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ObjectiveTo explore whether age at onset increased over time despite a shortened interval from the initial clinical demyelinating event to the diagnosis of multiple sclerosis (MS), as promoted by updated diagnostic criteria.MethodsThis was an independent, multicentre, retrospective study based on data from 4345 patients with relapsing-onset MS attending three tertiary MS Clinics in Italy. After stratifying the year of MS onset into four periods (<1991, 1991–2000, 2001–2010, 2011–2021), we analysed the temporal trends in age at onset and interval from onset to diagnosis; we then explored the female-to-male ratio and onset location across different classes of age at onset.ResultsWe observed an increased mean age at onset, and a shortened mean interval to diagnosis over time (p<0.0001). Accordingly, there were more MS onsets at the older age classes of 40-49, 50–59 and ≥60 years (p<0.0001). In cases with age at onset ≥40 years, we also found an increased female-to-male ratio (p=0.007), more frequent spinal cord (p=0.0004) and less frequent supratentorial onset (p=0.008).ConclusionOur study shows a forward shift towards an older age at onset of MS, thus suggesting considerable thought on the place-in-therapy of most currently used disease-modifying treatments, and on the standard of care to an older population.

ObjectiveTo identify risk factors for an increased lethality of COVID-19 in patients with multiple sclerosis (MS).MethodsWe searched scientific databases to identify cohort studies with the number of deaths in patients with MS. We fitted inverse-variance weighted meta-regressions with random-effects models to identify potential moderators (determinants) of COVID-19-related lethality (outcome).ResultsAfter an independent screening, 18 articles satisfied the eligibility criteria; all data were collected before anti-SARS-COV-2 vaccination was available. Out of 5,634 patients, 111 died, yielding a pooled death rate of 1.97% (95% confidence intervals 1.61–2.33). There was a substantial heterogeneity between the included studies (Q17 = 66.9, p < 0.001; I2 = 77.5%), but no relevant publication bias (p = 0.085). Higher lethality was observed in studies including older patients (β = 0.80, p = 0.025) and in studies with higher proportions of patients with comorbidity (β = 0.17, p = 0.046), progressive disease course (β = 0.15, p = 0.027), and current treatment with anti-CD20 agents (β = 0.18, p < 0.001). Otherwise, higher proportions of patients treated with interferon beta (β = – 0.16, p < 0.001) and teriflunomide (β = – 0.11, p = 0.035) were associated with lower lethality. These estimates did not change even in both multivariable meta-regressions including adjustment variables and leave-one-out sensitivity analyses.ConclusionExcept for age and comorbidities, risk factors in common with the general population, we identified MS-specific determinants influencing the lethality of COVID-19. Our findings suggest the implementation of a risk mitigation plan for patients with progressive MS and for those treated with anti-CD20 agents.

Background: Natalizumab (NTZ) is sometimes discontinued in patients with multiple sclerosis, mainly due to concerns about the risk of progressive multifocal leukoencephalopathy. However, NTZ interruption may result in recrudescence of disease activity. Objective: The objective of this study was to summarize the available evidence about NTZ discontinuation and to identify which patients will experience post-NTZ disease reactivation through meta-analysis of existing literature data. Methods: PubMed was searched for articles reporting the effects of NTZ withdrawal in adult patients (⩾18 years) with relapsing–remitting multiple sclerosis (RRMS). Definition of disease activity following NTZ discontinuation, proportion of patients who experienced post-NTZ disease reactivation, and timing to NTZ discontinuation to disease reactivation were systematically reviewed. A generic inverse variance with random effect was used to calculate the weighted effect of patients’ clinical characteristics on the risk of post-NTZ disease reactivation, defined as the occurrence of at least one relapse. Results: The original search identified 205 publications. Thirty-five articles were included in the systematic review. We found a high level of heterogeneity across studies in terms of sample size (10 to 1866 patients), baseline patient characteristics, follow up (1–24 months), outcome measures (clinical and/or radiological), and definition of post-NTZ disease reactivation or rebound. Clinical relapses were observed in 9–80% of patients and peaked at 4–7 months, whereas radiological disease activity was observed in 7–87% of patients starting at 6 weeks following NTZ discontinuation. The meta-analysis of six articles, yielding a total of 1183 patients, revealed that younger age, higher number of relapses and gadolinium-enhanced lesions before treatment start, and fewer NTZ infusions were associated with increased risk for post-NTZ disease reactivation (p ⩽ 0.05). Conclusions: Results from the present review and meta-analysis can help to profile patients who are at greater risk of post-NTZ disease reactivation. However, potential reporting bias and variability in selected studies should be taken into account when interpreting our data.

ObjectiveTo estimate whether the risk of death from COVID-19 in patients with multiple sclerosis (MS) exceeds that of the general population.MethodsWe conducted a pooled analysis of cohort studies on COVID-19 in patients with MS published until July 31, 2021. We calculated the pooled crude death rate (CDR) and estimated the indirectly-adjusted age-standardized lethality ratio (SLR) to assess the risk of death from COVID-19 in patients with MS as compared to general population.ResultsOut of 520 articles, 18 fulfilled criteria for pooled analysis, with a total of 5634 patients (28.6% males, mean age 41.8 years). Of them, 111 died, yielding a CDR of 1.97% (95% confidence intervals [CIs] 1.61–2.33). The estimated SLR was 1.24 (95% CIs 1.01–1.48) after indirect age-standardization using case-fatality rates obtained from the detailed surveillance data available at the World Health Organization (WHO) website. A leave-one-out sensitivity analysis and the analysis of temporal trends of SLR from March 2020 to July 2021 provided consistent findings.ConclusionsOur pooled analysis suggests a 24%-increased risk of death from COVID-19 in patients with MS. These findings must be interpreted with caution, mainly because of the difficulties in COVID-19 case detection (especially in the first pandemic wave) and heterogeneity of the analyzed cohorts. Confirmation in larger population-based studies is warranted.

ObjectiveTo evaluate systematically the efficacy of exergames for balance dysfunction in neurological conditions and to identify factors of exergaming protocols that may influence their effects.MethodsWe searched electronic databases for randomized clinical trials investigating the effect of commercial exergames versus alternative interventions on balance dysfunction as assessed by standard clinical scales in adults with acquired neurological disabilities. Standardized mean differences (Hedge’s g) were calculated with random-effects models. Subgroup analyses and meta-regression were run to explore potential modifiers of effect size.ResultsOut of 106 screened articles, 41 fulfilled criteria for meta-analysis, with a total of 1223 patients included. Diseases under investigation were stroke, Parkinson’s disease, multiple sclerosis, mild cognitive impairment or early Alzheimer’s disease, traumatic brain injury, and myelopathy. The pooled effect size of exergames on balance was moderate (g = 0.43, p < 0.001), with higher frequency (number of sessions per week) associated with larger effect (β = 0.24, p = 0.01). There was no effect mediated by the overall duration of the intervention and intensity of a single session. The beneficial effect of exergames could be maintained for at least 4 weeks after discontinuation, but their retention effect was specifically explored in only 11 studies, thus requiring future investigation. Mild to moderate adverse events were reported in a minority of studies. We estimated a low risk of bias, mainly attributable to the lack of double-blindness and not reporting intention-to-treat analysis.ConclusionsThe pooled evidence suggests that exergames improve balance dysfunction and are safe in several neurological conditions. The findings of high-frequency interventions associated with larger effect size, together with a possible sustained effect of exergaming, may guide treatment decisions and inform future research.

Delayed-release dimethyl fumarate (DMF), also known as gastroresistant DMF, is the most recently approved oral disease-modifying treatment (DMT) for relapsing multiple sclerosis. Two randomized clinical trials (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS [DEFINE] and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis [CONFIRM]) demonstrated significant efficacy in reducing relapse rate and radiological signs of disease activity, as seen on magnetic resonance imaging. The DEFINE study also indicated a significant effect of DMF on disability worsening, while the low incidence of confirmed disability worsening in the CONFIRM trial rendered an insignificant reduction among the DMF-treated groups when compared to placebo. DMF also demonstrated a good safety profile and acceptable tolerability, since the most common side effects (gastrointestinal events and flushing reactions) are usually transient and mild to moderate in severity. Here, we discuss the place in therapy of DMF for individuals with relapsing multiple sclerosis, providing a tentative therapeutic algorithm to manage newly diagnosed patients and those who do not adequately respond to self-injectable DMTs. Literature data supporting the potential role of DMF as a first-line therapy are presented. The possibility of using DMF as switching treatment or even as an add-on strategy in patients with breakthrough disease despite self-injectable DMTs will also be discussed. Lastly, we argue about the role of DMF as an exit strategy from natalizumab-treated patients who are considered at risk for developing multifocal progressive leukoencephalopathy.

