Evaluation of treatment response in adults with relapsing MOG-Ab-associated disease

Background: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are related to several acquired demyelinating syndromes in adults, but the therapeutic approach is currently unclear. We aimed to describe the response to different therapeutic strategies in adult patients with relapsing MOG-Ab-associated disease. Methods: This is a retrospective study conducted in France and Spain including 125 relapsing MOG-Ab patients aged ≥ 18 years. First, we performed a survival analysis to investigate the relapse risk between treated and non-treated patients, performing a propensity score method based on the inverse probability of treatment weighting. Second, we assessed the annualised relapse rates (ARR), Expanded Disability Status Scale (EDSS) and visual acuity pre-treatment and on/end-treatment. Results: Median age at onset was 34.1 years (range 18.0-67.1), the female to male ratio was 1.2:1, and 96% were Caucasian. At 5 years, 84% (95% confidence interval [CI], 77.1-89.8) patients relapsed. At the last follow-up, 66 (52.8%) received maintenance therapy. Patients initiating immunosuppressants (azathioprine, mycophenolate mophetil [MMF], rituximab) were at lower risk of new relapse in comparison to non-treated patients (HR, 0.41; 95CI%, 0.20-0.82; p = 0.011). Mean ARR (standard deviation) was reduced from 1.05(1.20) to 0.43(0.79) with azathioprine (n = 11; p = 0.041), from 1.20(1.11) to 0.23(0.60) with MMF (n = 11; p = 0.033), and from 1.08(0.98) to 0.43(0.89) with rituximab (n = 26; p = 0.012). Other immunosuppressants (methotrexate/mitoxantrone/cyclophosphamide; n = 5), or multiple sclerosis disease-modifying drugs (MS-DMD; n = 9), were not associated with significantly reduced ARR. Higher rates of freedom of EDSS progression were observed with azathioprine, MMF or rituximab. Conclusion: In adults with relapsing MOG-Ab-associated disease, immunosuppressant therapy (azathioprine, MMF and rituximab) is associated with reduced risk of relapse and better disability outcomes. Such an effect was not found in the few patients treated with MS-DMD

Primary brain calcification: an international study reporting novel variants and associated phenotypes.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic

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

Atypical inflammatory demyelinating disorders and atypical multiple sclerosis : clinico-radiological characterization and NKp46/NCR1 function in astrocytes

Aux côtés des formes dites classiques de Sclérose en plaques (SEP), un nombre important de patients présentent des caractéristiques atypiques qui vont être responsable d’une période, parfois longue, d’errance diagnostique. Certains de ces patients, malgré les atypies, font clairement partie du spectre de la SEP tandis-que d’autres présentent probablement des maladies inflammatoires démyélinisantes idiopathiques distinctes qui sont, à ce jour, toujours en attente d’individualisation.Les objectifs principaux de ce travail de thèse étaient de mieux caractériser ces formes atypiques de SEP et autres maladies inflammatoires démyélinisantes idiopathiques.Nous avons effectué un travail rétrospectif de caractérisation clinique et radiologique (sur les données d’IRM acquises en conditions de vie réelle) afin d’aider au diagnostic et à mieux définir le pronostic évolutif de ces patients. Nous avons également effectué une analyse anatomopathologique chez les patients présentant une lésion inflammatoire nécessitant une biopsie avec pour objectif de mieux positionner ces lésions au sein du spectre de la SEP et du spectre des Neuromyélites Optiques (NMOSD). Enfin nous avons effectué une caractérisation de l’expression astrocytaire du récepteur NKp46 au sein des lésions de SEP et des lésions inflammatoires démyélinisantes atypiques.Les principaux résultats sont :1) En l’absence d’autre lésion cérébrale évocatrice de SEP, le risque de développer une SEP cliniquement définie chez un patient présentant une lésion cérébrale inflammatoire démyélinisante isolée est faible.2) La SEP, notamment dans sa forme progressive, peut avoir des caractéristiques proches de celles rencontrées dans le cadre des léucoencéphalopathies héréditaires. Dans ces situations, l’analyse des lésions de la substance grise, de la topographie des lésions de la substance blanche et le caractère nodulaire (>3mm mais non diffus) sont en faveur du diagnostic de SEP.3) Les lésions inflammatoires démyélinisantes du système nerveux central sont extrêmement hétérogènes en IRM. Néanmoins, certaines caractéristiques leurs sont communes : liseré périphérique en hypersignal en diffusion, prise de contraste périphérique ouverte, respect de la substance grise. L’analyse anatomopathologique sur tissus provenant de biopsies réalisées pour incertitude diagnostique démontre une préservation quasi systématique du marquage AQP4.4) L’expression astrocytaire de NKp46, récepteur classiquement décrit comme spécifique des lymphocytes NK, est commune à de nombreuses conditions neuroinflammatoires et neurodégénératives y compris la SEP, les NMOSD et les autres maladies inflammatoires démyélinisantes. Nous n’avons, à ce jour, pas pu déterminer l’implication du récepteur NKp46 dans la réponse astrocytaire en conditions inflammatoires.En conclusion, l’étude de notre cohorte rétrospective multicentrique a permis de mieux préciser les caractéristiques clinique (y compris de suivi), anatomopathologiques et IRM de patients présentant des formes atypiques de SEP et de maladies inflammatoires démyélinisantes.L’identification de sous-types de SEP caractérisés par une atteinte extrêmement sévère tant sur le plan clinique que radiologique nous semble pouvoir être un modèle d’étude intéressant dans la recherche de biomarqueurs d’imagerie et biologiques de la maladie.Beside classical multiple sclerosis (MS), a significant proportion of patients can present some atypical clinical or radiological characteristics that will lead to diagnostic uncertainties. On one side, some of these patients belong to MS spectrum whereas some other probably have yet unidentified inflammatory demyelinating disorders.Our objectives were to describe those patients with atypical MS and atypical idiopathic inflammatory demyelinating disorders.We retrospectively gathered clinical and radiological (in a real-life setting) data from patient to better delineate diagnostic clues and to better assess prognosis of these patients. Moreover, a neuropathological analysis of patients’ tissue collected for diagnostic uncertainties was performed to assess AQP4 staining in patients with acute atypical inflammatory demyelinating disease. Finally, we characterized the expression of the activating receptor NKp46 within astrocytes in MS and other inflammatory neurological diseases.Our main results were the following:1) in the absence of any other lesion suggestive of MS, the overall risk of MS diagnosis and typical MS relapse is low.2) MS, notably primary progressive or bout-onset MS, can share MRI characteristics with inherited leukoencephalopathies and leukodystrophies. In this context, a thorough analysis of deep and cortical gray matter, topography of white matter lesions and size (typically nodular > 3mm but not confluent) strongly argues in favor of MS.3) In spite of a marked heterogeneity of central nervous system inflammatory demyelinating lesions, some characteristics such as a peripheral B1000 hyperintensity with open rim gadolinium enhancement (with or without central enhancement) and gray matter sparing are common to all of these conditions. Moreover, neuropathological analysis of these lesions suggests a systematic normal/increased AQP4 staining.4) NKp46 astrocytic expression, a classical NK cells marker is common to several neuroinflammatory diseases including MS, NMOSD and other inflammatory demyelinating disorders. To date, we were not able to ascertain NKp46 involvement in the context of neuroinflammation.To conclude, our analysis enabled to refine clinical, neuropathological and MRI characteristics of patients with atypical MS and atypical inflammatory demyelinating disorders.The identification of “clusters” of atypical MS with dramatic disability progression and early evidence of neurodegeneration should allow us to identify promising MRI and/or biological biomarkers of disease progression

Neuropathies ataxiantes chroniques (apport des explorations électrophysiologiques dans le diagnostic)

MONTPELLIER-BU Médecine UPM (341722108) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Sensitivity of [18F]-Fluorodeoxyglucose–Positron Emission Tomography in Patients With Active Myelopathy

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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

Low Signals on T2* and SWI Sequences in Patients with MS with Progressive Multifocal Leukoencephalopathy

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Brain Calcifications in Adult-Onset Genetic Leukoencephalopathies: A Review

International audienceImportance: Adult-onset genetic leukoencephalopathies and leukodystrophies are increasingly recognized as a heterogeneous group of disorders with new diagnostic approaches and potential treatments. In the new era of genomics, the challenging interpretation of individual genetic variations requires an accurate phenotypic description and classification. Clinical and magnetic resonance imaging (MRI)-based approaches have been proposed to improve the diagnostic process of adult-onset leukoencephalopathies. Cerebral calcifications, when associated with white matter hyperintensities, are of major importance in the decision-making process to focus the diagnosis among the diversity of rare causes. Observations: This literature review demonstrated that the morphologic features and topography of the calcifications observed in a careful combined analysis of computed tomographic and MRI scans may help indicate the diagnosis of adult-onset genetic leukoencephalopathies. Vascular genetic leukoencephalopathies are an important cause of leukoencephalopathy with calcifications. Among them, COL4A1-related disorders are frequently associated with spotlike calcifications in the basal ganglia. Adult-onset leukoencephalopathy with axonal spheroids, a probably underestimated disorder, is associated with a specific pattern of calcifications: small, symmetric, sparing the basal ganglia, and a stepping stone appearance in the frontal pericallosal region. Moreover, disorders primarily associated with basal ganglia calcifications, such as primary familial brain calcifications, can be associated with marked leukoencephalopathy. Conclusions and Relevance: The number of identified causes of adult-onset genetic leukoencephalopathies has recently increased. A diagnostic algorithm should take into account the pattern of calcifications to better target the genetic analyses

Intracranial stenting after the Wingspan withdrawal in France: Clinical experience using a low profile coronary stent

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