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ObjectiveTo analyze the effects of pregnancy on neuromyelitis optica spectrum disorder (NMOSD) according to patients' serostatus and immunosuppressive therapy (IST).MethodsWe performed a retrospective multicenter international study on patients with NMOSD. Patients were tested for aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). Informative pregnancies were reported when NMOSD onset occurred before or during pregnancy or up to 12 months postpartum. The mean annualized relapse rate (ARR) was calculated for the 12 months before conception, for each trimester of pregnancy, and postpartum. Events such as miscarriage, abortion, and preeclampsia were reported. IST was considered if taken in the 3 months before or during pregnancy.ResultsWe included 89 pregnancies (46 with AQP4-Ab, 30 with MOG-Ab, and 13 without either Ab) in 58 patients with NMOSD. Compared to the prepregnancy period, the ARR was lower during pregnancy in each serostatus group and higher during the postpartum period in patients with AQP4-Ab (p < 0.01). Forty-eight percent (n = 31) of pregnancies occurred during IST and these patients presented fewer relapses during pregnancy and the 12 months postpartum than untreated patients (26% vs 53%, p = 0.04). Miscarriages occurred in 10 (11%) pregnancies, and were mainly in patients with AQP4-Ab (with or without IST) and a previous history of miscarriage. Preeclampsia was reported in 2 (2%) patients who were AQP4-Ab-positive.ConclusionWe found a rebound in the ARR during the first postpartum trimester that was higher than the prepregnancy period only in AQP4-Ab-positive patients. Taking IST just before or during pregnancy reduces the risk of relapses in these conditions.

International audience; Our knowledge of the radiological spectrum of myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) is growing rapidly. An update on the radiological features of the disease, and its evolution is thus necessary. Magnetic resonance imaging (MRI) has an increasingly important role in the differential diagnosis of MOGAD particularly from aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and multiple sclerosis (MS). Differentiating these conditions is of prime importance because the management is different between the three inflammatory diseases, and thus could prevent further attack-related disability. Therefore, identifying the MRI features suggestive of MOGAD has diagnostic and prognostic implications. We herein review optic nerve, spinal cord and the brain MRI findings from MOGAD adult patients, and compare them to AQP4-NMOSD and MS.

International audience; Background: Studies have shown that oral high-dose methylprednisolone (MP) is non-inferior to intravenous MP in treating multiple sclerosis relapses in terms of effectiveness and tolerance. In order to assist with resource allocation and decision-making, its cost-effectiveness must also be assessed. Our objective was to evaluate the cost-utility of per os high-dose MP as well as the cost-savings associated with implementing the strategy.Methods: A cost-utility analysis at 28 days was carried out using data from the French COPOUSEP multicenter, double-blind randomized controlled non-inferiority trial and the statutory health insurance reimbursement database. Costs were calculated using a societal perspective, including both direct and indirect costs. An incremental cost-effectiveness ratio was calculated and bootstrapping methods assessed the uncertainty surrounding the results. An alternative scenario analysis in which MP was administered at home was also carried out. A budgetary impact analysis was carried at five years.Results: In the conditions of the trial (hospitalized patients), there was no significant difference in utilities and costs at 28 days. The incremental cost-effectiveness ratio was €15,360 per quality-adjusted life-year gained. If multiple sclerosis relapses were treated at home, oral MP would be more effective, less costly and associated with annual savings up to 25 million euros for the French healthcare system.Conclusions: Oral MP is cost-effective in the treatment of multiple sclerosis relapses and associated with major savings.

Resume Introduction Les infections urinaires (IU) sont frequemment rencontrees au cours de la sclerose en plaques en raison de facteurs de risque intrinseques (vessie neurologique) et extrinseques (traitements immunosuppresseurs). Le surrisque de morbi-mortalite doit donc etre pris en compte. Par ailleurs, la mise en jeu du systeme immunitaire, au cours des infections urinaires, pourrait etre un facteur declenchant de poussee ou d’aggravation neurologique. Le depistage et le traitement des IU deviendraient donc determinant dans la prise en charge de la maladie. Pour ces raisons, la Societe francaise de sclerose en plaques (SFSEP) a propose d’etablir des recommandations pratiques sur ce theme. Materiels et methodes Le groupe « recommandations » de la SFSEP a realise une revue de litterature systematique sur le sujet a partir de Pub Med et des bases universitaires de 01/1980 a 12/2019. La methode RAND/UCLA (Haute Autorite de sante, 2007) a ete utilisee pour synthetiser la litterature scientifique et les opinions d’experts afin de formaliser un accord pour chaque proposition. Resultats Les IU ne sont pas associees a un risque accru de poussee ou d’aggravation transitoire de l’incapacite chez les patients atteints de SEP. Seules les IU febriles sont associees a un risque accru d’aggravation transitoire de l’incapacite par l’intermediaire du phenomene d’Uhthoff. Certains traitements immunosuppresseurs augmentent le risque d’IU dans la SEP et necessitent une attention particuliere, surtout en cas d’hypogammaglobulinemie. Les experts recommandent de traiter les IU selon les recommandations de la population generale. La prevention des IU recidivantes passe, avant tout, par une stabilisation de l’etat vesicosphincterien. En cas d’IU recidivantes, les traitements complementaires et l’antibioprophylaxie au long cours ne sont pas recommandes ; seul l’antibiocycle hebdomadaire alterne peut etre propose apres avis d’experts. Les bacteriuries asymptomatiques (BA) ne doivent pas etre depistees ni traitees systematiquement chez les patients atteints de SEP, hormis en cas de grossesse et de geste invasif urologique. Avant un bilan urodynamique, il est recommande de traiter une bacteriurie asymptomatique uniquement en cas de facteurs de risque d’IU connus. En cas de sondages intermittents ou a demeure, il n’est pas recommande de depister ni de traiter les BA chez les patients atteints de SEP. Conclusion Ces recommandations ont pour objectif de mettre a disposition des differents acteurs du systeme de sante une synthese rigoureuse de l’etat de l’art et des donnees de la science, destinee a aider la prise de decision dans le choix des soins ; a harmoniser les pratiques et a reduire les traitements inappropries.

