in PD and schizophrenia. Furthermore, it requires only a short administration time so it may be ideal to detect response inhibition in clinical populations with cognitive fatigue.

Introduction Rhythmic auditory cueing improves certain gait symptoms of Parkinson's disease (PD). Cues are typically stimuli or beats with a fixed inter-beat interval. We show that isochronous cueing has an unwanted side-effect in that it exacerbates one of the motor symptoms characteristic of advanced PD. Whereas the parameters of the stride cycle of healthy walkers and early patients possess a persistent correlation in time, or long-range correlation (LRC), isochronous cueing renders stride-to-stride variability random. Random stride cycle variability is also associated with reduced gait stability and lack of flexibility. Method To investigate how to prevent patients from acquiring a random stride cycle pattern, we tested rhythmic cueing which mimics the properties of variability found in healthy gait (biological variability). PD patients (n = 19) and age-matched healthy participants (n = 19) walked with three rhythmic cueing stimuli: isochronous, with random variability, and with biological variability (LRC). Synchronization was not instructed. Results The persistent correlation in gait was preserved only with stimuli with biological variability, equally for patients and controls (p's

BackgroundPoor impulse control is a common feature in patients with Parkinson's disease (PD). However, before testing whether patients with PD and controls differ in impulsivity, one must assess whether impulsivity measures are invariant across groups. Consequently, we examined (a) the measurement and structural invariance of a scale assessing changes in four dimensions of impulsivity (urgency, lack of premeditation, lack of perseverance and sensation seeking) among patients with PD and controls; and (b) whether the four impulsivity traits relate differentially to risky decisions by patients.MethodClose relatives of 78 patients with idiopathic PD and 96 control participants were given the short Urgency–Premeditation–Perseverance–Sensation seeking Impulsive Behaviour Scale (UPPS), which assesses changes in four dimensions of impulsivity. Participants also completed the Game of Dice Task (GDT), a laboratory measure of risk taking.ResultsMultigroup confirmatory factor analyses supported measurement invariance across groups, whereas structural invariance was not confirmed. Patients with PD showed greater variability and higher impulsivity than controls. Furthermore, patients with impulse control disorders (ICDs) demonstrated even greater levels of sensation seeking than patients without ICDs. Finally, lower premeditation and greater perseverance were significantly associated with greater risk taking in patients with PD, and higher agonist dopaminergic doses with less risky choices on the GDT.ConclusionsThe questionnaire appears to function comparably across patients and controls. Thus, group comparisons on the questionnaire can be considered valid. Mean differences between groups on the dimensions of impulsivity may reflect executive impairments and/or abnormal reward processing in patients with PD, which may lead to risky behaviours.

Objective Supine sleep is associated with increased obstructive sleep apnea. People with Parkinson's disease (PD) complain about difficulties turning around in bed. The relationship between supine sleep and sleep-disordered breathing has never been explored in people with Parkinson's disease. Methods Fifteen consecutive people with PD with severe Obstructive Sleep Apnea Syndrome (OSAS) were compared to: (1) 15 age-matched, gender-matched, body mass index-matched and Unified Parkinson's Disease Rating Scale-III score-matched people with PD without sleep-disordered breathing; (2) 11 age-matched and gender-matched people with severe obstructive sleep apnea syndrome (OSAS) alone; and (3) 11 age-matched and gender-matched healthy controls. Outcomes were: number of position changes during the night and per hour of sleep, and the percentage of sleep time spent in supine. Results People with PD and severe OSAS spent most of their sleep time in the supine position (93 ± 11%); while people with PD without OSAS (61 ± 24%, p 0.001), people with isolated, severe OSAS (50 ± 28%, p 0.001), and the controls (40 ± 21, p 0.001) spent significantly less time on their back. People with PD and severe OSAS changed their position in bed per hour of sleep (0.4 ± 0.5) less frequently than those with PD without OSAS (1.1 ± 0.8, p = 0.002), those with isolated OSAS (1.2 ± 1.0, p = 0.006) and the controls (1.5 ± 0.5, p 0.001). Conclusion PD and severe OSAS are associated with a major reduction in the number of position changes and an increased supine sleep position during the night. For people with PD, alleviating the difficulties of turning around in bed might reduce the supine sleep position and improve sleep-disordered breathing.