Background Published literature suggests that early treatment with natalizumab (“escalation strategy”) is more effective than switch within the same class of immunomodulators (interferons/glatiramer acetate, “switching strategy”) in relapsing-remitting multiple sclerosis (RRMS) patients who failed first-line self-injectable disease-modifying treatment (DMT). The present analysis aims to evaluate the cost-effectiveness profile of escalation strategy vs. switching strategy, adopting the Italian societal perspective. Methods A lifetime horizon Markov model was developed to compare early escalation to natalizumab vs. switching among immunomodulators, followed by subsequent escalation to natalizumab. The two compared treatment algorithms were: a) early escalation until progression to Expanded Disability Status Scale (EDSS) = 7.0 vs. b) switching until EDSS = 4.0, followed by escalation until EDSS = 7.0. The model analyzed social costs, quality-adjusted survival and effects of therapies in prolonging time without disability progression and burden of relapses. Clinical data were mainly extracted from a published observational study. Results Lifetime costs of early escalation to natalizumab and switching among immunomodulators amounted to €699,700 and €718,600 per patient, respectively. Early escalation was associated with prolonged quality-adjusted survival (11.19 vs. 9.67 QALYs, + 15.8%). A slight overall survival increase was also observed (20.10 vs. 19.67 life years). Both deterministic and probabilistic sensitivity analyses confirmed the robustness of findings. Conclusions Adopting the Italian social perspective, early escalation to natalizumab is dominant vs. switching among immunomodulators, in RRMS patients who do not respond adequately to conventional immunomodulators.

Previous studies have reported an association between anti-tumor necrosis factor alpha (anti-TNFα) treatment and central nervous system (CNS) events. We described eight patients presenting with demyelinating CNS events while on treatment with anti-TNFα for autoimmune diseases and followed up for a medium period of 4 years. Four patients presented with isolated demyelinating events, three patients fulfilled the criteria for multiple sclerosis (MS), and one patient showed worsening of pre-existing MS after anti-TNF therapy initiation. All patients except one, showed a good medium-term prognosis. Our observation supports an association between anti-TNFα treatment and demyelinating events and suggests that a prompt discontinuation of the drug may lead to a favorable demyelinating disease outcome.

Multiple sclerosis (MS) is a disease that heavily affects postural control, predisposing patients to accidental falls and fall-related injuries, with a relevant burden on their families, health care systems and themselves. Clinical scales aimed to assess balance are easy to administer in daily clinical setting, but suffer from several limitations including their variable execution, subjective judgment in the scoring system, poor performance in identifying patients at higher risk of falls, and statistical concerns mainly related to distribution of their scores. Today we are able to objectively and reliably assess postural control not only with laboratory-grade standard force platform, but also with low-cost systems based on commercial devices that provide acceptable comparability to gold-standard equipment. The sensitivity of measurements derived from force platforms is such that we can detect balance abnormalities even in minimally impaired patients and predict the risk of future accidental falls accurately. By manipulating sensory inputs (dynamic posturography) or by adding a concurrent cognitive task (dual-task paradigm) to the standard postural assessment, we can unmask postural control deficit even in patients at first demyelinating event or in those with a radiologic isolated syndrome. Studies on neuroanatomical correlates support the multifactorial etiology of postural control deficit in MS, with the association with balance impairment being correlated with cerebellum, spinal cord, and highly ordered processing network according to different studies. Postural control deficit can be managed by means of rehabilitation, which is the most important way to improve balance in patients with MS, but there are also suggestions of a beneficial effect of some pharmacologic interventions. On the other hand, it would be useful to pay attention to some drugs that are currently used to manage other symptoms in daily clinical setting because they can further impair postural controls of patients with MS.

Rehabilitation is recognized to be important in ameliorating motor and cognitive functions, reducing disease burden, and improving quality of life in patients with multiple sclerosis (MS). In this systematic review, we summarize the existing evidences that motor and cognitive rehabilitation may enhance functional and structural brain plasticity in patients with MS, as assessed by means of the most advanced neuroimaging techniques, including diffusion tensor imaging and task-related and resting-state functional magnetic resonance imaging (MRI). In most cases, the rehabilitation program was based on computer-assisted/video game exercises performed in either an outpatient or home setting. Despite their heterogeneity, all the included studies describe changes in white matter microarchitecture, in task-related activation, and/or in functional connectivity following both task-oriented and selective training. When explored, relevant correlation between improved function and MRI-detected brain changes was often found, supporting the hypothesis that training-induced brain plasticity is specifically linked to the trained domain. Small sample sizes, lack of randomization and/or an active control group, as well as missed relationship between MRI-detected changes and clinical performance, are the major drawbacks of the selected studies. Knowledge gaps in this field of research are also discussed to provide a framework for future investigations.