Publications by authors named "Jean Pelletier"

140 Publications

Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts.

CNS Drugs 2021 Sep 18. Epub 2021 Sep 18.

Neurology Unit, Garibaldi Hospital, Catania, Italy.

Introduction: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined.

Objective: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest.

Methods: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients' sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed with weighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score.

Results: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15-41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65-0.88); in those aged ≤ 38 years (0.64; 0.54-0.76); in those with disease duration ≤ 7 years (0.63; 0.53-0.76); in those with EDSS score < 4 (0.75; 0.64-0.88), < 6 (0.80; 0.70-0.91), and ≥ 6 (0.52; 0.31-0.86); and in patients with pre-baseline relapses (0.74; 0.64-0.86). A higher probability of confirmed disability improvement on natalizumab versus fingolimod (hazard ratio [HR]; 95% CI) was observed among women (1.36; 1.10-1.66); those aged > 38 years (1.34; 1.04-1.73); those with disease duration > 7 years (1.33; 1.01-1.74); those with EDSS score < 6 (1.21; 1.01-1.46) and ≥ 6 (1.93; 1.11-3.34); and patients with no new MRI lesion (1.73; 1.19-2.51).

Conclusions: Overall, in women, younger patients, those with shorter disease durations, and patients with pre-treatment relapses, natalizumab was associated with a lower frequency of multiple sclerosis relapses than fingolimod. It was also associated with an increased chance of recovery from disability among most patients, particularly women and those with no recent MRI activity.
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http://dx.doi.org/10.1007/s40263-021-00860-7DOI Listing
September 2021

Decrease in the cortex/striatum metabolic ratio on [F]-FDG PET: a biomarker of autoimmune encephalitis.

Eur J Nucl Med Mol Imaging 2021 Aug 31. Epub 2021 Aug 31.

APHM, CNRS, Centrale Marseille, Institut Fresnel, Timone Hospital, CERIMED, Nuclear Medicine Department, Aix Marseille Univ, Marseille, France.

Purpose: The aim of this [F]-FDG PET study was to determine the diagnostic value of the cortex/striatum metabolic ratio in a large cohort of patients suffering from autoimmune encephalitis (AE) and to search for correlations with the course of the disease.

Methods: We retrospectively collected clinical and paraclinical data of patients with AE, including brain F-FDG PET/CT. Whole-brain statistical analysis was performed using SPM8 software after activity parametrization to the striatum in comparison to healthy subjects. The discriminative performance of this metabolic ratio was evaluated in patients with AE using receiver operating characteristic curves against 44 healthy subjects and a control group of 688 patients with MCI. Relationship between cortex/striatum metabolic ratios and clinical/paraclinical data was assessed using univariate and multivariate analysis in patients with AE.

Results: Fifty-six patients with AE were included. In comparison to healthy subjects, voxel-based statistical analysis identified one large cluster (p-cluster < 0.05, FWE corrected) of widespread decreased cortex/striatum ratio in patients with AE. The mean metabolic ratio was significantly lower for AE patients (1.16 ± 0.13) than that for healthy subjects (1.39 ± 0.08; p < 0.001) and than that for MCI patients (1.32 ± 0.11; p < 0.001). A ratio threshold of 1.23 allowed to detect AE patients with a sensitivity of 71% and a specificity of 82% against MCI patients, and 98% against healthy subjects. A lower cortex/striatum metabolic ratio had a trend towards shorter delay before F-FDG PET/CT (p = 0.07) in multivariate analysis.

Conclusion: The decrease in the cortex/striatal metabolic ratio has a good early diagnostic performance for the differentiation of AE patients from controls.
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http://dx.doi.org/10.1007/s00259-021-05507-9DOI Listing
August 2021

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

Ann Clin Transl Neurol 2021 08 7;8(8):1738-1744. Epub 2021 Jul 7.

Department of Neurology, CIC INSERM 1434, CHU de Strasbourg, Strasbourg, France.

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon.
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http://dx.doi.org/10.1002/acn3.51408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351392PMC
August 2021

Effects of High- and Low-Efficacy Therapy in Secondary Progressive Multiple Sclerosis.

Neurology 2021 Aug 30;97(9):e869-e880. Epub 2021 Jun 30.

From the CORe (I.R., C.M., T.K.), Department of Medicine, University of Melbourne; Melbourne MS Centre (I.R., K.B., C.M., T.K.), Department of Neurology, Royal Melbourne Hospital, Australia; Rennes University (E.L.), EHESP, REPERES EA 7449; Univ Rennes (E.L.), CHU Rennes, Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes); Université de Lyon (R.C.), Université Claude Bernard Lyon 1; Hospices Civils de Lyon (R.C.), Service de Neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Bron; Observatoire Français de la Sclérose en Plaques (R.C.), Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR 5292; EUGENE DEVIC EDMUS Foundation Against Multiple Sclerosis (R.C.), state-approved foundation, Bron, France; Department of Neurology and Center of Clinical Neuroscience (D.H., E.H.), First Faculty of Medicine, Charles University; General University Hospital (D.H., E.H.), Prague, Czech Republic; Hospital Universitario Virgen Macarena (G.I., S.E.M.), Sevilla, Spain; Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia; Multiple Sclerosis Center (F.P.), University of Catania, Italy; Centre hospitalier universitaire de Rennes (G.E.), Hôpital Pontchaillou, Service de neurologie, CIC1414 INSERM; Nancy University Hospital (M.D.), Department of Neurology; Université de Lorraine (M.D.), APEMAC, Nancy, France; Aix Marseille Univ (J.P.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, France; Dokuz Eylul University (S.O.), Konak/Izmir, Turkey; Department of Neurosciences, Psychology, Drugs and Child Health Area (NEUROFARBA) (M.P.A.), Section Neurosciences, University of Florence, Italy; CHU Clermont-Ferrand (P.C.), Department of Neurology; Université Clermont Auvergne (P.C.), Inserm, Neuro-Dol, Clermont-Ferrand, France; CISSS Chaudière-Appalache (P.G.), Lévis, Canada; KTU Medical Faculty Farabi Hospital (C.B.), Trabzon, Turkey; Department of Neurology (K.B., O.S., H.B.), Box Hill Hospital, Monash University; The Alfred Hospital (O.S.), Melbourne, Australia; CHU de Toulouse (J.C.), Hôpital Pierre-Paul Riquet, Department of Neurology, CRC-SEP, Toulouse Cedex 9, France; Department of Neurology (O.G.), Zuyderland Medical Center, Sittard-Geleen, the Netherlands; Neuro Rive-Sud (F.G.), Quebec, Canada; School of Medicine and Public Health (J.L.-S.), University Newcastle; Department of Neurology (J.L.-S.), John Hunter Hospital, Hunter New England Health, Newcastle; Central Clinical School (H.B.), Monash University; Department of Neurology (H.B.), The Alfred Hospital, Melbourne, Australia; Service de neurologie (S.V.), sclérose en plaques, pathologies de la myéline et neuro-inflammation; Hôpital Neurologique Pierre Wertheimer (S.V.), Hospices Civils de Lyon, Lyon/Bron; France Centre des Neurosciences de Lyon (S.V.), Observatoire Français de la Sclérose en Plaques, INSERM 1028 et CNRS UMR5292; and Université Claude Bernard Lyon 1 (S.V.), Faculté de médecine Lyon Est, France.

Objective: To compare the clinical effectiveness of high- and low-efficacy treatments in patients with recently active and inactive secondary progressive multiple sclerosis (SPMS) after accounting for therapeutic lag.

Methods: Patients treated with high-efficacy (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, fingolimod) or low-efficacy (interferon beta, glatiramer acetate, teriflunomide) therapies after SPMS onset were selected from MSBase and Observatoire Français de la Sclérose en Plaques (OFSEP), 2 large observational cohorts. Therapeutic lag was estimated for each patient from their demographic and clinical characteristics. Propensity score was used to match patients treated with high- and low-efficacy therapies. Outcomes after the period of therapeutic lag was disregarded were compared in paired, pairwise-censored analyses.

Results: One thousand patients were included in the primary analysis. Patients with active SPMS treated with high-efficacy therapy experienced less frequent relapses than those on low-efficacy therapy (hazard ratio [HR] 0.7, = 0.006). In patients with inactive SPMS, there was no evidence for a difference in relapse frequency between groups (HR 0.8, = 0.39). No evidence for a difference in the risk of disability progression was observed.

Conclusion: In treated patients with SPMS, high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active but not those with inactive SPMS. However, more potent therapies do not offer an advantage in reducing disability progression in this patient group.

Classification Of Evidence: This study provides Class III evidence that high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active SPMS, although we did not find a difference in disability progression between patients treated with high- and low-efficacy therapy.
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http://dx.doi.org/10.1212/WNL.0000000000012354DOI Listing
August 2021

The effectiveness of natalizumab vs fingolimod-A comparison of international registry studies.

Mult Scler Relat Disord 2021 Aug 8;53:103012. Epub 2021 May 8.

KTU Medical Faculty Farabi Hospital, Trabzon, Turkey.

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening.

Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting.

Results: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod.

Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.
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http://dx.doi.org/10.1016/j.msard.2021.103012DOI Listing
August 2021

TNF-α inhibitors used as steroid-sparing maintenance monotherapy in parenchymal CNS sarcoidosis.

J Neurol Neurosurg Psychiatry 2021 Jun 8. Epub 2021 Jun 8.

Service de Neurologie, Hôpital de la Timone, Hôpitaux Universitaires de Marseille, Marseille, France

Objective: To assess the efficacy of tumour necrosis factor-α (TNF-α) inhibitors used as steroid-sparing monotherapy in central nervous system (CNS) parenchymal sarcoidosis.

Methods: The French Multiple Sclerosis and Neuroinflammation Centers retrospectively identified patients with definite or probable CNS sarcoidosis treated with TNF-α inhibitors as steroid-sparing monotherapy. Only patients with CNS parenchymal involvement demonstrated by MRI and imaging follow-up were included. The primary outcome was the minimum dose of steroids reached that was not associated with clinical or imaging worsening during a minimum of 3 months after dosing change.

Results: Of the identified 38 patients with CNS sarcoidosis treated with TNF-α inhibitors, 23 fulfilled all criteria (13 females). Treatments were infliximab (n=22) or adalimumab (n=1) for a median (IQR) of 24 (17-40) months. At treatment initiation, the mean (SD) age was 41.5 (10.5) years and median (IQR) disease duration 22 (14-49.5) months. Overall, 60% of patients received other immunosuppressive agents before a TNF-α inhibitor. The mean (SD) minimum dose of steroids was 31.5 (33) mg before TNF-α inhibitor initiation and 6.5 (5.5) mg after (p=0.001). In all, 65% of patients achieved steroids dosing <6 mg/day; 61% showed clinical improvement, 30% stability and 9% disease worsening. Imaging revealed improvement in 74% of patients and stability in 26%.

Conclusion: TNF-α inhibitors can greatly reduce steroids dosing in patients with CNS parenchymal sarcoidosis, even refractory.

Classification Of Evidence: This study provides Class IV evidence that TNF-α inhibitor used as steroid-sparing monotherapy is effective for patients with CNS parenchymal sarcoidosis.
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http://dx.doi.org/10.1136/jnnp-2020-325665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292597PMC
June 2021

Severe Cystic Echinococcosis-Associated Immune Thrombocytopenic Purpura: A Case Report.

J Hematol 2021 Apr 27;10(2):71-75. Epub 2021 Apr 27.

Division of Hematology, Department of Medicine, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.

We present a case of immune thrombocytopenic purpura (ITP), which leads to the diagnosis of severe cystic echinococcosis. Our patient presented with platelets of 5 × 10/L, and investigations uncovered multiple large echinococcal hepatic cysts, the largest of which measured 19.4 × 15 × 12 cm, and peritoneal implants. While initially refractory to prednisone and immunoglobulins, the ITP responded to dexamethasone. The echinococcosis was treated with albendazole followed by surgical resection of all lesions. Our patient's disease course has evolved favorable since his initial treatment with an isolated episode of recurrent thrombocytopenia 2 years later, and has remained in remission for the past 2 years. While a causal association between echinococcosis and ITP cannot be confirmed, this case is a reminder of the importance of remaining inquisitive for atypical potential triggers of ITP. We also present a review of the limited literature on the association of parasitic infections and ITP.
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http://dx.doi.org/10.14740/jh789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110226PMC
April 2021

How Can We Raise Awareness of Physician's Needs in Order to Increase Adherence to Management and Leadership Training?

J Healthc Leadersh 2021 28;13:109-117. Epub 2021 Apr 28.

Département de Médecine Familiale et de Médecine d'urgence, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.

Due to the increasing complexity of medical education and practice, the training of healthcare professionals for leadership and management roles and responsibilities has become increasingly important. But gaps in physician leadership and management skills have been identified across a broad range of organizational and geographic settings. Many clinicians are inadequately prepared to meet their day-to-day clinical leadership responsibilities. Simultaneously, physicians' leadership and management skills play a central role and yield superior outcomes for patients and health care delivery organizations. Currently, there is a tremendous variability in the amount of time, structure and resources dedicated to leadership/management training for physicians. Physicians who have completed such trainings seem to be pleased with the outcome. However, only a limited number of physicians enroll in these types of trainings. Several reasons can explain this fact, but it seems crucial to investigate what could increase the involvement of medical leaders and managers in these training programs. This paper offers a framework for addressing the barriers to training commitment and for designing initial training interventions for physicians. This framework is rooted in two well-known theoretical models used in social sciences. It aims to promote self-assessed knowledge and expertise amongst physicians about to embrace leader/manager careers. By developing the ability to explore and be curious about one's own experience and actions, physicians may suddenly open up the possibilities of purposeful learning. The process we describe in this paper may be an essential step in fostering the involvement of physicians in leadership and management training processes. And this is essential to contribute to the advancement of medical discipline.
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http://dx.doi.org/10.2147/JHL.S288199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092641PMC
April 2021

Serum Neurofilament Levels and PML Risk in Patients With Multiple Sclerosis Treated With Natalizumab.

Neurol Neuroimmunol Neuroinflamm 2021 07 26;8(4). Epub 2021 Apr 26.

From the Servei de Neurologia-Neuroimmunologia (N.F., M.C.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain; CRC-SEP Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 CNRS UMR 5282 et Université de Toulouse III, UPS, France; Servei de Neurologia-Neuroimmunologia (J.R., X.M.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain; Univ. Lille (P.V.), Inserm U1172, CHU Lille, FHU Imminent, France; Université (A.R.), Bordeaux; CHU de Bordeaux (A.R.), INSERM-CHU CIC-P 0005, & Services de Neurologie; Neurocentre Magendie (A.R.), INSERM U1215; Department of Neurology (J.dS), Hôpital Civil, Strasbourg; Department of Neurology (P.L.), CHU Montpellier; Department of Neurology CHU Lyon (S.V.); Department of Neurology (C.P.), Hôpital de la Salpétrière, Paris; Chi Aix en Provence (L.M.-A.); Department of Neurology and Faculté de Médecine de Reims (A.T.), CHU de Reims, URCA; LPN EA2027 Université Paris VIII (A.T.), Saint-Denis; Department of Neurology (P.C.), CHRU Clermont Ferrand; Department of Neurology (T.M.), CHU Dijon; Aix-Marseille Univ (J.P.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, CNRS, CRMBM UMR 7339, Marseille; Service de Neurology (C.L.-F.), CHU de Nice Pasteur2, Université Nice Cote d'Azur UR2CA URRIS, Nice; Neurologie (B.B.), CHU Rouen; and Neurologie (G.D.), CHU Caen, France.

Objectives: The study aimed to assess the potential for serum neurofilament light chain (NFL) levels to predict the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab (NTZ)-treated patients with multiple sclerosis (MS) and to discriminate PML from MS relapses.

Methods: NFL levels were measured with single molecule array (Simoa) in 4 cohorts: (1) a prospective cohort of patients with MS who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr); (2) a cohort of patients whose blood was collected during PML; (3) an independent cohort of non-PML NTZ-treated patients with serum NFL determinations at 2 years (replication cohort); and (4) a cohort of patients whose blood was collected during exacerbations.

Results: Serum NFL levels were significantly increased after 2 years of NTZ treatment in pre-PML patients compared with NTZ-ctr. The prognostic performance of serum NFL levels to predict PML development at 2 years was similar in the NTZ-ctr group and replication cohort. Serum NFL levels also distinguished PML from MS relapses and were 8-fold higher during PML compared with relapses.

Conclusions: These results support the use of serum NFL levels in clinical practice to identify patients with relapsing-remitting MS at higher PML risk and to differentiate PML from clinical relapses in NTZ-treated patients.

Classification Of Evidence: This study provides Class I evidence that serum NFL levels can identify NTZ-treated patients with MS who will develop PML with a sensitivity of 67% and specificity of 80%.
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http://dx.doi.org/10.1212/NXI.0000000000001003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105883PMC
July 2021

Rituximab-Induced Hypogammaglobulinemia and Infections in AQP4 and MOG Antibody-Associated Diseases.

Neurol Neuroimmunol Neuroinflamm 2021 05 15;8(3). Epub 2021 Mar 15.

From the Service de Neurologie (A.A., A.M., C.B., S.D., J.P., B.A.), Pôle de Neurosciences Cliniques, and Département de Neuroradiologie (J.-P.S.), Hôpital de la Timone, APHM, Aix Marseille University; and Department of Neurology A (R.M.), Neurologic and Neurosurgical Hospital Pierre Wertheimer, Hospices Civils de Lyon, Bron, France.

Objective: To determine the potential association between infections and rituximab (RTX)-induced hypogammaglobulinemia among patients with CNS inflammatory diseases.

Methods: We included in a prospective observational study all consecutive adults with aquaporin 4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) antibody-positive disorders treated with RTX. Dosing schedule was adapted to memory B-cell measurement.

Results: We included 48 patients (mean age 47 [SD: 14] years; 77% females; 31 AQP4 positive and 17 MOG positive). The median follow-up was 3.6 years (range: 0.9-8.1 years). The median number of RTX infusions was 8 (range: 2-14). The median dosing interval was 6 months (range: 1.7-13.7 months). Sixty-seven symptomatic infections (SIs) were observed in 26 of 48 (54%) patients, including 13 severe infections in 9 (19%). Urinary and lower respiratory tract infections were the most frequent, representing 42% and 21% of SI. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 3 of 48 (6%) patients. After RTX, 15 (31%), 11 (23%), 3 (6%), and 0 of 48 patients showed sustained IgG level <7, <6, <4, and <2 g/L, respectively. On multivariate Cox proportional hazards analysis, the main variables explaining the risk of SI were the presence of urinary tract dysfunction (hazard ratio [HR] = 34, 95% CI 4-262, < 0.001), the dosing intervals (HR = 0.98, 95% CI 0.97-0.99, < 0.001), and the interaction between IgG level and urinary tract dysfunction (HR = 0.67, 95% CI 0.53-0.85, < 0.005). IgG level <6 g/L during RTX was associated with male sex (HR = 4, 95% CI 1.4-11.4, < 0.01) and previous immunosuppression (HR = 3.4, 95% CI 1.2-10, < 0.05).

Conclusions: RTX used as maintenance therapy in CNS inflammatory diseases is frequently associated with reduced IgG level and increases the infection risk of the most vulnerable patients.
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http://dx.doi.org/10.1212/NXI.0000000000000977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054961PMC
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

Novel insights for improving the therapeutic safety and efficiency of mesenchymal stromal cells.

World J Stem Cells 2020 Dec;12(12):1474-1491

Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada.

Mesenchymal stromal cells (MSCs) have attracted great interest in the field of regenerative medicine. They can home to damaged tissue, where they can exert pro-regenerative and anti-inflammatory properties. These therapeutic effects involve the secretion of growth factors, cytokines, and chemokines. Moreover, the functions of MSCs could be mediated by extracellular vesicles (EVs) that shuttle various signaling messengers. Although preclinical studies and clinical trials have demonstrated promising therapeutic results, the efficiency and the safety of MSCs need to be improved. After transplantation, MSCs face harsh environmental conditions, which likely dampen their therapeutic efficacy. A possible strategy aiming to improve the survival and therapeutic functions of MSCs needs to be developed. The preconditioning of MSCs would strength their capacities by preparing them to survive and to better function in this hostile environment. In this review, we will discuss several preconditioning approaches that may improve the therapeutic capacity of MSCs. As stated above, EVs can recapitulate the beneficial effects of MSCs and may help avoid many risks associated with cell transplantation. As a result, this novel type of cell-free therapy may be safer and more efficient than the whole cell product. We will, therefore, also discuss current knowledge regarding the therapeutic properties of MSC-derived EVs.
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http://dx.doi.org/10.4252/wjsc.v12.i12.1474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789128PMC
December 2020

Determinants of therapeutic lag in multiple sclerosis.

Mult Scler 2021 Jan 11:1352458520981300. Epub 2021 Jan 11.

CHU de Caen, MS Expert Centre, Department of Neurology, avenue de la Côte-de-Nacre, Normandy University, Caen, France.

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups.

Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation.

Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants.

Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5).

Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
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http://dx.doi.org/10.1177/1352458520981300DOI Listing
January 2021

First line treatment failure: Predictive factors in a cohort of 863 Relapsing Remitting MS patients.

Mult Scler Relat Disord 2021 Feb 13;48:102686. Epub 2020 Dec 13.

CRC SEP, Montpellier University Hospital, INSERM, Univ Montpellier, Montpellier. Electronic address:

Background: The advent of new, potent, disease-modifying therapies has dramatically changed the management of multiple sclerosis (MS). Along with these possibilities, it is crucial to better recognize patients who are at risk of first line treatment (FLT) failure and switch to highly effective therapies (HET).

