Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

To identify differentially expressed genes in multiple sclerosis, microarrays were used in a stringent experimental setting—leukapheresis from disease-discordant monozygotic twins and gene expression profiling in CD4⁺ and CD8⁺ T-cell subsets. Disease-related differences emerged only in the CD8⁺ T-cell subset. The five differentially expressed genes identified included killer cell lectin-like receptor subfamily B, member 1, also known as natural killer receptor protein 1a/CD161, presented by the International Multiple Sclerosis Genetics Consortium as one of the non-MHC candidate loci. Flow cytometric analysis on peripheral blood of healthy donors and patients with multiple sclerosis and rheumatoid arthritis confirmed an upregulation of CD161 at the protein level, showing also a significant excess of CD161^highCD8⁺ T cells in multiple sclerosis. This subset prevalently included chemokine (C-C motif) receptor 6⁺, cytokine-producing, effector-memory T cells with proinflammatory profiles. It also included all circulating interleukin-17⁺CD8⁺ T cells. In the CD161^highCD8⁺ subset, interleukin-12 facilitated proliferation and interferon-γ production, with CD161 acting as a co-stimulatory receptor. CD161⁺CD8⁺CD3⁺ T cells producing interferon-γ were part of intralesional immune infiltrates and ectopic B cell follicles in autopsy multiple sclerosis brains. Variations of CD161 expression on CD8⁺ T cells identify a subset of lymphocytes with proinflammatory characteristics that have not been previously reported in multiple sclerosis and are likely to contribute to disease immunopathology.

Background: The pleiotropic effects of riluzole may antagonize common mechanisms underlying chronic cerebellar ataxia, a debilitating and untreatable consequence of various diseases. Methods: In a randomized, double-blind, placebo-controlled pilot trial, 40 patients presenting with cerebellar ataxias of different etiologies were randomly assigned to riluzole (100 mg/day) or placebo for 8 weeks. The following outcome measures were compared: proportion of patients with a decrease of at least 5 points in the International Cooperative Ataxia Rating Scale (ICARS) total score after 4 and 8 weeks compared with the baseline score; mean changes from the baseline to posttreatment ICARS (total score and subscores at 8 weeks); and occurrence of adverse events. Results: Riluzole and placebo groups did not differ in baseline characteristics. The number of patients with a 5-point ICARS drop was significantly higher in the riluzole group than in the placebo group after 4 weeks (9/19 vs 1/19; odds ratio [OR] = 16.2; 95% confidence interval [CI ] 1.8–147.1) and 8 weeks (13/19 vs 1/19; OR = 39.0; 95% CI 4.2–364.2). The mean change in the riluzole group ICARS after treatment revealed a decrease (p < 0.001) in the total score (−7.05 [4.96] vs 0.16 [2.65]) and major subscores (−2.11 [2.75] vs 0.68 [1.94] for static function, −4.11 [2.96] vs 0.37 [2.0] for kinetic function, and −0.74 [0.81] vs 0.05 [0.40] for dysarthria). Sporadic, mild adverse events occurred. Conclusions: These findings indicate the potential effectiveness of riluzole as symptomatic therapy in diverse forms of cerebellar ataxia. Classification of evidence: This study provides Class I evidence that riluzole reduces, by at least 5 points, the ICARS score in patients with a wide range of disorders that cause cerebellar ataxia (risk difference 63.2%, 95% CI 33.5%–79.9%).

Alexander disease (AD) in its typical form is an infantile lethal leucodystrophy, characterized pathologically by Rosenthal fibre accumulation. Following the identification of glial fibrillary acidic protein (GFAP) gene as the causative gene, cases of adult-onset AD (AOAD) are being described with increasing frequency. AOAD has a different clinical and neuroradiological presentation with respect to early-onset AD, as abnormalities are mainly concentrated in the brainstem–spinal cord junction. We report detailed clinical and genetic data of 11 cases of AOAD, observed over a 4-year period, and a review of the previously reported 25 cases of genetically confirmed AOAD. In our series, onset occurred as late as age 62, and up to 71 in an affected deceased relative. Most cases appeared sporadic, but family history may be misleading. The most frequent symptoms were related to bulbar dysfunction—with dysarthria, dysphagia, dysphonia (seven patients)—, pyramidal involvement (seven patients) and cerebellar ataxia (seven patients). Four patients had palatal myoclonus. Sleep disorders were also observed (four cases). Bulbar symptoms, however, were infrequent at onset and two symptomatic patients had an almost pure pyramidal involvement. Two subjects were asymptomatic. Misdiagnosis at presentation was frequent and MRI was instrumental in suggesting the correct diagnosis by showing, in all cases, mild to severe atrophy of the medulla oblongata extending caudally to the cervical spinal cord. In ten patients, molecular studies revealed six novel missense mutations and three previously reported changes in GFAP. The last typical patient carried no definitely pathogenic mutation, but a missense variant (p.D157N), supposedly a rare polymorphism. Revision of the literature and the present series indicate that the clinical picture is not specific, but AOAD must be considered in patients of any age with lower brainstem signs. When present, palatal myoclonus is strongly suggestive. Pyramidal involvement, cerebellar ataxia and urinary disturbances are common. Less frequent findings include sleep disorders and dysautonomia. Fluctuations may occur. The course is variable, usually slowly progressive and less severe than the AD forms with earlier onset. AOAD is more common than previously thought and might even be the most common form of AD. The diagnosis is strongly suggested by MRI and confirmed by GFAP gene analysis.

Objective: To evaluate Bacille Calmette-Guérin (BCG) effects after clinically isolated syndromes (CIS). Methods: In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-β-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months. Results: Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was significantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI] 0.308–0.956; p = 0.03) for gadolinium-enhancing lesions (the primary endpoint), 0.364 (95% CI 0.207–0.639; p = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI 0.046–0.416; p = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were −0.09 ± 0.72 vs 0.75 ± 1.81 (p = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 (p = 0.08), and −0.21 ± 1.03 vs 1.00 ± 2.49 (p = 0.02). After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52, 95% CI 0.27–0.99; p < 0.05), and more vaccinated people remained DMT-free (odds ratio = 0.20, 95% CI 0.04–0.93; p = 0.04). Conclusions: Early BCG may benefit CIS and affect its long-term course. Classification of evidence: BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence).