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Background: Venous sinus stenting (VSS) is an increasingly performed procedure for the treatment of idiopathic intracranial hypertension (IIH) refractory to medical treatment. VSS is typically performed under general anesthesia., Objective: To present our experience of VSS in patients with IIH performed under conscious sedation., Methods: Retrospective review of a prospectively maintained database of all patients with IIH who underwent VSS in a single center between September 2019 and January 2024. The sedation protocol consisted of a remifentanil-based target-controlled infusion. Patients' clinical and radiological data, dosage of anesthesia, procedural characteristics, and outcomes were collected., Results: Twenty-six patients with IIH underwent venous manometry (VM) and VSS under awake sedation and were included in our study. Patients were predominantly women (24/26) with a median age (IQR) of 33 (13) years. The median (IQR) body mass index was 34 (10) kg/m 2 . There was no need for general anesthesia conversion. Technical success was achieved in all patients. Median (IQR) follow-up after stenting was 7 (2) months. All patients reported resolution of the pulsatile tinnitus; headaches regressed in 20/24 (83.3%) patients and papilledema improved in 16/20 (80%). Only one non-neurological complication (retroperitoneal hematoma) occurred, without any permanent morbidity or mortality., Conclusion: Our study confirms that performing VM and VSS under conscious sedation is safe and feasible. Conscious sedation is a viable alternative to general anesthesia for managing IIH in these patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In clinical practice, the diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed, retrospective and non-reproducible, as there are no consensus criteria that define the advent of SPMS. Early identification of SPMS is essential to improve patient care., Methods: Eight regional board meetings in France involving 56 multiple sclerosis (MS) experts (neurologists) were convened to discuss diagnostic criteria for SPMS. Subsequently, a national board meeting of 13 neurologists (with an expert representing each geographical region) was held to review points of convergence or divergence between regions and to develop a national consensus document., Results: Based on the discussions from the regional boards, the MS experts at the national board retained the worsening of the EDSS score, with compatible clinical features, as the only consensus criterion for the diagnosis of SPMS in clinical practice. The patient should have experienced during at least the previous 6 months and in the absence of any relapse, a worsening in the EDSS score of +1.0 point (if the previous EDSS was≤5.0) or of +0.5 point (if the previous EDSS was≥5.5), with a pyramidal or cerebellar functional system score≥2 and without setting a minimum EDSS score; or, in case of a stable EDSS score≥4.0, a worsening of a functional score. This worsening should be confirmed within 3 to 6 months. According to the MS experts, the patient's age, duration of illness and a minimal threshold EDSS score are only risk factors for transition to SPMS. Patient reports during consultation and cognitive impairment are important warning signs, which should trigger an objective assessment with specific tests or closer monitoring. Clinical relapse and/or MRI activities are non-discriminatory for making the diagnosis of SPMS., Conclusions: The experts defined precise diagnostic criteria adapted to clinical practice for earlier identification of SPMS, paving the way for better management of this stage of the disease., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: The perception of diagnosis announcement, the social support and the coping strategies seem to be determining factors for the quality of life of multiple sclerosis (MS) patients, with possible transcultural variations. This study explores these psychosocial dimensions in Lebanese and French MS patients., Methods: For this cross-sectional multi-center study, 8 questionnaires were used to assess quality of life, family support, coping strategies, mood, fatigue, stress, and hopelessness in MS patients. 7 were translated into Arabic and then back translated into French. These were administered to a group of Lebanese MS patients and compared to an MS sample from France. The data was collected for both populations and analyzed., Results: A total of 107 patients were included, 46 Lebanese and 61 French. The majority of MS patients were young females with a high level of education, relapsing remitting form of MS and a low level of disability. Both populations exhibited comparable quality of life and answers on the questionnaires regarding mood disorders, hopelessness, and perceived stress. However, the French patients had significantly more fatigue. Perceived social support given by family was considered greater in the French group compared to the Lebanese one. Also, maladaptive coping strategies (such as self-distraction, denial, behavioral disengagement, substance use, self-blame, venting) were used more frequently by the French population compared to the Lebanese, and this correlated with higher anxiety scores. Diagnosis communication was overall brief, informative, and satisfying in both populations., Conclusion: This study highlighted transcultural differences between French and Lebanese MS patients mainly in social support and coping strategies., (Copyright © 2022. Published by Elsevier B.V.)

Multiple sclerosis (MS) is associated with deficits in social cognition, the process underlying social interaction and cognitive function. However, the relationships between executive impairment and social cognition remain unclear in MS. Previous studies exclusively focused on group comparisons between healthy controls and patients with MS, treating the latter as a homogeneous population. The variability of socio- and neurocognitive profiles in this pathology therefore remains underexplored. In the present study, we used a cluster analytic approach to explore the heterogeneity of executive and social cognition skills in MS. A total of 106 patients with MS were compared with 53 healthy matched controls on executive (e.g., working memory) and social cognition (facial emotion recognition and theory of mind) performances. A cluster analysis was then performed, focusing on the MS sample, to explore the presence of differential patterns of interaction between executive and social cognition difficulties and their links to sociodemographic, clinical and cognitive variables. We identified three distinct functional profiles: patients with no executive or social cognition deficits (Cluster 1); patients with difficulties in facial emotion recognition and theory of mind and, to a lesser extent, executive functioning (Cluster 2); and patients with executive functioning difficulties only (Cluster 3). Clinical characteristics (disease duration, disability, fatigue) did not differ between clusters. CONCLUSIONS: These results suggest that there are qualitative differences in the social cognition and executive difficulties that are commonly found among patients with MS. If replicated, the identification of these profiles in clinical practice could allow for more individualized rehabilitation., (© 2021 The British Psychological Society.)