Objectives: To identify baseline prognostic factors associated with FLT failure in relapsing remitting MS (RR-MS) patients.

Methods: We included recently diagnosed RR-MS patients starting an FLT identified from 3 French MS centers databases. Baseline characteristics were included in a multivariable Cox analysis to identify the main factors associated with FLT failure.

Results: Eight hundred sixty-three patients were included. We observed an overall rate of treatment failure of 23.5%. The main baseline characteristics associated with treatment failure were age <26 years at treatment start (HR= 2.1, p<0.001), EDSS ≥2 (HR=2.1, p<0.001) and ≥2relapses in the previous year (HR=1.5, p=0.04). The association with the presence of gadolinium enhancement on MRI was not statistically significant. EDSS progression was only significantly associated with age at treatment start and treatment failure.

Conclusion: Our series demonstrates that some clinical and imaging factors are associated with treatment failure, and should be considered when planning treatment strategy in patients with recently diagnosed RR-MS.
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http://dx.doi.org/10.1016/j.msard.2020.102686DOI Listing
February 2021

Assessing the experience of the quality of care of patients living with multiple sclerosis and their caregivers: The MusiCare questionnaire.

Eur J Neurol 2021 03 5;28(3):910-920. Epub 2021 Jan 5.

Public Health: Quality of Life and Chronic Diseases EA3279, Aix-Marseille University, Marseille, France.

Background And Purpose: Patients with a chronic illness, such as multiple sclerosis (MS), and their natural caregivers have a specific experience of healthcare and health services. These experiences need to be assessed to evaluate the quality of care. Our objective was to develop a French-language questionnaire to evaluate the quality of care as experienced by MS patients and their natural caregivers.

Methods: Eligible patients had been diagnosed with MS according to the McDonald criteria. Eligible caregivers were individuals designated by the patients. The MusiCare questionnaire was developed in two standard phases: (i) item generation, based on interviews with patients and caregivers; and (ii) validation, consisting of validity, reliability, external validity, reproducibility, and responsiveness measures.

Results: In total, 1088 patients (n = 660) and caregivers (n = 488) were recruited. The initial 64-item version of MusiCare was administered to a random subsample (n = 748). The validation process generated a 35-item questionnaire. Internal consistency and scalability were satisfactory. Testing of the external validity revealed expected associations between MusiCare scores and sociodemographic and clinical data. The questionnaire showed good reproducibility and responsiveness.

Conclusions: The availability of a reliable and validated French-language self-report questionnaire probing the experience of the quality of care for MS will allow the feedback of patients and caregivers to be incorporated into a continuous healthcare quality-improvement strategy.
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http://dx.doi.org/10.1111/ene.14685DOI Listing
March 2021

Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study.

Mult Scler 2021 Aug 3;27(9):1458-1463. Epub 2020 Dec 3.

INSERM U 1195, Le Kremlin-Bicêtre, France.

Background: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy.

Objective: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo.

Methods: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo.

Results: Recruitment was stopped prematurely due to slow inclusions ( = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58-1.39), placebo = 0.97 (0.63-1.50) ( = 0.79)).

Conclusion: POPARTMUS failed showing efficacy of a NOMAc-E2 combination in preventing post-partum relapses.
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http://dx.doi.org/10.1177/1352458520978218DOI Listing
August 2021

Relapses in Patients Treated with High-Dose Biotin for Progressive Multiple Sclerosis.

Neurotherapeutics 2021 01 22;18(1):378-386. Epub 2020 Sep 22.

CHU de Clermont-Ferrand, F-63000, Clermont-Ferrand, France.

High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Several reports have suggested that HDB treatment may be associated with an increased risk of relapse. We aimed to determine whether HDB increases the risk of clinical relapse in PMS and describe the characteristics of the patients who experience it. We conducted a French, multicenter, retrospective study, comparing a group of PMS patients treated with HDB to a matched control group. Poisson regression was applied to model the specific statistical distribution of the annualized relapse rate (ARR). A propensity score (PS), based on the inverse probability of treatment weighting (IPTW), was used to adjust for indication bias and included the following variables: gender, primary PMS or not, age, EDSS, time since the last relapse, and co-prescription of a DMT. Two thousand six hundred twenty-eight patients treated with HDB and 654 controls were analyzed with a follow-up of 17 ± 8 months. Among them, 148 validated relapses were observed in the group treated with biotin and 38 in the control group (p = 0.62). After adjustment based on the PS, the ARR was 0.044 ± 0.23 for the biotin-treated group and 0.028 ± 0.16 for the control group (p = 0.18). The more relapses there were before biotin, the higher the risk of relapse during treatment, independently from the use of HDB. While the number of relapses reported for patients with no previous inflammatory activity receiving biotin has gradually increased, the present retrospective study is adequately powered to exclude an elevated risk of relapse for patients with PMS treated with HDB.
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http://dx.doi.org/10.1007/s13311-020-00926-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116391PMC
January 2021

T1-Based Synthetic Magnetic Resonance Contrasts Improve Multiple Sclerosis and Focal Epilepsy Imaging at 7 T.

Invest Radiol 2021 Feb;56(2):127-133

Pôle de Neurosciences Cliniques, Service de Neurophysiologie, APHM, Hôpital de la Timone, Marseille, France.

