Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Borrélioses de Lyme hospitalisées dans un CHU : étude rétrospective descriptive

International audienceObjectif - IntroductionDans un contexte de polémiques sur le fardeau sanitaire associé à la borréliose de Lyme, nous avons mené une étude rétrospective sur les patients hospitalisés pour borréliose de Lyme dans une région de forte prévalence. Matériels (ou Patients) et méthodesCette étude descriptive rétrospective a été menée au CHU de Limoges et concerne la période 2008-2016. La sélection des dossiers a été réalisée à partir : 1) des comptes rendus d’hospitalisation codés « Maladie de Lyme » et 2) des résultats de synthèses intra-thécale d’anticorps anti-borrelia (SIT) positives. Seuls les dossiers compatibles avec la définition des cas élaborée par un panel d’experts européens et publiée en 2010, ont été retenus. Pour chaque patient, les caractéristiques d’exposition, démographiques et cliniques ont été recueillies. RésultatsLe diagnostic a été retenu chez 64 patients, après avoir revu 209 dossiers codés « maladie de Lyme » et 1418 ponctions lombaires prescrites pour une recherche de SIT. La majorité des cas présentait une neuroborréliose (95% soit 61/64) avec une répartition variable selon l’âge : 57% (8/14) des moins de 20 ans présentent une forme crânienne (exclusivement des paralysies faciales) alors que 73% (38/52) des plus de 30 ans présentent une méningoradiculite extracrânienne. Les 3 formes non neurologiques de borréliose sont : cardite (1), acrodermatite chronique atrophiante (1) et arthrite (1). Toutes les tranches d’âges étaient représentées avec un sexe ratio de 1 et la moyenne d’âge était de 50 ans (1 an – 89 ans). Les femmes représentaient 65% (23/35) des moins de 60 ans et 31% (9/29) des plus de 60 ans. Deux pics de saisonnalité Juillet-Aout avec 20 cas (31%) et Janvier avec 8 cas (13%) sont observés. Seuls 17 cas (27%) mentionnaient une piqûre de tique dans l’année précédant la neuroborréliose.ConclusionLa borréliose de Lyme n’est pas un motif fréquent d’hospitalisation et les cas hospitalisés sont très majoritairement des neuroborrélioses. Malgré un sexe ratio équilibré, nous constatons une prépondérance féminine pour les cas observés avant l’âge de 60 ans et masculine après l’âge de 60 ans

Genetic analysis of CHCHD10 in French familial amyotrophic lateral sclerosis patients

International audienceMutations in CHCHD10 have been reported as the cause of a large panel of neurological disorders. In order to confirm the contribution of this gene to amyotrophic lateral sclerosis (ALS) disease we analyzed the 4 coding exons of CHCHD10 by Sanger sequencing in a cohort of 118 French familial ALS already excluded for all known ALS related genes. We did not find any pathogenic mutation suggesting that CHCHD10 is not a major genetic cause of familial ALS, in France

The French national protocol for Kennedy’s disease (SBMA): consensus diagnostic and management recommendations

International audienceBackground:Kennedy’s disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). Theobjective of the French national diagnostic and management protocol is to provide evidence-based best practicerecommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review andconsensus multidisciplinary observations.Results:The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referralcentre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists,cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowlyprogressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria anddysphagia) is often a later manifestation of the disease. Gynecomastia isnot a constant feature, but is suggestive of asuspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement oftenwith asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessmentshould ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs ofandrogen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). Inthe absence of effective disease modifying therapies, the mainstay of management issymptomatic support usingrehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, andenteral nutrition (gastrostomy) may berequired. Respiratory management centres on the detection and treatment ofbronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breathstacking, mechanical insufflation-exsufflation, cough assistmachnie, antibiotics). Non-invasive mechanical ventilation isseldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions.There is no evidence for androgen substitution therapy

The French national protocol for Kennedy’s disease (SBMA): consensus diagnostic and management recommendations

International audienceAbstract Background Kennedy’s disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations. Results The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breath stacking, mechanical insufflation-exsufflation, cough assist machnie, antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy. Conclusion The French national Kennedy’s disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines

Evaluation of the application of the European guidelines for diagnosis and clinical care of Amyotrophic Lateral Sclerosis.

