JAMA Neurol

Importance: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus.Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity.Design, setting, and participants: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate.Exposure: HET or MET at treatment initiation.Main outcomes and measures: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions.Results: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09).Conclusions and relevance: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.Observatoire Français de la Sclérose en Plaque

Neurology

The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery). We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18-45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up). We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [-0.16 to 0.15]) or on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93-1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate. Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.Observatoire Français de la Sclérose en Plaque

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR&nbsp;=&nbsp;2.05, 95%CI&nbsp;=&nbsp;1.39–3.02, p&nbsp;&lt;&nbsp;0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR&nbsp;=&nbsp;0.42, 95%CI&nbsp;=&nbsp;0.18–0.99, p&nbsp;=&nbsp;0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Bases neurales de la théorie de l'esprit (étude clinique et IRM fonctionnelle d'une population témoin et de patients ayant présenté une méningo-encéphalite herpétique)

Percevoir et décoder les différents signaux sociaux qui nous parviennent, savoir les interpréter en fonction de leur contexte, sont des processus que nous acquérons au cours de nos premières années et développons par la suite. Cet apprentissage aboutit à la mise en place d'une fonction cognitive particulière : la théorie de l'esprit (TDE). Cette fonction, qui vise à inférer l'état mental, les intentions des autres à partir de leur regard, leur comportement, ou de leur discours, favorise l'insertion dans notre société, tant sur le plan familial, social ou professionnel. Les patients présentant une méningo-encéphalite herpétique (MEH) ont vu le pronostic de leur affection se transformer par l'avènement de la mise en route précoce du traitement par acyclovir. Les séquelles neurologiques sont de plus en plus réduites et sont actuellement dominées par les troubles mnésiques, et des modifications de l'humeur et du comportement générant des difficultés d'adaptation sociale. Nous avons fait l'hypothèse que les difficultés sociales et professionnelles consécutives à une MEH étaient en rapport avec une atteinte du réseau de la TDE. Nous avons mené une étude rétrospective chez les patients ayant présenté une MEH au CHU de Grenoble depuis 1998 et en âge d'exercer une activité professionnelle comprenant 2 parties : Une partie clinique explorant les fonctions cognitives et la TDE et une partie visant à investiguer en IRM fonctionnelle les régions cérébrales lors de tâches de TDE, dans la population MEH comparée à une population de 20 sujets sains. La combinaison de ces approches anatomo-clinique, et anatomo-fonctionnelle réalisées chez nos huit patients comparée aux résultats de deux populations contrôles (20 sujets sains pour l'IRMf, 74 patients pour l'étude clinique) nous a permis de mettre en évidence le rôle clef de deux régions impliquées de la TDE : (1) Le sulcus temporal supérieur (STS) paraît avoir un rôle de détection des stimuli sociaux. La latéralité de son activation semble liée à la nature du stimulus présenté (gauche pour le matériel verbal, droite pour le matériel visuospatial). Son activation paraît également liée à la performance des sujets. (2) Le cortex frontal médial voit son activation liée à la mentalisation d'hypothèses et à leur vérification. La " surdétection " de faux pas dans des saynètes associées au pattern d'activation excluant le cortex frontal médial en IRMf chez nos patients, suggère l'importance de cette région dans l'analyse du stimulus et/ou l'intégration dans son contexte social. Mots clés : Théorie de l'esprit, faux-pas, Reading the Mind in the eyes, Cortex frontal médiherpétique, , Sulcus temporal supérieur,Perceiving and understanding the social stimuli surrounding us, reading them in their context, are functions we gain during the first years of our life and that we improve afterwards. This allows the setting of a special cognitive function: the Theory of Mind (ToM). This function aims at inferring the other's mental states from their behaviour, speech, or gaze. It helps our social, familial and professional adaptation. The prognosis of herpes simplex encephalitis (HSE) has dramatically changed since the arrival of early antiviral therapy by acyclovir and neurological sequels come nowadays to little. These sequels are predominantly: memory impairments, mood and behaviour modifications leading to social adaptation difficulties. We hypothesised that these social and professional adaptation impairments after HSE could be due to ToM network lesions. We lead a case-control study among patients with a history of HSE diagnosed at Grenoble University Hospital since 1998. The age criterion selected (18-65years) allowed all the patients selected to handle a job. The clinical investigations comprised classical cognitive functions and ToM evaluations among our patients (8) and healthy volunteers (74). The fMRI study's aim was to evidence the cortical activation patterns during ToM tasks (Reading the Mind in the Eyes, faux-pas ) among patients and healthy volunteers (20). The combination of anatomoclinical correlations and functional approaches among HSE patients and the control subjects provided evidences of the key-role in ToM tasks of two regions. (1) The superior temporal sulcus' role seems to detect social stimuli. The side of its activation depended on the stimuli's nature (left hand-side with verbal stimuli, right hand-side with visuospatial stimuli). The STS activation also seems linked to the subject's performance in both tasks. (2) The anterior medial frontal cortex's activation is associated with mentalisation. The fact that HSE patients identify faux-pas when there is none, combined with the exclusion of this area during the fMRI faux-pas task suggests that this cortical region plays a crucial role in analysing the congruence between a social stimulus and the context of its occurrence.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Prise en charge de la migraine de l adulte en médecine générale (évaluation des pratiques thérapeutiques en aigu et en chronique à l échelle régionale)

La migraine est une pathologie fréquente en médecine générale. Malgré un fort retentissement fonctionnel, elle reste sous-médicalisée. L objectif de cette étude était de réaliser un état des lieux des pratiques thérapeutiques aiguës et chroniques de la migraine en médecine générale. Le but était aussi d observer l évaluation de la qualité de vie par les praticiens. Un questionnaire destiné aux médecins généralistes de Rhône-Alpes a été réalisé. Nous avons reçu 76 réponses. Nous avons aussi effectué une analyse des passages pour migraine aux urgences du CHU de Grenoble en 2011. Notre étude a mis en évidence que les recommandations sur l instauration d un traitement de crise sont bien suivies. L efficacité de ces traitements est peu évaluée. Il en est de même pour les thérapeutiques préventives. Le recours au spécialiste se fait en cas de doute diagnostique ou d échec thérapeutique. Les praticiens se disent partiellement satisfaits de leur évaluation de la qualité de vie des patients migraineux, celle-ci reposant sur l écoute du patient et la consommation médicamenteuse. Ils n utilisent pas les moyens structurés publiés et souhaitent des formations sur des thérapies non médicamenteuses et des programmes d éducation pour les patients. Dans le service d urgences, une imagerie est fréquemment prescrite, les pratiques thérapeutiques sont en accord avec les recommandations. L évaluation des thérapeutiques et du retentissement fonctionnel de la migraine devrait ainsi être au centre de la prochaine révision des recommandations. L utilisation de traitements recommandés dépendant du facteur consultation médicale , il parait donc important de réserver à celle-ci la place qu elle mérite.Migraine is a frequent condition in general practice. However, it remains under-medicalised despite a significant functional impact. The objective of this study was to make an inventory practices for the treatment of acute and chronic migraine in general medicine. The objective was also to observe the evaluation of the quality of life by practitioners to elaborate propositions to improve this. A questionnaire for general practitioners (GPs) in Rhône-Alpes has been achieved. We received 76 responses. Besides, we conducted an analysis of consultation for migraine in emergency department of CHU de Grenoble in 2011. Our study showed that the recommendations on a crisis treatment are followed. The effectiveness of these treatments, however, is poorly evaluated. It is the same for preventive therapeutic. The use of specialist is not systematic and is mainly in situations of diagnostic uncertainty or treatment failure. Concerning the measurement of the quality of life of migraine patients, GPs say they are partially satisfied with their assessment, based primarily on listening to the patient and drug consumption. They do not use the means structured and published and are seeking training on non-drug therapies and education for patients. At the emergency department, imaging is commonly prescribed, and therapeutic practices are consistent with the recommendations.Evaluation of therapeutic and functional impact of migraine should be the focus of the next revision of the recommendations of the HAS. The use of recommended treatments depending on the factor "medical consultation", then it seems important to book this consultation the place it deserves.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Traitement de la sclérose en plaques par le natalizumab (évaluation des indications, de l efficacité, de la tolérance, de la qualité de vie et du retentissement médico-économique au sein de la cohorte grenobloise)

Le natalizumab (NTZ), indiqué dans la sclérose en plaques rémittente-récurrente (SEP-RR), est plus efficace que les traitements classiquement utilisés. Ses risques rares mais graves, tels la leucoencéphalopathie multifocale progressive en ont restreint les indications officielles. Nos objectifs étaient d évaluer les indications, les données d efficacité et tolérance du NTZ comparées à l étude pivot AFFIRM. Puis, ce travail a été centré sur l évaluation des connaissances des patients sur le NTZ, sur leur qualité de vie (QDV) et sur l impact médico-économique de cette prescription. Les indications, l efficacité, et la tolérance du NTZ ont été évaluées rétrospectivement au CHU de Grenoble entre 2007 et 2012. Les connaissances des patients sur le NTZ et l impact médico-économique de celui-ci ont été évalués par des questionnaires conçus spécifiquement. La QDV préalable et postérieure à la mise en route du NTZ a été évaluée, chez les patients traités depuis au moins 18 mois, grâce au questionnaire SEP-59. En adéquation avec l AMM, notre étude a confirmé l efficacité radioclinique du NTZ, avec un bon profil de tolérance, comme dans l étude AFFIRM. Une amélioration de la QDV globale sous NTZ, ainsi qu une tendance à limiter les conséquences socioprofessionnelles de la SEP a également été montrée. Enfin, la connaissance des patients sur le NTZ était globalement bonne, mais plus inégale sur les effets indésirables. A court et moyen terme, le NTZ est efficace sur l activité inflammatoire de la SEP-RR et sur la QDV des patients, bien toléré, et semble limiter la dégradation de la vie sociale et professionnelle induite par la SEP, avec possiblement un rapport coût-efficacité favorable.Natalizumab (NTZ), indicated in relapsing-remitting forms of multiple sclerosis (RR-MS), is more effective than treatments used until now. Its rare but serious risks, like progressive multifocal leukoencephalopathy led to restrict the official indications. Objectives of our work were to assess prescription indications, to compare efficacy and tolerance data to those of pivotal studies (AFFIRM and SENTINEL). Then, we focused on assessment of knowledge of patients on NTZ, quality of life (QoL), and medico-economic impact of this prescription. Indications, efficacy, and tolerance of NTZ were assessed retrospectively in University Hospital of Grenoble between 2007 and 2012. Patients knowledge assessment on NTZ as well as social and professional impact were performed by questionnaires made specifically. Assessment of current quality of life was analyzed by SEP-59 questionnaire, completed by patients treated for more than 18 months, then asking them to complete it about their previous status before treatment introduction. In accordance with MA recommendations, our study confirmed clinical and radiological efficacy of NTZ, well tolerated, as in AFFIRM study. An improvement of general QoL of patients undergoing NTZ, as well as a treatment tendency to limit social and professional consequences of MS has been shown. Finally, knowledge of patients on NTZ was generally good, but more heterogeneous on adverse effects. In short and medium term, NTZ is efficient on inflammatory activity of the RR-MS, and on QoL of patients, well tolerated, and seems to minimize the frequent deterioration of social and professional life induced by MS, with possibly a relatively good cost-effectiveness.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Risk Assessment for Hospital-Acquired Diseases: A Risk-Theory Approach.

International audienceWe introduce a new approach to hospital-acquired disease risk assessment from public health databases. In a spirit similar to actuarial risk theory, we define an adjustment coefficient that can quantify the risk associated with a hospital department, allowing comparisons of similar departments. The adjustment coefficient characterizes the tail of the distribution of the total patient length of stay in a department before the first disease event occurs. We show that this coefficient is the solution of a Lundberg-like equation, and we provide a nonparametric estimation procedure for this measure, based on a Cram?Lundberg approximation for the tail of the distribution. Using simulations, we provide evidence of the robustness of the approximation to various individual risk models. In addition, we illustrate the relevance of this approach by evaluating the risk associated with a standard patient safety indicator in 20 hospitals of southeastern France

Metacognition and self-awareness in Multiple Sclerosis

International audienc