Resume La sclerose en plaques est une maladie inflammatoire chronique du systeme nerveux central d’etiologie auto-immune. Son phenotype et son evolution peuvent differer d’un patient a l’autre. L’epidemiologie et la presentation de la sclerose en plaques ont connu des modifications remarquables au cours des dernieres decennies notamment dans les pays du Maghreb. Une augmentation de la prevalence et de l’incidence surtout chez la femme a ete notee. Une severite particuliere de la maladie a ete decrite chez les patients d’origine maghrebine par rapport aux Caucasiens. Dans des etudes recentes, la progression du handicap, comparee entre les patients vivant en Afrique du Nord, les immigrants nord-africains et les Caucasiens, etait plus severe chez les patients d’origine nord-africaine. En outre, la severite de la maladie chez les Nord-Africains vivant en France, en particulier chez ceux de la deuxieme generation, a ete demontree. En effet, l’evolution de la maladie serait due a une interaction complexe entre les facteurs genetiques et environnementaux. Au cours des dix dernieres annees, les chercheurs ont valide de nombreux facteurs genetiques et expositions environnementales qui augmentent la susceptibilite a la sclerose en plaques. L’allele HLA-DRB1 * 15/01 a ete associe a un risque plus important de developper la maladie. A la predisposition genetique, s’ajoutent les facteurs environnementaux. L’infection par le virus de l’Epstein-Barr, le tabagisme, et l’alimentation etaient associes au phenotype de la maladie. Ainsi, Son heterogeneite clinique pourrait resulter d’interactions gene-environnement. Des etudes supplementaires sont necessaires pour evaluer l’effet des facteurs environnementaux et genetiques sur la sclerose en plaques aux pays du Maghreb, afin d’etablir les mecanismes en cause et etudier les strategies preventives sous nos latitudes.

Background: Yellow fever vaccine (YFV) is not advised for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses. Objective: To assess the risk of relapsing-remitting multiple sclerosis (RR-MS) worsening after YFV. Methods: Non-interventional observational retrospective, exposed/non-exposed cohort study nested in the French national cohort including MS. Results: 128 RR-MS were included. The 1-year annualized relapse rate (ARR) following YFV did not differ between exposed: 0.219 (0.420) and non-exposed subjects: 0.208 (0.521) ( p = 0.92). Time to first relapse was not different between groups (adjusted hazard ratio (HR) = 1.33; 95% confidence interval (CI) = 0.53–3.30, p = 0.54). Conclusion: These results suggest that YFV does not worsen the course of RR-MS.

Objectives Establish recommendations for the management of UTIs in MS patients. Background Urinary tract infections (UTIs) are common during multiple sclerosis (MS) and are one of the most common comorbidities potentially responsible for deaths from urinary sepsis. Methods The recommendations attempt to answer three main questions about UTIs and MS. The French Group for Recommendations in MS (France4MS) did a systematic review of articles from PubMed and universities databases (01/1980–12/2019). The RAND/UCLA appropriateness method, which has been developed to synthesize the scientific literature and expert opinions on health care topics, was used for reaching a formal agreement. 26 MS experts worked on the full-text review and a group of 70 multidisciplinary health care specialists validated the final evaluation of summarized evidences. Results UTIs are not associated with an increased risk of relapse and permanent worsening of disability. Only febrile UTIs worsen transient disability through the Uhthoff phenomenon. Some immunosuppressive treatments increase the risk of UTIs in MS patients and require special attention especially in case of hypogammaglobulinemia. Experts recommend to treat UTIs in patients with MS, according to recommendations of the general population. Prevention of recurrent UTIs requires stabilization of the neurogenic bladder. In some cases, weekly oral cycling antibiotics can be proposed after specialist advice. Asymptomatic bacteriuria should not be screened for or treated systematically except in special cases (pregnancy and invasive urological procedures). Conclusion Physicians and patients should be aware of the updated recommendations for UTis and MS.

International audience; Background: Outcomes of coronavirus disease 2019 (COVID-19) in patients with neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), often treated with immunosuppressive therapies, are still unknown.Methods: We conducted a multicenter, retrospective, observational cohort study among all French expert centers for neuromyelitis optica and related disorders. Patients with NMOSD or MOGAD included in the study received a confirmed or highly suspected diagnosis of COVID-19 between 1 March 2020 and 30 June 2020. Main outcome was COVID-19 severity score assessed on a seven-point ordinal scale ranging from 1 (not hospitalized with no limitations on activities) to 7 (death).Results: Fifteen cases (mean [SD] age: 39.3 [14.3] years, 11 female) were included. Five patients (33.3%) were hospitalized, all receiving rituximab. A 24-year-old patient with positive aquaporine-4 antibody, with obesity as comorbidity, needed mechanical ventilation. Outpatients were receiving anti-CD20 (5), mycophenolate mofetil (3) or azathioprine (3). They were younger (mean [SD] age: 37.0 [13.4] years), with a longer disease duration (mean [SD]: 8.3 [6.3] years) and had a lower expanded disability severity score (EDSS) score (median [range] EDSS: 2.5 [0-4]) relative to patients requiring hospitalization (mean [SD] age: 44.0 [16.4] years, mean [SD] disease duration: 5.8 [5.5] years, median [range] EDSS: 4 [0-6.5]).Conclusions: COVID-19 outcome was overall favorable in this cohort. Larger international studies are needed to identify risk factors of severe COVID-19; however, we recommend personal protective measures to reduce risk of SARS-CoV-2 infection in this immunocompromised population.

International audience; Background and purposeThree different sets of criteria have been proposed for the diagnosis of neuromyelitis optica spectrum disorder (NMOSD). The objective was to compare the specificity, sensitivity and diagnostic accuracy of the three different sets of NMOSD criteria in patients presenting with inflammatory disorders of the central nervous system suggestive of NMOSD.MethodsFor 236 suspected NMOSD patients referred for serum aquaporin-4 immunoglobulin G antibody (AQP4-IgG) testing between 2012 and 2014, the three sets of NMOSD criteria [1999, 2006 NMO criteria and 2015 International Panel for NMO Diagnosis (IPND) criteria] were applied and compared to the final diagnosis. ResultsSeventy-six patients fulfilled at least one set of criteria and 28 patients fulfilled all NMOSD sets of criteria. The final diagnosis was NMOSD in 66 cases, multiple sclerosis according to the MacDonald 2010 criteria in 85 cases and another diagnosis in 85 cases. The 2006 NMO criteria have the highest specificity (99%) and the 2015 IPND NMOSD criteria the highest sensitivity (97%). For the 1999, 2006 and 2015 IPND NMOSD criteria, the accuracy was respectively 82%, 87% and 97%.ConclusionsOur study highlights the limitations of the first set of criteria that include the optico-spinal form of multiple sclerosis. The accuracy of NMOSD diagnostic criteria improved from 1999 to 2015. It confirms the increased performance of the last set of criteria which covers a larger spectrum of clinical presentation. This study raises some concerns for classifying patients with seronegative transverse myelitis or optic neuritis, and myelin oligodendrocyte glycoprotein (MOG) antibody- associated disease.

International audience; Background: Timely treatment switching is an important strategy in optimising management of patients with relapsing remitting multiple sclerosis (RRMS). Patient preferences, as well as clinical benefit, may contribute to the switch decision. Information on reasons determining switching choices and on outcome according to the reason for switching is scarce. Study objectives were to describe the consequences of switching to fingolimod in terms of clinical improvement according to the reasons underlying the switch and to evaluate treatment acceptability from the patient's perspective. Methods: This prospective observational study was conducted by 71 neurologists in France and included patients with RRMS switching to fingolimod following ≥6 months treatment with a first-line disease modifying treatment (DMT). Reasons for switching were documented. Patients were evaluated at inclusion and 12 months after initiating fingolimod. Physicians documented clinical status by relapse activity, disability (EDSS) at each visit and improvement with the Clinical Global Impression – Change (CGI-C) at Month 12. Patients rated improvement at Month 12 with the Patient Global Impression – Change (PGI-C) and treatment acceptability with the ACCEPT® questionnaire. Adverse events reported during fingolimod treatment were documented. Results: Overall 232 patients were recruited of whom 190 could be analysed. Multiple reasons for switching were frequently given; 113 patients (59.4%) switched from a first-line injectable DMT. Switching was motivated by disease worsening in 161 patients (84.7%), tolerability in 35 (18.4%) and patient preference in 58 (30.5%). During the follow-up period, 38 patients (20.0%) experienced at least one exacerbation. The mean EDSS score was stable (2.0 ± 1.3 at inclusion; 2.0 ± 1.5 at M12). With the CGI-C, 67 patients (38.7%) were considered improved and 23 (13.3%) worsened. Although no obvious differences in CGI-C ratings were observed as a function of the reason for switching, when patient preferences entered into the decision, the proportion of patients considered minimally improved was somewhat higher (37.7%) and the proportion considered unchanged somewhat lower (41.5%). With the PGI-C, more patients rated themselves improved than were rated as improved by the physician: of 64 patients rated as ‘no change’ on the CGI-C, 21 (32.8%) rated themselves as ‘improved’ and 10 (15.6%) as ‘worsened’. The overall level of agreement between the two measures was moderate (κ = 0.48 [95% CI: 0.35 – 0.60]). The mean general treatment acceptability score on the ACCEPT® questionnaire was 42.7 [95%CI: 34.5 – 50.9] at inclusion (reflecting acceptability of the previous DMT) and 64.6 [95%CI: 57.6 – 71.6] at M12 (reflecting acceptability of fingolimod). Mean dimension scores ranged from 36.7 for effectiveness to 72.2 for medication inconvenience at inclusion and from 63.4 for effectiveness to 96.8 for medication inconvenience at M12. The frequency and nature of reported adverse events was consistent with the well-characterised safety profile of fingolimod. Conclusion: Most patients switching from a first DMT to fingolimod do so due to persistent disease activity during the initial treatment, although patient preferences are also important. Switching is followed by a reduction in disease activity, perceived improvement in the clinical state of the patient and improved acceptability of treatment.

There is growing evidence of a preventive effect of Rituximab (RTX) in neuromyelitis optica spectrum disorders (NMO-SD). This monoclonal antibody against CD20 is becoming the most widely used preventive therapy in NMO-SD, as a first-line therapy or as a rescue therapy. Nevertheless, considerable heterogeneity still exists concerning the pre-treatment work-up, the vaccinations required before and under treatment, the number and dosage of infusions, prevention of the risk of infusion-related reactions, prevention of infections under treatment, and frequency of therapeutic cycles. Thanks to a collaborative work among NMO-SD experts belonging to the NOMADMUS project, we provide here recommendations for all these topics concerning RTX use in NMO-SD.

Objectives To establish recommendations on immunization for patients with multiple sclerosis (MS). Background Vaccines have been suspected in the past to trigger MS and relapses. With the extension of the immunoactive treatment arsenal, other concerns have been raised more recently about an increased risk of infection or a decreased effectiveness of immunization in immunosuppressed patients. Methods The French Group for Recommendations into Multiple Sclerosis (France4MS) performed a systematic search of papers in Medline and other university databases (January 1975–June 2018). The RAND/UCLA appropriateness method was chosen to review the scientific literature and to formalize the degree of agreement among experts on 5 clinical questions related to immunization and MS. Readers from the steering committee conducted a systematic analysis, wrote a critical synthesis and prepared a list of proposals that were evaluated by a rating group of 28 MS experts. The final version of the recommendations was finally reviewed by a reading group of 110 health care professionals and classified as appropriate, inappropriate or uncertain. Results Neurologists should verify the vaccination status as soon as MS is diagnosed and before disease-modifying treatments (DMTs) are introduced. The French vaccination schedule applies to MS patients and seasonal influenza vaccination is recommended. In the case of treatment-induced immunosuppression, MS patients should be informed about the risk of infection and the vaccination standards of the French High Council of Health should be applied. Live attenuated vaccines are contra-indicated in patients recently treated with immunosuppressive drugs, including corticosteroids; other vaccines can be proposed whatever the treatment, but their effectiveness may be partly reduced with some drugs. Conclusion Physicians and patients should be aware of the updated recommendations for immunizations of patients with MS.

Background Cognitive impairment is frequent in multiple sclerosis (MS), affecting approximately 40 to 70% of patients. We developed a psycho-educational program (ADACOG program) to allow patients to cope with cognitive deficits. The purpose of this exploratory study was to investigate the impact of the ADACOG program on subjective self-reported cognitive impairments, quality of life, anxiety, depression and self-esteem in MS patients. Methods ADACOG program is a psycho-educational program focusing on cognitive and emotional dysfunctions in MS consisting of three modules in small groups lasting two hours every two weeks. Forty-five MS patients with self-reported cognitive impairments and objective cognitive deficits were enrolled consecutively in two groups: (i) the ADACOG group (N = 24) and (ii) the control group (N = 21). Both groups of patients completed questionnaires evaluating self-reported cognitive impairments (Multiple Sclerosis Neuropsychological Screening Questionnaire), quality of life (Multiple Sclerosis Impact Scale), anxiety and depression (Hospital Anxiety and Depression Scale, HAD) and self-esteem (Rosenberg Scale) at inclusion (M0), one month later (M1) and seven months after inclusion (M7). The evolution of outcomes within ADACOG group and between both groups was analyzed. Results The analyses within the ADACOG group showed that patients reported better quality of life and fewer anxiety symptoms at M1 compared to M0 (respectively P = 0.03 and P = 0,04). Moreover, patients presented less subjective self-reported cognitive deficits at M7 compared to M0 (P = 0.003). Score evolution for HAD depression and self-esteem were not significant within the ADACOG group. The change M1-M0 for MSIS-29 and HAD anxiety scores was significantly different between both groups (respectively P = 0.04 and P = 0.008), with improvement of quality of life and anxiety in the ADACOG group. The evolution of scores between groups was not significant for the other outcomes. Discussion This study showed a small effect of a psycho-educational program focusing on cognitive and emotional disorders in MS patients with subjective self-reported cognitive deficits and objective cognitive deficits. Interest of psycho-education focusing on cognition in MS patients is discussed.

Background and purpose There are few clinico-radiological data on optic neuritis (ON) with myelin oligodendrocyte glycoprotein antibody (MOG-IgG). The objective was to characterize the clinico-radiological phenotype and outcome of patients with MOG-IgG-related ON. Methods The records of all adult patients admitted in three medical centres with MOG-IgG-associated ON who underwent orbital and brain magnetic resonance imaging (MRI) at the acute phase were reviewed. Spinal cord MRI within 1 month from the ON and all of the follow-up MRI were reviewed. Results Of 62 patients, 41.9% had bilateral ON and 66.2% optic disc swelling. On initial MRI, lesions were anterior (92%), extensive (63%) and associated with optic perineuritis (46.6%). Silent brain lesions were found in 51.8% of patients but were mainly non-specific (81%). Of 39 individuals with spinal MRI at onset, nine had abnormal findings (four were asymptomatic). Two symptomatic patients had longitudinally extensive myelitis with concurrent H-sign. At last follow-up, 5% of patients had visual acuity ≤0.1. Brain MRI remained unchanged in 41 patients (87%). Conclusions Our study supports a mostly benign ophthalmological course of MOG-IgG-associated ON, despite initially longitudinally extensive lesions and development of optic nerve atrophy on orbital MRI. Spinal MRI could be of interest in detecting silent suggestive lesions.

Revue Neurologique - In Press.Proof corrected by the author Available online since jeudi 1 decembre 2016

Introduction Le vaccin contre la fievre jaune est requis pour voyager en zone d’endemie de fievre jaune mais il est deconseille chez les patients atteints de sclerose en plaques (SEP) en raison du risque potentiel de poussees post-vaccinales mis en evidence dans une seule publication incluant 7 patients. Materiels et methodes Evaluer chez les patients SEP recurrentes-remittentes, ayant beneficie d’une vaccination fievre jaune, le risque de survenue d’une activite de la maladie dans les 12 mois suivant la vaccination. Dans cette etude retro-prospective et observationnelle exposes/non-exposes, chaque patient vaccine contre la fievre jaune apres le debut de la maladie SEP a ete apparie a 3 patients SEP sans historique de vaccination contre la fievre jaune et identifies par la base de donnees locale European Database for Multiple Sclerosis (EDMUS). Les criteres d’appariement etaient : l’âge et l’activite de la maladie avant vaccination. Le delai de survenue d’une poussee des exposes et non-exposes a ete analyse par un test log-rank. Un modele de Cox a estime les hazard ratio bruts et ajustes. Resultats Trente et un (20 F/11 H) patients vaccines ont ete inclus. L’âge moyen de debut de la maladie etait de 38 ans et la duree moyenne de la maladie avant la vaccination etait de 10,8 ans. Parmi les patients, 19,35 % avaient une activite clinique l’annee precedant la vaccination, l’Expanded Disability Status Scale (EDSS) moyen etait a 0,78 lors de la vaccination. La moitie des patients n’etaient pas traites pour le SEP au moment de la vaccination (51,6 %), 41,9 % d’entre eux avaient un traitement de 1re ligne et 6,4 % etaient traites par natalizumab. Les resultats complets de cette etude exposes/non-exposes seront disponibles fin fevrier. Conclusion La fievre jaune est une maladie grave potentiellement mortelle, pouvant etre contractee en zones d’endemie (Afrique subsaharienne et Amerique du Sud) et ne disposant pas de traitement. Le vaccin anti-amaril, tres efficace, est exige pour entrer sur le territoire de certains pays en zone d’endemie. Ce vaccin vivant attenue est contre-indique chez les patients traites par immunosuppresseurs. Les resultats de cette etude epidemiologique cas/temoin permettront de faire evoluer les pratiques et les recommandations vaccinales contre la fievre jaune et de conseiller au mieux les patients atteints de SEP se rendant en zone d’endemie.

Introduction Le fingolimod (Fg) est un immunosuppresseur utilise pour le traitement de la forme recurrente remittente de sclerose en plaques (SEP), disponible en France depuis 2012. En 2018, des infections causees par des papillomavirus humains (PVH) ont ete rapportees sous Fg. Le but de cette etude est de decrire une serie de cas de patients presentant des lesions cutaneomuqueuses causees par PVH survenues sous Fg, en particulier le type de lesions liees a PVH, le typage PVH si realise et la prise en charge. Materiels et methodes Il s’agit d’une etude descriptive, retrospective sur une cohorte de patients atteints de SEP developpant sous Fg des lesions cutaneomuqueuses liees a PVH. Nous avons collecte des donnees sur l’histoire de leur maladie neurologique, sur l’aspect clinique et therapeutique de la maladie a PVH, sur le taux de lymphocytes au moment de l’apparition des lesions, et sur l’evolution de la SEP apres le diagnostic de la pathologie a PVH. Resultats Nous rapportons 14 patients (9 femmes), âges de 37 ans en mediane (IQR : 32–40) au moment du diagnostic du PVH, sous Fg depuis 3 ans en mediane (IQR : 1,5–5), avec une SEP evoluant depuis 13,5 ans (IQR : 11–16). Huit patientes (54 %) presentaient des dysplasies cervicales, dont 4 de bas grade (LSIL) et 4 de haut grade (HSIL), 6 patients (43 %) presentaient des condylomes acumines, dont 4 au niveau genital et 2 anal, et 3 (21 %) presentaient des verrues vulgaires. Des PVH a risque oncogene eleve ont ete retrouves chez 2 patientes avec HSIL. Le taux de lymphocytes median au moment du diagnostic des lesions etait de 422/mm3 (IQR : 340–559). Le Fg a du etre arrete chez 4 patients devant les echecs de traitement local des lesions (cryotherapie, acide salicylique, imiquimod, laser, electrocoagulation). Six patients ont ete vaccines contre le PVH par vaccin quadrivalent sans poussee de la SEP. Conclusion L’infection a PVH chez les patients traites par Fg, sans doute favorisee par la lymphopenie induite par le Fg, est une problematique peu connue et tres probablement sous-estimee, d’evolution chronique avec un impact important sur la qualite de vie des patients et des complications potentiellement severes, pouvant entrainer des cancers gynecologiques ou ORL. Le traitement de ces lesions peut etre complique, pouvant necessiter l’arret du Fg, parfois a l’origine de poussees de SEP. Un examen dermatologique et gynecologique est recommande avant la mise en route du traitement par Fg, et la vaccination anti-PVH doit etre discutee au cas par cas. La prevention et le depistage systematique des lesions liees a PVH chez des patients atteints de SEP remittente sous fingolimod sont essentiels pour eviter la survenue de lesions cancereuses.

