Publications by authors named "Bruno Brochet"

99 Publications

Comparative effectiveness of dimethyl fumarate in multiple sclerosis.

Br J Clin Pharmacol 2021 Sep 9. Epub 2021 Sep 9.

Univ. Bordeaux, INSERM CIC-P1401, Bordeaux PharmacoEpi, Bordeaux, France.

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).
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http://dx.doi.org/10.1111/bcp.15071DOI Listing
September 2021

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

Front Neurol 2021 20;12:675244. Epub 2021 May 20.

UMR1219 Bordeaux Population Health Center (Team VINTAGE), INSERM-University of Bordeaux, Bordeaux, France.

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. 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. 78/1,867 participants had at least one IF [4.2%, 95% Confidence Interval (CI) 3.4-5.2%]. IFs requiring medical referral ( = 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. 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.
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http://dx.doi.org/10.3389/fneur.2021.675244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173138PMC
May 2021

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

Front Neurol 2021 19;12:667531. Epub 2021 May 19.

Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux, France.

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.
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http://dx.doi.org/10.3389/fneur.2021.667531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170471PMC
May 2021

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

BMC Med Res Methodol 2021 05 1;21(1):95. Epub 2021 May 1.

INSERM CIC-P1401, Bordeaux PharmacoEpi, Univ. Bordeaux, Bordeaux, France.

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.
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http://dx.doi.org/10.1186/s12874-021-01285-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088022PMC
May 2021

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

Eur J Neurol 2021 06 19;28(6):2026-2036. Epub 2021 Mar 19.

Service de Neurologie, Hôpital Maison-Blanche, Centre Hospitalier Universitaire de Reims, Reims, France.

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.
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http://dx.doi.org/10.1111/ene.14790DOI Listing
June 2021

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

Mult Scler Relat Disord 2021 Feb 17;48:102692. Epub 2020 Dec 17.

CHU de Bordeaux, F-33000 Bordeaux, France; Inserm U1215 - Neurocentre Magendie, F-33000 Bordeaux, France; Univ. Bordeaux, F-33076 Bordeaux, France.

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.
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http://dx.doi.org/10.1016/j.msard.2020.102692DOI Listing
February 2021

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

Mult Scler 2021 04 7;27(4):559-567. Epub 2020 Dec 7.

University of Bordeaux, Bordeaux, France; Inserm U1215 - Neurocentre Magendie, Bordeaux, France; CHU Pellegrin Bordeaux, Bordeaux, France.

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.
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http://dx.doi.org/10.1177/1352458520971807DOI Listing
April 2021

Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial.

Lancet Neurol 2020 12 29;19(12):998-1009. Epub 2020 Oct 29.

Department of Neurology, University of California, San Francisco, CA, USA.

Background: The safety and efficacy of ocrelizumab in primary progressive multiple sclerosis were shown in the phase 3 ORATORIO trial. In this study, we assessed the effects of maintaining or switching to ocrelizumab therapy on measures of disease progression and safety in the open-label extension phase of ORATORIO.

Methods: ORATORIO was an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done at 182 study locations including academic centres, hospitals, and community speciality centres within 29 countries across the Americas, Australia, Europe, Israel, New Zealand, and Russia. Patients with primary progressive multiple sclerosis aged 18-55 years who had an Expanded Disability Status Scale (EDSS) score of 3·0-6·5 were eligible for enrolment. Those who had previous treatment with B-cell-targeted therapies or other immunosuppressive medications were excluded. Eligible participants were randomly assigned (2:1) to receive either intravenous infusion of 600 mg of ocrelizumab (two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks until a prespecified number (n=253) of disability events occurred. After the double-blind phase, patients entered an extended controlled period of variable duration, during which they and investigators became aware of treatment allocation. Following this period, patients could enter an optional open-label extension, during which they continued ocrelizumab or switched from placebo to ocrelizumab. Time to onset of disability progression was confirmed at 24 weeks with four measures (ie, increase in EDSS score, ≥20% increase in time to complete the 9-Hole Peg Test [9HPT], ≥20% increase in time to perform the Timed 25-Foot Walk [T25FW], and composite progression defined as the first confirmed occurrence of any of these three individual measures), as was time to requiring a wheelchair (EDSS ≥7). Conventional MRI measures were also analysed. The intention-to-treat population was used for the safety and efficacy analyses; all analyses, and their timings, were done post hoc. ORATORIO is registered with ClinicalTrials.gov, NCT01194570, and is ongoing.

Findings: From March 3, 2011, to Dec 27, 2012, 488 patients were randomly assigned to the ocrelizumab group and 244 to the placebo group. The extended controlled period started on July 24, 2015, and ended on April 27, 2016, when the last patient entered the open-label extension. Overall, 544 (74%) of 732 participants completed the double-blind period to week 144; 527 (97%) of 544 entered the open-label extension phase, of whom 451 (86%) are ongoing in the open-label extension. After at least 6·5 study years (48 weeks per study year) of follow-up, the proportion of patients with progression on disability measures was lower in those who initiated ocrelizumab early than in those initially receiving placebo for most of the measures of 24-week confirmed disability progression: EDSS, 51·7% vs 64·8% (difference 13·1% [95% CI 4·9-21·3]; p=0·0018); 9HPT, 30·6% vs 43·1% (12·5% [4·1-20·9]); p=0·0035); T25FW, 63·2% vs 70·7% (7·5% [-0·3 to 15·2]; p=0·058); composite progression, 73·2% vs 83·3% (10·1% [3·6-16·6]; p=0·0023); and confirmed time to requiring a wheelchair, 11·5% vs 18·9% (7·4% [0·8-13·9]; p=0·0274). At study end, the percentage change from baseline was lower in those who initiated ocrelizumab early than in those initially receiving placebo for T2 lesion volume (0·45% vs 13·00%, p<0·0001) and T1 hypointense lesion volume (36·68% vs 60·93%, p<0·0001). Over the entire period, in the ORATORIO all ocrelizumab exposure population, the rate of adverse events was 238·09 (95% CI 232·71-243·57) per 100 patient-years and serious adverse events was 12·63 (95% CI 11·41-13·94) per 100 patient-years; the most common serious adverse events were infections at 4·13 (95% CI 3·45-4·91) per 100 patient-years. No new safety signals emerged compared with the double-blind phase of ORATORIO.

Interpretation: Compared with patients switching from placebo, earlier and continuous ocrelizumab treatment provided sustained benefits on measures of disease progression over the 6·5 study years of follow-up. Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis. Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods.

Funding: F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1474-4422(20)30342-2DOI Listing
December 2020

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

Mult Scler 2021 09 30;27(10):1556-1563. Epub 2020 Oct 30.

Service de Neurologie, CRCSEP, Unité de Recherche Clinique Cote d'Azur (UR2CA), Centre Hospitalier Universitaire Pasteur 2, Nice, France.

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 ( = 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,  = 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.
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http://dx.doi.org/10.1177/1352458520969145DOI Listing
September 2021

Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension.

Neurology 2020 09 20;95(13):e1854-e1867. Epub 2020 Jul 20.

From the Department of Neurology (S.L.H.), University of California, San Francisco; Neurologic Clinic and Policlinic (L.K.), Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Switzerland; NeuroRx Research (D.L.A.); Departments of Neurology and Neurosurgery (D.L.A.), McGill University, Montreal, Canada; Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (A.B.-O.), University of Pennsylvania, Philadelphia; Department of Neurology (B.B.), CHU de Bordeaux, France; Department of Neurology (R.T.N.), Washington University School of Medicine, St. Louis, MO; Division of Neurology (A.T.), Department of Medicine, University of British Columbia, Vancouver, Canada; Department of Neurology (J.S.W.), McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth); F. Hoffmann-La Roche Ltd (S.B., H.K., M.M., F.M., S.H.), Basel, Switzerland; Genentech, Inc. (V.L., L.M.), South San Francisco, CA; Division of Neurology (X.M.), University of Toronto, Canada; and Department of Neurology-Neuroimmunology (X.M.), Vall d'Hebron University Hospital, Barcelona, Spain. During completion of the work related to this article, S.B. and L.M. were employees of F. Hoffmann-La Roche Ltd; current affiliations are Biogen (S.B.), Cambridge, MA; and Alder Biopharmaceuticals Inc. (L.M.), Bothell, WA.

Objective: To assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA: I/II studies in relapsing multiple sclerosis.

Methods: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.

Results: Of patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-β-1a (16.1% vs 21.3% at year 5; = 0.014). Patients continuing OCR maintained and those switching from IFN-β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3-5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-β-1a (-1.87% vs -2.15% at year 5; < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.

Conclusion: Compared with patients switching from IFN-β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.

Classification Of Evidence: This study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.

Clinical Trial Identifiers: NCT01247324/NCT01412333.
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http://dx.doi.org/10.1212/WNL.0000000000010376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682822PMC
September 2020

Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients.

Mult Scler Relat Disord 2020 Sep 2;44:102251. Epub 2020 Jun 2.

Department of Pediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, Witten, Germany.

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 CD19B-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.
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http://dx.doi.org/10.1016/j.msard.2020.102251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895306PMC
September 2020

Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis.

JAMA Neurol 2020 09;77(9):1079-1088

Service de Neurologie, Clinical Investigation Center Institut National de la Santé et de la Recherche Médicale 1434, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France.

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.
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http://dx.doi.org/10.1001/jamaneurol.2020.2581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320356PMC
September 2020

Double-blind, randomized controlled trial of therapeutic plasma exchanges vs sham exchanges in moderate-to-severe relapses of multiple sclerosis.

J Clin Apher 2020 Aug 5;35(4):281-289. Epub 2020 May 5.

CHU de Bordeaux, Service de Neurologie, Bordeaux, France.

Introduction: No randomized controlled clinical trial of therapeutic plasma exchanges (TPE) has yet been performed for moderate-to-severe relapses of multiple sclerosis (MS).

Objective: To compare TPE to sham-TPE in patients with a recent steroid-resistant moderate-to-severe MS relapse.

Methods: Patients presenting with an MS relapse of less than 2 months without improvement and 15 days after a course of steroids were randomized. Specific criteria were used for each relapse type to define moderate-to-severe disability. The primary endpoint was the proportion of patients with at least a moderate improvement based on objective and functional evaluation after 1 month.

Results: Thirty-eight patients were randomized. The intention-to-treat analysis included 14 patients in the TPE group and 17 in the Sham-TPE group. The proportion of patients with at least moderate improvement at 1 month did not differ between the groups (P = .72), although 57.1% of the TPE group had full recovery compared with 17.6% of the sham group. Considering optic neuritis (ON), a significant difference in the proportion of different levels of improvement was observed in favor of the TPE group (P = .04). The combined Kurtzke's functional systems scores were significantly more improved in the TPE group than in the sham-TPE group at months 1 (P < .01), 3 (P < .05), and 6 (P < .05). No major side effects were observed.

Conclusions: A significant difference between TPE and Sham-TPE at the primary endpoint was only observed in patients with ON. Neurological function improved significantly more often in the TPE group than in the sham-TPE group.
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http://dx.doi.org/10.1002/jca.21788DOI Listing
August 2020

Evaluation of emotional disorders before and during treatment with interferon beta in patients with multiple sclerosis.

J Neurol Sci 2020 06 19;413:116739. Epub 2020 Feb 19.

Faculty of Economics, Louvain University, Belgium; Faculty of Medicine, University of Melbourne, Australia.

Background: Domains encompassing emotional disorders in relapsing-remitting MS (RRMS) patients are still unclear.

Methods: We performed a 24-month, multicenter, single-arm, prospective study. RRMS patients started IFN-β treatment at baseline. The primary endpoint was lack of emotional control, measured using the "Echelle d'HumeurDépressive" (EHD) scale three times at baseline and at 10 post-treatment visits. Secondary endpoints were emotional blunting, irritability, fatigue, depression and anxiety. A linear mixed covariance model assessed change from baseline on an intention-to-treat basis, under the assumption of no mood disorder effect (one-sided 97.5% level), in which autoregressive type of autocorrelation was tested.

Results: Out of 79 recruited patients, 70 were analyzed: 80% female; mean (SD) age, 37.0 (11.5) years. Mean (SD) lack of emotional control score at baseline and Month 24 was 12.7 (4.4) and 12.6 (5.5), respectively, versus 10.1 (3.2) in a healthy control population matched for age and sex. Stepwise analysis identified younger age, male sex and antidepressant use as significant predictors of higher lack of emotional control values.

Conclusions: Based on 24 months of prospective follow-up, the results of this study highlights a broad spectrum of emotional disorders in the MS population at the time of disease modifying drugs initiation but no major IFN-β-related emotional disorders (mood dyscontrol, anxiety, depression) were observed. However, sporadic occurrences of severe mood disorders and suicidality cannot be excluded.
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http://dx.doi.org/10.1016/j.jns.2020.116739DOI Listing
June 2020

Dynamic modular-level alterations of structural-functional coupling in clinically isolated syndrome.

Brain 2019 11;142(11):3428-3439

University of Bordeaux, F Bordeaux, France.

Structural and functional connectivity abnormalities have been reported previously in multiple sclerosis. However, little is known about how each modality evolution relates to the other. Recent studies in other neurological disorders have suggested that structural-functional coupling may be more sensitive in detecting brain alterations than any single modality. Accordingly, this study aimed to investigate the longitudinal evolution of structural-functional coupling, both at the global and modular levels, in the first year following clinically isolated syndrome. We hypothesized that during the course of multiple sclerosis, patients exhibit a decoupling between functional and structural connectivity due to the disruptive nature of the disease. Forty-one consecutive patients with clinically isolated syndrome were prospectively enrolled in this study, along with 19 age-, sex- and educational level-matched healthy control subjects. These participants were followed for 1 year and underwent resting-state functional MRI and diffusion tensor imaging at each time point, along with an extensive neuropsychological assessment. Graph theory analysis revealed structural reorganization at baseline that appeared as an increase in the clustering coefficient in patients compared to controls (P < 0.05), as well as modular-specific alterations. After 1 year of follow-up, both structural and functional reorganization was depicted with abnormal modular-specific connectivity and an increase of the functional betweenness centrality in patients compared to controls (P < 0.01). More importantly, structural-functional decoupling was observed in the salience, visual and somatomotor networks. These alterations were present along with preserved cognitive performance at this stage. These results depict structural damage preceding functional reorganization at a global and modular level during the first year following clinically isolated syndrome along with normal cognitive performance, suggesting a compensation mechanism at this stage of the disease. Principally, structural-functional decoupling observed for the first time in multiple sclerosis suggests that functional reorganization occurs along indirect anatomical pathways.
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http://dx.doi.org/10.1093/brain/awz270DOI Listing
November 2019

Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis.

Neurology 2019 08 12;93(7):e635-e646. Epub 2019 Jul 12.

From INSERM (D.-A.L., L.B.), CIC 0004, Nantes; CRTI-INSERM UMR U1064 (D.-A.L.), Université de Nantes; Service de Neurologie (D.-A.L., S.W., L. Michel), CHU Nantes; Centre des Neurosciences de Lyon (R.C., F.R., S.V.), Observatoire Français de la Sclérose en Plaques, INSERM 1028 and CNRS UMR5292, Lyon; Université Claude Bernard Lyon 1 (R.C., F.R., S.V.), Université de Lyon; Department of Neurology (M.D.), Nancy University Hospital; Université de Lorraine (M.D.), EA 4360 APEMAC, Vandoeuvre-Lès-Nancy; Department of Neurology and Clinical Investigation Center (J.D.S.), CHU de Strasbourg, INSERM 1434; Department of Neurology (D.B.), CHU de Toulouse; Service de Neurologie (B. Brochet), CHU de Bordeaux; Service de Neurologie (J.P.), Hôpital de la Timone, CRMBM, CNRS, APHM, Aix Marseille Univ, Marseille; Univ Lille (P.V.), CHU Lille, LIRIC (Lille Inflammation Research International Center), INSERM UMR995; Service de Neurologie (G.E., L. Michel), CHU de Rennes; CRCSEP Nice (C.L.-F.), Neurologie Pasteur 2, Université Nice Cote d'Azur, Nice; Service de Neurologie (P. Clavelou), CHU de Clermont-Ferrand; Service de Neurologie (E.T.), CHU de Nîmes; Department of Neurology (J.-P.C.), Hôpital Nord, CHU Saint-Étienne; Service de Neurologie et Faculté de Médecine de Reims (A.T.), CHU de Reims, URCA; Service de Neurologie (B.S.), CHU Saint-Antoine; Service de Neurologie (A.A.K.), CHU d'Amiens; Service de Neurologie (P. Cabre), CHU de Fort de France; Service de Neurologie (C. Lubetzki, C.P.), CHU Pitié-Salpêtrière; Service de Neurologie (E.B.), CHU de Besançon; Service de Neurologie (O.H.), CH de Poissy; Service de Neurologie (T.D.), CH de Saint-Denis; Service de Neurologie (T.M.), CHU de Dijon; Service de Neurologie (O.G.), Fondation Rothschild; Service de Neurologie (B. Bourre), CHU de Rouen; Department of Neurology (A.W.), Hôpital Henri Mondor, Créteil; Service de Neurologie (P.L.), CHU de Montpellier; Service de Neurologie (L. Magy), CHU de Limoges; Service de Neurologie (G.D.), CHU de Caen; CRC SEP and Department of Neurology (A.-M.G.), CHU Bretonneau, Tours; Department of Neurology (N.M.), CHU La Milétrie, Poitiers; Department of Neurology (C. Labeyrie), CHU Bicêtre, Le Kremlin Bicêtre; Department of Neurology (I.P.), Hôpital Sud Francilien, Corbeil Essonnes; Department of Neurology (C.N.), CHU Versailles; Department of Neurology (O.C.), CHU de Grenoble; Ecole des Hautes Etudes en Santé Publique (E.L.), Rennes; Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation (S.V.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon/Bron; and INSERM (Y.F.), UMR 1246-SPHERE, Nantes University, Tours University, Nantes, France.

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, < 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, < 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, < 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.
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http://dx.doi.org/10.1212/WNL.0000000000007938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715507PMC
August 2019

Frequency and characteristics of short versus longitudinally extensive myelitis in adults with MOG antibodies: A retrospective multicentric study.

Mult Scler 2020 07 31;26(8):936-944. Epub 2019 May 31.

Claude Bernard Lyon 1 University, Villeurbanne, France.

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),  = 0.007 and  = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group,  = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%),  < 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)),  = 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,  = 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.
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http://dx.doi.org/10.1177/1352458519849511DOI Listing
July 2020

Cognitive Impairment in Multiple Sclerosis With Regards to Disease Duration and Clinical Phenotypes.

Front Neurol 2019 20;10:261. Epub 2019 Mar 20.

Service de Neurologie, CHU de Bordeaux, Bordeaux, France.

The relationships between cognitive impairment that exist during the clinical course of multiple sclerosis (MS) remain poorly described. The effect of disease duration has been studied in a few longitudinal cohorts and some cross-sectional studies that suggest that cognitive deficits tend to extend with disease duration. However, the effect of disease duration seems to be confounded by the effect of age. At the pre-clinical stage, cognitive deficits have been observed in patients with radiologically isolated syndromes, and their profile is similar than in clinically isolated syndromes (CIS) and relapsing-remitting MS (RRMS). The frequency of cognitive impairment tends to be higher in RRMS than in CIS. In these phenotypes, slowness of information processing speed (IPS) and episodic verbal and visuo-spatial memory deficits are frequently observed, but executive functions, and in particular verbal fluency, could also be impaired. More frequent and severe deficits are reported in SPMS than in RRMS with more severe deficits for memory tests, working memory and IPS. Similarly to what is observed in SPMS, patients with primary progressive MS (PPMS) present with a wide range of cognitive deficits in IPS, attention, working memory, executive functions, and verbal episodic memory with more tests and domains impaired than RRMS patients. Altogether these data suggested that not only the duration of the disease and age play an important role in the cognitive profile of patients, but also the phenotype itself, probably because of its specific pathological mechanism.
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http://dx.doi.org/10.3389/fneur.2019.00261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435517PMC
March 2019

First clinical inflammatory demyelinating events of the central nervous system in a population aged over 70 years: A multicentre study.

Mult Scler Relat Disord 2019 Feb 14;28:309-312. Epub 2018 Dec 14.

Service de Neurologie, CHU de Bordeaux, Place Amélie Raba Léon, F-33076, Bordeaux, France. Electronic address:

Background: Few data are available regarding patients with very late-onset inflammatory demyelinating events. (VLO-IDE).

Objectives: The aim of this study was to describe the clinical, biological, and radiological characteristics and aetiological diagnosis of very late first inflammatory demyelinating events of the central nervous system.

Methods: We conducted a national descriptive retrospective multicentre study on a case series of patients aged >70 years at the time of VLO-IDE. Patients were recruited from a national call on behalf of the 'Société Francophone de la Sclérose en Plaques' (French Multiple Sclerosis Society).

Results: Twenty-five patients were referred (F:M sex ratio 2.1:1). The most frequent clinical impairment was a spinal cord deficit (23/25), usually severe (disability score, median EDSS 4.5 [2-9.5]). Spinal cord lesions were usually extensive, spanning at least three segments (11/25), and large brain lesions were also observed (lesions >20 mm in 6/25). The final aetiological diagnoses comprised multiple sclerosis (9/25), neuromyelitis optica spectrum disorders (7/25), neurosystemic lupus erythematosus (2/25), transverse myelitis without aetiological diagnosis (6/25) and optic neuritis (1/25).

Conclusions: This study highlights a particular phenotype of first clinical inflammatory demyelinating events in predominantly female patients aged >70 years who have severe motor impairment with common longitudinal extensive myelitis and large and common very active radiological inflammatory lesions. Neuromyelitis optica spectrum disorders seem overrepresented.
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http://dx.doi.org/10.1016/j.msard.2018.12.016DOI Listing
February 2019

The cognitive effects of anxiety and depression in immune-mediated inflammatory diseases.

Neurology 2019 Jan 11. Epub 2019 Jan 11.

From the Department of Psychiatry (A.F.), Sunnybrook and Women's College Health Science Centre, Toronto, Canada; Inserm U 862 and Department of Neurology (B.B.), University of Bordeaux and CHU of Bordeaux, France; and Department of Neurology (J.S.), Icahn School of Medicine at Mount Sinai, New York, NY.

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http://dx.doi.org/10.1212/WNL.0000000000006840DOI Listing
January 2019

Observatoire Français de la Sclérose en Plaques (OFSEP): A unique multimodal nationwide MS registry in France.

Mult Scler 2020 01 13;26(1):118-122. Epub 2018 Dec 13.

Department of Neurology, CHU de Toulouse, Toulouse, France.

The care of multiple sclerosis (MS) in France is based on two complementary interlinked networks: MS expert centers in university hospitals and regional networks of neurologists. The routine use of European database for multiple sclerosis (EDMUS) in all those centers has paved the way for the constitution of a national registry, designated as Observatoire Français de la Sclérose En Plaques (OFSEP). It promotes a prospective, standardized, high-quality, and multimodal collection of data. On June 2018, there were 68.097 files, with 71.1% females, representing 761,185 person-years. This huge database is open to the scientific community and might contribute exploring unresolved issues and unmet needs in MS.
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http://dx.doi.org/10.1177/1352458518815602DOI Listing
January 2020

Longitudinal study of functional brain network reorganization in clinically isolated syndrome.

Mult Scler 2020 02 27;26(2):188-200. Epub 2018 Nov 27.

University of Bordeaux, Bordeaux, France/Inserm U1215, Neurocentre Magendie, Bordeaux, France/CHU Pellegrin, CHU de Bordeaux, Bordeaux, France.

Background: There is a lack of longitudinal studies exploring the topological organization of functional brain networks at the early stages of multiple sclerosis (MS).

Objective: This study aims to assess potential brain functional reorganization at rest in patients with CIS (PwCIS) after 1 year of evolution and to characterize the dynamics of functional brain networks at the early stage of the disease.

Methods: We prospectively included 41 PwCIS and 19 matched healthy controls (HCs). They were scanned at baseline and after 1 year. Using graph theory, topological metrics were calculated for each region. Hub disruption index was computed for each metric.

Results: Hub disruption indexes of degree and betweenness centrality were negative at baseline in patients ( < 0.05), suggesting brain reorganization. After 1 year, hub disruption indexes for degree and betweenness centrality were still negative ( < 0.00001), but such reorganization appeared more pronounced than at baseline. Different brain regions were driving these alterations. No global efficiency differences were observed between PwCIS and HCs either at baseline or at 1 year.

Conclusion: Dynamic changes in functional brain networks appear at the early stages of MS and are associated with the maintenance of normal global efficiency in the brain, suggesting a compensatory effect.
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http://dx.doi.org/10.1177/1352458518813108DOI Listing
February 2020

Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome.

Front Neurol 2018 11;9:824. Epub 2018 Oct 11.

Univ. Bordeaux, Bordeaux, France.

Whether some gray matter (GM) regions are differentially vulnerable at the early stages of MS is still unknown. The objective of this study is to investigate whether deep and cortical GM are differentially vulnerable after a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). Fifty-six patients with CIS (PwCIS) and 38 healthy controls (HC) had conventional and diffusion tensor imaging (DTI) at baseline and 46 PwCIS and 20 HC were rescanned after 1 year. Deep GM (DGM) volumes, cortical thickness (CTh), and DTI metrics (FA: fractional anisotropy; MD: mean diffusivity) within these structures were calculated for each participant at each time-point and compared between PwCIS and HC. Linear regression models were used to investigate whether baseline DTI parameters could predict GM volume loss over time. At baseline, GM volumes did not differ between PwCIS and HC, but hippocampal MD was higher in PwCIS than HC ( < 0.01). Over 1 year, GM alterations became more widespread with putamen and hippocampus volumes decreasing in PwCIS ( < 0.01), and cortical thinning in different parts of the cortex along with a significant increase of MD. Hippocampus MD at baseline could predict its volume loss ( = 0.159; < 0.05) and cortical thinning was associated to microstructural damage (Spearman's rho ranging from -0.424 to -0.603 with < 0.003). Along with MS being a diffuse inflammatory disease, GM showed a differential vulnerability at the early stage spreading from hippocampus to the cortex. Hippocampus volume loss could be predicted by its MD at baseline.
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http://dx.doi.org/10.3389/fneur.2018.00824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193084PMC
October 2018

Efficacy of rituximab in refractory RRMS.

Mult Scler 2019 05 3;25(6):828-836. Epub 2018 May 3.

Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Marseille, France/CRMBM UMR 7339, CNRS, Aix-Marseille Université, Marseille, France.

Objective: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT).

Methods: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts.

Results: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5-6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab ( p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4-18.4) months after rituximab ( p < 0.0001).

Conclusion: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.
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http://dx.doi.org/10.1177/1352458518772748DOI Listing
May 2019

Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study.

Neurology 2018 05 25;90(21):e1858-e1869. Epub 2018 Apr 25.

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 ( = 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.
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http://dx.doi.org/10.1212/WNL.0000000000005560DOI Listing
May 2018

Cognitive assessment in patients with multiple sclerosis: From neuropsychological batteries to ecological tools.

Ann Phys Rehabil Med 2020 Mar 17;63(2):154-158. Epub 2018 Feb 17.

Université de Bordeaux, 33076 Bordeaux, France; Centre hospitalo-universitaire de Bordeaux, 33076 Bordeaux, France; Inserm U1215 - Neurocentre Magendie, 33000 Bordeaux, France.

Background: Cognitive impairment (CI) is frequent in patients with multiple sclerosis (PwMS) and could negatively affect family social and vocational activities. Detecting CI is clinically relevant, so the emerging question is the strategy for assessing cognition in MS.

Objective: An update on cognitive assessment in PwMS with use of standard neuropsychological (NP) tests and ecological tools.

Results: The minimal cognitive assessment in MS should include at least NP tests assessing information processing speed (IPS) and verbal and visuospatial episodic memory. The IPS could be easily and quickly evaluated with symbol digit substitution tests by using paper for the oral version of the Symbol Digit Modalities Test or a laptop for the Computerised Speed Cognitive Test. The comprehensive NP battery must be performed by a qualified neuropsychologist to adequately characterize the extent and severity of CI in PwMS. The quiet and controlled environment used for this standardized assessment could be a limitation for generalizing the results because it does not reflect real daily life conditions. Thus, this context could decrease the ability to detect some cognitive deficits that could occur only in more complex situations. Thus, ecological evaluation seems a complementary and promising approach for detecting cognitive abnormalities in daily activities.

Conclusion: Recent efforts have been made to detect and characterize cognitive deficits in PwMS. Some IPS and episodic memory NP tests have been validated in MS and should be proposed to patients in the clinical setting. Besides NP tests, ecological tools are becoming important for detecting cognitive dysfunction in everyday-like conditions. Further research is needed to validate relevant tools for monitoring cognition in MS and the ability to detect clinically meaningful change in longitudinal studies.
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http://dx.doi.org/10.1016/j.rehab.2018.01.006DOI Listing
March 2020

Preliminary evidence of the cerebellar role on cognitive performances in clinically isolated syndrome.

J Neurol Sci 2018 02 2;385:1-6. Epub 2017 Dec 2.

CHU de Bordeaux, INSERM-CHU CIC-P 0005, Service de Neurologie, Bordeaux F-33076, France; Université de Bordeaux, Bordeaux F-33076, France; Neurocentre Magendie, INSERM U1215, Team Glia-neuron Interactions, Bordeaux F-33077, France. Electronic address:

Background: Cerebellar and cognitive dysfunction can occur early in clinically isolated syndrome (CIS). Eye tracking is a reliable tool for the evaluation of both subtle cerebellar symptoms and cognitive impairment.

Objectives: To investigate the early cognitive profile using neuropsychological and ocular motor (OM) testing in CIS with and without cerebellar dysfunction with OM testing compared to healthy subjects (HS).

Methods: Twenty-eight patients and 12 HC underwent OM and neuropsychological testing. Cerebellar impairment was defined by the registration of saccadic intrusions and/or at least 10% of dysmetria during ocular motor recording. Visually guided saccade (VGS), memory-guided saccade (MGS) and antisaccade (AS) paradigms were compared to neuropsychological assessments.

Results: The group of patients with cerebellar dysfunction (n=16) performed worse on MGS latencies and error rates, and had worse working memory, executive function and information processing speed (IPS) z scores than patients without cerebellar dysfunction. IPS was correlated with the AS error rate in all patients and with the VGS error rate and the MGS final eye position ratio in cerebellar patients.

Conclusion: Eye tracking is a sensitive tool to assess cognitive and cerebellar dysfunctions in CIS. In CIS patients, cerebellar impairment is associated with working memory, executive functions and IPS slowness.
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http://dx.doi.org/10.1016/j.jns.2017.11.037DOI Listing
February 2018

Regional hippocampal vulnerability in early multiple sclerosis: Dynamic pathological spreading from dentate gyrus to CA1.

Hum Brain Mapp 2018 04 13;39(4):1814-1824. Epub 2018 Jan 13.

Univ. Bordeaux, Bordeaux, F-33000, France.

Background: Whether hippocampal subfields are differentially vulnerable at the earliest stages of multiple sclerosis (MS) and how this impacts memory performance is a current topic of debate.

Method: We prospectively included 56 persons with clinically isolated syndrome (CIS) suggestive of MS in a 1-year longitudinal study, together with 55 matched healthy controls at baseline. Participants were tested for memory performance and scanned with 3 T MRI to assess the volume of 5 distinct hippocampal subfields using automatic segmentation techniques.

Results: At baseline, CA4/dentate gyrus was the only hippocampal subfield with a volume significantly smaller than controls (p < .01). After one year, CA4/dentate gyrus atrophy worsened (-6.4%, p < .0001) and significant CA1 atrophy appeared (both in the stratum-pyramidale and the stratum radiatum-lacunosum-moleculare, -5.6%, p < .001 and -6.2%, p < .01, respectively). CA4/dentate gyrus volume at baseline predicted CA1 volume one year after CIS (R  = 0.44 to 0.47, p < .001, with age, T2 lesion-load, and global brain atrophy as covariates). The volume of CA4/dentate gyrus at baseline was associated with MS diagnosis during follow-up, independently of T2-lesion load and demographic variables (p < .05). Whereas CA4/dentate gyrus volume was not correlated with memory scores at baseline, CA1 atrophy was an independent correlate of episodic verbal memory performance one year after CIS (ß = 0.87, p < .05).

Conclusion: The hippocampal degenerative process spread from dentate gyrus to CA1 at the earliest stage of MS. This dynamic vulnerability is associated with MS diagnosis after CIS and will ultimately impact hippocampal-dependent memory performance.
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http://dx.doi.org/10.1002/hbm.23970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866595PMC
April 2018

[Towards a national strategy on the diagnosis of neurocognitive disorders. A shared approach among the French National College of General Practitioners and specialists of neurocognitive disorders].

Presse Med 2018 Jan 26;47(1):75-83. Epub 2017 Dec 26.

Collège de médecine générale, 92200 Neuilly-Sur-Seine, France.

Neurocognitive disorders leading to progressive cognitive, functional and behavioural impairment are often undiagnosed or diagnosed lately. But tailored care and therapeutics help in implementing secondary and tertiary prevention dynamics aiming at preserving quality of life and delaying, anticipating or preventing behavioural crisis and severe stages of dementia. Moreover, the diagnosis of numerous diseases induces specific care and therapeutics, as well access to research and clinical trials. For the first time, the representatives of the National College of General Practitioners, the French Federation of Memory Centres, the French Federation of Gerontology and Geriatrics, the French Federation of Neurology, the French Society of Psychogeriatrics and the national plan on neurodegenerative diseases propose a graduated and tailored diagnosis strategy involving primary care and specialists of neurocognitive disorders. This strategy has been built in the context of the national plan on neurodegenerative diseases, the European Joint Action "Act on dementia", and has been consensually agreed after a seminar animated by the National College of General Practitioners in March 2017.
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January 2018
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