International audience; We aimed to compare adult patients with attention deficit hyperactivity disorder (ADHD) and matched controls on four dimensions of impulsivity (urgency, lack of premeditation, lack of perseverance, and sensation seeking) and to examine the association between impulsivity and ADHD symptoms. The study was conducted on 219 participants: 72 adult ADHD patients and 147 aged and gender matched controls. All participants completed questionnaires measuring the various facets of impulsivity (UPPS Impulsive Behavior Scale), ADHD and depressive symptoms severity. Patients were also assessed for ADHD subtypes, mood disorders, and addictive behaviors. ADHD patients exhibited higher urgency, lower premeditation and lower perseverance in comparison to controls. Lack of perseverance showed the strongest association with ADHD (area under curve=0.95). Patients with combined inattentive and hyperactive/impulsive subtypes reported more frequently substance abuse problems and had higher scores on urgency and sensation seeking dimensions of impulsivity than those with predominantly inattentive subtype. We report for the first time a multidimensional evaluation of impulsivity in adult ADHD patients. The UPPS Impulsive Behavior Scale may constitute a useful screening tool for ADHD in adults and may help to further understanding the psychological mechanisms underlying the differences between the ADHD subgroups.

International audience

Background. Apathy and reduced emotion-based decision-making are two behavioral modifications independently described in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI).Objectives. The aims of this study were to investigate decision-making based on emotional feedback processing in AD and aMCI and to study the impact of reduced decision-making performances on apathy.Methods. We recruited 20 patients with AD, 20 participants with aMCI, and 20 healthy controls. All participants completed the Lille apathy rating scale (LARS) and the Iowa gambling task (IGT).Results. Both aMCI and AD participants had reduced performances on the IGT and were more apathetic compared to controls without any difference between aMCI and AD groups. For the entire sample, LARS initiation dimension was related to IGT disadvantageous decision-making profile.Conclusions. We provide the first study showing that both aMCI and AD individuals make less profitable decisions than controls, whereas aMCI and AD did not differ. Disadvantageous decision-making profile on the IGT was associated with higher level of apathy on the action initiation dimension. The role of an abnormal IGT performance as a risk factor for the development of apathy needs to be investigated in other clinical populations and in normal aging.

Contains fulltext : 137735.pdf (Publisher’s version ) (Closed access) STUDY OBJECTIVE: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. DESIGN: Retrospective case-control study. SETTING: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. PATIENTS AND PARTICIPANTS: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included. MEASUREMENTS AND RESULTS: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified. CONCLUSION: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

No reliable biomarkers are identified in KLS. However, few functional neuroimaging studies suggested hypoactivity in thalamic and hypothalamic regions during symptomatic episodes. Here, we investigated relative changes in regional brain metabolism in Kleine-Levin syndrome (KLS) during symptomatic episodes and asymptomatic periods, as compared to healthy controls., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

Major advances in the past decade have led a better understanding of the pathophysiology of narcolepsy with cataplexy (NC) caused by the early loss of hypothalamic hypocretin neurons. Although a role for hypocretin in the regulation of sleep/wakefulness state is widely recognized, other functions, not necessarily related to arousal, have been identified. Hence, the hypocretin system enhances signaling in the mesolimbic pathways regulating reward processing, emotion and mood regulation, and addiction. Although studies on hypocretin-deficient mice have shown that hypocretin plays an essential role in reward-seeking, depression-like behavior and addiction, results in human narcolepsy remained subject to debate. Most of studies revealed that hypocretin-deficient narcolepsy patients either drug-free or medicated with psychostimulant had preferences toward risky choices in a decision-making task under ambiguity together with higher frequency of depressive symptoms and binge eating disorder compared to controls. However, human studies mostly reported the lack of association with pathological impulsivity and gambling, and substance and alcohol abuse in the context of narcolepsy-cataplexy. Prospective larger studies are required to confirm these findings in drug-free and medicated patients with narcolepsy. Inclusion of patients with other central hypersomnias without hypocretin deficiency will provide answer to the major question of the role of the hypocretin system in reward-based behaviors and emotional processing in humans.

