In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their ...association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research‐based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non‐inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non‐MS cases), yielded high specificity (93%) in differentiating MS from non‐MS. Future prospective multicenter studies should validate their role as a diagnostic biomarker. ANN NEUROL 2020;88:1034–1042
Background
Evidence of immune-mediated neurological syndromes associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is limited. We therefore investigated clinical, ...serological and CSF features of coronavirus disease 2019 (COVID-19) patients with neurological manifestations.
Methods
Consecutive COVID-19 patients with neurological manifestations other than isolated anosmia and/or non-severe headache, and with no previous neurological or psychiatric disorders were prospectively included. Neurological examination was performed in all patients and lumbar puncture with CSF examination was performed when not contraindicated. Serum anti-gangliosides antibodies were tested when clinically indicated.
Results
Of the 349 COVID-19 admitted to our center between March 23rd and April 24th 2020, 15 patients (4.3%) had neurological manifestations and fulfilled the study inclusion/exclusion criteria. CSF examination was available in 13 patients and showed lymphocytic pleocytosis in 2 patients: 1 with anti-contactin-associated protein 2 (anti-Caspr2) antibody encephalitis and 1 with meningo-polyradiculitis. Increased serum titer of anti-GD1b antibodies was found in three patients and was associated with variable clinical presentations, including cranial neuropathy with meningo-polyradiculitis, brainstem encephalitis and delirium. CSF PCR for SARS-CoV-2 was negative in all patients.
Conclusions
In SARS-Cov-2 infected patients with neurological manifestations, CSF pleocytosis is associated with para- or post-infectious encephalitis and polyradiculitis. Anti-GD1b and anti-Caspr2 autoantibodies can be identified in certain cases, raising the question of SARS-CoV-2-induced secondary autoimmunity.
Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.
We identified all patients with ...relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).
The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).
The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.
Multiple sclerosis (MS) is thought to be a Th17-mediated dysimmune disease of the central nervous system. However, recent publications have questioned the pathogenicity of IL-17 per se and rather ...suggest the implication of other Th17-related inflammatory mediators. Therefore, we studied the expression of GM-CSF, IL-22, IL-24, IL-26 and CD39 in peripheral blood mononuclear cells (PBMCs) from MS patients during relapses, remission and following corticosteroid treatment. We performed qPCR to measure mRNA levels from ex vivo or in vitro-stimulated PBMCs. Cytokine levels were determined by ELISA. We used flow cytometry to assess GM-CSF+, IL-22+ and CD39+ cells in relationship to IL-17+ CD4+ T cells. Our results showed that IL-22 mRNA and IL-22+CD4+ lymphocytes are increased in circulating cells of relapsing MS patients compared to remitting patients while GM-CSF was unchanged. We have further shown that 12.9, 39 and 12.4% of Th17 cells from MS patients during relapses expressed IL-22, GM-CSF and CD39 respectively. No changes in these proportions were found in stable MS patients. However, the majority of GM-CSF+ or IL-22+ T cells did not co-express IL-17. GM-CSF mRNA, but not IL-22 mRNA, was dramatically decreased ex vivo by ivMP. Our results contribute to a better characterisation of Th17, Th22 and ThGM-CSF cells in the setting of MS and according to disease activity.
The pathogenic role of IL‐17 and GM‐CSF has been unravelled in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). However, in most models, EAE is ...characterised by a monophasic attack which is not representative of the relapsing nature nor the chronicity displayed in MS. Here, we used proteolipid protein peptide (PLP139‐151) to trigger EAE‐relapses (EAE‐II) in SJL mice that had recovered from a primary‐EAE episode (EAE‐I). This procedure resulted in severe and irreversible disease that, unlike EAE‐I, was not abolished by anti‐IL‐17‐mAb. In contrast, prophylactic anti‐GM‐CSF‐mAb treatment prevented EAE‐I and ‐II. Strikingly, the expression of T‐cell transcription factors and cytokines/chemokines in mice treated with anti‐GM‐CSF during both EAE episodes was silenced. Anti‐GM‐CSF‐mAb treatment administered only during EAE‐II did not completely prevent relapses but mice ultimately reached full recovery. Anti‐GM‐CSF treatment also strongly impaired and ultimately resolved monophasic MOG35‐55‐induced EAE in C57Bl/6 mice. In such protected mice, anti‐GM‐CSF treatment also prevented a further relapse induced by MOG‐revaccination. These results underscore the critical role of GM‐CSF on pro‐inflammatory mediator production. Furthermore, we observed a strong preventive and curative effect of anti‐GM‐CSF neutralisation in two EAE models, relapsing and chronic. Altogether these findings are relevant for further MS research.
We investigated a chronic model of experimental autoimmune encephalomyelitis (relapse‐EAE), more representative of multiple sclerosis than primary‐EAE, to study the pathogenic role of IL‐17 and GM‐CSF. Prophylactic treatment with anti‐GM‐CSF but not anti‐IL‐17 prevented both primary‐ and relapse‐EAE. These results highlight the predominant role of GM‐CSF in chronic neuro‐inflammation.
Background and purpose
This study assessed the effect of patient characteristics on the response to disease‐modifying therapy (DMT) in multiple sclerosis (MS).
Methods
We extracted data from 61,810 ...patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow‐up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12‐month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.
Results
Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio HR = 0.52, 95% confidence interval CI = 0.45–0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41–0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09–1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.
Conclusions
DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
Aging is characterized, amongst other features, by a complex process of cellular senescence involving both innate and adaptive immunity, called immunosenescence and associated to inflammaging, a ...low-grade chronic inflammation. Both processes fuel each other and partially explain increasing incidence of cancers, infections, age-related autoimmunity, and vascular disease as well as a reduced response to vaccination. Multiple sclerosis (MS) is a lifelong disease, for which considerable progress in disease-modifying therapies (DMTs) and management has improved long-term survival. However, disability progression, increasing with age and disease duration, remains. Neurologists are now involved in caring for elderly MS patients, with increasing comorbidities. Aging of the immune system therefore has relevant implications for MS pathogenesis, response to DMTs and the risks mediated by these treatments. We propose to review current evidence regarding markers and molecular mechanisms of immunosenescence and their relevance to understanding MS pathogenesis. We will focus on age-related changes in the innate and adaptive immune system in MS and other auto-immune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The consequences of these immune changes on MS pathology, in interaction with the intrinsic aging process of central nervous system resident cells will be discussed. Finally, the impact of immunosenescence on disease evolution and on the safety and efficacy of current DMTs will be presented.
There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as ...the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.
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