Publications by authors named "Christine Lebrun-Frenay"

71 Publications

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome.

JAMA Netw Open 2021 Oct 1;4(10):e2128271. Epub 2021 Oct 1.

Centre de Resssource et Competence Sclérose En Plaques Nice, Unité Recherche Clinique Cote d'Azur Unité de Recherche sur le Syndrome Radiologique Isolé, Université Nice Côte d'Azur, Neurologie Centre Hospitalier Universitaire Pasteur 2, Nice, France.

Importance: Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown.

Objectives: To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria.

Design, Setting, And Participants: This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021.

Exposure: Diagnosis of RIS.

Main Outcomes And Measures: Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors.

Results: Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96]; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%.

Conclusions And Relevance: This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.28271DOI Listing
October 2021

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

The multiple sclerosis prodrome is just unspecific symptoms in radiologically isolated syndrome patients - No.

Mult Scler 2021 Oct 8;27(12):1824-1826. Epub 2021 Sep 8.

CRCSEP, UR2CA-URRIS Neurology, CHU Pasteur 2, Nice Cote d'Azur University, Nice, France.

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http://dx.doi.org/10.1177/13524585211035951DOI Listing
October 2021

Should we still only rely on EDSS to evaluate disability in multiple sclerosis patients? A study of inter and intra rater reliability.

Mult Scler Relat Disord 2021 Sep 9;54:103144. Epub 2021 Jul 9.

URRIS, Unité de Recherche Clinique Cote d'Azur - UR2CA- CRCSEP - Hôpital Pasteur 2 Neurologie, 30 Voie Romaine, 06002 Nice, France.

Background: Few studies assessed reliability and inter-rater variability of EDSS and functional parameters (FP) rating.

Objective: To evaluate inter-rater variability and errors in EDSS and FP rating in junior (JN) and MS Neurologists (MSN).

Method: Patients with MS were examined by a JN and a MSN on the same day. Each assessor rated FP and EDSS, then used a smartphone app to get an automated calculation for each FP ("smartphone" FP, sFP) and for EDSS ("smartphone" EDSS, sEDSS) from the description of the neurological exam. Inter-rater variability was assessed comparing JN and MSN ratings for each method. Intra-rater variability was assessed comparing traditional and digital rating for a given assessor.

Result: 103 patients were included. Perfect agreement between JN and MSN was met for 67% and 70% of patients regarding EDSS and sEDSS. Disagreement that could lead to a significant difference in terms of level of disability occurred in 17% for EDSS and 12% for sEDSS (p=0.07). Regarding intra-rater reliability, we found 38 rating discrepancies for JN and 14 for MSN (p=0.04).

Conclusion: We found a significant inter-rater variability as well as a substantial frequency of rating errors in JN. The use of less subjective, easier-to-rate scales should be encouraged.
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http://dx.doi.org/10.1016/j.msard.2021.103144DOI Listing
September 2021

How to switch disease-modifying treatments in multiple sclerosis: Guidelines from the French Multiple Sclerosis Society (SFSEP).

Mult Scler Relat Disord 2021 Aug 10;53:103076. Epub 2021 Jun 10.

Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Background: Today, there are no recommendations on switching disease-modifying treatments (DMTs) in multiple sclerosis (MS).

Objectives: To establish guidelines on switching DMTs MS.

Methods: A Steering Committee composed of seven MS experts from the French Group for Recommendations in Multiple Sclerosis (France4MS) defined 15 proposals. These proposals were then submitted to a Rating Group, composed of 48 French MS experts, for evaluation. The proposals were classified as 'appropriate', 'inappropriate' or 'uncertain'.

Results: Switching from a first-line therapy to another first-line therapy or a second-line therapy could be done without a washout period. Switching from a second-line therapy to a first-line therapy could be done without a washout period with fingolimod or natalizumab, after 3 months with ocrelizumab or mitoxantrone, and, if disease activity occurs with alemtuzumab or cladribine. The switch from a second-line therapy to another second-line therapy could be done after a washout period of 1 month with fingolimod or natalizumab, after 3 months with ocrelizumab, after 6 months with mitoxantrone, and, if disease activity occurs, with alemtuzumab or cladribine.

Conclusion: This expert consensus approach provides physicians with some guidelines on optimizing the benefit/risk ratio when switching DMTs in patients with MS.
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http://dx.doi.org/10.1016/j.msard.2021.103076DOI Listing
August 2021

Cerebrospinal Fluid IL-17A Could Predict Acute Disease Severity in Non-NMDA-Receptor Autoimmune Encephalitis.