International audienceObjective: To evaluate the degree of application of the recommendations edited by the European Academy of Neurology (EAN) on the management of amyotrophic lateral sclerosis (ALS) in clinical practice. Background: The management of ALS is based on a multidisciplinary approach led by guidelines published by scientific communities. The EAN published guidelines in 2005 and 2012. Methods: Multicenter cross-sectional observational study involving six French ALS-referral centers and including prevalent and incident cases. Good practice points were translated into ad-hoc questions referring to key steps in the management. The application was evaluated by an independent clinical research assistant who examined the medical charts (MCs). When needed, an independent board-certified neurologist was in charge of answering the questions based on the examination of MCs and interview of the caring neurologist. Questions regarding diagnosis and communication were asked to patients through a self-administered questionnaire. Results: We included 376 ALS patients (176 incident, 200 prevalent cases). Median age at diagnosis was 62.8 years (IQR 55.7-72.3) and the sex-ratio was 1.37. A bulbar onset was present in 27.3[percnt] of cases. We evaluated all the topics covered in the EAN guidelines: diagnosis delay (e.g.mean 13.6 months, associated with age and onset), breaking the news (e.g.in more than 90[percnt], satisfaction of criteria for communication quality), multidisciplinary and sustained support (e.g.in 90[percnt], clinic visits scheduled at every 2-3 months), riluzole (e.g.offered and safety monitored in all patients), symptom management, genetic testing, ventilation, troubles of communication, enteral nutrition, and palliative and end-of-care. We also identified characteristics associated with poor compliance to guidelines. Conclusion: This is the first time for ALS clinicians to evaluate the application of the EAN recommendations for the management of ALS. This work will also allow us to propose (i) eventual modifications of impractical recommendations and (ii) sources of improvement for caring neurologists

Exploring the diagnosis delay and ALS functional impairment at diagnosis as relevant criteria for clinical trial enrolment*

International audienceObjectives were: i) to describe the phenotypic heterogeneity of incident amyotrophic lateral sclerosis (ALS) patients diagnosed in 2012 in French ALS centres; ii) to look at the associations between ALSFRS-R score and ALSFRS-R slope (ΔFS) at time of diagnosis with diagnosis delay, ALS phenotypes and Airlie House diagnosis criteria (AHDC); iii) to describe the rate of progression on ΔFS, according to diagnosis delay.METHODS:Incident ALS cases diagnosed in French ALS centres were included. The rate of progression was evaluated as follows: ΔFS = (48 - ALSFRS-R at time of diagnosis)/duration from onset to diagnosis (months). Fast and slow progressors were defined by ΔFS >1 and <0.5, respectively.RESULTS:At time of diagnosis, 476 patients were classified into eight phenotypes: bulbar (33.0%), spinal lumbar (28.2%), spinal cervical (23.1%), flail leg (4.4%), ALS/FTD (4.2%), possible flail arm (4.0%), respiratory (2.1%), dropped-head (1.0%). Median ΔFS (n = 358/476) was 1.0 [0.5-2.0]. ΔFS was associated with AHDC (p = 0.009), but not with clinical phenotype (p = 0.902). Stratification on diagnosis delay (<12 months or ≥18 months) allowed to differentiate fast progressors from slow progressors.CONCLUSION:At time of inclusion in therapeutic trial closed to diagnosis, ΔFS or diagnosis delay may discriminate the rate of progression

Fluoxetine for the Symptomatic Treatment of Multiple System Atrophy: The MSA-FLUO Trial

BACKGROUND: There are no effective treatments for multiple system atrophy (MSA). OBJECTIVE: The objective of this study was to assess the efficacy and safety of the serotonin reuptake inhibitor fluoxetine (40 mg/d) for the symptomatic treatment of MSA. METHODS: This was a double-blind, parallel-group, placebo-controlled, randomized trial in patients with "probable" MSA. The primary outcome was the change from baseline to week 12 in the mean total score of the Unified MSA Rating Scale (UMSARS Parts I + II). Secondary outcomes included change from baseline to week 6 in total UMSARS, and change from baseline to week 12 in the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction, Beck Depression Inventory, and different domains of the MSA-Quality of Life Questionnaire. Exploratory outcomes included change from baseline to week 12 in the UMSARS Parts I and II separately and change from baseline to week 24 in the total UMSARS score. RESULTS: A total of 81 patients were randomly assigned, with no significant difference in the primary outcome (-2.13 units [95% confidence interval, CI, -4.55 to 0.29]; P = 0.08). There was a greater reduction on fluoxetine in the change from baseline to 12-week in UMSARS Part II (exploratory outcome: -1.41 units [95% CI, -2.84; 0.03]; p = 0.05) and in MSA-QoL emotional/social dimension (secondary outcome: -6.99 units [95% CI, -13.40; -0.56]; p < 0.03). A total of 5 deaths occurred (3 on fluoxetine and 2 on placebo). CONCLUSION: The MSA-FLUO failed to demonstrate fluoxetine superiority over placebo on the total UMSARS score, whereas trends in motor and emotional secondary/exploratory outcomes deserve further investigation. © 2021 International Parkinson and Movement Disorder Society

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Long-Term Effectiveness, Safety and Tolerability of Fingolimod in Patients with Multiple Sclerosis in Real-World Treatment Settings in France: The VIRGILE Study

Online ahead of printInternational audienceIntroduction: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing-remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS.Methods: Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator's discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator's discretion.Results: Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI - 0.51 to - 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9).Conclusions: The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis