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Relapses (episodic exacerbations of neurological signs or symptoms) are a defining feature of relapsing-remitting multiple sclerosis (MS), the most prevalent MS phenotype. While their diagnostic value relates predominantly to the definition of clinically definite MS, their prognostic value is determined by their relatively high associated risk of incomplete remission resulting in residual disability. The mechanisms governing a relapse incidence are unknown, but numerous modifiers of relapse risk have been described, including demographic and clinical characteristics, many of which represent opportunities for improved disease management. Also relapse phenotypes have been associated with patient and disease characteristics and an individual predisposition to certain phenotypic presentations may imply individual neuroanatomical disease patterns. While immunomodulatory therapies and corticosteroids represent the mainstay of relapse prevention and acute management, respectively, their effect has only been partial and further search for more efficient relapse therapies is warranted. Other areas of research include pathophysiology and determinants of relapse incidence, recurrence and phenotypes, including the characteristics of the relapsing and non-relapsing multiple sclerosis variants and their responsiveness to therapies.

Background: Using the local divergence exponent (LDE), it has been concluded that walking stability is impaired in people with multiple sclerosis (pwMS). However, the use of several calculation approaches hinders comparisons across studies. We aimed to determine whether using different parameters for state space reconstruction to calculate LDE affects the classification of pwMS. Methods: A total of 55 pwMS and 23 controls walked up and down a 20 m corridor for 5 min. The LDE was calculated using three different combinations of n-dimensions (dE) and time delays (τ): (a) trial-specific, (b) median across subjects, and (c) fixed dE = 5 and τ = 10. The LDE was calculated using vertical (VT), mediolateral (ML), and anteroposterior (AP) accelerations, the norm (N), and 3D data from sensors placed on the sternum and lumbar. Classification accuracy across results obtained with different parameter combinations was compared using a Quadratic Discriminant Analysis (QDA). Results: The best classification accuracy, 84%, was achieved when using the LDE obtained with norm acceleration data from the sternum sensor with a fixed dE = 5 and τ = 10 and considering speed as a covariate. Lumbar LDEs were less accurate than sternum LDEs. Conclusions: LDEs calculated with a fixed dE = 5 and τ = 10 for the norm acceleration from a sternum-placed sensor can best classify pwMS. Using fixed parameters for the state space reconstruction, and consequently LDE calculation, can simplify the implementation of the LDE as a mobility biomarker in MS and provides evidence for future consensus for its calculation.

B cell-depleting agents are emerging as important disease-modifying drugs for multiple sclerosis, but their effectiveness in relation to established treatments remains uncertain. To cast light on this issue, several studies have provided head-to-head comparisons of the anti-CD20 antibody rituximab with natalizumab, fingolimod and dimethyl fumarate in patients with multiple sclerosis.

BackgroundThe ASCEND trial did not find benefit of natalizumab during secondary progressive multiple sclerosis compared with placebo; however, its open-label extension suggests this may be obscured by therapeutic lag.We aimed to compare the efficacy of natalizumab and interferon β-1a in slowing disease progression in secondary progressive multiple sclerosis after accounting for therapeutic lag.MethodsWe analysed pooled data from the ASCEND (natalizumab vs placebo) and SPECTRIMS (interferon β-1a vs placebo) trials. Cumulative hazards of 6-month confirmed disability progression during secondary progressive multiple sclerosis were compared using Cox proportional hazards models adjusted for confounding variables. We accounted for therapeutic lag in each patient based on baseline expanded disability status scale, annualised relapse rate and sex. Differences between SPECTRIMS and ASCEND placebo arms were used to adjust the differences between interferon β-1a and natalizumab arms.ResultsBaseline characteristics of 1156 patients were similar between SPECTRIMS and ASCEND cohorts, except for a higher proportion of older patients and lower relapse rates in the ASCEND trial. Natalizumab exhibited a lower cumulative hazard of disability progression compared with interferon β-1a (HR 0.15, 95% CI 0.08 to 0.29, p<0.0001). After adjusting for the difference in cumulative hazards between placebo groups (HR 0.36, 95% CI 0.20 to 0.63, p=0.0004), natalizumab remained associated with a lower hazard of disability progression compared with interferon β-1a (HR 0.42, 95% CI 0.22 to 0.77, p=0.0016).ConclusionAfter accounting for therapeutic lag and differences between ASCEND and SPECTRIMS trials, natalizumab, compared with interferon β-1a, reduces disability progression during secondary progressive multiple sclerosis.

Background: Multiple sclerosis (MS) cognitive tests are resource intensive and limited by practice effects that prevent frequent retesting. Brief, reliable and valid monitoring tools are urgently needed to detect subtle, subclinical cognitive changes in people with MS. Cognitive monitoring over time could contribute to a new definition of disease progression, supplementing routine clinical monitoring. Methods: MSReactor is a web-based battery that measures psychomotor (processing) speed, visual attention and working memory, using simple reaction time tasks. Clinic-based tasks were completed at baseline and 6 monthly with home testing 1–3 monthly. Acceptability, quality of life, depression and anxiety surveys were completed. We studied its correlation with the Symbol Digit Modalities Test, practice effects, test–retest reliability and the discriminative ability of MSReactor. Results: A total of 450 people with MS were recruited over 18 months, with 81% opting to complete home-based testing. Most participants (96%) would be happy (or neutral) to repeat the tasks again and just four reported the tasks made them ‘very anxious’. Persistence of home testing was high and practice effects stabilized within three tests. MSReactor tasks correlated with Symbol Digit Modalities Test scores and participants with MS performed slower than healthy controls. Conclusion: MSReactor is a scalable and reliable cognitive screening tool that can be used in the clinic and remotely. MSReactor task performance correlated with another highly validated cognitive test, was sensitive to MS and baseline predictors of cognitive performance were identified.

Background: Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) is of clinical relevance. Objectives: Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizumab or a BRACETD therapy (interferon beta, glatiramer acetate, teriflunomide, or dimethyl fumarate). Design: This retrospective analysis utilized data from MSBase to create a matched population allowing comparison of first-line natalizumab to first-line BRACETD. Methods: This study included patients who initiated treatment either with natalizumab or a BRACETD DMT within 1 year of MS diagnosis and continued treatment for ⩾6 months, after which patients could switch DMTs or discontinue treatment. Patients had a minimum follow-up time of ⩾60 months from initiation. A subgroup analysis compared the natalizumab group to patients in the BRACETD group who escalated therapy after 6 months. Outcomes included unadjusted annualized relapse rates (ARRs), time-to-first relapse, time-to-first confirmed disability improvement (CDI), and time-to-first confirmed disability worsening (CDW). Results: After 1:1 propensity score matching, 355 BRACETD patients were matched to 355 natalizumab patients. Patients initiating natalizumab were less likely to experience a relapse over the duration of follow-up, with ARRs [95% confidence interval (CI)] of 0.080 (0.070–0.092) for natalizumab patients and 0.191 (0.178–0.205) for BRACETD patients (p < 0.0001). A Cox regression model of time-to-first relapse showed a reduced risk of relapse for natalizumab patients [hazard ratio (95% CI) of 0.52 (0.42–0.65); p < 0.001] and a more favorable time-to-first CDI. The risk of CDW was similar between groups. The subgroup analysis showed an increased relapse risk as well as a significantly higher risk of CDW for BRACETD patients. Conclusion: Early initiation of natalizumab produced long-term benefits in relapse outcomes in comparison with BRACETD, regardless of a subsequent escalation in therapy.

Key Points The repertoire of disease-modifying therapies for relapsing–remitting multiple sclerosis (MS) has broadened greatly in the past decade Evidence-based recommendations from randomized clinical trials are insufficient to guide choices between most available MS drugs The combination of increasing worldwide availability of and access to large MS registries and databases and the growing ability to share and analyse large datasets is enabling real-world observational studies to be conducted Observational real-world studies are providing insights into predictors of MS treatment response, comparative effectiveness of disease-modifying therapies, and long-term treatment effectiveness that is useful for directing daily clinical practice Several new statistical methods are available, and continue to evolve, to minimize biases and limitations of real-world observational studies, thereby optimizing their validity and reliability In future, datasets from individual MS databases and registries should be aggregated into big data algorithms to develop new tools that will enable the implementation of personalized medicine Real-world observational studies have the potential to answer questions about multiple sclerosis (MS) treatment that randomized controlled trials cannot. Trojano and colleagues discuss the pitfalls and necessary safeguards in observational studies, and the insights that such studies have provided into treatment decisions for patients with MS. The complexity of multiple sclerosis (MS) treatment means that doctors and decision-makers need the best available evidence to make the best decisions for patient care. Randomized controlled trials (RCTs) are accepted as the gold standard for assessing the efficacy and safety of any new drug, but conclusions of these trials do not always aid in daily decision-making processes. Indeed, RCTs are usually conducted in ideal conditions, so can measure efficacy only in restricted and unrepresentative populations. In the past decade, a growing number of MS databases and registries have started to produce long-term outcome data from large cohorts of patients with MS treated with disease-modifying therapies in real-world settings. Such observational studies are addressing issues that are otherwise difficult or impossible to study. In this Review, we focus on the most recently published observational studies designed to identify predictors of poor outcome and treatment response or failure, and to evaluate the relative and long-term effectiveness of currently used MS treatments. We also outline the statistical approaches that are most commonly used to reduce bias and limitations in these studies, and the challenges associated with the use of 'big MS data' to facilitate the implementation of personalized medicine in MS.

Chimeric antigen receptor (CAR)-T cell therapies have transformed the management of relapsed or refractory haematological malignancies and are now being adapted for severe B-cell mediated autoimmune disease, including neuroimmunological disorders. Their appeal lies in deep and durable B-cell depletion within lymphoid tissues and target organs, with the potential to induce long-lasting, treatment-free remission. At the same time, broader application is constrained by serious toxicities, in particular, neurological complications such as immune effector cell-associated neurotoxicity syndrome (ICANS) and more recently recognised movement, cerebellar, cranial nerve and peripheral nerve syndromes. In this review, we outline the biological principles of CAR-T cell therapy and summarise the emerging experience in neuroimmunology. We draw on data from both oncology and early autoimmune trials to describe the clinical spectrum, timing and proposed mechanisms of CAR-T cell-related neurotoxicity and to distinguish ICANS from later and more focal toxicities. As CAR-T cell therapies move from cancer centres into the care of patients with refractory neuroimmunological disease, neurologists will need a detailed understanding of both their therapeutic promise and their neurological risks, and close collaboration within multidisciplinary teams will be essential to deliver these treatments safely.

Rationale To determine the prevalence of epileptic seizures in multiple sclerosis (MS) at an Australian tertiary hospital and to define their clinical features. Methods We retrospectively analysed adult patients at the Royal Melbourne Hospital electronically identified to have ICD codes for MS and seizures and/or epilepsy between 1996 to 2019, utilising paper and electronic-based records. Results Of the 2,125 MS patients identified, 16 (0.75%) experienced epileptic seizures during a mean follow-up period of 12.9 years. Median age of MS diagnosis (SD) was 38 (9.3) years. Four patients had relapsing remitting MS (25%), 10 secondary progressive MS (63.5%), and 2 primary progressive MS (12.5%). More than two-thirds of patients had seizure onset following the diagnosis of MS, and the majority of these had advanced disease (approximate EDSS >6) at the time of seizure onset. Focal onset-seizures occurred in 87.5% of patients with seizures. Conclusion The estimated prevalence of seizures in our cohort was lower than in previous studies (0.75 vs 2–4%). In most cases, seizures occurred after the diagnosis of MS in the context of advanced disease. Further studies are required to determine if MS disease modifying treatments reduce the risk of seizures in this cohort.

To compare clinical and MRI parameters between patients with clinically isolated syndrome and those converting to clinically definite multiple sclerosis within 2 years, to identify volumetric MRI predictors of this conversion and to assess effect of early relapses. The SET study comprised 220 patients with clinically isolated syndrome treated with interferon beta (mean age, 29 years; Expanded Disability Status Scale, 1.5). Three patients with missing data were excluded from the analysis. Physical disability, time to clinically definite multiple sclerosis and volumetric MRI data were recorded for 2 years. Patients reaching clinically definite multiple sclerosis showed impaired recovery of neurological function, faster decrease in corpus callosum cross-sectional area, higher T2 lesion volume and more contrast-enhancing lesions. Six-month decrease in corpus callosum cross-sectional area (≥ 1%) and baseline T2 lesion volume (≥ 5 cm(3)) predicted clinically definite multiple sclerosis within 2 years (hazard ratios 2.5 and 1.8, respectively). Of 22 patients fulfilling both predictive criteria, 83% reached clinically definite multiple sclerosis (hazard ratio 6.5). More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy. Neurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory activity is greater in patients converting to clinically definite multiple sclerosis. Six-month corpus callosum atrophy and baseline T2 lesion volume jointly help predict individual risk of clinically definite multiple sclerosis. Early relapses contribute to permanent damage of the central nervous system.