Front Immunol 2021 13;12:673021. Epub 2021 May 13.

URRIS, Unité de Recherche Clinique Cote d'Azur-UR2CA, CRCSEP, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France.

Introduction: Most of our knowledge into autoimmune encephalitis (AE) comes from N-Methyl-D-Aspartate Receptor (NMDAR) encephalitis. The concentrations of cytokines in cerebrospinal fluid (CSF) including IL-17A have been found to be increased and associated with poor outcome. However, data on the cytokine concentration in CSF and its correlation with outcome is lacking for other types of AE.

Objective: To report the concentrations of CSF sIL-2R, IL-6, IL-8, IL-10 and IL-17A and to correlate it with acute disease severity and the 1-year outcome in non-NMDAR AE.

Methods: We measured the CSF concentration of each cytokine in 20 AE patients, and compared IL-6 and IL-17A concentrations with 13 patients with CNS demyelinating diseases and 20 non-inflammatory controls. Patients were > 18yr and had at least 1-year clinical follow-up. Intracellular and NMDAR antibody (Ab) -mediated encephalitis were excluded. A mRS ≤ 2 was retained as a 1-year good outcome.

Results: The IL-17A concentration in CSF was higher in AE patients than in both control groups (<0.01). No difference was observed in CSF concentration of IL-6 between groups. At disease onset, a high CSF IL-17A concentration correlated with a high modified Rankin Scale (<0.05), a high Clinical Assessment Scale for Autoimmune Encephalitis score (<0.001) and ICU admission (<0.01). There was no correlation between the concentration of all CSF cytokines and the 1-year clinical outcome.

Conclusion: Our results show that CSF IL-17A could be interesting to assess initial severity in non-NMDAR AE. Thus, CSF IL-17A could be an interesting therapeutic target and be useful to assess early selective immunosuppressive therapy.
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http://dx.doi.org/10.3389/fimmu.2021.673021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158812PMC
May 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

Multiple sclerosis: Is there a risk of worsening after yellow fever vaccination?

Mult Scler 2021 Apr 19:13524585211006372. Epub 2021 Apr 19.

Department of Neurology Pitié-Salpêtrière Hospital, APHP-6, Sorbonne University, Paris, France.

Background: Yellow fever vaccine (YFV) is not advised for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses.

Objective: To assess the risk of relapsing-remitting multiple sclerosis (RR-MS) worsening after YFV.

Methods: Non-interventional observational retrospective, exposed/non-exposed cohort study nested in the French national cohort including MS.

Results: 128 RR-MS were included. The 1-year annualized relapse rate (ARR) following YFV did not differ between exposed: 0.219 (0.420) and non-exposed subjects: 0.208 (0.521) ( = 0.92). Time to first relapse was not different between groups (adjusted hazard ratio (HR) = 1.33; 95% confidence interval (CI) = 0.53-3.30, = 0.54).

Conclusion: These results suggest that YFV does not worsen the course of RR-MS.
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http://dx.doi.org/10.1177/13524585211006372DOI Listing
April 2021

Comparison of Simoa and Ella to assess serum neurofilament-light chain in multiple sclerosis.

Ann Clin Transl Neurol 2021 05 8;8(5):1141-1150. Epub 2021 Apr 8.

Department of Neurology, CHU Nîmes, Univ Montpellier, Nîmes, France.

We compared Simoa and Ella immunoassays to assess serum neurofilament-light chain levels in 203 multiple sclerosis patients from the OFSEP HD study. There was a strong correlation (ρ = 0.86, p < 0.0001) between both platforms. The Ella instrument overestimated values by 17%, but as the data were linear (p = 0.57), it was possible to apply a correction factor to Ella results. As for Simoa , serum neurofilament-light chain levels measured by Ella were correlated with age and EDSS and were significantly higher in active multiple sclerosis, suggesting that these assays are equivalent and can be used in routine clinical practice.
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http://dx.doi.org/10.1002/acn3.51355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108418PMC
May 2021

MRI findings in blinded trials should be available to treating physicians - Yes.

Mult Scler 2021 05 29;27(6):812-813. Epub 2021 Mar 29.

CRCSEP Côte d'Azur, URRIS UR2CA, CHU de Nice Pasteur, Nice, France/Université Nice Côte d'Azur, Nice, France.

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http://dx.doi.org/10.1177/1352458520984744DOI Listing
May 2021

Memory B Cells Predict Relapse in Rituximab-Treated Myasthenia Gravis.

Neurotherapeutics 2021 04 25;18(2):938-948. Epub 2021 Mar 25.

Service de Neurologie, Pasteur2, CHU de Nice, Université Côte d'Azur, Nice, France.

Myasthenia gravis can be efficiently treated with rituximab but there is no consensus regarding administration and dose schedules in this indication. No marker has yet been described to predict the clinical relapse of patients. Our objective was to identify the B cell subpopulations predicting clinical relapse in patients suffering from generalized myasthenia gravis and treated with rituximab. Clinical and biological data of 34 patients followed between 2016 and 2019 were prospectively collected every 3 months. Using multiparameter flow cytometry, we assessed the percentage in leucocytes of lymphocytes and several B cell subpopulations measured in residual disease conditions. CD19+ were also measured in non-residual disease conditions. Clinical examinations were performed by neurologists using the Osserman score. Clinical relapse occurred in 14 patients (41%). No patients required ICU or ventilatory assistance. The mean improvement of the Osserman score was 17.18 (3-45) after the first rituximab treatment (p < 0.0001). The mean delay between the first rituximab maintenance cycle and clinical relapse was 386.8 days. At the time of relapse, CD27+ increased (p = 0.0006) with AUC = 0.7654, while CD19+ did not. At a threshold of 0.01%, the sensitivity and specificity of CD19+CD27+ were 75.8% and 72.8%, respectively, and the positive and negative predictive values were 28.0% and 95.6%, respectively. The percentage of memory B cells in whole blood cells can accurately predict clinical relapse in myasthenia gravis patients treated with rituximab. This monitoring allows physicians to tailor rituximab administration and to decrease the number of infusions over time.
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http://dx.doi.org/10.1007/s13311-021-01006-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423951PMC
April 2021

Vaccinations in multiple sclerosis patients receiving disease-modifying drugs.

Curr Opin Neurol 2021 06;34(3):322-328

CRCSEP Côte d'Azur, CHU de Nice Pasteur2, Université Nice Cote d'Azur UR2CA-URRIS, Nice, France.

Purpose Of Review: This review focuses on new evidence supporting the global immunization strategy for multiple sclerosis (MS) patients receiving disease-modifying drugs (DMDs), including the recently available vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Recent Findings: New data strengthen the evidence against a causal link between MS and vaccination. Recent consensus statements agree on the need to start vaccination early. Timings for vaccine administration should be adjusted to ensure safety and optimize vaccine responses, given the potential interference of DMDs. Patients treated with Ocrelizumab (and potentially other B-cell depleting therapies) are at risk of diminished immunogenicity to vaccines. This has relevant implications for the upcoming vaccination against SARS-CoV-2.

Summary: An early assessment and immunization of MS patients allows optimizing vaccine responses and avoiding potential interference with treatment plans. Vaccinations are safe and effective but some specific considerations should be followed when vaccinating before, during, and after receiving immunotherapy. A time-window for vaccination taking into account the kinetics of B cell repopulation could potentially improve vaccine responses. Further understanding of SARS-CoV-2 vaccine response dynamics in MS patients under specific therapies will be key for defining the best vaccination strategy.
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http://dx.doi.org/10.1097/WCO.0000000000000929DOI Listing
June 2021

Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome.

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

From the Department of Neurology (G.T., P.L.), CHU Montpellier, Hospital Gui de Chauliac; Pôle de Neurosciences Cliniques (E.K.), CHU Timone, Assistance Publique Hôpitaux de Marseille; Clinical Research and Epidemiology Unit (C.D.), CHU Montpellier, University Montpellier; Unité de recherche clinique côte d'azur UR2CA (URRIS) (C.L.-F.), CRCSEP Nice; Department of Pathology (V.R.), CHU Montpellier, Hospital Gui de Chauliac; Department of Neurology (E.T.), CHU Carémeau, Nîmes; Department of Neurology (E.D.-G.), CH Valenciennes; Department of Neurology (R.L.), Rouen University Hospital; APHP (K.H.-X.), Sorbonne Université, IHU, ICM, Department of Neurology Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris; Department of Neurology (S.C.), CH Gonesse; Department of Neurology (J.C.O.), CHU de Bordeaux; Department of Neuroradiology (N.M.C.), CHU Montpellier, Hospital Gui de Chauliac; Department of Neurology (C.T.), CHU Strasbourg; Université de Paris (C.P., M.F., F.E.S., G.S.B.), Imagine Institute, INSERM U 1163; Centre d'Etude des Déficits Immunitaires (C.P., M.F., G.S.B.), AP-HP, Hôpital Necker-Enfants Malades, Paris; and Centre national de la recherche scientifique (CNRS) (F.E.S.), Paris, France.