Importance: Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown., Objectives: To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria., Design, Setting, and Participants: This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021., Exposure: Diagnosis of RIS., Main Outcomes and Measures: Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors., Results: Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96]; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%., Conclusions and Relevance: This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.

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., (© 2020 European Academy of Neurology.)

Background: A previous clinical study showed the high specificity, sensitivity and reliability of MSCopilot, a software medical device designed by Ad Scientiam for the self-assessment of people with Multiple Sclerosis (PwMS), compared to the traditional Multiple Sclerosis Functional Composite (MSFC). We conducted further analyses to assess MSCopilot's performance with respect to the Expanded Disability Status Scale (EDSS)., Methods: The data of 116 PwMS were analysed. We studied the correlations between MSCopilot scores and the EDSS, and their ability to distinguish PwMS with high and low EDSS through a study of the distribution of the digital test scores as well as logistic regression models. The same analyses were performed using the MSFC tests., Results: MSCopilot composite scores were as highly correlated to the EDSS (|r| = 0.65, p < 0.01) as their MSFC counterparts, confirming the known correlation of the MSFC with the EDSS. In a linear regression framework, the Walking digital tests have good explanatory power, especially for PwMS with EDSS > 3.5 (R² adj =0.47). The mean values of each MSCopilot subscore were significantly different between patients with an EDSS > 3.5 and others (p < 0.05), which could not be proved for the MSFC Cognition tests. MSCopilot4 was the best model to predict an EDSS score > 3.5 (AUC = 0.92)., Conclusion: These analyses confirm the reliability of MSCopilot and show interesting correlations with the EDSS (similar results obtained with the MSFC). MSCopilot was able to highlight nuances in the different stages of MS the MSFC could not capture., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: The study aimed to assess the potential for serum neurofilament light chain (NFL) levels to predict the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab (NTZ)-treated patients with multiple sclerosis (MS) and to discriminate PML from MS relapses., Methods: NFL levels were measured with single molecule array (Simoa) in 4 cohorts: (1) a prospective cohort of patients with MS who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr); (2) a cohort of patients whose blood was collected during PML; (3) an independent cohort of non-PML NTZ-treated patients with serum NFL determinations at 2 years (replication cohort); and (4) a cohort of patients whose blood was collected during exacerbations., Results: Serum NFL levels were significantly increased after 2 years of NTZ treatment in pre-PML patients compared with NTZ-ctr. The prognostic performance of serum NFL levels to predict PML development at 2 years was similar in the NTZ-ctr group and replication cohort. Serum NFL levels also distinguished PML from MS relapses and were 8-fold higher during PML compared with relapses., Conclusions: These results support the use of serum NFL levels in clinical practice to identify patients with relapsing-remitting MS at higher PML risk and to differentiate PML from clinical relapses in NTZ-treated patients., Classification of Evidence: This study provides Class I evidence that serum NFL levels can identify NTZ-treated patients with MS who will develop PML with a sensitivity of 67% and specificity of 80%., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD)., Methods: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model)., Results: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3-14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3-24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19-52%, p<0.001) overall, 63% (95%CI=35-79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2-44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19 + B-cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses., Conclusion: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities., Objective: To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity., Design, Setting, and Participants: The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020., Exposures: COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms., Main Outcomes and Measures: The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes., Results: A total of 347 patients (mean [SD] age, 44.6 [12.8] years, 249 women; mean [SD] disease duration, 13.5 [10.0] years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 [95% CI, 1.4-2.5]), EDSS (OR for EDSS ≥6, 6.3 [95% CI. 2.8-14.4]), and obesity (OR, 3.0 [95% CI, 1.0-8.7]) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01)., Conclusions and Relevance: In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.

Objectives: We aim to (1) determine the frequency and distinctive features of short myelitis (SM) and longitudinally extensive transverse myelitis (LETM) in a cohort of adults with myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated myelitis and (2) determine baseline prognostic factors among MOG-Ab-positive patients whose disease started with myelitis., Material and Methods: We retrospectively analyzed clinical and paraclinical variables from a multicentric French cohort of adults with MOG-Ab-associated myelitis. At last follow-up, patients were classified into two groups according to the severity of the Expanded Disability Status Scale (EDSS) as ⩽2.5 or ⩾3.0., Results: Seventy-three patients with at least one episode of myelitis over disease course were included; among them, 28 (38.4%) presented with SM at the time of the first myelitis. Motor and sphincter involvement was less frequently observed in SM (51.9% and 48.2%, respectively) than in LETM patients (83.3% and 78.6%, respectively), p  = 0.007 and p  = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group, p  = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%), p  < 0.001. EDSS at last follow-up was higher in LETM (median 3.0 (interquartile range: 2.0-4.0)) compared to SM patients (2.0, (1.0-3.0)), p  = 0.042. Finally, a higher EDSS at onset was identified as the only independent risk factor for EDSS ⩾3.0 (odds ratio, 1.40, 95% confidence interval (CI): 1.01-1.95, p  = 0.046)., Conclusion: SM in MOG-Ab-associated disease is not rare. The severity at onset was the only independent factor related to the final prognosis in MOG-Ab-associated myelitis.

