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Data from cohorts, registries, randomised trials, electronic medical records and administrative claims databases have increasingly been used to inform the use of therapies for neurological diseases. While novel sophisticated methods are enabling us to use existing data to guide treatment decisions, the complexity of statistical methodology is making appraisal of clinical evidence increasingly demanding. In this narrative review, we provide a brief overview of the most commonly used methods for evaluation of treatment effectiveness in neurology. This primer discusses complementarity of randomised and non-randomised study designs, sources of observational data, different forms of bias and the appropriate mitigation strategies, statistical significance, Bayesian approaches and provides an overview of multivariable regression models, propensity score-based models, causal inference, mediation analysis and Mendelian randomisation.

BACKGROUND: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. METHODS: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on

BACKGROUND: In patients with relapsing remitting multiple sclerosis (RRMS) on low-efficacy disease modifying therapies (DMT), the optimal strategy on how to escalate treatment once needed, remains unknown. METHODS: We studied RRMS patients on low-efficacy DMTs listed in the Swiss National Treatment Registry, who underwent escalation to either medium- or high-efficacy DMTs. Propensity score-based matching was applied using 12 clinically relevant variables. Both groups were also separately matched with control subjects who did not escalate therapy. Time to relapse and to disability worsening were evaluated using Cox proportional hazard models. RESULTS: Of 1037 eligible patients, we 1:1 matched 450 MS patients who switched from low-efficacy to medium-efficacy (n = 225; 76.0% females, aged 42.4 ± 9.9 years [mean ± SD], median EDSS 3.0 [IQR 2-4]) or high-efficacy DMTs (n = 225; 72.4% females, aged 42.2 ± 10.6 years, median EDSS 3.0 [IQR 2-4]). Escalation to high-efficacy DMTs was associated with lower hazards of relapses than medium-efficacy DMTs (HR = 0.67, 95% CI 0.47-0.95, p = .027) or control subjects (HR = 0.61, 95% CI 0.44-0.84, p = .003). By contrast, escalation from low to medium-efficacy DMTs did not alter the hazard for relapses when compared to controls (i.e. patients on low-efficacy DMT who did not escalate DMT during follow-up) CONCLUSION: Our nationwide registry analysis suggests that, once escalation from a low-efficacy DMT is indicated, switching directly to a high-efficacy treatment is superior to a stepwise escalation starting with a moderate-efficacy treatment.

The capacity and power of data from cohorts, registries and randomized trials to provide answers to contemporary clinical questions in neurology has increased considerably over the past two decades. Novel sophisticated statistical methods are enabling us to harness these data to guide treatment decisions, but their complexity is making appraisal of clinical evidence increasingly demanding. In this review, we discuss several methodological aspects of contemporary research of treatment effectiveness in observational data in neurology, aimed at academic neurologists and analysts specializing in outcomes research. The review discusses specifics of the sources of observational data and their key features. It focuses on the limitations of observational data and study design, as well as statistical approaches aimed to overcome these limitations. Among the examples of leading clinical themes typically studied with analyses of observational data, the review discusses methodological approaches to comparative treatment effectiveness, development of diagnostic criteria and definitions of clinical outcomes. Finally, this review provides a brief summary of key points that will help clinical audience critically evaluate design and analytical aspects of studies of disease outcomes using observational data.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients wa

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.

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

IMPORTANCE: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). OBJECTIVE: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. DESIGN, SETTING, AND PARTICIPANTS: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. EXPOSURE: AHSCT vs fingolimod, natalizumab, or ocrelizumab. MAIN OUTCOMES: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. RESULTS: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730

IMPORTANCE: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab. OBJECTIVE: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country. EXPOSURE: Treatment with ocrelizumab or rituximab after 2015. MAIN OUTCOMES AND MEASURES: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups. RESULTS: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). O

Background: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. Methods: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. Results: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. Conclusions: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

BACKGROUND: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. OBJECTIVE: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. METHODS: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. RESULTS: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. CONCLUSIONS: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Background: the prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. Objective: to determine whether early non-disabling relapses predict disability accumulation in RRMS. Methods: we redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. Results: people who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. Conclusion: this study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (fellowship nos.1140766 and 1080518, project grant nos. 1129189 and 1083539), the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), National Institute for Health and Care Research (UK) Advanced Fellowship (grant no. 301728; recipient JWLB) and Academic Clinical Fellowship (grant no. EAN/ACA-006/7488627/C; recipient CD). The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme, and Teva. Role of the Funder/Sponsor: The National Health and Medical Research Council of Australia, the University of Melbourne and the National Institute for Health and Care Research (UK) had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHOD(S): This was a retrospective cohort study from two large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12-months were included in the analysis. The primary study outcome was annualised relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULT(S): 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for seven therapies. Annualised rates of relapse (ARR) started to increase 2-months after natalizumab cessation (month 2-4 ARR, 95% confidence interval): 0.47, 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89), and stabilised faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01-0.29). Magnitude of disease reactivation for other therapies was low, but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were higher relapse rate in the year before cessation, female sex, younger age and higher EDSS. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95%CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). CONCLUSION(S): The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different t

BACKGROUND: There is growing interest in the issue of disease reactivation in multiple sclerosis following fingolimod cessation. Relatively little is known about modifiers of the risk of post-cessation relapse, including the delay to commencement of new therapy and prior disease activity. OBJECTIVE: We aimed to determine the rate of relapse following cessation of fingolimod and to identify predictors of relapse following cessation. METHODS: Data were extracted from the MSBase registry in March 2019. Inclusion criteria were (a) clinically definite relapsing multiple sclerosis, (b) treatment with fingolimod for ≥ 12 months, (c) follow-up after cessation for ≥ 12 months, and (d) at least one Expanded Disability Status Scale score recorded in the 12 months before cessation. RESULTS: A total of 685 patients were identified who met criteria. The mean annualised relapse rate was 1.71 (95% CI 1.59, 1.85) in the year prior to fingolimod, 0.50 (95% CI 0.44, 0.55) on fingolimod and 0.43 (95% CI 0.38, 0.49) after fingolimod. Of these, 218 (32%) patients experienced a relapse in the first 12 months. Predictors of a higher relapse rate in the first year were: younger age at fingolimod cessation, higher relapse rate in the year prior to cessation, delaying commencement of new therapy and switching to low-efficacy therapy. CONCLUSIONS: Disease reactivation following fingolimod cessation is more common in younger patients, those with greater disease activity prior to cessation and in those who switch to a low-efficacy therapy.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has precipitated expansion of telemedicine in outpatient management of chronic diseases including multiple sclerosis (MS). Studies conducted pre-pandemic, when telehealth was an alternative to in-person consultations, represent a different setting to current practice. The aim of this study was to assess the impact of telehealth on MS outpatient care in a tertiary metropolitan hospital in Melbourne, Australia during the COVID-19 pandemic. METHOD: From March-December 2020, patients and clinicians in the MS outpatient clinic were surveyed regarding their attitudes towards telehealth. Scores on the Expanded Disability Status Scale (EDSS) from telehealth and face-to-face appointments during the study period were compared to scores from face-to-face consultations before and after this period. Medical records were reviewed to compare management decisions made during telehealth versus face-to-face consultations. Diagnoses and treatment of MS relapses were compared to 2019. RESULTS: Telehealth was used in 73% of outpatient appointments. Patient satisfaction was generally high. Patients and clinicians preferred face-to-face consultations but were willing to use telehealth longer term. Overall, there were no significant delays in identifying patients experiencing disability worsening via telehealth, but EDSS increase was recorded in more face-to-face than telehealth appointments particularly for those with lower baseline disability. Disease-modifying therapy commencement rates were similar, but symptomatic therapy initiation and investigation requests occurred more frequently in face-to-face visits. Comparable numbers of MS relapses were diagnosed and treated with corticosteroids in 2019 and 2020. CONCLUSIONS: Patient satisfaction with telehealth was high, but both clinicians and patients preferred in-person appointments. Telehealth implementation did not lead to high rates of undetected disability worsening or undia

