Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early MS is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up >/= 5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline (HR = 1.19; 95CI 1.13-1.25, p < 0.001), having a relapsing-remitting course at baseline (HR = 1.44; 95CI 1.28-1.61, p < 0.001), longer disease duration at baseline (HR = 1.56; 95%CI 1.28-1.90, p < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95CI 0.88-0.96, p < 0.001), lower number of relapses before the event (HR = 0.76; 95CI 0.73-0.80, p < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95CI 0.81-0.93, p < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95CI 1.35-1.79, p < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95CI 0.89-0.99, p = 0.017), higher number of relapses before the event (HR = 1.04; 95CI 1.01-1.07, p < 0.001). Longer exposure to disease modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (p < 0.001). This study provides evidence that in early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18–49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5–17.9) for paediatric-onset and 6.3 (4.9–8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9–4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.

Background: The spread of Coronavirus disease-19 (COVID-19) poses unique challenges in the management of people with multiple sclerosis (PwMS). Objectives: To collect data about the impact of COVID-19 emergency on access to care for PwMS and on MS treatment practices. Methods: Between March and July 2020, the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) promoted an online survey covering patient access to care, management of relapses and visits, disease-modifying therapy (DMT) and experience with COVID-19. Results: Three-hundred and sixty neurologists from 52 countries (68% from Europe) completed the survey. 98% reported COVID-19-related restrictions. Telemedicine was adopted to overcome the limited access to care and was newly activated (73%) or widely implemented (17%). 70% reported changes in DMT management. Interferons and glatiramer were considered safe. Dimethyl fumarate, teriflunomide and fingolimod were considered safe except for patients developing lymphopenia. No modifications were considered for natalizumab in 64%, cladribine in 24%, anti-CD20 in 22% and alemtuzumab in 17%; 18% (for alemtuzumab and cladribine) and 43% (for anti-CD20) considered postponing treatment. Conclusion: The ECTRIMS survey highlighted the challenges in keeping standards of care in clinical practice. Telemedicine clearly needs to be implemented. Gathering data on DMT safety will remain crucial to inform treatment decisions.

BackgroundMany potentially modifiable risk factors for MS are investigated. It is not known, however, if these factors also apply to MS-related cognitive impairment (CI), a frequent consequence of MS.ObjectiveThe aim of our study was to assess risk factors for CI in MS patients, focusing on environmental exposures, lifestyle and comorbidities.MethodsWe included MS patients referring to MS Centers in Florence and Barletta between 2014 and 2017. Neuropsychological performance was assessed through the Rao’s battery and Stroop test, cognitive reserve (premorbid intelligence quotient–IQ) was evaluated using the National Adult Reading Test (NART). Potential risk factors were investigated through a semi-structured questionnaire.Results150 patients were included. CI was detected in 45 (30%) subjects and was associated with older age (p<0.005), older age at MS onset (p = 0.016), higher EDSS score (p<0.005), progressive disease course (p = 0.048) and lower premorbid IQ score (p<0.005). As for risk factors, CI was related with lower physical activity in childhood-adolescence (p<0.005). In women, hormonal therapy resulted to be protective against CI (p = 0.041). However, in the multivariable analysis, the only significant predictors of CI were older age (p<0.05; OR 1.06, 95% CI 1.02–1.10) and lower premorbid IQ (p<0.05; OR 0.93, 95% CI: 0.88–0.98). Removing IQ from the model, CI was associated with higher EDSS (p = 0.030; OR 1.25, 95% CI 1.02–1.53) and, marginally, previous physical activity (p = 0.066; OR 0.49, 95% CI: 0.23–1.05)ConclusionsOur findings suggest that physical activity in childhood-adolescence could be a contributor to cognitive reserve building, thus representing a potential protective factors for MS-related CI susceptible to preventive strategies.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

Here, we report the case of a 36-year-old patient with a diagnosis of de novo mutation of the WDR45 gene, responsible for beta-propeller protein-associated neurodegeneration, a phenotypically distinct, X-linked dominant form of Neurodegeneration with Brain Iron Accumulation. The clinical history is characterized by a relatively stable intellectual disability and a hypo-bradykinetic and hypertonic syndrome with juvenile onset. Genetic investigations and T1 and T2-weighted MR images align with what is described in literature. The patient was also subjected to PET with 18-FDG investigation and DaT-Scan study. In reporting relevant clinical data, we want to emphasize the fact that the patient received a chelation therapy with deferiprone (treatment already used in other forms of NBIA with encouraging results), which, however, had to be interrupted because the parkinsonian symptoms worsened. Conversely, the patient has benefited from non-drug therapies and, in particular, from an adapted motor activity with assisted pedaling (method in the process of validation in treatments of parkinsonian syndromes), which started before the treatment with deferiprone and still continues.

Background: There is emerging evidence that intrathecal IgM synthesis (ITMS) is a risk factor for conversion to clinically defined multiple sclerosis (CDMS) in clinically isolated syndrome (CIS) patients. Objectives: The objective of this study is to verify the prognostic role of ITMS as a risk factor for the second clinical attack in patients after the first demyelinating event. Methods: Monocentric observational study performed on prospectively acquired clinical data and retrospective evaluation of magnetic resonance imaging (MRI) data. ITMS was assessed according to Reiber’s non-linear function. We compared time to the second attack by using Kaplan–Meier curves and performed adjustment by Cox regression analysis. Results: Demographics and clinical data were collected prospectively in a cohort of 68 patients. ITMS occurred in 40% (27/68) of patients who had a higher T1-hypointense lesion load at brain MRI ( p = 0.041). In multivariate Cox regression analysis (adjusted for age, sex, baseline Expanded Disability Status Scale, IgG oligoclonal bands and disease-modifying treatment exposure), relapsing-remitting multiple sclerosis (MS) patients with ITMS were at higher risk to experience a second clinical attack (adjusted hazard ratio (aHR) = 6.3, 95% confidence interval (CI) = 2.1–18.4, p = 0.001). Conclusion: Together with previous studies, our findings support the role of ITMS as a prognostic biomarker in MS.

Background: Matrix metalloproteinases (MMPs) are pleiotropic enzymes involved in extracellular protein degradation and turnover. MMPs are implicated in the pathogenesis of many neurological diseases, including multiple sclerosis (MS).Objective: To search the level of MMPs in the cerebrospinal fluid (CSF) of MS patients and detect possible disease-specific patterns.Methods: CSF samples from 32 MS patients and, from 15 control subjects with other inflammatory neurological diseases (OIND) were analyzed. The Bio-Plex Pro Human MMP 9-Plex Panel (Bio-Rad) was used for the quantification of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, and MMP-13.Results: CSF MMP-1 and MMP-12 levels were significantly reduced in MS as compared with OIND. In MS patients' CSF: (i) MMP-1 levels were significantly higher in women vs. men; (ii) MMP-10 concentrations were higher in patients with CSF-restricted IgG oligoclonal bands, and (iii) MMP-7 levels were increased in patients with longer disease duration. In the OIND group MMP-7 and MMP-12 levels significantly and directly correlated with age.Conclusions: Our study contributes to investigating the role of MMPs in MS, with regard to CSF immunological features and disease duration. Sex-specific differences were also detected in MMPs CSF levels.