Background and Purpose: Assessing patients' disability in multiple sclerosis (MS) requires time-consuming batteries of hospital tests. MSCopilot is a software medical device for the self-assessment of patients with MS (PwMS), combining four tests: walking, dexterity, cognition and low contrast vision. The objective was to validate MSCopilot versus the Multiple Sclerosis Functional Composite (MSFC)., Methods: This multicentre, open-label, randomized, controlled, crossover study enrolled 141 PwMS and 76 healthy controls (HCs). All participants performed MSCopilot and MSFC tests at day 0. To assess reproducibility, 46 PwMS performed the same tests at day 30 ± 3. The primary end-point was the validation of MSCopilot versus MSFC for the identification of PwMS against HCs, quantified using the area under the curve (AUC). The main secondary end-point was the correlation of MSCopilot z-scores with MSFC z-scores., Results: In all, 116 PwMS and 69 HCs were analysed. The primary end-point was achieved: MSCopilot performance was non-inferior to that of MSFC (AUC 0.92 and 0.89 respectively; P = 0.3). MSCopilot and MSFC discriminated PwMS and HCs with 81% and 76% sensitivity and 82% and 88% specificity respectively. Digital and standard test scores were highly correlated (r = 0.81; P < 0.001). The test-retest study demonstrated the good reproducibility of MSCopilot., Conclusion: This study confirms the reliability of MSCopilot and its usability in clinical practice for the monitoring of MS-related disability., (© 2019 European Academy of Neurology.)

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated., Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013., Design, Setting, and Participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018., Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation., Main Outcomes and Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016)., Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016., Conclusions and Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

Objectives: In the management of multiple sclerosis (MS), defining criteria for identification of suboptimal therapy responses and switching treatment is essential to avoid worsening. Despite the lack of a standardised definition, criteria for first-line treatment are well documented in the literature, based on clinical measures or magnetic resonance imaging (MRI) (gadolinium enhancing [Gd + ] lesions or new/enlarging T2 lesions) assessed during the first 6-18 months after treatment initiation. However, it is unknown whether the same criteria can be used for second-line treatment failure., Methods: Five regional boards involving 36 French MS experts were convened to discuss published literature regarding criteria for first- and second-line treatment failure, and to identify differences in local therapeutic practices. A national board of 11 experts was subsequently conducted to identify convergences and differences between regions, and to propose second-line criteria for the definition of therapeutic failure., Results: Published information is lacking regarding second-line treatment failure criteria. In light of this, regional differences in current therapeutic practices are justifiable. Due to the risk-benefit ratio of these treatments and limited options for third-line treatments, the authors recommend a different therapeutic approach when assessing second-line treatment failure. The treatment switch for second-line treatment should be informed by confirmed disease progression, after 6 months, or combined clinical and MRI outcomes, but only after at least 1 year of treatment., Conclusions: Experts compared therapeutic attitudes and practices regarding second-line treatment failure between French regions. They identified convergences that were used to propose a national agreement on second-line treatment failure criteria, which should be evaluated in real-life prospective cohorts., (Copyright © 2019. Published by Elsevier B.V.)

Objective: In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la Sclérose en Plaques., Methods: A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated., Results: The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio [OR] 0.60, p < 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54, p < 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, p < 0.001)., Conclusions: After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness., Classification of Evidence: This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Social support has been identified as a buffering or intervening variable in stressful life events. Research has demonstrated that greater social support is associated with better mental health in multiple sclerosis (MS), but little is known about its links to specific aspects of mental health. We therefore investigated if and how perceived social support modulates depression, anxiety and fatigue in patients with MS., Methods: We recruited 112 patients with MS from three French hospitals and administered a demographic and clinic interview, and self-report measures of perceived social support (Multidimensional Scale of Perceived Social Support), depression and anxiety (Hospital Anxiety and Depression Scale), and fatigue (Fatigue Severity Scale). We then analyzed the relationships between these domains using path analysis., Results: The causal path model provided an excellent fit for the data (χ 2  = 9.8, p = .778, standardized root mean square residual = 0.043, comparative fit index = 1.00). Results indicated that the level of social support from friends is a predictor of anxiety symptomatology. Thus, anxiety may have both a direct and an indirect impact on fatigue and depression levels., Conclusions: This study highlights the important roles played by perceived social support and anxiety in MS. These should be key pharmacological and non-pharmacological targets for optimizing patient care. (NCT 02-880-553)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Identifying in vivo the processes that determine lesion severity in multiple sclerosis (MS) remains a challenge., Objectives: To describe the dynamics of ultrasmall superparamagnetic iron oxide (USPIO) enhancement in MS lesions and the relationship between USPIO enhancement and microstructural changes over 3 years., Methods: Lesion development was assessed at baseline, Months 3, 6, and 9, using magnetic resonance imaging (MRI) with gadolinium and USPIO. Microstructural changes were assessed at baseline, Months 3, 6, 9, 12, 18, 24, and 36, using relaxometry, magnetization transfer, and diffusion-weighted imaging., Results: We included 15 patients with clinically isolated syndrome. In the 52 MRI scans acquired with USPIO, 22 lesions were USPIO and gadolinium positive, and 44 were USPIO negative but gadolinium positive. Lesions no longer exhibited sustained USPIO enhancement 3 months later. At baseline, lesions that were both USPIO and gadolinium positive had lower magnetization transfer ratio values (common language effect size = 0.84, p  = 0.0005) and lower fractional anisotropy values (0.83, p  = 0.001) than gadolinium-positive-only lesions. USPIO-positive lesions remained associated with greater damage than gadolinium-positive-only lesions throughout the 3-year follow-up., Conclusion: USPIO enhancement, mainly reflecting monocyte infiltration, is transient and is associated with persistent tissue damage after 3 years.

Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are two neurological disorders that seem, theoretically, completely divergent according to epidemiological, clinical, pathophysiological, and therapeutic data. However, some reports that have mentioned the occurrence of both conditions within the same patient underpin the suggestion that this co-occurrence might not be random. We report six co-occurrences of ALS and MS cases, focusing on epidemiological and clinical diseases findings. We then compare our cohort to those in the literature. Our cohort was composed of five females and one male. The age of onset for MS ranged from 27 to 54 years with either primary or secondary prominence while all being progressive. Both diseases occurred sequentially in all but one the cases. Concerning ALS, the age of onset ranged from 51 to 60 years and the site of onset was the legs in 5/6 cases. The disease lasted from four to 29 months. Although infrequent, this co-occurrence supports the hypothesis of common, pathophysiological mechanisms between ALS and MS. We discuss some arguments favoring a potential link between both conditions.

Background: Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS., Objective: The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss., Methods: The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed., Results: Ninety-three patients received MD1003 (n = 65) or placebo (n = 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (- 0.061 logMAR, + 3.1 letters) than with placebo (- 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (- 0.058 logMAR) with MD1003 and worsened by - 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo., Conclusions: MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated., Trial Registration: EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244 FUNDING: MedDay Pharmaceuticals.

Objective: To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis., Methods: Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included., Results: Median age at onset was 36.46 (range 18.0-76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26-0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22-0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07-0.72). Finally, MOG-Ab titers were higher at relapse than in remission ( p = 0.009)., Conclusion: In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients., (© 2018 American Academy of Neurology.)

Cognition and health-related quality of life (HRQoL) are early involved in multiple sclerosis (MS). The aim of QUALICIS study was to monitor cognition and HRQoL prospectively in a cohort of clinically isolated syndrome (CIS) patients starting a treatment with subcutaneous beta-1b interferon as a first disease modifying treatment (DMT), and to assess their correlation with the clinical outcome 6years later. Relapse history, EDSS and yearly standardized brain MRI data were also collected. 37 patients were included. Cognition and HRQoL remained stable over treatment period. At baseline, we found that SDMT was moderately correlated to T2 lesion load (r=-0.47, p=0.04). Baseline SDMT was predictive of HRQoL at year 2 (r=0.53, p=0.02). Regarding 6-year outcome, the most specific predictive factor of favorable outcome was achieving "No Evidence of Disease Activity" (NEDA) status at year 1. In this group, all the patients had a stable EDSS score and none switched to a second line therapy. In the "non-NEDA" group, 44% of patients experienced EDSS worsening and 38.9% switched to a second line therapy. The number of gadolinium enhancing lesions on baseline scan was the only predictive factor of poor outcome in this subgroup of patients (2 vs. 0.13, p=0.03). Our results suggest that NEDA at 1year could be used to predict long term outcome after initiation of DMT in CIS. For non-NEDA patients, monitoring SDMT and brain atrophy could be potentially relevant, but this should be confirmed on a larger sample., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Multiple sclerosis (MS) can be associated with impaired social cognition. However, social cognition skills have never been explored in the different subtypes of MS. The first aim of this study was to examine whether MS subtypes differ on the course of social cognition. The second aim was to explore the relationship between social cognition performances and executive abilities and mood variables., Methods: Sixty-two patients with MS and 33 healthy matched controls performed experimental tasks assessing facial emotion recognition, theory of mind (ToM), and cognitive functioning, in particular executive functions., Results: Patients differed from controls on both measures of social cognition. On the ToM measures, patients with progressive MS scored significantly lower than healthy participants. Patients with primary progressive MS performed worse than both healthy participants and patients with relapsing-remitting MS on the recognition of fearful facial expressions, while patients with secondary progressive MS performed worse on the recognition of facial expressions of sadness. Patients' social cognition difficulties were correlated with processing speed, working memory, and verbal fluency., Conclusions: These preliminary results suggested that there may be qualitative differences in social cognition difficulties among the phenotypes. Furthermore, these impairments were related to executive functions, but unrelated to patients' disability or level of depression. These data highlight the need for research to determine the real impact of these deficits on interpersonal relationships among patients and to confirm these disorders in a larger population with progressive forms of MS. (JINS, 2017, 23, 653-664).

