Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system (CNS), clinically defined by an acute polyfocal neurological syndrome usually with ...monophasic course. ADEM often occurs after infections, but 5%–10% of cases are preceded by vaccinations. Several cases of ADEM have been described after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas no case has been reported after adenovirus-vectored or mRNA COVID-19 vaccine administration. Here we describe a case of ADEM presenting 2 weeks after receiving the first dose of ChAdOx1 nCoV-19 vaccine. Patient clinical/magnetic resonance imaging (MRI) status spontaneously improved and rapidly resolved with corticosteroids. A 4-month follow-up showed complete recovery and no relapses.
Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, has been associated with multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), but direct proof of ...its involvement in the disease is still missing. To test the idea that MS might result from perturbed EBV infection in the CNS, we investigated expression of EBV markers in postmortem brain tissue from MS cases with different clinical courses. Contrary to previous studies, we found evidence of EBV infection in a substantial proportion of brain-infiltrating B cells and plasma cells in nearly 100% of the MS cases examined (21 of 22), but not in other inflammatory neurological diseases. Ectopic B cell follicles forming in the cerebral meninges of some cases with secondary progressive MS were identified as major sites of EBV persistence. Expression of viral latent proteins was regularly observed in MS brains, whereas viral reactivation appeared restricted to ectopic B cell follicles and acute lesions. Activation of CD8+ T cells with signs of cytotoxicity toward plasma cells was also noted at sites of major accumulations of EBV-infected cells. Whether homing of EBV-infected B cells to the CNS is a primary event in MS development or the consequence of a still unknown disease-related process, we interpret these findings as evidence that EBV persistence and reactivation in the CNS play an important role in MS immunopathology.
Multiple Sclerosis (MS) progresses at an unpredictable rate, but predictions on the disease course in each patient would be extremely useful to tailor therapy to the individual needs. We explore ...different machine learning (ML) approaches to predict whether a patient will shift from the initial Relapsing-Remitting (RR) to the Secondary Progressive (SP) form of the disease, using only "real world" data available in clinical routine. The clinical records of 1624 outpatients (207 in the SP phase) attending the MS service of Sant'Andrea hospital, Rome, Italy, were used. Predictions at 180, 360 or 720 days from the last visit were obtained considering either the data of the last available visit (Visit-Oriented setting), comparing four classical ML methods (Random Forest, Support Vector Machine, K-Nearest Neighbours and AdaBoost) or the whole clinical history of each patient (History-Oriented setting), using a Recurrent Neural Network model, specifically designed for historical data. Missing values were handled by removing either all clinical records presenting at least one missing parameter (Feature-saving approach) or the 3 clinical parameters which contained missing values (Record-saving approach). The performances of the classifiers were rated using common indicators, such as Recall (or Sensitivity) and Precision (or Positive predictive value). In the visit-oriented setting, the Record-saving approach yielded Recall values from 70% to 100%, but low Precision (5% to 10%), which however increased to 50% when considering only predictions for which the model returned a probability above a given "confidence threshold". For the History-oriented setting, both indicators increased as prediction time lengthened, reaching values of 67% (Recall) and 42% (Precision) at 720 days. We show how "real world" data can be effectively used to forecast the evolution of MS, leading to high Recall values and propose innovative approaches to improve Precision towards clinically useful values.
Summary Background Our previous study in patients with cerebellar ataxias of different causes showed significant benefit of riluzole after 8 weeks. We aimed to confirm these results in patients with ...spinocerebellar ataxia or Friedreich's ataxia in a 1-year trial. Methods Patients with spinocerebellar ataxia or Friedreich's ataxia (2:1 ratio) from three Italian neurogenetic units were enrolled in this multicentre, double-blind, placebo-controlled trial, and randomly assigned to riluzole (50 mg orally, twice daily) or placebo for 12 months. The randomisation list was computer-generated and a centralised randomisation system was implemented. Participants and assessing neurologists were masked to treatment allocation. The primary endpoint was the proportion of patients with improved Scale for the Assessment and Rating of Ataxia (SARA) score (a drop of at least one point) at 12 months. An intention-to-treat analysis was done. This trial is registered at ClinicalTrials.gov , number NCT01104649. Findings Between May 22, 2010, and Feb 25, 2013, 60 patients were enrolled. Two patients in the riluzole group and three in the placebo group withdrew their consent before receiving treatment, so the intention-to-treat analysis was done on 55 patients (19 with spinocerebellar ataxia and nine with Friedreich's ataxia in the riluzole group, and 19 with spinocerebellar ataxia and eight with Friedreich's ataxia in the placebo group). The proportion with decreased SARA score was 14 (50%) of 28 patients in the riluzole group versus three (11%) of 27 in the placebo group (OR 8·00, 95% CI 1·95–32·83; p=0·002). No severe adverse events were recorded. In the riluzole group, two patients had an increase in liver enzymes (less than two times above normal limits). In two participants in the riluzole group and two participants in the placebo group, sporadic mild adverse events were reported. Interpretation Our findings lend support to the idea that riluzole could be a treatment for cerebellar ataxia. Longer studies and disease-specific trials are needed to confirm whether these findings can be applied in clinical practice. Funding Agenzia Italiana del Farmaco.
Interferon-beta (IFN-β) for Multiple Sclerosis (MS) is turning 30. The COVID-19 pandemic rejuvenated the interest in interferon biology in health and disease, opening translational opportunities ...beyond neuroinflammation. The antiviral properties of this molecule are in accord with the hypothesis of a viral etiology of MS, for which a credible culprit has been identified in the Epstein-Barr Virus. Likely, IFNs are crucial in the acute phase of SARS-CoV-2 infection, as demonstrated by inherited and acquired impairments of the interferon response that predispose to a severe COVID-19 course. Accordingly, IFN-β exerted protection against SARS-CoV-2 in people with MS (pwMS). In this viewpoint, we summarize the evidence on IFN-β mechanisms of action in MS with a focus on its antiviral properties, especially against EBV. We synopsize the role of IFNs in COVID-19 and the opportunities and challenges of IFN-β usage for this condition. Finally, we leverage the lessons learned in the pandemic to suggest a role of IFN-β in long-COVID-19 and in special MS subpopulations.
A key role of both coagulation and vascular thrombosis has been reported since the first descriptions of multiple sclerosis (MS). Subsequently, the observation of a close concordance between ...perivascular fibrin(ogen) deposition and the occurrence of clinical signs in experimental allergic encephalomyelitis (EAE), an animal model of MS, led to numerous investigations focused on the role of thrombin and fibrin(ogen). Indeed, the activation of microglia, resident innate immune cells, occurs early after fibrinogen leakage in the pre-demyelinating lesion stage of EAE and MS. Thrombin has both neuroprotective and pro-apoptotic effects according to its concentration. After exposure to high concentrations of thrombin, astrocytes become reactive and lose their neuroprotective and supportive functions, microglia proliferate, and produce reactive oxygen species, IL-1β, and TNFα. Heparin inhibits the thrombin generation and suppresses EAE. Platelets play an important role too. Indeed, in the acute phase of the disease, they begin the inflammatory response in the central nervous system by producing of IL-1alpha and triggering and amplifying the immune response. Their depletion, on the contrary, ameliorates the course of EAE. Finally, it has been proven that the use of several anticoagulant agents can successfully improve EAE. Altogether, these studies highlight the role of the coagulation pathway in the pathophysiology of MS and suggest possible therapeutic targets that may complement existing treatments.
Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg ...cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.
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•SLC7A11 controls Treg cell proliferation induced by signals of pseudo-starvation•SLC7A11 coordinates the antioxidant response in proliferating Treg cells•Growth-defective Treg cells from RRMS patients fail to induce SLC7A11•DMF therapy restores Treg cell proliferation, inducing SLC7A11 in RRMS patients
Altered immunological self-tolerance in relapsing-remitting multiple sclerosis (RRMS) associates with a reduced regulatory T cell proliferation. Procaccini et al. show a key role for the amino acid transporter SLC7A11 in this process, as its induction is impaired in RRMS patients and can be restored by treatment with dimethyl fumarate.
Summary Clonal expansion of B cells and the production of oligoclonal IgG in the brain and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) have long been interpreted as ...circumstantial evidence of the immune-mediated pathogenesis of the disease and suggest a possible infectious cause. Extensive work on intrathecally produced antibodies has not yet clarified whether they are pathogenetically relevant. Irrespective of antibody specificity, however, the processes of antibody synthesis in the CNS of patients with MS are becoming increasingly clear. Likewise, targeting B cells might be therapeutically relevant in MS and other autoimmune diseases that are deemed to be driven predominantly by T cells. Accumulating evidence indicates that in MS, similar to rheumatoid arthritis, B cells aggregate into lymphoid-like structures in the target organ. The process of aggregation is mediated through the expression of lymphoid-homing chemokines. In the brain of a patient with MS, ectopic B-cell follicles preferentially adjoin the pial membrane within the subarachnoid space. Recent findings indicate that substantial numbers of B cells that are infected with Epstein-Barr virus (EBV) accumulate in these intrameningeal follicles and in white matter lesions and are probably the target of a cytotoxic immune response. These findings, which await confirmation, could be an explanation for the continuous B-cell and T-cell activation in MS, but leave open concerns about the possible pathogenicity of autoantibodies. Going beyond the antimyelin-antibody dogma, the above data warrant further work on various B-cell-related mechanisms, including investigation of B-cell effector and regulatory functions, definition of the consistency of CNS colonisation by Epstein-Barr virus-infected B cells, and understanding of the mechanisms that underlie the formation and persistence of tertiary lymphoid tissues in patients with MS and other chronic autoimmune diseases (ectopic follicle syndromes). This work will stimulate new and unconventional ways of reasoning about MS pathogenesis.
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