ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial.

INTRODUCTION: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. METHODS: ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. RESULTS: At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. CONCLUSION: ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions. CLINICAL TRIALS REGISTRATION: Substudy of ENSEMBLE (NCT03085810). REGISTRATION: March 21, 2017.

Vulnerability of Thalamic Nuclei at CSF Interface During the Entire Course of Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Thalamic atrophy can be used as a proxy for neurodegeneration in multiple sclerosis (MS). Some data point toward thalamic nuclei that could be affected more than others. However, the dynamic of their changes during MS evolution and the mechanisms driving their differential alterations are still uncertain. METHODS: We paired a large cohort of 1,123 patients with MS with the same number of healthy controls, all scanned with conventional 3D-T1 MRI. To highlight the main atrophic regions at the thalamic nuclei level, we validated a segmentation strategy consisting of deep learning-based synthesis of sequences, which were used for automatic multiatlas segmentation. Then, through a lifespan-based approach, we could model the dynamics of the 4 main thalamic nuclei groups. RESULTS: All analyses converged toward a higher rate of atrophy for the posterior and medial groups compared with the anterior and lateral groups. We also demonstrated that focal MS white matter lesions were associated with atrophy of groups of nuclei when specifically located within the associated thalamocortical projections. The volumes of the most affected posterior group, but also of the anterior group, were better associated with clinical disability than the volume of the whole thalamus. DISCUSSION: These findings point toward the thalamic nuclei adjacent to the third ventricle as more susceptible to neurodegeneration during the entire course of MS through potentiation of disconnection effects by regional factors. Because this information can be obtained even from standard T1-weighted MRI, this paves the way toward such an approach for future monitoring of patients with MS.

Improvements in quality of life over 2 years with cladribine tablets in people with relapsing multiple sclerosis: The CLARIFY-MS study.

BACKGROUND: Multiple sclerosis (MS) negatively affects health-related quality of life (HRQoL). OBJECTIVE: To evaluate HRQoL in people with highly active relapsing MS treated with cladribine tablets (CladT; 3.5 mg/kg cumulative dose over 2 years) in CLARIFY-MS. METHODS: Changes in the MS quality of life (MSQoL)-54 scores were analysed using a repeated mixed-effects linear model. Subgroup analyses were performed for participants who were pretreatment-naïve and those pretreated with disease-modifying therapies (DMTs) before initiating CladT. Safety and tolerability of CladT were also assessed. RESULTS: MSQoL-54 physical (mean change = 4.86; 95% confidence interval (CI) = 3.18, 6.53) and mental health (4.80; 95% CI = 3.13, 6.46) composite scores (primary endpoints) showed significant improvement at Month 24 versus Baseline (p < 0.0001). Changes in the MSQoL-54 scores were consistent across the pretreatment-naïve and DMT-pretreated subgroups. No new severe or opportunistic infections occurred. Most post-baseline lymphopenia events were Grade 1-2 in severity. Transient Grade-3 lymphopenia was observed in 19.7% (95/482) of participants. Grade-4 lymphopenia was not observed. CONCLUSIONS: CladT treatment significantly improved the mean MSQoL-54 physical and mental health composite scores over 2 years. CladT efficacy in HRQoL, relapse rates and Expanded Disability Status Scale scores demonstrates its multidimensional effects in MS treatment.

Natalizumab Treatment Induces Proinflammatory CD4 T Cells Preferentially in the Integrin ß7+ Compartment.

BACKGROUND AND OBJECTIVES: Natalizumab, a monoclonal humanized antibody targeting integrin α4, inhibits the transmigration of lymphocytes into the CNS by preventing the interaction of integrin α4ß1 with V-CAM expressed on brain vascular endothelial cells. Although natalizumab treatment reduces the clinical relapse rate in patients with relapsing-remitting MS, its discontinuation after reactivation of the JC virus is associated with a rebound of the disease in 20% of patients. The mechanisms of this rebound are not elucidated, but natalizumab increases the frequencies of circulating CD4 T cells expressing proinflammatory cytokines as well as the proportion of circulating Th17/Th1 cells (Th1-like Th17 cells). Gut-derived memory CD4 T cells are a population of growing interest in the pathogenesis of MS, but whether and how their properties are affected by natalizumab is not known. Here, we studied the phenotype and cytokine expression profile of circulating gut-derived memory CD4 T cells in patients with relapsing-remitting MS under natalizumab. METHODS: We identified gut-derived memory CD4 T cells by their expression of integrin ß7 and compared their properties and those of integrin ß7- memory CD4 T cells across healthy donors and patients with relapsing-remitting MS treated or not with natalizumab. We also compared the capacity of integrin ß7- and integrin ß7+ CD4 T-cell subsets to transmigrate in vitro across a model of blood-brain barrier. RESULTS: The proportions of proinflammatory Th17/Th1 cells as well as of IL-17A+IFNγ+ and IL-17A+GM-CSF+ cells were higher in memory CD4 T cells expressing integrin ß7 in patients receiving natalizumab compared with healthy donors and patients with relapsing-remitting MS not receiving natalizumab. By contrast, integrin ß7 negative memory CD4 T cells only presented a modest increased in their proportion of Th17/Th1 cells under natalizumab. We further observed that integrin ß7+ Th17/Th1 cells migrated as efficiently as integrin ß7- Th17/Th1 across a monolayer of brain microvascular endothelial cells. DISCUSSION: Our study shows that circulating integrin ß7+ memory CD4 T cells of patients with relapsing-remitting MS under natalizumab are enriched in proinflammatory cells supporting the hypothesis that integrin ß7+ memory CD4 T cells could play a pathogenic role in the disease rebound observed at natalizumab discontinuation.

Differential vulnerability of thalamic nuclei in multiple sclerosis.

OBJECTIVES: Investigating differential vulnerability of thalamic nuclei in multiple sclerosis (MS). METHODS: In a secondary analysis of prospectively collected datasets, we pooled 136 patients with MS or clinically isolated syndrome and 71 healthy controls all scanned with conventional 3D-T1 and white-matter-nulled magnetization-prepared rapid gradient echo (WMn-MPRAGE) and tested for cognitive performance. T1-based thalamic segmentation was compared with the reference WMn-MPRAGE method. Volumes of thalamic nuclei were compared according to clinical phenotypes and cognitive profile. RESULTS: T1- and WMn-MPRAGE provided comparable segmentations (0.84 ± 0.13 < volume-similarity-index < 0.95 ± 0.03). Medial and posterior thalamic groups were significantly more affected than anterior and lateral groups. Cognitive impairment related to volume loss of the anterior group. CONCLUSION: Thalamic nuclei closest to the third ventricle are more affected, with cognitive consequences.

Altered functional brain states predict cognitive decline 5 years after a clinically isolated syndrome.

BACKGROUND: Cognitive impairment occurs in the earliest stages of multiple sclerosis (MS) together with altered functional connectivity (FC). OBJECTIVE: The aim of this study was to investigate the evolution of dynamic FC states in early MS and their role in shaping cognitive decline. METHODS: Overall, 32 patients were enrolled after their first neurological episode suggestive of MS and underwent cognitive evaluation and resting-state functional MRI (fMRI) over 5 years. In addition, 28 healthy controls were included at baseline. RESULTS: Cognitive performance was stable during the first year and declined after 5 years.At baseline, the number of transitions between states was lower in MS compared to controls (p = 0.01). Over time, frequency of high FC states decreased in patients (p = 0.047) and increased in state with low FC (p = 0.035). Cognitive performance at Year 5 was best predicted by the mean connectivity of high FC state at Year 1. CONCLUSION: Patients with early MS showed reduced functional network dynamics at baseline. Longitudinal changes showed longer time spent in a state of low FC but less time spent and more connectivity disturbance in more integrative states with high within- and between-network FC. Disturbed FC within this more integrative state was predictive of future cognitive decline.

Treatment satisfaction, safety, and tolerability of cladribine tablets in patients with highly active relapsing multiple sclerosis: CLARIFY-MS study 6-month interim analysis.

Background Multiple sclerosis (MS) is a chronic disabling disease that is associated with negative effects on health-related quality of life (HRQoL) due to reduced physical and psychosocial functioning. Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) have been approved for the treatment of adult patients with highly active relapsing multiple sclerosis (RMS). The ongoing CLARIFY-MS study (NCT03369665; EudraCT number: 2017-002632-17) aims to assess the effect of cladribine tablets 3.5 mg/kg on HRQoL of patients with highly active RMS. Objective To report on the design of the CLARIFY-MS study, baseline patient characteristics, and results of a pre-planned interim analysis focusing on treatment satisfaction, safety, and tolerability that includes all data reported till 6 months after start of treatment. Methods The CLARIFY-MS study is a 2-year, open-label, single-arm, prospective, multicenter, phase IV study. Eligible patients with highly active RMS were assigned to receive cladribine tablets 3.5 mg/kg over 2 years. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM, v1.4; scale range from 0 to 100, higher values indicating higher satisfaction). Safety assessments, including occurrence of treatment-emergent adverse events (TEAEs; any adverse event reported after drug administration), serious adverse events (SAEs), and lymphocyte counts, were summarized descriptively. Results A total of 482 patients from 85 sites in Europe were treated with cladribine tablets. Mean patient age was 37.4 years, 338 (70.1%) were women, median EDSS was 2.5, and 345 (71.6%) were prior users of disease-modifying therapy (DMT). During the first 6 months after the start of treatment, and before reaching the full dose of cladribine tablets, mean TSQM global satisfaction score for the overall population was 70.4 (standard deviation, ± 18.48). The side effects score was 91.9 (± 17.68), convenience scored 86.6 (± 13.57), and effectiveness was 65.8 (± 21.14). A total of 275 patients (57.1%) reported at least one TEAE and 9 patients (1.9%) had a SAE. The majority of observed lymphopenia cases were of grade 1 or 2; 33 (6.8%) of the total study cohort had grade 3 lymphopenia, and no grade 4 lymphopenia was reported. Conclusion Patients reported high treatment satisfaction (TSQM) with cladribine tablets in this pre-planned interim analysis at 6 months. Few serious, and no unexpected, adverse events were reported, and there were no instances of grade 4 lymphopenia over the first 6 months. These preliminary data indicate good tolerability and convenience of administration of cladribine tablets in patients with highly active RMS.

Cognitive Impairment in Secondary Progressive Multiple Sclerosis: Effect of Disease Duration, Age, and Progressive Phenotype.

BACKGROUND: Cognitive deficits are common in multiple sclerosis (MS) and affect patients at all stages of the disease, regardless of phenotype. AIMS: This literature review focuses the cognitive deficits observed in secondary progressive MS (SPMS). It is mainly based on studies that compared the frequency and main characteristics of cognitive deficits in SPMS with other phenotypes. METHODS: A bibliographic search was carried out using the PubMed database with the following keywords: multiple sclerosis, secondary-progressive, cognition. RESULTS: Thirteen studies were initially selected that were published in English, reporting the neuropsychological data of a sample of at least 30 patients with SPMS, comparing them with patients with other phenotypes. Studies suggest that there is an association between the duration of the disease and the frequency and extent of the cognitive disorders. Studies also showed that the SP form is associated with an increased frequency of cognitive impairment and with an increased severity as compared to relapsing-remitting MS (RRMS). Compared to RRMS, progressive forms of MS are associated with more severe impairment in certain cognitive areas, such as episodic verbal memory, information processing speed, working memory, or verbal fluency. Two studies showed that cognitive performances decline overtime in SPMS. CONCLUSION: Cognitive disorders are more frequent and more severe in the SP form than in relapsing course of MS. The profile of cognitive impairment encountered in the SP form also appears to be different from those found in the other phenotypes.

Comparing diagnostic criteria for the diagnosis of neurocognitive disorders in multiple sclerosis.

BACKGROUND: People with multiple sclerosis (MS) commonly experience cognitive impairment associated with the disease, but there is currently no agreed-upon operational definition for identifying the presence of that impairment, in either research or clinic contexts. The International MS Cognition Society (IMSCOGS) established a task force to begin to examine this issue and this paper represents the results of an initial pilot investigation. The aim of this paper was to compare two criterion sets to determine how to identify cognitive impairment among people with MS: the general Diagnostic and Statistical Manual (DSM-5) Criteria for neurocognitive disorders and criteria derived from existing MS research (scores in two domains fall 1.5 standard deviations below normative controls). METHODS: Two hundred and ten people with MS presented for a brief cognitive evaluation in an MS Multidisciplinary Clinic at a midwestern academic medical center in the United States. Participants were generally middle aged (average 51.5 years), female (73.8%), and white (93.3%). McNemar's test was computed to compare the number of individuals whose cognitive test score performance was deemed cognitively normal, mildly impaired, or more significantly impaired. RESULTS: DSM-5 criteria classified 87.2% of the sample as cognitively impaired, where 66.7% were more mildly impaired and 20.5% more significantly impaired. By contrast, research-based criteria classified 63.3% of the sample as cognitively impaired, with 49.5% as mildly impaired and 13.8% as more significantly impaired. CONCLUSIONS: These findings indicate that compared to research criteria, the DSM-5 criteria classified far more people with MS as having cognitive impairment secondary to the disease. The paper discusses the potential benefits and drawbacks of the two diagnostic methods, highlighting that more work will be needed in order to establish a standardized and validated method for characterizing these impairments.

Comparative effectiveness of dimethyl fumarate in multiple sclerosis.

AIMS: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse subject to treatment (ARRt) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real-life setting. METHODS: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between 1 July 2015 and 12 December 2017, with 4.5 years of database history and 1-3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional propensity score. Negative binomial regression and a logistic regression model were used to estimate the relative risk (RR ± [95% CI]) of ARRt and the odds ratio (OR ± [95% CI]) of disability progression, respectively. RESULTS: Overall, 9304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF-IMM patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARRt compared to IMM (RR 0.72 [0.61-0.86]) and TERI (0.81 [0.68-0.96]) and did not show any significant difference when compared with FTY. The risk of the progression of MS-specific disability was not significantly different for any matched cohorts. CONCLUSION: DMF is associated with lower risk of treated relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).

Validation of a Brief Computerized Cognitive Assessment in Multiple Sclerosis (BCCAMS) and comparison with reference batteries.

BACKGROUND: The Brief Computerized Cognitive Assessment in Multiple Sclerosis (BCCAMS) is a short neuropsychological battery for persons with multiple sclerosis (PwMS). OBJECTIVES: The main objective of the study is to validate the BCCAMS. METHODS: PwMS and healthy subjects (HS) were evaluated using the BCCAMS which include two computerized tests, the Computerized Speed Cognitive Test and the Computerized Episodic Visual Memory Test (CEVMT), a newly developed visuospatial memory test, and the French learning test. The Minimal Assessment of Cognitive Function in MS (MACFIMS), including the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) tests, was also administered. Regression-based norms of the BCCAMS were calculated in 276 HS. BCCAMS was compared with BICAMS and MACFIMS for detection of cognitive impairment (CI). RESULTS: Out of 120 PwMS, CI was detected using the BCCAMS, BICAMS (one impaired test), and MACFIMS (two impaired tests) in 59.1%, 50%, and 37.9%, respectively. The BCCAMS produced the same predictive value as that of the BICAMS battery for detecting CI in the MACFIMS. CONCLUSION: This study validated the BCCAMS as a validated computerized short assessment for information processing speed and learning in MS.

Amygdala network reorganization mediates the theory of mind performances in multiple sclerosis.

Theory of mind (ToM) seems to be affected in multiple sclerosis (MS). MRI studies suggested a role of the amygdala in social cognitive performances. Therefore, we explored the role of the amygdala network in ToM using a multimodal MRI approach. In MS, patients with impaired ToM showed contradictory dysexecutive neuropsychological profile. Therefore, we compared neural networks involved in ToM and executive functions (EFs). Twenty patients with relapsing-remitting MS and 15 matched healthy controls were selected. ToM (Faux Pas test and mind stories) and EFs were assessed within and outside the scanner. All subjects underwent a battery of neuropsychological tests. Multimodal MRI with structural (diffusion imaging) and functional (resting-state and task-based) sequences was used to analyze the role and connections of the amygdala in ToM functioning. Cognitive and ToM performances were similar between patients and controls. Resting-state data revealed decreased connectivity of the left amygdala with frontal areas in patients compared to controls (p < 0.0001). During the task-based functional MRI, patients demonstrated increased connectivity between the amygdala and several cerebellar and left temporal regions (all p < 0.05). The microstructural alterations between the left amygdala and left temporal regions were associated with increased functional connectivity within the same pathway (r = 0.74; p < 0.01). No overlap was observed between functional networks involved in ToM and EFs. Our study demonstrates more connectivity recruitment between the amygdala and cerebellar and temporal regions in MS patients to reach preserved ToM performance. Microstructural abnormalities have been related to this compensatory network. Finally, different networks were involved in EFs and ToM.

Insights on the Relationship Between Hippocampal Connectivity and Memory Performances at the Early Stage of Multiple Sclerosis.

While memory impairment in multiple sclerosis (MS) is known to be associated with hippocampal alterations, whether hippocampal networks could dynamically reorganize as a compensation mechanism is still a matter of debate. In this context, our aim was to identify the patterns of structural and functional connectivity between the hippocampus and the rest of the brain and their possible relevance to memory performances in early MS. Thirty-two patients with a first episode suggestive of MS together with 10 matched healthy controls were prospectively explored at baseline, 1 and 5 years follow up. They were scanned with MRI and underwent a neuropsychological battery of tests that included the Selective Reminding Test and the Brief Visual Memory Test Revised to assess verbal and visuo-spatial memory, respectively. Hippocampal volume was computed together with four graph theory metrics to study the structural and functional connectivity of both hippocampi with the rest of the brain. Associations between network parameters and memory performances were assessed using linear mixed-effects (LME) models. Considering cognitive abilities, verbal memory performances of patients decreased over time while visuo-spatial memory performances were maintained. In parallel, hippocampal volumes decreased significantly while structural and functional connectivity metrics were modified, with an increase in hippocampal connections over time. More precisely, these modifications were indicating a reinforcement of hippocampal short-distance connections. LME models revealed that the drop in verbal memory performances was associated with hippocampal volume loss, while the preservation of visuo-spatial memory performances was linked to decreased hippocampal functional shortest path length. In conclusion, we demonstrated a differential impairment in memory performances in the early stages of MS and an important interplay between hippocampal-related structural and functional networks and those performances. As the structural damage increases, functional reorganization seems to be able to maintain visuo-spatial memory performances with strengthened short-distance connections.

Prevalence, Severity, and Clinical Management of Brain Incidental Findings in Healthy Young Adults: MRi-Share Cross-Sectional Study.

Background and Objectives: Young adults represent an increasingly large proportion of healthy volunteers in brain imaging research, but descriptions of incidental findings (IFs) in this age group are scarce. We aimed to assess the prevalence and severity of IFs on brain MRIs of healthy young research participants aged 18-35 years, and to describe the protocol implemented to handle them. Methods: The study population comprised 1,867 participants aged 22.1 ± 2.3 years (72% women) from MRi-Share, the cross-sectional brain MRI substudy of the i-Share student cohort. IFs were flagged during the MRI quality control. We estimated the proportion of participants with IFs [any, requiring medical referral, potentially serious (PSIFs) as defined in the UK biobank]: overall, by type and severity of the final diagnosis, as well as the number of IFs. Results: 78/1,867 participants had at least one IF [4.2%, 95% Confidence Interval (CI) 3.4-5.2%]. IFs requiring medical referral (n = 38) were observed in 36/1,867 participants (1.9%, 1.4-2.7%), and represented 47.5% of the 80 IFs initially flagged. Referred IFs were retrospectively classified as PSIFs in 25/1,867 participants (1.3%, 0.9-2.0%), accounting for 68.4% of anomalies referred (26/38). The most common final diagnosis was cysts or ventricular abnormalities in all participants (9/1,867; 0.5%, 0.2-0.9%) and in those with referred IFs (9/36; 25.0%, 13.6-41.3%), while it was multiple sclerosis or radiologically isolated syndrome in participants with PSIFs (5/19; 26.3%, 11.5-49.1%) who represented 0.1% (0.0-0.4%) and 0.2% (0.03-0.5%) of all participants, respectively. Final diagnoses were considered serious in 11/1,867 participants (0.6%, 0.3-1.1%). Among participants with referred IFs, 13.9% (5/36) required active intervention, while 50.0% (18/36) were put on clinical surveillance. Conclusions: In a large brain imaging study of young healthy adults participating in research we observed a non-negligible frequency of IFs. The etiological pattern differed from what has been described in older adults.

Intra-database validation of case-identifying algorithms using reconstituted electronic health records from healthcare claims data.

BACKGROUND: Diagnosis performances of case-identifying algorithms developed in healthcare database are usually assessed by comparing identified cases with an external data source. When this is not feasible, intra-database validation can present an appropriate alternative. OBJECTIVES: To illustrate through two practical examples how to perform intra-database validations of case-identifying algorithms using reconstituted Electronic Health Records (rEHRs). METHODS: Patients with 1) multiple sclerosis (MS) relapses and 2) metastatic castration-resistant prostate cancer (mCRPC) were identified in the French nationwide healthcare database (SNDS) using two case-identifying algorithms. A validation study was then conducted to estimate diagnostic performances of these algorithms through the calculation of their positive predictive value (PPV) and negative predictive value (NPV). To that end, anonymized rEHRs were generated based on the overall information captured in the SNDS over time (e.g. procedure, hospital stays, drug dispensing, medical visits) for a random selection of patients identified as cases or non-cases according to the predefined algorithms. For each disease, an independent validation committee reviewed the rEHRs of 100 cases and 100 non-cases in order to adjudicate on the status of the selected patients (true case/ true non-case), blinded with respect to the result of the corresponding algorithm. RESULTS: Algorithm for relapses identification in MS showed a 95% PPV and 100% NPV. Algorithm for mCRPC identification showed a 97% PPV and 99% NPV. CONCLUSION: The use of rEHRs to conduct an intra-database validation appears to be a valuable tool to estimate the performances of a case-identifying algorithm and assess its validity, in the absence of alternative.

Untreated patients with multiple sclerosis: A study of French expert centers.

BACKGROUND AND PURPOSE: Disease-modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment. METHODS: We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. RESULTS: Of the 21,189 patients with MS (age 47.1 ± 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 ± 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7-31.9) were not receiving any DMT. Although patients with a relapsing-remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95% CI 14.2-15.4) were still untreated (6.8% never treated). After multivariate analysis among patients with relapsing-remitting MS, the main factors explaining never having been treated were: not having ≥9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44-0.61]) and lower EDSS score (OR 0.78 [95% CI 0.74-0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT. CONCLUSION: A significant proportion of patients with MS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of patients with MS.

Cognitive Rehabilitation in Multiple Sclerosis in the Period from 2013 and 2021: A Narrative Review.

BACKGROUND: In recent years, several blinded randomized controlled trials (RCT) have been conducted on cognitive rehabilitation (CR) in adults with multiple sclerosis (MS). OBJECTIVE: To review all blinded RCTs on CR in MS published since 2013. METHODS: The National Library of Medicine database (Medline) and PSYCINFO were searched using the keywords MS and CR or cognitive training or NP rehabilitation or memory rehabilitation or attention rehabilitation. RESULTS: After the exclusion of some papers not specifically focused on CR, a final list of 26 studies was established. The papers belong to three main categories: individual specific rehabilitation (8studies), group rehabilitation (4 studies), and computerized training (CT) (14 studies), while one study combined group rehabilitation and CT. Among the individual rehabilitation studies, 5 were devoted to memory, and most of the 19 other selected studies were about several cognitive domains. Most of the studies mainly concerned RRMS patients, except for 2 studies that were carried out exclusively in progressive forms. Despite the methodological limitations of some studies and the great heterogeneity of the protocols, the results are generally in favor of the efficacy of CR in neuropsychological tests. CONCLUSION: Recent blinded RCTs about CR in MS show promising results.

BEST-MS: A prospective head-to-head comparative study of natalizumab and fingolimod in active relapsing MS.