Objectives: Ultra-high field magnetic resonance imaging (MRI) (≥7 T) is a unique opportunity to improve the clinical diagnosis of brain pathologies, such as multiple sclerosis or focal epilepsy. However, several shortcomings of 7 T MRI, such as radiofrequency field inhomogeneities, could degrade image quality and hinder radiological interpretation. To address these challenges, an original synthetic MRI method based on T1 mapping achieved with the magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) sequence was developed. The radiological quality of on-demand T1-based contrasts generated by this technique was evaluated in multiple sclerosis and focal epilepsy imaging at 7 T.

Materials And Methods: This retrospective study was carried out from October 2017 to September 2019 and included 21 patients with different phenotypes of multiple sclerosis and 35 patients with focal epilepsy who underwent MRI brain examinations using a whole-body investigative 7 T magnetic resonance system. The quality of 2 proposed synthetic contrast images were assessed and compared with conventional images acquired at 7 T using the MP2RAGE sequence by 4 radiologists, evaluating 3 qualitative criteria: signal homogeneity, contrast intensity, and lesion visualization. Statistical analyses were performed on reported quality scores using Wilcoxon rank tests and further multiple comparisons tests. Intraobserver and interobserver reliabilities were calculated as well.

Results: Radiological quality scores were reported higher for synthetic images when compared with original images, regardless of contrast, pathologies, or raters considered, with significant differences found for all 3 criteria (P < 0.0001, Wilcoxon rank test). None of the 4 radiologists ever rated a synthetic image "markedly worse" than an original image. Synthetic images were rated slightly less satisfying for only 3 epileptic patients, without precluding lesion identification.

Conclusion: T1-based synthetic MRI with the MP2RAGE sequence provided on-demand contrasts and high-quality images to the radiologist, facilitating lesion visualization in multiple sclerosis and focal epilepsy, while reducing the magnetic resonance examination total duration by removing an additional sequence.
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http://dx.doi.org/10.1097/RLI.0000000000000718DOI Listing
February 2021

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

Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond?

Neurol Neuroimmunol Neuroinflamm 2020 09 25;7(5). Epub 2020 Jun 25.

From the Service de Neurologie, Pôle de Neurosciences Cliniques, APHM, Hôpital de la Timone, Aix Marseille Univ, France.

Objective: To evaluate disease activity in patients with relapsing-remitting MS (RRMS) receiving rituximab with an extended dosing interval.

Methods: In the context of COVID-19 pandemic, this was an interim analysis of an ongoing prospective observational study of patients who were stable on rituximab for at least 6 months and who had a planned extended dosing interval of 24 months. Only data for patients with active RRMS before rituximab were analyzed.

Results: Among 177 patients receiving rituximab, 33 had RRMS and MRI activity before rituximab and at least 8 months of follow-up after the last infusion. The mean (SD) age was 40 (14) years, 25 were females, the mean disease duration was 10 (6.8) years, the mean annual relapse rate (ARR) before rituximab was 1.7 (1.3), and the median Expanded Disability Status Scale (EDSS) score before rituximab was 4.5 (1-7). Before extended dosing, when rituximab was infused every 6 months, the mean (SD) ARR decreased to 0.04 (0.1) ( < 0.0001) and the EDSS score to 4 (0-7) ( = 0.04). At the time of this analysis, the median follow-up since the last infusion was 11 (8-31) months. No patient showed relapse or disability progression. In total, 30 patients had at least 1 MRI performed since the last infusion (median time between the last MRI and the last infusion 10 [8-31] months). No MRI showed activity. The CD19 cell proportion was >1% for 10 of 25 patients at the last count (median time 8 [6-25] months).

Conclusions: An extended dosing interval for rituximab for patients with stable MS during the COVID-19 pandemic may be associated with a low risk of disease activity.
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http://dx.doi.org/10.1212/NXI.0000000000000825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357416PMC
September 2020

Fatal underhanded chronic enterovirus infection associated with anti-CD20 monotherapy for central nervous system demyelinating disease.

Mult Scler 2021 02 25;27(2):320-323. Epub 2020 Jun 25.

Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France; Laboratoire de microbiologie (Assistance Publique - Hôpitaux de Marseille; IHU Méditerranée Infection) Marseille, France.

We report a fatal case of coxsackievirus B4 chronic infection in a 30-year-old woman with a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disorder controlled by rituximab monotherapy for 3 years. Initially presenting as self-limited meningitis, the infection remained silent for 8 months before the sudden onset of fulminant myocarditis. Analysis of the complete genome showed that the same virus was responsible for both episodes.
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http://dx.doi.org/10.1177/1352458520923978DOI Listing
February 2021

Multiple sclerosis lesions in motor tracts from brain to cervical cord: spatial distribution and correlation with disability.

Brain 2020 07;143(7):2089-2105

Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.

Despite important efforts to solve the clinico-radiological paradox, correlation between lesion load and physical disability in patients with multiple sclerosis remains modest. One hypothesis could be that lesion location in corticospinal tracts plays a key role in explaining motor impairment. In this study, we describe the distribution of lesions along the corticospinal tracts from the cortex to the cervical spinal cord in patients with various disease phenotypes and disability status. We also assess the link between lesion load and location within corticospinal tracts, and disability at baseline and 2-year follow-up. We retrospectively included 290 patients (22 clinically isolated syndrome, 198 relapsing remitting, 39 secondary progressive, 31 primary progressive multiple sclerosis) from eight sites. Lesions were segmented on both brain (T2-FLAIR or T2-weighted) and cervical (axial T2- or T2*-weighted) MRI scans. Data were processed using an automated and publicly available pipeline. Brain, brainstem and spinal cord portions of the corticospinal tracts were identified using probabilistic atlases to measure the lesion volume fraction. Lesion frequency maps were produced for each phenotype and disability scores assessed with Expanded Disability Status Scale score and pyramidal functional system score. Results show that lesions were not homogeneously distributed along the corticospinal tracts, with the highest lesion frequency in the corona radiata and between C2 and C4 vertebral levels. The lesion volume fraction in the corticospinal tracts was higher in secondary and primary progressive patients (mean = 3.6 ± 2.7% and 2.9 ± 2.4%), compared to relapsing-remitting patients (1.6 ± 2.1%, both P < 0.0001). Voxel-wise analyses confirmed that lesion frequency was higher in progressive compared to relapsing-remitting patients, with significant bilateral clusters in the spinal cord corticospinal tracts (P < 0.01). The baseline Expanded Disability Status Scale score was associated with lesion volume fraction within the brain (r = 0.31, P < 0.0001), brainstem (r = 0.45, P < 0.0001) and spinal cord (r = 0.57, P < 0.0001) corticospinal tracts. The spinal cord corticospinal tracts lesion volume fraction remained the strongest factor in the multiple linear regression model, independently from cord atrophy. Baseline spinal cord corticospinal tracts lesion volume fraction was also associated with disability progression at 2-year follow-up (P = 0.003). Our results suggest a cumulative effect of lesions within the corticospinal tracts along the brain, brainstem and spinal cord portions to explain physical disability in multiple sclerosis patients, with a predominant impact of intramedullary lesions.
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http://dx.doi.org/10.1093/brain/awaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364770PMC
July 2020

Effect of hyperglycemia on stroke outcome is not homogeneous to all patients treated with mechanical thrombectomy.

Clin Neurol Neurosurg 2020 07 26;194:105750. Epub 2020 Feb 26.

Stroke Unit - University Hospital of Marseille (France), La Timone Hospital, 278 Rue Saint-Pierre, 13005 Marseille, France.

Objectives: Admission hyperglycemia is a penumbra-modifying factor that is associated with poor functional outcome in acute ischemic stroke (AIS) patients treated with intravenous rt-PA and/or mechanical thrombectomy (MT). Insulin therapy has failed to demonstrate a clinical benefit and the question of the patient selection remains under debate. We assessed the relationship between admission glycemia (AG) and functional outcome in AIS patients treated by MT according to both penumbra characteristics and reperfusion status.

Patients And Methods: We performed a retrospective analysis of a multi-center registry of consecutive AIS (NIHSS ≥ 10) due to middle cerebral artery occlusion treated by MT (± tissue Plasminogen Activator (tPA)). To evaluate the association between AG and the 3-month functional outcome (modified Rankin Scale (mRS) ≤2), univariable and multivariable analyses were used. Subgroup analyses were performed according to both clinical-ASPECTS Mismatch (CAM2) and the complete recanalization (CR) status defined by a mTICI scale (modified Thrombolysis in Cerebral Infarction) 2b/3.

Results: 216 AIS patients were included (Median Age: 68.43[58.12-77.95], median NIHSS: 18[15-21]). 104/216 (48.15%) patients had mRS≤2 at 3 months. AG was an independent predictor of functional outcome (/1 g/L OR: 0.10[0.03-0.37]) after adjusting for potential cofounders. Among subgroups formed by combining CAM2 and CR, AG was found to be predictor of functional outcome only in CAM2/CR and specifically when recanalization was early.

Conclusion: This study highlights the fact that the relationship between AG and prognosis is not homogeneous for all patients and indicates that AG has a deleterious effect on the ischemic penumbra, thus explaining its statistical association with functional outcome. Stroke neuroprotection by targeting hyperglycemia should be considered in acute stroke patients with mismatch and early complete recanalization. More prospective randomized trials are needed to generalize the conclusions.
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http://dx.doi.org/10.1016/j.clineuro.2020.105750DOI Listing
July 2020

Maintenance of natalizumab during the first trimester of pregnancy in active multiple sclerosis.

Mult Scler 2021 04 23;27(5):712-718. Epub 2020 Mar 23.

Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Aix-Marseille University, Marseille, France.

Background: Planning pregnancy in patients with active multiple sclerosis (MS) is highly challenging because treatment withdrawn may be associated with dramatic disease reactivation.

Objective: To compare two strategies for women with active MS who were planning pregnancy: stopping natalizumab (1) at the end of the first trimester and (2) at conception.

Methods: Standardized strategy for women with active MS was initiated in our department. Maintenance of natalizumab until the end of first trimester was recommended ("secured first trimester" (SFT)). When patients refused, they were advised to continue until conception ("secured conception" (SC)). Predictors of disease activity during pregnancy were assessed.

Results: Forty-six pregnancies were prospectively followed (30 with SFT and 16 with SC). One congenital anomaly occurred in the SC group. The proportions of patients with relapse and disability progression during pregnancy were lower in the SFT than in the SC group (3.6% vs 38.5%,  < 0.005 and 3.6% vs 30.8%,  < 0.05, respectively). Predictors of relapse and disability progression during pregnancy were the time when natalizumab was stopped (conception vs end of first trimester) and the number of relapses during the year before natalizumab.

Conclusion: Maintaining natalizumab during the first trimester may reduce the risk of disease reactivation during pregnancy in patients with active MS.
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http://dx.doi.org/10.1177/1352458520912637DOI Listing
April 2021

Comparison of rituximab originator (MabThera) to biosimilar (Truxima) in patients with multiple sclerosis.

Mult Scler 2021 04 17;27(4):585-592. Epub 2020 Mar 17.

Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Aix-Marseille University, Marseille, France.

Background: Rituximab's originator MabThera or Rituxan has demonstrated high efficacy in multiple sclerosis (MS). Because of the patent expiration, rituximab biosimilars have been developed. However, because a biosimilar is not the exact copy of the originator, the efficacy and safety of a biosimilar may significantly differ.

Objectives: To compare the efficacy and safety of the biosimilar Truxima and the originator MabThera in MS.

Methods: Consecutive MS patients receiving MabThera or Truxima were prospectively followed during 1 year after treatment introduction. Allocation to each treatment depended on the period of introduction and not the physician's choice. Lymphocyte count, clinical and magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS), and adverse events were compared.

Results: In total, 105 and 40 patients received MabThera and Truxima, respectively. The two groups did not differ in baseline characteristics. Effect on CD19+ lymphocytes and disease activity were similar during follow-up. EDSS remained stable, with no difference between groups. Adverse events were similar between groups.

Conclusion: The efficacy and safety of the rituximab biosimilar Truxima seem equivalent to the originator MabThera in MS patients. Truxima could represent a relatively cheap and safe therapeutic alternative to MabThera and could improve access to highly efficient therapy for MS in low- or middle-income countries.
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http://dx.doi.org/10.1177/1352458520912170DOI Listing
April 2021

Comparison of the Response to Rituximab between Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 Antibody Diseases.

Ann Neurol 2020 02 27;87(2):256-266. Epub 2019 Nov 27.

Public Assistance Hospitals of Marseille, Department of Neurology, Timone Hospital, Marseille.

Objective: To compare response to rituximab (RTX) between adult patients positive for myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibodies.

Methods: We prospectively studied adult patients with MOG or AQP4 antibodies who received RTX under an individualized dosing schedule adapted to the biological effect of RTX monitored by memory B-cell measurement. Memory B cells were counted monthly and when relapse occurred. The biological effect of RTX was considered significant with <0.05% memory B cells in peripheral blood lymphocytes.

Results: In 16 patients with MOG antibodies and 29 with AQP4 antibodies, mean follow-up was 19 (range = 9-38) and 38 (13-79) months. Under RTX, 10 relapses occurred in 6 of 16 (37.5%) patients with MOG antibodies, and 13 occurred in 7 of 29 (24%) with AQP4 antibodies. The median time of relapse after the most recent infusion was 2.6 (0.6-5.8) and 7 (0.8-13) months, respectively (p < 0.001). Memory B cells had reemerged in 2 of 10 (20%) relapses in patients with MOG antibodies and 12 of 13 (92.5%) with AQP4 antibodies (p < 0.001).

Interpretation: In AQP4 antibody-associated disorder, relapse mostly occurs when the biological effect of RTX decreases, which argues for treatment efficacy. In MOG antibody-associated disorder, the efficacy of RTX is not constant, because one-third of patients showed relapse despite an effective biological effect of RTX. In this subpopulation, memory B-cell depletion was unable to prevent relapse, which was probably caused by different immunological mechanisms. These findings should be used to improve treatment strategies for MOG antibody-associated disorder. ANN NEUROL 2020;87:256-266.
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http://dx.doi.org/10.1002/ana.25648DOI Listing
February 2020

Prospective validation of the PML risk biomarker l-selectin and influence of natalizumab extended intervals.

Neurology 2019 09 22;93(12):550-554. Epub 2019 Aug 22.

From the Department of Neurology with Institute of Translational Neurology (N.S., T.S.-H., P.O., L.K., C.C.G., S.G.M., H.W.), University of Münster, Münster, Germany; CRC-SEP-Neurosciences Department (B.P., F.B., L.S., J.C., D. Biotti, D. Brassat), CHU Toulouse, Toulouse, France; CPTP-INSERM U1043-CNRS U5282-Université Toulouse III (B.P., F.B., L.S., D. Brassat), Toulouse, France; APHM (C.L.-F.), Hôpital de la Timone, Pôle de Neurosciences Cliniques, Marseille, France; CHU of Nice (G.M.), Nice, France; CHU Montpied, Neurology, Clermont-Ferrand, France (P.C.); APHM (J.P.), Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, CRCSEP Marseille, France; Institute of Clinical Neuroimmunology (I.M.), Ludwig-Maximilians University, Munich, Germany; Department of Neurology (S.W.), Clinics Osnabrück, Osnabrück, Germany; and Department of Neurology (F.G.), Innsbruck Medical University, Innsbruck, Austria.

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http://dx.doi.org/10.1212/WNL.0000000000008135DOI Listing
September 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

Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS.

Mult Scler 2019 04 20;25(4):591-600. Epub 2018 Mar 20.

Service de Neurologie A, Hôpital Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France/Observatoire Français de la Sclérose en Plaques (OFSEP), Lyon, France/Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR5292, Equipe Neuro-Oncologie et Neuro-Inflammation, Lyon, France/Université de Lyon 1, Lyon, France.

Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses.

Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy.

Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992-1995 and 2005-2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis.

Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78).

Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.
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http://dx.doi.org/10.1177/1352458518763080DOI Listing
April 2019

CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS.

J Neurol Neurosurg Psychiatry 2019 09 9;90(9):1027-1038. Epub 2019 May 9.

Department of Neurology, University Hospital of Montpellier, Montpellier, France.

Objective: To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).

Methods: We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria.

Results: After a median follow-up of 50 months (IQR 25-82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma.

Conclusions: Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.
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http://dx.doi.org/10.1136/jnnp-2018-318957DOI Listing
September 2019
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