BACKGROUND AND OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHODS: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULTS: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). DISCUSSION: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued di

Based on reported trends in relapse incidence among patients with relapsing-remitting multiple sclerosis, an original model for the response to disease modifying therapies is proposed. With a population approach and separate states for patients accounting for their risk of relapses, a system of nonlinear equations is formulated, similarly to established epidemiological models. Different parameters describe the effect of drugs and treatment switch in reducing the frequency of relapses. The model allows for a good fit to previously published data for experiments where different drugs are used. It also shows that different treatments maintain a high degree of similarity, with analogous dynamical features: a pre-treatment increment in relapse frequency leading to a distinct peak, a rapid drop after treatment switch and a plateau corresponding to a new base relapse activity, which seems dependant on the treatment chosen. A sensitivity analysis shows that the uncertainty in the initial proportions of different populations and the frequency of relapses can modify the overall dynamics of the response to treatment. Drugs are observed to induce effects that depend on patient sample's intrinsic characteristics, producing two clearly distinct and independent dynamics of relapse response. This confirms the clinical observation that certain drugs may be overall more successful in lowering the rate of relapses more significantly than others, notwithstanding the fact that patients behave differently across experiments.

Introduction: Ocrelizumab, a monoclonal antibody targeted against CD20+ B cells, has become a popular treatment for relapsing-remitting multiple sclerosis (MS). The effectiveness of ocrelizumab compared to other treatments is however unknown. Aim(s): To compare the effectiveness of ocrelizumab with interferon-beta, fingolimod and natalizumab in relapsing-remitting MS. Method(s): Using the MSBase registry, we identified patients with relapsing-remitting MS treated for >=6 months with ocrelizumab, interferon- beta (interferon beta-1a, interferon beta-1b subcutaneous or interferon beta-1b intramuscular), fingolimod or natalizumab. All patients required >12-month pre-treatment follow up and the minimum dataset. Patients with comparable baseline characteristics were matched with propensity score on age, sex, MS duration, EDSS, prior relapse rate, prior therapy, disease activity, MRI lesion burden (missing values imputed), reason for discontinuation of preceding therapy (imputed) and country. Annualised rate of relapses (ARR) and cumulative hazard of relapses were compared in pairwise-censored groups. Result(s): 106 patients treated with ocrelizumab were matched with 209 patients on interferon therapies with a mean age of 39 years, 0.8 relapses per year and mean EDSS of 2.4-2.5. Over a pairwise-censored mean follow up of 1.3 years, ocrelizumab was associated with lower relapse rates (ARR 0.08 vs 0.27, p<0.001) and lower risk of relapse (HR 0.30, 95%CI 0.15-0.57) than interferon-beta. 297 patients treated with ocrelizumab were matched with 811 fingolimod-treated patients with a mean age of 41 years, 0.6 relapses per year and mean EDSS of 2.7-2.8. Over a pairwisecensored mean follow up of 1.5 years, ocrelizumab was associated with lower relapse rates (ARR 0.03 vs 0.14, p<0.001) and lower risk of relapse than fingolimod (HR 0.21, 0.13-0.32). 262 ocrelizumab- treated patients were matched with 343 natalizumab treated patients with a mean age of 39 years, 0.8 relapses per year

Background: Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS. Objective(s): We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016). Method(s): Inclusion required adult-onset progressive MS; >= 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS <= 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if >= 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over >= 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS >= 7 (wheelchair required) was assessed (Kaplan-Meier). Result(s): 5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 +/- 10.2, vs. 41.5 +/- 10.7 [mean +/- SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78-0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98-0.99); and higher in males (1.18; 1.12-1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71