Objective Using positron emission tomography (PET) with [11C]flumazenil ([11C]FMZ), an antagonist of the central benzodiazepine site located within the GABAA receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric. Methods A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [11C]FMZ PET imaging and brain magnetic resonance imaging. [11C]FMZ binding was estimated using the partial saturation protocol providing voxel-wise absolute quantification of GABAA receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis. Results [11C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (–10%). Cortical mapping of benzodiazepine receptor concentration ([11C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [11C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsing-remitting forms of the disease and correlated with WM T2-weighted lesion load. [11C]FMZ cortical binding correlated with cognitive performance. Interpretation This pilot study showed that PET with [11C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS. Ann Neurol 2015;78:554–567

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS), characterized by CNS-restricted inflammation with subsequent demyelination and neurodegeneration. Current disease-modifying therapies efficiently reduce relapse rate and new lesions appearance, but still fail to impact the progressive course of the disease. There is a great need for the avenue of new therapies aimed at promoting myelin repair or reducing neurodegeneration that should result in the prevention of neurological disability in this chronic disease. This review will focus on the potentials and limitations of biotherapies that are currently developed for the promotion of CNS repair in MS, either monoclonal antibodies targeting axonal growth and remyelination, or cell therapies aimed at replacing the depleted myelinating cells within the CNS. As other researches aimed at promoting neuroprotection or remyelination are following a classical pharmacological approach, they will not be described in this review, which will focus on antibody-based therapies and cell therapies.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, whose incidental peak occurs around 30 years. This review focuses on epidemiologic, physiopathological, clinical and therapeutic characteristics of MS in elderly patients in two different situations: 1) late-onset MS (after 50 years), 2) aging in MS with young adult-onset. Epidemiologic studies established that MS occurs after 50 years in 5% of cases. As opposed to young adult-onset MS, late-onset MS is characterized by a predominant progressive course, a longer diagnosis delay, a higher prevalence of motor disability, while cognitive impairment is similar in terms of frequency and affected cognitive domains. Improvement of MS patients' global healthcare together with life expectancy increase has led to an increased number of elderly patients with MS, regardless of age at onset. Care providers must take into account the potential more frequent comorbidities in this specific population and pharmacological differences with younger subjects to adapt and optimize the risk/balance benefit of disease-modifying therapies.

Acute transverse myelitis had many names and definitions, based primarily on clinical criteria. The role of MRI in the exploration of myelitis has increased recently after the individualization of neuromyelitis optica (NMO) in 2004. This approach has enabled clarification of the diagnostic and prognostic value of acute longitudinally extensive transverse myelitis (LETM), defined by an extensive T2 lesion affecting three vertebral segments in the sagittal plane. The limitations of this definition, the multiplicity of terms used to characterize it as well as the large number of etiologies associated with it led our group of experts to clarify its etiology and nosology. We conducted a national survey on this subject in order to propose a new definition of LETM. Additional first- and second-intention examinations were determined according to the clinical context. Infectious/para-infectious, inflammatory or paraneoplastic causes can thus be identified. To determine within a short time the cause of LETM is essential, since most of its causes are severe and require urgent treatment.

Background and purpose BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing−remitting multiple sclerosis (MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment. Methods Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y). Results NTZ was discontinued in 17.78% of BIONAT2Y. The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZantibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found. Conclusions The efficacy of NTZ therapy on relapsing−remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events.

Non-medicinal treatments of spasticity may be proposed in patients with multiple sclerosis as either an adjunct to pharmacological treatments or the first line of treatment. Assessment of non-medicinal treatments, whether manual, surgical or with instrumentation, shows it to be beneficial for limb spasticity. Studies also reveal that, contrary to expectations, physical exercise does not increase spasticity. This means that physical exercise may be prioritized and that sports practice should not be forbidden, provided that the patient has an adequate neurological status and takes sufficient breaks to avoid fatigue.

International audience; BackgroundHome care for patients with multiple sclerosis relies largely on informal caregivers (ICs).MethodsWe assessed ICs objective burden (Informal Care Time, ICT) and ICs subjective burden (Zarit Burden Inventory, ZBI) and their explanatory factors.ResultsICs (n = 99) were spouses (70%), mean age 52 years, assisting disabled patients with a mean Expanded Disability Status Scale (EDSS) of 5.5, with executive dysfunction (mean DysExecutive Questionnaire [DEX] of 25) and a duration of MS ranging from 1 to 44 years. Objective burden was high (mean ICT = 6.5 hours/day), mostly consisting of supervision time. Subjective burden was moderate (mean ZBI = 27.3). Multivariate analyses showed that both burdens were positively correlated with higher levels of EDSS and DEX, whereas co-residency and IC's female gender correlated with objective burden only and IC's poor mental health status with subjective burden only. When considering MS aggressiveness, it appeared that both burdens were not correlated with a higher duration of MS but rather increased for patients with severe and early cognitive dysfunction and for patients classified as fast progressors according to the Multiple Sclerosis Severity Scale.ConclusionMS disability course and IC's personal situation must be evaluated to understand the burden process and to implement adequate interventions in MS.

Background. Home care for patients with Multiple Sclerosis (MS) relies largely on informal caregivers (ICs). Methods. We assessed ICs objective burden (Resource Utilization in Dementia measuring informal care time (ICT)) and ICs subjective burden (Zarit Burden Inventory (ZBI)). Results. ICs (N=99) were spouses (70%), mean age 52 years, assisting disabled patients with a mean EDSS (Expanded Disability Status Scale) of 5.5, with executive dysfunction (mean DEX (Dysexecutive questionnaire) of 25) and a duration of MS ranging from 1 to 44 years. Objective burden was high (mean ICT = 6.5 hours/day), mostly consisting of supervision time. Subjective burden was moderate (mean ZBI = 27.3). Multivariate analyses showed that both burdens were positively correlated with higher levels of EDSS and DEX, whereas coresidency and IC’s female gender correlated with objective burden only and IC’s poor mental health status with subjective burden only. When considering MS aggressiveness, it appeared that both burdens were not correlated with a higher duration of MS but rather increased for patients with severe and early dysexecutive function and for patients classified as fast progressors according to the Multiple Sclerosis Severity Score. Conclusion. Evaluation of MS disability course and IC’s personal situation is crucial to understand the burden process and to implement adequate interventions in MS.

Resume Introduction La sclerose concentrique de Balo est une forme neuropathologique de sclerose en plaques, caracterisee par une alternance d’anneaux sains et d’anneaux demyelinises. Le diagnostic repose actuellement sur un aspect evocateur en imagerie par resonance magnetique (IRM), mais il n’existe que peu de donnees sur les caracteristiques de ces lesions en spectroscopie protonique par resonance magnetique (SRM). Methodes Nous rapportons un cas de sclerose concentrique de Balo avec la description en SRM des lesions et de leur evolution. Resultats L’etude en SRM de deux lesions au stade aigu (prenant le contraste en bulbe d’oignon sur l’IRM apres injection de gadolinium) a montre une diminution du pic de N-acetylaspartate (NAA), une augmentation du pic de la choline, la presence d’un doublet de lactates et d’un pic de lipides centre a 0,9 ppm. Six mois plus tard, le pic de NAA restait bas, tandis que le pic de choline avait diminue et le doublet de lactates avait disparu. Conclusion Ces donnees spectrometriques sont conformes a l’evolution habituelle des lesions demyelinisantes, comme cela peut etre observe dans la sclerose en plaques. Dans le cadre d’une sclerose concentrique de Balo, la SRM peut donc apporter des arguments neurochimiques en faveur de la nature inflammatoire et demyelinisante des lesions, et permet en outre de preciser le degre d’atteinte et de recuperation axonale.

La sclerose en plaques est une maladie inflammatoire et demyelinisante du systeme nerveux central touchant les adultes jeunes. Plusieurs immunomodulateurs ont ete testes depuis une decennie dans les formes remittentes de la maladie (c’est-a-dire les formes evoluant par poussees). Recemment, un anticorps monoclonal, le natalizumab (Tysabri® ), dirige contre l’integrine VLA-4 qui controle le passage transendothelial des effecteurs de l’immunite, a suscite beaucoup d’espoir compte tenu de son efficacite, mais l’immunosuppression qu’il engendre fait aussi courir le risque de complications infectieuses opportunistes, et la survenue de plusieurs cas de leucoencephalite multifocale progressive a incite a restreindre son utilisation aux formes remittentes graves. Cet exemple illustre la difficulte a laquelle les medecins sont confrontes : celle de l’evaluation du rapport benefice/risque de ces nouveaux biomedicaments efficaces, mais non denues de risque, que sont les anticorps monoclonaux.

Resume Nous rapportons le cas d’une patiente ayant presente une ophtalmoplegie complete compliquant un zona ophtalmique. La decouverte d’un meningiome temporal interne ipsilateral envahissant le sinus caverneux fait discuter l’origine tumorale ou infectieuse des signes ophtalmiques.

Acute transverse myelitis had many names and definitions, based primarily on clinical criteria. The role of MRI in the exploration of myelitis has increased recently after the individualization of neuromyelitis optica (NMO) in 2004. This approach has enabled clarification of the diagnostic and prognostic value of acute longitudinally extensive transverse myelitis (LETM), defined by an extensive T2 lesion affecting three vertebral segments in the sagittal plane. The limitations of this definition, the multiplicity of terms used to characterize it as well as the large number of etiologies associated with it led our group of experts to clarify its etiology and nosology. We conducted a national survey on this subject in order to propose a new definition of LETM. Additional first- and second-intention examinations were determined according to the clinical context. Infectious/para-infectious, inflammatory or paraneoplastic causes can thus be identified. To determine within a short time the cause of LETM is essential, since most of its causes are severe and require urgent treatment.

Non-medicinal treatments of spasticity may be proposed in patients with multiple sclerosis as either an adjunct to pharmacological treatments or the first line of treatment. Assessment of non-medicinal treatments, whether manual, surgical or with instrumentation, shows it to be beneficial for limb spasticity. Studies also reveal that, contrary to expectations, physical exercise does not increase spasticity. This means that physical exercise may be prioritized and that sports practice should not be forbidden, provided that the patient has an adequate neurological status and takes sufficient breaks to avoid fatigue.

We report the case of a young woman with multiple sclerosis who discontinued natalizumab twice and experienced a severe relapse following each natalizumab withdrawal. The first relapse was successfully treated by intravenous methylprednisolone (IVMP). In contrast the second relapse was unresponsive to IVMP. Subsequent treatment by plasma exchanges (PLEX) was followed by a dramatic neurological worsening. This case suggests that PLEX after natalizumab discontinuation may increase relapse severity.

Introduction Myotonic dystrophy type 1 (DM1) is a genetic disorder caused by expanded CTG repeats within the 3’ untranslated region of the dystrophia myotonia protein kinase (DMPK) gene on chromosome 19. Diplopia is rare in this disease and has only been reported in patients with diffuse neuromuscular disorders. Observation We report here on the case of a 58-year-old woman in whom ophthalmoplegia was the first neuromuscular manifestation of DM1 and led to the diagnosis. Among the multisystem abnormalities associated with DM1, muscle-related symptoms are prominent, and usually involve the facial and neck muscles early on in the disease. This case provides additional evidence of oculomotor muscle involvement in DM1. Conclusion DM1 should, therefore, be considered during the diagnostic workup of any unexplained ophthalmoplegia of muscle origin, especially if there has been a previous history of cataract, even in the absence of typical muscle-related features.

Multiple sclerosis (MS) is a neurological disease mostly affecting women of childbearing age. When counseling MS patients, many questions arise on the reciprocal influence of MS and pregnancy. However, little is known on the impact of MS and its treatments on the time to pregnancy. The objective was to evaluate fecundity (pregnancy and time to pregnancy) in a French cohort of MS women. One hundred and fifteen women with MS were included consecutively in this observational retrospective study. Pregnancy and time to pregnancy were collected using self-questionnaires. Among the 115 patients, 216 pregnancies (from 84 women) were reported. Mean time to pregnancy, which was available for 124 of these pregnancies, was 8.57 months when pregnancy occurred before MS onset, and 7.53 months after MS onset. Among the 95 patients who had a parental project, 2.27 spontaneous pregnancies per woman were recorded. The mean number of children per woman with MS was 1.37. Spontaneous pregnancies per woman and time to pregnancy were not different from the general French population. However, despite a normal fecundity, the mean number of children per woman with MS (1.37) was lower than in the general French population (1.99).

We report a case of a 73-year-old patient with complete ophthalmoplegia following an episode of ophthalmic herpes zoster. MRI showed an associated ipsilateral temporal meningioma with cavernous sinus extension. We discuss the possible responsibility of these two conditions in the ocular motor signs.

Balo's concentric sclerosis is a neuropathological type of multiple sclerosis characterized by alternating rings of spared myelin and demyelination. Diagnosis is based on MRI, but very few data are available concerning the lesion features using serial proton magnetic resonance spectroscopy (1H-MRS).We report 1H-MRS initial findings and disease course in one case of Balo's concentric sclerosis.The first 1H-MRS study of 2 concentric ring-enhanced lesions showed a decreased N-acetyl-aspartate (NAA) peak, an increased choline peak, 2 broad lactate peaks and the presence of a lipid peak at 0.9 ppm. Six months later, 1H-MRS showed a decrease of choline peak, whereas the lactate peak had disappeared. The NAA peak was still at a low level.These findings are similar to those reported in demyelinating disorders, such as multiple sclerosis. Thus, in Balo's concentric sclerosis, 1H-MRS may provide neurochemical arguments for inflammation and demyelination, and indicate the severity of axonal damage and recovery.

Introduction Le Natalizumab (NZ) est un anticorps monoclonal qui a montre son efficacite sur la reduction de la frequence des poussees et l’allongement du delai d’apparition du handicap chez les patients atteints de sclerose en plaques (SEP) evoluant par poussees. En pratique clinique, le NZ peut etre arrete soit par crainte du risque de survenue d’une leuco- encephalopathie multifocale progressive (LEMP), soit en raison d’une inefficacite ou de l’apparition d’effets secondaires ou il peut aussi etre stoppe pour un desir de grossesse. Dans les etudes de phase II, l’activite clinique apres arret du NZ revient a un niveau identique a celui observe avant l’initiation du traitement. Cependant, des observations recentes rapportent la survenue, dans les mois qui suivent l’arret du traitement, de poussees d’une severite inhabituelle, et/ou d’une elevation importante de la charge lesionnelle T2 en IRM et/ou de l’apparition de prises de contraste multiples. Objectif Evaluer l’activite de la maladie dans les 12 mois qui suivent l’arret du Tysabri chez les patients inclus dans la base de donnees nationale TYSEDMUS. Methode En France, les patients exposes au moins une fois au NZ sont inclus dans la base de donnees nationale TYSEDMUS dans le cadre du plan francais de gestion des risques des medicaments. L’evolution clinique de tous les patients qui ont arrete le Tysabri a ete analysee durant les 12 mois suivant l’arret du traitement. Le taux de rechute, le handicap residuel (EDSS) ont ete evalues a 6 mois et 12 mois apres l’arret du Tysabri et compares a ceux de la periode avant et pendant traitement. Le delai de survenue d’une poussee a l’arret du traitement a ete estime en utilisant une analyse de Kaplan- Meier. Les resultats preliminaires En mai 2011, 3351 patients SEP traites par Natalizumab etait inclus dans la base de donnees TYSEDMUS et 2386 dossiers etaient analysables. Parmi eux 393 patients (16.5 %) avaient arrete le traitement pour differentes raisons. Un effort particulier a ete mene pour collecter les informations les plus completes possibles chez les patients ayant arrete le traitement. La base de donnees a ete cloturee en Septembre 2011 et les resultats complets seront presentes au cours de la Journee des Nouveautes de la Recherche Clinique. Conclusions Cette etude systematique, en condition de vie reelle, des patients SEP apres arret du Tysabri, permettra d’evaluer le risque d’augmentation de l’activite de la maladie apres l’interruption du traitement. A notre connaissance cette etude nationale, multicentrique, est unique par son caractere systematique et son vaste effectif.