Posterior fossa involvement in the diagnosis of adult-onset inherited leukoencephalopathies

International audienceAdult-onset genetic leukoencephalopathies are increasingly recognized. They are heterogeneous groups of disorders that commonly have distinct pathologic mechanisms but they share the presence of supratentorial bilateral and symmetric white matter hyperintensities. Although these abnormalities are usually non-specific, some specific MRI findings exist and sometimes help to distinguish these disorders. In this review, our aim is to describe posterior fossa abnormalities seen in the main adult-onset genetic leukoencephalopathies enabling clinicians to perform oriented genetic/metabolic screening

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

International audienceObjective 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) ( p 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

Life-threatening autoimmune warm hemolytic anemia following treatment for multiple sclerosis with alemtuzumab

International audienceBackground: Alemtuzumab is a humanized monoclonal antibody directed at CD52 approved as a disease-modifying therapy for relapsing forms of multiple sclerosis (MS). Objective: To describe a case of a life-threatening autoimmune anemia occurring after a first course of alemtuzumab for relapsing-remitting MS in a 28-year-old male. Methods: Case report. Results: A 28-year-old male developed a life-threatening autoimmune anemia occurring 11 months after first alemtuzumab course. Conclusion: We report the third case of autoimmune hemolytic anemia following treatment with alemtuzumab in a young MS patient. Due to the severity of this adverse event, neurologists using this treatment should be alert

Depletion of memory B cells is effective to prevent relapses in AQP4 antibody NMOSD but not in MOG antibody disorder

International audienceObjective: To assess if monitoring of memory B cells is relevant to individualize the frequency of rituximab administration in MOG-antibody disorder as previously demonstrated for AQP4-antibody disorder.Background: NADesign/Methods: 16 adult patients with MOG-antibody disorder and 29 adult patients with AQP4-antibody disorder were included in a prospective monocentric observational study. All patients were treated with rituximab using an individualized dosing schedule according to memory B cells count. Memory B cells were measured monthly from the second month after rituximab infusion and in case of relapse. Memory B cells were considered to be depleted if their frequency was less than 0.05% in peripheral blood mononuclear cells by flow cytometric analysis. Relapses, memory B cells count during relapses and EDSS were collected.Results: Mean follow-ups were 38 months (13–79) in AQP4-positive patients and 19 months (9–38) in MOG-positive patients. After rituximab initiation, 13 relapses occurred in 7 out of 29 AQP4-positive patients (24%). In MOG-positive patients, 10 relapses occurred in 6 out of 16 patients (37.5%). While memory B cells have reemerged in 12 out of 13 relapses (92.5%) occurring in AQP4-positive patients, they have reemerged in only 2 out of 10 relapses (20%) occurring in MOG-positive patients (p<0.001). These relapses occurred after a median time of 2.6 months (range 0.6 – 5.8), since the last infusion, in MOG positive patients, and 7 months (range 0.8 – 13) in AQP4 positive patients (p < 0.001).Conclusions: Identification of patients with short reemergence of memory B cells occurring before 6 months appears relevant to improve the efficacy of rituximab in AQP4-antibody disorder but not in MOG-antibody disorder where most relapses occur despite accurate depletion of memory B cells. This argues for a distinct pathophysiological mechanisms underlying relapses in MOG- vs AQP4-antibody disorder providing another clue to individualize MOG-antibody disorder as a novel disease entity.Disclosure: Dr. Durozard has nothing to disclose. Dr. Rico Lamy has nothing to disclose. Dr. Boutiere has nothing to disclose. Dr. Lacroix has nothing to disclose. Dr. Brunet has nothing to disclose. Dr. Fritz has nothing to disclose. Dr. Maarouf has nothing to disclose. Dr. Pelletier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Sanofi-Genzyme, Novartis, Teva, Merck-Serono, Roche, and MedDay. Dr. Pelletier has received research support from Biogen, Novartis, Roche, and Merck-Serono. Dr. Audoin has nothing to disclose

Hypogammaglobulinemia and Infections in Patients With Multiple Sclerosis Treated With Rituximab

International audienceBackground and Objectives To determine the frequency of hypogammaglobulinemia and infections in patients with multiple sclerosis (PwMS) receiving rituximab (RTX). Methods This prospective observational study included all consecutive PwMS receiving RTX at the university hospital of Marseille, France, between 2015 and 2020. Patient visits occurred at least every 6 months. Results We included 188 patients (151 with relapsing-remitting MS; the mean age was 43.4 years [SD 12.9], median disease duration 10 years [range 0–36], median Expanded Disability Status Scale 5 [range 0–8], median follow-up 3.5 years [range 1–5.8], and median number of RTX infusions 5 [range 1–9]). Overall, 317 symptomatic infections and 13 severe infections occurred in 133 of 188 (70.7%) and 11 of 188 (5.9%) patients, respectively. After 4 years, 24.4% of patients (95% CI 18.0–33.1) were free of any infection and 92.0% (95% CI 87.1–97.1) had not experienced a severe infection. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 32 of 188 (17%) patients. After RTX, IgG level was <7, <6, <4 and <2 g/L for 83 (44%), 44 (23.4%), 8 (4.2%) and 1 (0.53%) patients, respectively. The risk of infection was associated with reduced IgG levels (multivariate Cox proportional hazards hazard ratio [HR] = 0.86, 95% CI 0.75–0.98, p = 0.03). The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.05–1.75, p = 0.01). Discussion In PwMS receiving RTX, reduced IgG level was frequent and interacted with the risk of infection

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

International audienceObjective 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, p < 0.001), the dosing intervals (HR = 0.98, 95% CI 0.97-0.99, p < 0.001), and the interaction between IgG level and urinary tract dysfunction (HR = 0.67, 95% CI 0.53-0.85, p < 0.005). IgG level <6 g/L during RTX was associated with male sex (HR = 4, 95% CI 1.4-11.4, p < 0.01) and previous immunosuppression (HR = 3.4, 95% CI 1.2-10, p < 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

Grey-matter sodium concentration as an individual marker of multiple sclerosis severity

International audienceObjective: Quantification of brain injury in patients with variable disability despite similar disease duration may be relevant to identify the mechanisms underlying disability in MS. We aimed to compare grey-matter sodium abnormalities (GMSA), a parameter reflecting neuronal and astrocyte dysfunction, in MS patients with benign MS (BMS) and non-benign MS (NBMS). Methods: We identified never-treated BMS patients in our local MS database of 1352 patients. A group with NBMS was identified with same disease duration. All participants underwent 23 Na MRI. The existence of GMSA was detected by statistical analysis. Results: In total, 102 individuals were included (21 BMS, 25 NBMS and 56 controls). GMSA was detected in 10 BMS and 19 NBMS (11/16 RRMS and 8/9 SPMS) patients (p=0.05). On logistic regression including the presence or absence of GMSA, thalamic volume, cortical grey matter volume and T2-weighted lesion load, thalamic volume was independently associated with BMS status (OR=0.64 for each unit). Nonetheless, the absence of GMSA was independently associated when excluding patients with significant cognitive alteration (n=7) from the BMS group (OR=4.6). Conclusion: Detection of GMSA in individuals and thalamic volume are promising to differentiate BMS from NBMS as compared with cortical or whole grey-matter atrophy and T2-weighted lesions

Pure Relapsing Short Myelitis

International audienceBackground and Objectives Pure relapsing short myelitis with clinical and paraclinical features suggesting multiple sclerosis (MS) has been described recently. Here, we evaluated the existence of this potential new form of MS by retrospectively searching for similar cases in the databases of the French tertiary MS centers. Methods Patients were included based on the present criteria: at least 2 short (<3 vertebral segments) myelitis episodes; minimum follow-up of 3 years; no MS-like brain lesion during all the followup; tested negative for both anti-myelin oligodendrocyte glycoprotein and anti-aquaporin 4 antibodies in serum; presence of oligoclonal bands in CSF; and comprehensive workup to exclude alternative diagnoses. Results Eighteen patients fulfilled all criteria. The sex ratio (females/males) was 5/1; the median (range) age at first relapse was 35.5 (25-54) years, the disease duration was 80.5 (50-308) months, and the annualized relapse rate was 0.36 (0.1-0.5). The median (range) number of relapses per patient was 2 (2-5), and the median (range) Expanded Disability Status Scale score at last follow-up was 1 (0-7.5). In CSF, the median (range) protein level was 0.34 g/L (0.18-0.77), and the median (range) number of mononuclear cells was 3 (0-28). Spinal cord MRI demonstrated a median (range) number of 2 (1-5) lesions per examination and 3 [1-7] on the last examination. Fifty-five percent of lesions involved the cervical levels. Secondary progressive evolution occurred in 3 of 18 (17%) patients. Discussion Pure spinal MS could be a rare entity in the MS disease spectrum. However, the existence of a distinct entity in the inflammatory CNS disorders cannot be excluded

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

International audienceObjective 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.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 refractor