BACKGROUND: Ocrelizumab safety outcomes have been well evaluated in clinical trials and open-label extension (OLE) studies. However, risk factors for infection in patients with multiple sclerosis (MS) receiving ocrelizumab have not been extensively studied in the real-world setting. OBJECTIVE: The aim of this study was to examine factors determining risk of self-reported infections and antimicrobial use in patients receiving ocrelizumab for MS. METHODS: A retrospective, observational cohort study was conducted in patients receiving ocrelizumab at the Royal Melbourne Hospital. Infection type and number were reported by patients, and the associations of potential clinical and laboratory risk factors with self-reported infection and antimicrobial use were estimated using univariate and multivariable logistic regression models. RESULTS: A total of 185 patients were included in the study; a total of 176 infections were reported in 89 patients (46.1%), and antimicrobial use was identified in 47 patients (25.3%). In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25-0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88-0.99), higher serum IgA (OR 0.37, 95% CI 0.17-0.80) and higher serum IgG (OR 0.81, 95% CI 0.67-0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75-0.96) and higher serum IgA (OR 0.23, 95% CI 0.07-0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06-1.41) and higher Expanded Disability Status Scale (EDSS) score (OR 1.99, 95% CI 1.02-3.86) were associated with increased odds of antimicrobial use. CONCLUSIONS: Higher serum IgA and IgG and older age were associated with reduced odds of infection. Our findings highlight that infection risk is not uniform in patients with MS receiving ocrelizumab and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy.

Objective: Patients with Multiple Sclerosis (MS) and on disease modifying therapies (DMTs) that can be immunosuppressive or immunomodulatory form a special group where risk of continuation of DMT needs to be taken into account with risk of contracting Covid-19. This concept can pose a degree of anxiety for patients as well as neurologists. We aimed to evaluate patient perspectives regarding the use of Natalizumab and anti-CD20 therapies (Rituximab and Ocrelizumab) in the context of the COVID-19 pandemic. Methods: cross-sectional study conducted via voluntary survey filled in by patients with MS and related disorders receiving their infusional treatment in one MS centre in Australia, exploring their concerns regarding their therapy, their therapy and COVID-19, precautions undertaken in response to the pandemic, and factors impacting their decision-making. Results: 170 patients completed the survey. Of patients on Natalizumab, the majority had either no or mild concern regarding their DMT and COVID-19, and of patients on B-cell depleting therapies, again, the majority had no or mild concern, though a slightly higher proportion had a moderate level of concern. Asked to delineate their concerns, an increased risk of contracting COVID-19 was more commonly conveyed than MS-specific factors or poor outcomes pertaining to COVID-19 if contracted, by patients in both groups. Conversely, being invited to specifically consider the possibility of contracting COVID-19 or experience a relapse of MS, almost half of the cohort rated both of equal of concern. More than half of the cohort were self-isolating more stringently than general government advice and government-related resources followed by information provided by patient's neurologist where the commonest means of information to guide decision making. Conclusions: Whilst a large proportion of patients had some concern regarding the impact of their DMT on COVID-19, whether on their risk of contracting COVID-19 or a theoretical

BACKGROUND: The association of the anti-aquaporin-4 (AQP-4) water channel antibody with neuromyelitis optica (NMO) syndrome has been described from various parts of the world. There has been no large study describing this association from southern Africa, an HIV endemic area. HIV patients often present with visual disturbance or features of a myelopathy but seldom both either simultaneously or consecutively. We report our experience of NMO in the era of AQP-4 testing in HIV-positive and HIV-negative patients seen in KwaZulu-Natal, South Africa. METHODS: A retrospective chart review was undertaken of NMO cases seen from January 2005 to April 2016 in two neurology units serving a population of 7.1 million adults. The clinical, radiological and relevant laboratory data were extracted from the files and analysed. RESULTS: There were 12 HIV-positive patients (mean age 33 years), 9 (75%) were women and all 12 were black patients. Of the 17 HIV-negative patients (mean age 32 years), 15 (88%) were women and 10 (59%) were black people. The clinical features in the two groups ranged from isolated optic neuritis, isolated longitudinally extensive myelitis or combinations. Recurrent attacks were noted in six HIV-positive patients and six HIV-negative patients. The AQP-4 antibody was positive in 4/10 (40%) HIV-positive patients and 11/13 (85%) HIV-negative patients. The radiological changes ranged from longitudinal hyperintense spinal cord lesions and long segment enhancing lesions of the optic nerves. Three patients, all HIV-positive, had tumefactive lesions with incomplete ring enhancement. CONCLUSION: This study confirms the presence of AQP-4-positive NMO in southern Africa in both HIV-positive and HIV-negative patients. The simultaneous or consecutive occurrence of optic neuritis and myelitis in an HIV-positive patient should alert the clinician to test for the AQP-4 antibody. It is important to recognise this clinical syndrome as specific therapy is available. We further po