Objective: To determine whether adult cases of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) may be related to familial hemophagocytic lymphohistiocytosis (HLH) causes, we have screened patients with adult-onset CLIPPERS for mutations in primary HLH-associated genes.

Methods: In our cohort of 36 patients fulfilling the criteria for probable or definite CLIPPERS according to the CLIPPERS-2017 criteria, we conducted a first study on 12 patients who consented to genetic testing. In these 12 patients, systemic HLH criteria were searched, and genetic analysis of 8 genes involved in primary HLH was performed.

Results: Four definite and 8 probable CLIPPERS were enrolled (n = 12). Mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS (4/12). Three of them had biallelic mutations with reduced perforin expression in natural killer cells. The remaining patient had biallelic mutations with cytotoxic lymphocyte impaired degranulation. None of the mutated patients reached the criteria for systemic HLH. During follow-up, 3 of them displayed atypical findings for CLIPPERS, including emergence of systemic non-Hodgkin lymphoma (1/3) and confluent gadolinium-enhancing lesions on brain MRI (3/3).

Conclusions: In our patients presenting with adult-onset CLIPPERS, one-third have HLH gene mutations. This genetic treatable condition should be searched in patients with CLIPPERS, especially in those presenting with atypical findings.
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http://dx.doi.org/10.1212/NXI.0000000000000970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963436PMC
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

Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV.

JAMA Netw Open 2021 01 4;4(1):e2031190. Epub 2021 Jan 4.

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey.

Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date.

Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide.

Design, Setting, And Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019.

Main Outcomes And Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status.

Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004).

Conclusions And Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.31190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811179PMC
January 2021

Determinants of therapeutic lag in multiple sclerosis.

Mult Scler 2021 Oct 11;27(12):1838-1851. 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
October 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

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

Mult Scler 2021 Sep 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

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

Effects on Melanoma Cell Lines Suggest No Significant Risk of Melanoma Under Cladribine Treatment.

Neurol Ther 2020 Dec 25;9(2):599-604. Epub 2020 Jul 25.

Université Côte d'Azur, INSERM, C3M, Nice, France.

Cladribine is an oral synthetic purine analog that depletes lymphocytes and induces a dose-dependent reduction of T and B cells. It was approved for the therapy of highly active relapsing-remitting multiple sclerosis. Given cladribine's mechanism of action, an increased risk of malignancies was suspected from the number of cancers that occurred in the 3.5 mg/kg-treated arm (CLARITY study). We showed that cladribine inhibits cell proliferation on three melanoma cell lines tested, irrespectively of their mutational oncogenic status and invasive/metastatic potential. Aggregated safety data demonstrated that the risk of melanoma is not confirmed.
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http://dx.doi.org/10.1007/s40120-020-00204-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606413PMC
December 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

Radiologically Isolated Syndrome: 10-Year Risk Estimate of a Clinical Event.

Ann Neurol 2020 08 29;88(2):407-417. Epub 2020 Jun 29.

University of Texas Southwestern Medical Center, Dallas, TX, USA.

Objective: We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5-year risk for evolution from radiologically isolated syndrome (RIS) to multiple sclerosis. Here, we investigate risk factors for the development of a clinical event using a 10-year, multinational, retrospectively identified RIS dataset.

Methods: RIS subjects were identified according to 2009 RIS criteria and followed longitudinally as part of a worldwide cohort study. We analyzed data from 21 individual databases from 5 different countries. Associations between clinical and magnetic resonance imaging (MRI) characteristics and the risk of developing a first clinical event were determined using multivariate Cox regression models.

Results: Additional follow-up data were available in 277 of 451 RIS subjects (86% female). The mean age at RIS diagnosis was 37.2 years (range, 11-74 years), with a median clinical follow-up of 6.7 years. The cumulative probability of a first clinical event at 10 years was 51.2%. Age, positive cerebrospinal fluid for oligoclonal bands, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium-enhanced lesions during follow-up was also associated with the risk of a seminal event. The reason for MRI and gadolinium-enhancing lesions at baseline did not influence the risk of a subsequent clinical event.

Interpretation: Approximately half of all individuals with RIS experience a first clinical event within 10 years of the index MRI. The identification of independent predictors of risk for symptom onset may guide education and clinical management of individuals with RIS. ANN NEUROL 2020;88:407-417.
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http://dx.doi.org/10.1002/ana.25799DOI Listing
August 2020

Outcome and risk of recurrence in a large cohort of idiopathic longitudinally extensive transverse myelitis without AQP4/MOG antibodies.

J Neuroinflammation 2020 Apr 23;17(1):128. Epub 2020 Apr 23.

Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, and Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677, Lyon/Bron, France.

Background: Longitudinally extensive transverse myelitis (LETM) is classically related to aquaporin (AQP4)-antibodies (Ab) neuromyelitis optica spectrum disorders (NMOSD) or more recently to myelin oligodendrocyte glycoprotein (MOG)-Ab associated disease. However, some patients remain negative for any diagnosis, despite a large work-up including AQP4-Ab and MOG-Ab. Data about natural history, disability outcome, and treatment are limited in this group of patients. We aimed to (1) describe clinical, biological, and radiological features of double seronegative LETM patients; (2) assess the clinical course and identify prognostic factors; and (3) assess the risk of recurrence, according to maintenance immunosuppressive therapy.

Methods: Retrospective evaluation of patients with a first episode of LETM, tested negative for AQP-Ab and MOG-Ab, from the French nationwide observatory study NOMADMUS.

Results: Fifty-three patients (median age 38 years (range 16-80)) with double seronegative LETM were included. Median nadir EDSS at onset was 6.0 (1-8.5), associated to a median EDSS at last follow-up of 4.0 (0-8). Recurrence was observed in 24.5% of patients in the 18 following months, with a median time to first relapse of 5.7 months. The risk of recurrence was lower in the group of patients treated early with an immunosuppressive drug (2/22, 9%), in comparison with untreated patients (10/31, 32%).

Conclusions: A first episode of a double seronegative LETM is associated to a severe outcome and a high rate of relapse in the following 18 months, suggesting that an early immunosuppressive treatment may be beneficial in that condition.
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http://dx.doi.org/10.1186/s12974-020-01773-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178729PMC
April 2020

Validation of a rapid and easy-to-perform screening test for neurocognitive impairment in HIV+ patients.

J Neurol Sci 2020 Mar 28;410:116664. Epub 2019 Dec 28.

Centre de Ressources et de Compétences sclérose en plaques (CRCSEP), Department of Neurology, Pasteur 2 Hospital, Côte d'Azur University of Nice, France.

Objective: Information Processing Speed (IPS) is one of the earliest cognitive domains impaired in both multiple sclerosis (MS) and HIV-infected patients. Our aim was to study whether the Computerized Speed Cognitive Test (CSCT), an ultra-rapid tool which detects IPS impairment and is already used in MS subjects, could also be useful to screen for HIV-associated neurocognitive disorders (HAND).

Methods: The Neuracog study was an open-label prospective trial conducted in Nice and Cannes hospitals. Each patient performed a wide range of neuropsychological (NP) tests. Patients were defined as no-HAND or HAND. Groups were compared to measure sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CSCT for detecting HAND.

Results: Eighty-six subjects were included (26 women, 60 men, mean age: 53.1 years). HAND was diagnosed in 67/86 patients. The CSCT z-score showed a highly significant difference between the no-HAND and the HAND groups (No HAND mean: -0.1, SD: 1.0 versus HAND mean: -1.1, SD: 1.6; p = .002). The sensitivity, specificity, PPV and NPV were 81%, 53%, 86% and 43%, respectively.

Conclusions: The CSCT is an easy-to-perform test allowing detection of mild forms of HAND, to be considered among screening tools for neurocognitive impairment.
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http://dx.doi.org/10.1016/j.jns.2019.116664DOI Listing
March 2020

Complementary and alternative medicine use in glioma patients in France.

J Neurooncol 2019 Dec 21;145(3):487-499. Epub 2019 Oct 21.

Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland.

Purpose: Complementary and alternative medicine (CAM) use increases in cancer patients, including adult patients with diffuse gliomas.

Methods: Questionnaires addressing CAM use were distributed to adult patients with gliomas of WHO grades II-IV and ECOG performance score of 0-2 during hospital visits and filled in anonymously. The study was conducted in nine centers in France from May 2017 to May 2018. Descriptive cohort analyses and comparative analyses according to gender, age, WHO grade, and recurrent versus newly diagnosed disease were conducted.

Results: Two hundred twenty-seven questionnaires were collected; 135 patients (59%) were male. Median age was 48 years, 105 patients (46%) declared having glioblastoma, 99 patients (43%) declared having recurrent disease. Hundred-three patients (45%) had modified their alimentary habits after the glioma diagnosis. At the time of the questionnaire, 100 patients (44%) were on complementary treatment, mainly vitamins and food supplements, and 73 patients (32%) used alternative medicine approaches, mainly magnetism and acupuncture. In total, 154 patients (68%) declared using at least one of these approaches. Expenditures exceeding 100 € per month were reported by users in 14% for modification of alimentary habits, in 25% for complementary treatment, and in 18% for alternative medicines. All approaches were commonly considered as improving quality of life and experienced as efficient, notably those associated with more expenditures.

Conclusions: CAM are frequently used by glioma patients in France. Underlying needs and expectations, as well as potential interactions with tumor-specific treatments, and financial and quality of life burden, should be discussed with patients and caregivers.
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http://dx.doi.org/10.1007/s11060-019-03315-8DOI Listing
December 2019

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France.

JAMA Neurol 2020 01;77(1):94-102

Department of Neurology, Assistance Publique des Hôpitaux de Paris, Hôpital Henri Mondor, Université Paris Est, Créteil, France.

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated.

Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013.

Design, Setting, And Participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018.

Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation.

Main Outcomes And Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016).

Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016.

Conclusions And Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.
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http://dx.doi.org/10.1001/jamaneurol.2019.2670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724170PMC
January 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

Immunoglobulin G4-related hypertrophic pachymeningitis: A case-oriented review.

Neurol Neuroimmunol Neuroinflamm 2019 07 7;6(4):e568. Epub 2019 May 7.

Service de Médecine Interne (M.L., N.M.), Hôpital l'Archet 1, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur; Service de Cytologie Pathologique (F.B.-V.), Hôpital l'Archet 1, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur; and Service de Neurologie (M.C., S.B., C.G., V.B., C.L.-F.), Service de Radiologie (L.M.), Service de Radiologie Interventionnelle (J.S.), and Service de Neurochirurgie (D.F.), Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, France.

Objective: Meningeal involvement in Immunoglobulin G (IgG)-4-related disease is rare and only described in case reports and series. Because a review into the disease is lacking, we present 2 cases followed by a literature review of IgG4-related hypertrophic pachymeningitis (IgG4-HP).

Methods: Two IgG4-HP cases were reported, one involving the spinal cord and responding to surgical management and a second involving the brain and responding to Rituximab therapy. We then review clinical cases and case-series of histologically proven IgG4-HP that were published in the PubMed-NCBI database.

Results: Forty-two case reports and 5 case-series were studied (60 patients, 20 women). The median age was 53. Eighteen patients had systemic involvement and 24 had single-organ IgG4-HP. Fifty-five percent of patients had an elevated serum IgG4. Treatment was surgical in 20/53 cases. Steroid therapy and immunosuppressors were effective in 85% and more than 90% of the cases, respectively. The rate of disease relapse was 42.1% after steroid therapy was discontinued.

Discussion/conclusion: IgG4-HP is characterized by the lack of extra-neurologic organ-involvement and systemic signs. Histopathologic studies should be performed as it is crucial for diagnosis because serum markers are rarely informative. 18F-FDG positon tomography can be useful to characterize systemic forms. There is no specific CSF marker for IgG4-HP and the diagnostic value of CSF IgG4 levels needs to be studied with larger samples. We provide a treatment algorithm for IgG4-HP. Such treatment strategies rely on early surgery, steroids, and early immunosuppressive therapy to prevent neurologic complications.
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http://dx.doi.org/10.1212/NXI.0000000000000568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624094PMC
July 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

Impact of executive dysfunction on naming ability in multiple sclerosis.

Rev Neurol (Paris) 2019 Oct 17;175(9):552-559. Epub 2019 Jun 17.

Service neurologie, Zone C1, pôle neurosciences cliniques, centre de ressources et compétences SEP (CRC SEP), neurologie, université Nice Côte d'Azur, hôpital Pasteur 2, centre hospitalier universitaire de Nice, CHU Pasteur 2, 30, voie Romaine, 06001 Nice cedex 1, France.

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http://dx.doi.org/10.1016/j.neurol.2019.02.008DOI Listing
October 2019
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