Abnormal decision-making has been described as a key-concept to understand some behavioral disturbances in schizophrenia. However, whether schizophrenia patients display impairments in profitable decision-making on experimental designs is still controversial (1) to assess performance on decision-making paradigms under ambiguity and under risk conditions in a large sample of schizophrenia patients and (2) to study the impact of clinical variables on decision-making performance in schizophrenia. The Iowa gambling task (IGT) and the game of dice task (GDT) were administered to assess, respectively, decision-making under ambiguity and under risk in 63 schizophrenia patients and 67 healthy controls. In addition, clinical variables (e.g., schizophrenic symptoms, self-reported depression, and impulsivity) were evaluated using appropriate questionnaires the same day. Pharmacological treatments were reported. Schizophrenia patients had impaired performances on both IGT and GDT tasks. No correlation between the decision-making tasks performance and clinical variables was found. Lower gains on the GDT were associated with executive dysfunctioning in schizophrenia. These findings give evidence that schizophrenia patients display impairments in both decision-making under ambiguity and under risk.

International audience; The associations between depressive symptoms and hypersomnia are complex and often bidirectional. Of the many disorders associated with excessive sleepiness in the general population, the most frequent are mental health disorders, particularly depression. However, most mood disorder studies addressing hypersomnia have assessed daytime sleepiness using a single response, neglecting critical and clinically relevant information about symptom severity, duration and nighttime sleep quality. Only a few studies have used objective tools such as polysomnography to directly measure both daytime and nighttime sleep propensity in depression with normal mean sleep latency and sleep duration. Hypersomnia in mood disorders, rather than a medical condition per se, is more a subjective sleep complaint than an objective finding. Mood symptoms have also been frequently reported in hypersomnia disorders of central origin, especially in narcolepsy. Hypocretin deficiency could be a contributing factor in this condition. Further interventional studies are needed to explore whether management of sleep complaints improves mood symptoms in hypersomnia disorders and, conversely, whether management of mood complaints improves sleep symptoms in mood disorders.

We compared periodic and non-periodic leg movements during sleep and polysomnography in patients with narcolepsy with cataplexy (NC) with or without restless legs syndrome (RLS) with matched idiopathic RLS (iRLS) and control subjects. We enrolled 100 patients with NC: 17 having RLS were compared with 34 sex- and age-matched patients without RLS and with 17 normal controls and 17 iRLS subjects. Periodic leg movements were highest in iRLS and lowest in controls, with those in NC with RLS very close to iRLS, but higher than those in NC without RLS. The periodicity indexes showed the highest value in iRLS followed by NC with or without RLS and, finally, by controls. The inter-leg movement intervals peaked between 10 and 50 s in NC with RLS and in iRLS, the former did not display the nocturnal gradual decrease of periodic leg movements typical of iRLS. Periodic leg movements during sleep and polysomnography displayed specific features in RLS and NC, respectively, with NC with RLS showing an intermediate pattern. Even if RLS is only detected by targeted interview in NC, its frequency and impact on night-time sleep architecture and continuity suggest that this condition should be routinely searched for in NC.

International audience; Schizophrenia is characterized by heterogeneous brain abnormalities involving cerebral regions implied in the executive functioning. The dysexecutive syndrome is one of the most prominent and functionally cognitive features of schizophrenia. Nevertheless, it is not clear to what extend executive deficits are heterogeneous in schizophrenia patients. Furthermore, it is still unknown if the executive impairments observed in schizophrenia are better characterized as specific or as reflecting generalized cognitive factors. The four executive processes (i.e. updating, inhibition, shifting and divided attention) described in Miyake et al.’s (2000) theoretical model were examined in 62 individuals with schizophrenia and 49 healthy controls. At group level, impairments in all four executive processes confirmed the marked impairment in executive functioning in patients with schizophrenia. Statistical analysis indicated that executive performances in schizophrenia patients were more heterogeneous than in healthy controls. Compared with standardized norms, 94% of patients exhibited impairment in at least one of the executive tasks. Twenty-one percent of patients exhibited impairment in one executive task, 27% in two tasks, 23% in three executive tasks and 23% exhibited impairments in the four executive tasks. Six percent of patients had normal executive profile. Regression analysis indicated that only premorbid intellectual quotient and a general slowing in processing speed predicted the executive dysfunction severity. Executive functioning was not affected by age, duration of illness, psychotic status, or by antipsychotic dosage. Our results emphasize the heterogeneity of the dysexecutive syndrome in schizophrenia when individual profile analysis is considered, and extend the view that individual cognitive differences in schizophrenia are largely underlined by general cognitive factors such as intellectual level and general processing speed.

STUDY OBJECTIVES Excessive daytime sleepiness (EDS) and high daytime REM sleep pressure are important sleep features of myotonic dystrophy (DM1). Small and uncontrolled studies have focused on EDS phenotype; none have focused on nocturnal REM sleep characteristics in DM1. Our objectives were to compare polysomnographic and multiple sleep latency test (MSLT) parameters, and both tonic and phasic components of REM sleep between DM1 and controls. DESIGN AND PATIENTS Forty consecutive DM1 patients and 40 sex- and age-matched controls were included. All subjects underwent overnight polysomnography followed by a MSLT. RESULTS About 80% of DM1 patients complained of EDS through clinical interview: 31.4% had Epworth scores > 10, and 12.5% had objective sleepiness (latency < 8 min). Higher apnea and central apnea indexes, and a greater proportion of subjects with severe apnea/hypopnea syndrome were found in DM1. The number of SOREMP differed between DM1 and controls, one and two SOREMPs being present in 47.5% and 32.5%, and one control had one SOREMP. Higher percentages of slow wave sleep and REM sleep were found in DM1. DM1 patients had significantly more PLMW, PLMS in both NREM and REM sleep, and PLMS-associated microarousals. Higher REM density was found in DM1 with similar tendencies for either REM sleep without atonia or phasic EMG activity. CONCLUSIONS This is the first case-control sleep study in DM1 to demonstrate higher frequency of daytime sleepiness and abnormalities in REM sleep regulation, with an increased daytime and nighttime REM sleep propensity, REM density, and PLMS. These data suggest a primary central sleep regulation dysfunction in DM1.

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.

NARCOLEPSY-CATAPLEXY, A DISEASE CAUSED BY THE LOSS OF ∼70,000 HYPOCRETIN CELLS IN THE HYPOTHALAMUS AFFECTS ∼20 PER 100,000 INDIVIDUALS, with an incidence of ∼ 0.3–0.6 per 100,000 person-years.1,2 Onset is most typically in the teens, and cases with onset before age 6 or after 40 are rare in Western Europe and North America.3 The disease is extremely tightly associated with human leukocyte antigen (HLA) DQB1*06024, so that DQB1*0602 negative cases without documented loss of hypocretin cells, as measured by cerebrospinal fluid (CSF) hypocretin levels, are exceptional; only 5 such cases have been reported in the literature. The cause of narcolepsy is likely autoimmune based on the HLA association, association with T-cell receptor polymorphisms,5 and recently reported Tribbles 2 autoantibodies.6 As for most autoimmune diseases, twin pairs are most often discordant (65% to 80%), and environmental triggers are suspected to play a critical role.1 Most notably, two recent reports have found an association with past streptococcus infections,7,8 leading to the speculation that upper airway infections could be involved in many cases as a cofactor. The possibility that narcolepsy could be a rare side effect of H1N1 flu vaccination was first reported by the Swedish Medical Product agency in August 2010 (6 cases). Additional cases (up to 14) were also reported in Finland, potentially linked to Pandemrix vaccination, an H1N1 vaccination formulation containing the adjuvant ASO3. Vaccination has been suspended in these countries.9 In three major centers of reference for narcolepsy—Montpellier, France; Montreal, Canada; and Stanford University, United States—we noticed in the first months of 2010 an unusual increase in abrupt onset narcolepsy-cataplexy diagnosed within a few months of H1N1 onset. These observations were made independently and first discussed among directors of the 3 centers at a sleep meeting in spring 2010, prior to any media attention. From September 2008 to August 2009, 9 recent-onset cases (symptoms of less than one year duration before being diagnosed) were identified in the 3 centers. The following year (September 2009–August 2010), 31 recent onset cases were identified (8 cases in Montpellier, 9 in Montreal, 14 at Stanford). These cases were examined for past H1N1 exposure or vaccination by review of clinical charts, and when possible additional interviews by phone or in person. Of the 31 cases, 14 post-vaccination cases were identified at Montpellier (n = 6), Montreal (n = 4), and Stanford University (2 of 4 US cases were vaccinated in Europe). In addition, 2 cases following H1N1 infection (as opposed to vaccination) were also reported at Stanford. These patients were interviewed to specify the date of cataplexy onset. Information regarding date of vaccination and type of vaccine was also obtained in all cases. Multiple sleep latency tests (MSLTs) were performed in all cases older than 9 years old. Serum, CSF, and DNA were collected for biochemical measurements. Serum samples were tested for the presence of antistreptolysin O (ASO).7 The presence of anti-TRIB2 antibodies was tested in Lausanne, Switzerland, for the 6 French cases6 or at Stanford, USA, for the remaining cases.10 DNA was tested for the presence of DQB1*0602. CSF hypocretin-1 levels were measured as previously described.11 A summary description of the 16 post-H1N1 cases is reported in Table 1. All cases were HLA DQB1*0602 positive with severe sleepiness and definite/severe cataplexy. All were Caucasian except case 3 (African American), and 50% were male. In 10 cases, CSF hypocretin-1 was found to be extremely low ( 200 pg/mL). MSLTs were performed in 11 cases, with confirmation of diagnosis in all cases, i.e., mean sleep latency < 8 minutes and ≥ 2 SOREMPs. The post streptococcal marker ASO was positive in 11 cases (68.7%), confirming a previous report in recent-onset cases.7 None of our post-H1N1 subjects were anti-TRIB2 positive, in contrast to recent-onset cases collected in prior years.6,10,12 Brain MRI (performed in 6 cases) were unremarkable except for the presence of a pineal cyst in 2 cases. The most striking features of our sample were the abrupt onset and the unusual severity of both sleepiness and cataplexy. Rapid weight gain was frequently noted, as is typical with abrupt onset cases. Finally, we noted that age at onset was often atypical, with 5 cases with onset after age 38, and 2 with very early onset (under 5 years of age from the United States). Of the 14 post-vaccination cases, 11 cases followed adjuvanated vaccination, while 3 were vaccinated without adjuvant. Delay between vaccination and cataplexy onset in these cases ranged from 2 days (strong local response followed by a generalized reaction following vaccination) to 5 months, although in 9 of the 14 post-vaccination cases the onset occurred 2–8 weeks following vaccination. As the delay between onset and diagnosis is often long,1,13 more cases are likely to be identified in the future. Table 1 Characteristics of post H1N1 narcolepsy patients How could H1N1 vaccination or infection trigger narcolepsy? Possible hypotheses include a specific immune response to H1N1 (and possibly subsequent molecular mimicry) or generalized stimulation of the immune system. In Europe and Canada, as well as the cases reported in Scandinavia, most cases followed vaccination with ASO3. This vaccine has been reported to be associated with side effects suggestive of stronger immune stimulation.14 In the United States, where vaccination did not contain the ASO3 adjuvant, only 2 post-vaccination cases were documented. The strength of the immune response (higher with adjuvant, or after actual infections), rather than the specificity of the immune response to H1N1, may thus be involved. Several of our patients showed high ASO titers, suggesting that they had recent or recurrent streptococcus infections. An association between streptococcal infection and recent-onset narcolepsy was reported previously, in the absence of H1N1 vaccination. One possibility is that streptococcus infection could also act as a nonspecific immune trigger, for example via superantigen stimulation of dormant autoreactive T-cell clones. It is possible that these factors increase brain inflammation or blood brain penetration nonspecifically, allowing the autoimmune process to reach hypocretin cells. Fever and the administration of various adjuvants have been reported to increase blood brain penetration and activate brain microglia in animal models.15 Cases reported here with their temporal link between vaccination and disease onset and unusual clinical presentation, with rapid development and severity of both excessive daytime somnolence and cataplexy, suggest that H1N1 vaccination or exposure may trigger narcolepsy. However, there are several limitations and potential confounding factors, such as increased awareness of narcolepsy and more efficient diagnostic processes leading to faster diagnosis and increased identification of recent-onset cases. Another limitation is that a large portion of the population was either vaccinated or had H1N1 infection, including many unrecognized instances of infection, increasing the difficulty to document a specific association between narcolepsy onset and H1N1 infection or vaccination. Nevertheless, these correlative findings indicate an urgent need for further examination of a possible link. Even if confirmed, as for other better-established post-vaccination autoimmune reactions such as Guillain-Barree, post-flu vaccination narcolepsy is likely to be an exceptionally rare complication.16–18 To our knowledge, vaccination has not previously been reported as a triggering factor for narcolepsy. The consequences of withholding vaccination should be weighed against the risk of potentially lethal H1N1 infections (that may also trigger narcolepsy based on our data). Considering that all cases reported here were HLA DQB1*0602 positive, HLA typing prior to vaccination could be considered in the future and would represent the first vaccinogenomic intervention.

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 per se is associated with mild/moderate dysfunction in a quarter of patients.