BACKGROUND: There are few head-to-head studies to compare highly active treatments in multiple sclerosis (MS). OBJECTIVE: The aim of this study was to compare the effectiveness between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting MS. METHOD: Best Escalation STrategy in Multiple Sclerosis (BEST-MS) is a multicentric, prospective study with a 12-month follow-up including patients with active MS. Treatment choice was at the discretion of physician. Clinical and magnetic resonance imaging (MRI) data were collected at baseline and at 12 months. The primary outcome was the proportion of patients reaching no evidence of disease activity (NEDA) at 12 months. Secondary outcomes included annualized relapse rate and MRI activity. RESULTS: A total of 223 patients were included (NTZ: 109 and FTY: 114). Treatment groups were well balanced at baseline. Proportion of NEDA patients was 47.8% in NTZ group versus 30.4% in FTY group (p = 0.015). This superiority was driven by annualized relapse rate and MRI activity. In the multivariate analysis, treatment group was the only factor associated with NEDA at 12 months with a lower probability in FTY group (odds ratio (OR) = 0.49, p = 0.029). CONCLUSION: BEST-MS is a prospective study that compared head-to-head the effectiveness of NTZ and FTY in active relapsing-remitting MS. Our results suggest a superiority of NTZ over FTY.

Validation of the French version of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS).

BACKGROUND: The Minimal Assessment of Cognitive Function in Multiple sclerosis (MACFIMS) is an internationally recognised battery of neuropsychological tests for patients with multiple sclerosis (MS). OBJECTIVES: To establish regression-based norms for the MACFIMS in French-speaking healthy subjects (HS) and validate its use in persons with multiple sclerosis (PwMS). METHODS: 136 PwMS, including 43 with relapsing-remitting MS, 46 with secondary progressive MS and 45 with primary progressive MS, as well as 276 HS were enrolled. Regression-based norms and validity were established for the seven tests of the MACIMS: the Symbol Digit Modalities Test (SDMT), the Paced Auditory Serial Addition Test (PASAT), the French learning test (FLT) a French-adapted memory test (or the California Verbal Learning Test (CVLT) at re-testing), the Judgment of Line Orientation Test (JLO), the 'épreuve de classement de cartes de Champagne' (ECCC), a French adaptation of the DKEF-sorting test, the Brief Visuospatial Memory Test (BVMT-R) and the Controlled Oral Word Association Test (COWAT). RESULTS: Regression-based norms of MACFIMS tests were established in the HS population. The MACFIMS battery was able to identify cognitive impairment (CI) (at least two abnormal tests in different domains) in 32.7% of PwMS. The domains with more frequent impairment were (in descending order): learning followed by IPS, delayed memory, verbal fluency and working memory. CONCLUSION: This study established the regression-based norms for French subjects of the French adaptation of the MACFIMS and its validity in PwMS.

Structural constraints of functional connectivity drive cognitive impairment in the early stages of multiple sclerosis.

BACKGROUND: The relationship between structural and functional deficits in multiple sclerosis (MS) is unclear. OBJECTIVE: This study explored structure-function relationships during the 5 years following a clinically isolated syndrome and their role in cognitive performance. METHODS: Thirty-two patients were enrolled after their first neurological episode suggestive of MS and followed for 5 years, along with 10 matched healthy controls. We assessed structural (using diffusion tensor imaging) and functional (using resting-state functional magnetic resonance imaging (fMRI)) brain network metrics, clinical and cognitive scores at each follow-up visit. Structural-functional coupling, calculated as the correlation coefficient between strengths of structural and functional networks, was used to assess structure-function relationships. RESULTS: Structural clustering coefficient was significantly increased after 5 years, whereas characteristic path length decreased. Structural connections decreased after 1 year and increased after 5 years. Functional connections and related path lengths were decreased after 5 years. Structural-functional coupling had increased significantly after 5 years. This structural-functional coupling was associated with cognitive and clinical evolution, with stronger coupling associated with a decline in both domains. CONCLUSION: Our findings provide novel biological evidence that MS leads to a more constrained anatomical-dependant functional connectivity. The collapse of this network seems to lead to both cognitive worsening and clinical disability.