Objective: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ)., Methods: Relapsing-remitting MS patients who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1- and 2-year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme-linked immunosorbent assays, respectively., Results: Among top differentially expressed genes in the RNA sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre-PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients, and levels remained lower at later time points during NTZ treatment., Interpretation: The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MS patients treated with NTZ. Ann Neurol 2017;82:186-195., (© 2017 American Neurological Association.)

Objective: To describe the clinico-radiologic outcome of MS patients with natalizumab-related progressive multifocal leukoencephalopathy (Nz-PML) surviving and receiving disease-modifying therapy (DMT)., Methods: We describe clinical and radiologic evolution of Nz-PML survivors in an observational retrospective multicenter cohort to clarify the effect of different subsequent MS DMT strategies. Twenty-three patients from 11 centers were analyzed. Outcomes were (1) clinical efficacy of post-PML MS DMT, (2) radiologic efficacy of post-PML MS DMT, (3) radiologic evolution of PML lesion, and (4) disability progression., Results: There was no clinical worsening of PML symptoms with a stability of Expanded Disability Status Scale at the last follow-up. No relapse was reported with fingolimod and dimethyl fumarate. No radiologic worsening of Nz-PML lesion was observed at the end of the follow-up., Conclusion: In this large cohort of patients with Nz-PML, MS therapies given after Nz discontinuation were not associated with PML worsening. A larger cohort with longer follow-up will be necessary to confirm this therapeutic strategy.

Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study., Objective: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study., Methods: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits., Results: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo., Conclusion: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Prof. Ayman Tourbah has received consulting fees, travel grants and reports institutional financial compensation for patient visits during the trial from MedDay Pharmaceuticals and consulting and lecturing fees, travel grants and research support from Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono, Teva Pharmaceuticals and Roche. Prof. Gilles Edan reports personal fees from Biogen Idec and Novartis and grants and personal fees from Merck Serono, Teva, Sanofi and Bayer, outside the submitted work. Prof. Sandra Vukusic reports clinical trial support from MedDay Pharmaceuticals, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals and Genzyme; advisory or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis and Teva Pharmaceuticals; and invited congress support from Biogen Idec, Merck Serono, Novartis and Genzyme. Prof. Jérôme De Sèze reports clinical trial support from MedDay Pharmaceuticals, Biogen Idec, Merck Serono, Bayer, LFB, UCB, AB Sciences, Sanofi-Aventis, Teva Pharmaceuticals and Genzyme; advisory or consultancy fees from Biogen Idec, Merck Serono, Bayer, LFB, Sanofi-Aventis, Teva Pharmaceuticals, Almirall and Allergan; and invited congress support from Biogen Idec, Merck Serono, Bayer, LFB, Sanofi-Aventis, Teva Pharmaceuticals, Genzyme and Allergan. Dr Olivier Gout reports personal fees and non-financial support from Biogen Idec, Teva Pharmaceuticals, Genzyme and Novartis and personal fees from Merck, outside the submitted work. Prof. Gilles Defer reports personal fees from Biogen Idec, Novartis, Sanofi-Aventis, Genzyme and Teva Pharmaceuticals; grants from Novartis, Merck Serono and Teva Pharmaceuticals; and funding for travel from Merck Serono, Biogen Idec, Guerbet, Sanofi-Aventis, Novartis, Genzyme and Teva Pharmaceuticals, outside the submitted work. Prof. David-Axel Laplaud reports personal fees from Biogen and Teva Pharmaceuticals and grants and personal fees from Novartis and Genzyme, outside the submitted work. Prof. Thibault Moreau reports personal fees and non-financial support from Biogen, Novartis, Sanofi-Genzyme, Bayer, Merck, Teva Pharmaceuticals and Almirall, outside the submitted work. Prof. Bruno Brochet received grants from MedDay Pharmaceuticals during the conduct of the study; personal fees and non-financial support from Biogen Idec, Novartis and Genzyme; grants from Merck Serono; grants, personal fees and non-financial support from Teva Pharmaceuticals; and grants and non-financial support from Bayer, outside the submitted work. Dr Frédéric Sedel is CEO and a shareholder at MedDay Pharmaceuticals (the study sponsor). Prof. Jean Pelletier has received consulting and lecturing fees, travel grants and unconditional research support from Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono and Teva Pharmaceuticals. Dr Christine Lebrun-Frenay, Prof. Michel Clanet, Dr Caroline Papeix, Prof. Marc Debouverie, Prof. Pierre Clavelou and Prof. Pierre Labauge have nothing to disclose., (© The Author(s), 2016.)

This article establishes the basics of a theoretical model for the constitutive law that describes the skin temperature and thermolysis heat losses undergone by a subject during a session of whole-body cryotherapy (WBC). This study focuses on the few minutes during which the human body is subjected to a thermal shock. The relationship between skin temperature and thermolysis heat losses during this period is still unknown and have not yet been studied in the context of the whole human body. The analytical approach here is based on the hypothesis that the skin thermal shock during a WBC session can be thermally modelled by the sum of both radiative and free convective heat transfer functions. The validation of this scientific approach and the derivation of temporal evolution thermal laws, both on skin temperature and dissipated thermal power during the thermal shock open many avenues of large scale studies with the aim of proposing individualized cryotherapy protocols as well as protocols intended for target populations. Furthermore, this study shows quantitatively the substantial imbalance between human metabolism and thermolysis during WBC, the explanation of which remains an open question., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Macrophages are important components of inflammatory processes in multiple sclerosis, closely linked to axonal loss, and can now be observed in vivo using ultra-small superparamagnetic iron oxide (USPIO). In the present 1-year longitudinal study, we aimed to determine the prevalence and the impact on tissue injury of macrophage infiltration in patients after the first clinical event of multiple sclerosis., Methods: Thirty-five patients, 32 years mean age, were imaged in a mean of 66 days after their first event using conventional magnetic resonance imaging, gadolinium (Gd) to probe blood-brain barrier integrity, USPIO to study macrophage infiltration and magnetization transfer ratio (MTR) to assess tissue structure integrity. Statistics were performed using two-group repeated-measures ANOVA. Any patient received treatment at baseline., Results: At baseline, patients showed 17 USPIO-positive lesions reflecting infiltration of macrophages present from the onset. This infiltration was associated with local higher loss of tissue structure as emphasized by significant lower MTRnorm values (p<0.03) in USPIO(+)/Gd(+) lesions (n=16; MTRnormUSPIO(+)/Gd(+)=0.78 at baseline, MTRnormUSPIO(+)/Gd(+)=0.81 at M12) relative to USPIO(-)/Gd(+) lesions (n=67; MTRnormUSPIO(-)/Gd(+)=0.82 at baseline, MTRnormUSPIO(-)/Gd(+)=0.85 at M12). No interaction in MTR values was observed during the 12 months follow-up (lesion type × time)., Conclusion: Infiltration of activated macrophages evidenced by USPIO enhancement, is present at the onset of multiple sclerosis and is associated with higher and persistent local loss of tissue structure. Macrophage infiltration affects more tissue structure while tissue recovery during the following year has a similar pattern for USPIO and Gd-enhanced lesions, leading to relative higher persistent local loss of tissue structure in lesions showing USPIO enhancement at baseline., (© The Author(s), 2015.)

Niemann-Pick disease type C (NP-C) is a fatal progressive neurolipidosis involving neuronal storage of cholesterol and gangliosides. Miglustat, an inhibitor of glycosphingolipid synthesis, has been approved to treat neurological manifestations in adults and children with NP-C. This open-label observational study in adults with confirmed NP-C evaluated the efficacy of miglustat (200 mg t.i.d.) based on composite functional disability (CFD) scores and brain proton magnetic resonance spectroscopy (H-MRS) measurement of choline (Cho)/N-acetyl aspartate (NAA) ratio in the centrum ovale. Overall, 16 patients were included and received miglustat for a mean period of 30.6 months: 12 continued on miglustat throughout follow up, and 4 discontinued miglustat because of adverse effects (n = 2) or perceived lack of efficacy (n = 2). In the 'continued' subgroup, the mean (SD) annual progression of CFD scores decreased from 0.75 (0.94) before treatment to 0.29 (1.29) during the period between miglustat initiation and last follow-up. In the discontinued subgroup, CFD progression increased from 0.48 (0.44) pre-treatment to 1.49 (1.31) at last follow up (off treatment). Mean (SD) Cho/NAA ratio [normal level 0.48 (0.076)] decreased during miglustat treatment in the continued subgroup: 0.64 (0.12) at baseline (miglustat initiation), 0.59 (0.17) at 12-month follow up, and 0.48 (0.09) at 24-month follow up. Cho/NAA ratio remained relatively stable in the discontinued subgroup: 0.57 (0.15), 0.53 (0.04) and 0.55 (0.09), respectively. In conclusion, H-MRS Cho/NAA ratio might serve as an objective, quantitative neurological marker of brain dysfunction in NP-C, allowing longitudinal analysis of the therapeutic effect of miglustat.

Unlabelled: Memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA)-type glutamate receptors that was approved for the treatment of moderate to severe Alzheimer's disease, has been negatively evaluated for the treatment of cognitive disorders of multiple sclerosis, but these studies were conducted only during short-term administration and on a heterogeneous group of patients with different forms of the disease. In addition, many adverse reactions were observed in these patients., Aims: The purpose of the "EMERITE" (NCT01074619) study was to examine the efficacy and safety of the long-term administration of memantine as a symptomatic treatment for cognitive disorders in patients with relapsing-remitting multiple sclerosis (RR-MS)., Methods: The study was supported by the French Ministry of Health and received additional support from Lundbeck. In this double-blind, placebo-controlled, parallel group, randomized trial, the participants were assigned to receive memantine (20 mg/day) or a placebo for 52 weeks. The participants included males and females, 18-60 years of age, with a diagnosis of RR-MS and presenting with a cognitive complaint and/or demonstrating moderate cognitive impairment. The data were collected in the Department of Neurology in 19 French centers. The primary outcome was the Paced Auditory Serial Addition Test (PASAT) score at week 52. Secondary measurements included additional neuropsychological tests and the annualized relapse rate. The scores were adjusted according to the baseline scores in the analysis. The safety was assessed by the number of adverse events. The random sequence was generated using the Excel software. At each center, only the pharmacist had access to the allocation sequence and could be asked to unblind the trial., Results: Fifty patients were allocated to the memantine group, and 43 to the placebo group. The intent-to-treat (ITT) population included 31 patients in each group. After adjusting for the PASAT scores at baseline, the PASAT scores at the end point did not differ between the memantine and the placebo groups (p=0.88). Adjusted mean score difference (memantine minus placebo), was -0.40 (95% confidence interval: -5.5; +4.7). No significant differences were observed for the secondary outcomes (short term memory and attention scores, EDSS, and relapse rate). The findings remained unchanged after multiple imputation of the missing values. Neurological and psychiatric adverse events were significantly higher in the memantine group than in the placebo group, and these parameters were higher than those reported in the product literature of memantine., Conclusions: No differences between the placebo and memantine groups were observed. Nevertheless, the tolerability of memantine was significantly worse than expected., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To compare natalizumab and fingolimod on both clinical and MRI outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) from 27 multiple sclerosis centers participating in the French follow-up cohort Observatoire of Multiple Sclerosis., Methods: Patients with RRMS included in the study were aged from 18 to 65 years with an Expanded Disability Status Scale score of 0-5.5 and an available brain MRI performed within the year before treatment initiation. The data were collected for 326 patients treated with natalizumab and 303 with fingolimod. The statistical analysis was performed using 2 different methods: logistic regression and propensity scores (inverse probability treatment weighting)., Results: The confounder-adjusted proportion of patients with at least one relapse within the first and second year of treatment was lower in natalizumab-treated patients compared to the fingolimod group (21.1% vs 30.4% at first year, p = 0.0092; and 30.9% vs 41.7% at second year, p = 0.0059) and supported the trend observed in nonadjusted analysis (21.2% vs 27.1% at 1 year, p = 0.0775). Such statistically significant associations were also observed for gadolinium (Gd)-enhancing lesions and new T2 lesions at both 1 year (Gd-enhancing lesions: 9.3% vs 29.8%, p < 0.0001; new T2 lesions: 10.6% vs 29.6%, p < 0.0001) and 2 years (Gd-enhancing lesions: 9.1% vs 22.1%, p = 0.0025; new T2 lesions: 16.9% vs 34.1%, p = 0.0010) post treatment initiation., Conclusion: Taken together, these results suggest the superiority of natalizumab over fingolimod to prevent relapses and new T2 and Gd-enhancing lesions at 1 and 2 years., Classification of Evidence: This study provides Class IV evidence that for patients with RRMS, natalizumab decreases the proportion of patients with at least one relapse within the first year of treatment compared to fingolimod., (© 2016 American Academy of Neurology.)

Competing Interests: A. Tourbah déclare avoir reçu des aides à la recherche et des invitations lors de congrès réunions et symposium de la part de Medday, Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono, Teva Pharma, et Roche.

Objective: Using positron emission tomography (PET) with [(11) C]flumazenil ([(11) C]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 [(11) C]FMZ PET imaging and brain magnetic resonance imaging. [(11) C]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: [(11) C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([(11) C]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 [(11) C]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. [(11) C]FMZ cortical binding correlated with cognitive performance., Interpretation: This pilot study showed that PET with [(11) C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS., (© 2015 American Neurological Association.)

Background: No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis., Objectives: The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS., Study Design: Uncontrolled, non-blinded proof of concept study, Methods: 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures., Results: In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset., Conclusions: These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

The introduction of the McDonald criteria has enabled earlier diagnosis of multiple sclerosis (MS). However, even with the 2010 revised criteria, nearly 50% of patients remain classified as "possible MS" following the first MRI. The present study aimed to demonstrate that time to MS diagnosis could be shorter than 2010 revised criteria, and established after a single early MRI in most patients with the association of the symptomatic lesion and at least one suggestive asymptomatic lesion. We also evaluated the short-term predictive capacity of an individual suggestive lesion on disease activity. We analyzed initial MRI results from 146 patients with MS from a multicenter retrospective study. Visualization of the symptomatic lesion was used as a primary criterion. Secondary criteria included one suggestive lesion (SL) aspect or topography on MRI, or one non-specific lesion associated with positive CSF. The proposed criteria led to a positive diagnosis of MS in 100% of cases, from information available from the time of the first MRI for 145 patients (99.3%). At least one SL was observed for 143 patients (97.9%), and positive CSF for the 3 others. Compared to the McDonald criteria, the proposed criteria had 100% sensitivity, with a significantly shorter mean time to reach a positive diagnosis. Furthermore, the simultaneous presence of corpus callosum, temporal horn, and ovoid lesions was associated with radiological or clinical activity after a year of follow-up. The proposed diagnostic criteria are easy to apply, have a good sensitivity, and allow an earlier diagnosis than the 2010 McDonald criteria. Nevertheless, prospective studies are needed to establish specificity and to confirm these findings.

Background and Objective: Cognitive and behavioural symptoms are common in multiple sclerosis (MS), but they are rarely the inaugural and predominant manifestation of the disease. Our objective is to characterize the clinical and radiological features of cognitive-multiple sclerosis (cog-MS), defined as MS subjects who entered into the disease with cognitive symptoms, which subsequently remain the predominant manifestation., Methods: We describe the disease course, and clinical and radiological features of 18 subjects with a cognitive form of MS., Results: Memory loss and behavioural changes were the primary symptoms at disease onset. They remained prominent and led to severe cognitive impairment during disease course. The main associated manifestations were depression, pathological laughing and/or crying, urinary incontinence and gait disturbance suggestive of high-level gait disorder. Motor, sensory or cerebellar abnormalities were uncommon. During disease course, superimposed neurological relapses occurred in 61% of cases. Brain MRI revealed multiple periventricular lesions that were extensive and confluent in half of cases, and a severe atrophy measured as an increase in the third ventricular width compared to age-matched healthy controls. Gadolinium-enhancing lesions were common (72%). The mean diagnosis delay from disease onset was 2 years. A principal component analysis on the neuropsychological results revealed that verbal memory assessment is complementary to global cognitive functioning evaluation in these patients with severe cognitive deficit. Verbal memory deficit was associated with high EDSS., Conclusions: cog-MS patients might represent a challenging diagnosis, which needs to be individualized for an early management., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Severe cognitive impairment involving multiple cognitive domains can occur early during the course of multiple sclerosis (MS). We investigated resting state functional connectivity changes in large-scale brain networks and related structural damage underlying cognitive dysfunction in patients with early MS. Patients with relapsing MS (3-5 years disease duration) were prospectively assigned to two groups based on a standardized neuropsychological evaluation: (1) cognitively impaired group (CI group, n = 15), with abnormal performances in at least 3 tests; (2) cognitively preserved group (CP group, n = 20) with normal performances in all tests. Patients and age-matched healthy controls underwent a multimodal 3T magnetic resonance imaging (MRI) including anatomical T1 and T2 images, diffusion imaging and resting state functional MRI. Structural MRI analysis revealed that CI patients had a higher white matter lesion load compared to CP and a more severe atrophy in gray matter regions highly connected to networks involved in cognition. Functional connectivity measured by integration was increased in CP patients versus controls in attentional networks (ATT), while integration was decreased in CI patients compared to CP both in the default mode network (DMN) and ATT. An anatomofunctional study within the DMN revealed that functional connectivity was mostly altered between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) in CI patients compared to CP and controls. In a multilinear regression model, functional correlation between MPFC and PCC was best predicted by PCC atrophy. Disconnection in the DMN and ATT networks may deprive the brain of compensatory mechanisms required to face widespread structural damage., (Copyright © 2014 Wiley Periodicals, Inc.)

Importance: The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of patients with multiple sclerosis (MS) to our knowledge., Objective: To collect data from patients with MS switching from natalizumab to fingolimod., Design, Setting, and Participants: The Enquête Nationale sur l'Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod., Main Outcomes and Measures: Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod., Results: Thirty-six French MS tertiary referral centers participated. In total, 333 patients with MS switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for patients receiving natalizumab. Twenty-seven percent of patients relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). Patients who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of patients relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05)., Conclusions and Relevance: In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

Objectives: A novel characterization of Clinically Isolated Syndrome (CIS) patients according to lesion patterns is proposed. More specifically, patients are classified according to the nature of inflammatory lesions patterns. It is expected that this characterization can infer new prospective figures from the earliest imaging signs of Multiple Sclerosis (MS), since it can provide a classification of different types of lesions across patients., Methods: The method is based on a two-tiered classification. Initially, the spatio-temporal lesion patterns are classified. The discovered lesion patterns are then used to characterize groups of patients. The patient groups are validated using statistical measures and by correlations at 24-month follow-up with hypointense lesion loads., Results: The methodology identified 3 statistically significantly different clusters of lesion patterns showing p-values smaller than 0.01. Moreover, these patterns defined at baseline correlated with chronic hypointense lesion volumes by follow-up with an R(2) score of 0.90., Conclusions: The proposed methodology is capable of identifying three major different lesion patterns that are heterogeneously present in patients, allowing a patient classification using only two MRI scans. This finding may lead to more accurate prognosis and thus to more suitable treatments at early stage of MS.

Introduction: Neuropsychiatric signs and MRI abnormalities can occur in patients with phenylketonuria in adulthood. We describe clinical and radiological features of phenylketonuric patients and we discuss the advantage of continuing diet in adulthood., Method: We report late onset neuropsychiatric symptoms of four phenylketonuric patients (33-45years) diagnosed in infancy and report the case of a patient (33years) diagnosed with phenylketonuria because of late onset neurological signs. We describe clinical and radiological features of these 5 patients, and their evolution under diet and propose a review of the literature., Results: The main neurological abnormalities in phenylketonuric patients diagnosed in infancy are: brisk reflexes, spastic paraparesis, psychiatric signs that appear 10.5years after the diet arrest. A leukoencephalopathy was present in 93% of cases and 91.7% improve clinically after poor phenylalanine diet reintroduction. In 4 patients, neurological abnormalities (spastic paraparesis, dementia, Parkinsonism) led to the late diagnosis. Two of them had a leukoencephalopathy on brain MRI. Patients had high levels of phenylalanine (above 1500μmol/L) when neuropsychiatric signs occurred. Improvement after diet suggests that hyperphenylalaninemia has a direct toxic effect on the brain., Discussion/conclusion: The long-term follow-up of phenylketonuric patients is mandatory to depict and treat neurological complications in time. Diet reintroduction is efficacious in most cases., (Copyright © 2014. Published by Elsevier Masson SAS.)