Background Value-based health care has been proposed as a unifying force to drive improved outcomes and cost containment. Objective To develop a standard set of multidimensional patient-centered health outcomes for tracking, comparing, and improving localized prostate cancer (PCa) treatment value. Design, setting, and participants We convened an international working group of patients, registry experts, urologists, and radiation oncologists to review existing data and practices. Outcome measurements and statistical analysis The group defined a recommended standard set representing who should be tracked, what should be measured and at what time points, and what data are necessary to make meaningful comparisons. Using a modified Delphi method over a series of teleconferences, the group reached consensus for the Standard Set. Results and limitations We recommend that the Standard Set apply to men with newly diagnosed localized PCa treated with active surveillance, surgery, radiation, or other methods. The Standard Set includes acute toxicities occurring within 6 mo of treatment as well as patient-reported outcomes tracked regularly out to 10 yr. Patient-reported domains of urinary incontinence and irritation, bowel symptoms, sexual symptoms, and hormonal symptoms are included, and the recommended measurement tool is the Expanded Prostate Cancer Index Composite Short Form. Disease control outcomes include overall, cause-specific, metastasis-free, and biochemical relapse-free survival. Baseline clinical, pathologic, and comorbidity information is included to improve the interpretability of comparisons. Conclusions We have defined a simple, easily implemented set of outcomes that we believe should be measured in all men with localized PCa as a crucial first step in improving the value of care. Patient summary Measuring, reporting, and comparing identical outcomes across treatments and treatment centers will provide patients and providers with information to make informed

Onderzoek naar de huidige toestand van de Noordersluis., Beste TU Delft, Op de repository Hydraulic Engineering van de TU Delft tref ik enkele rapporten aan die in het kader van het project Zeetoegang IJmond zijn opgesteld door DHV en Iv-Infra. Als opdrachtgever (Rijkswaterstaat) van de rapporten zouden we graag zien dat dergelijke informatie niet op internet wordt verspreid. We zouden daarom ook graag willen weten hoe en door wie de rapporten op internet zijn geplaatst. Overigens heeft Iv-Infra duidelijk vermeld in haar rapporten dat verspreiding van deze informatie niet is toegestaann. Het gaat om het T0 onderzoek op de Noordersluis. G. (Gökhan) Dilsiz Projectondersteuner RINK Rijkswaterstaat Dienst Infrastructuur antwoord HJ verhagen op 16-5-2013: Wij hebben al enige jaren een overeenkomst met Rijkswaterstaat dat wij niet-vertrouwelijke onderzoeken die door of in opdracht van Rijkswaterstaat gemaakt zijn op onze Repository mogen plaatsen. De achtergrond hiervan is geweest dat veel materiaal binnen Rijkswaterstaat, met name bij reorganisaties, verloren is gegaan. Dit kan op deze wijze enigszins voorkomen worden. In principe zijn documenten van de overheid of gemaakt voor de overheid openbaar en opvraagbaar middels beroep op de WUB. Omdat WUB procedures voor alle partijen veel tijd kosten, is er besloten om hier een algemene overeenkomst van te maken. Het feit dat IV-infra en DHV in het rapport zetten dat het niet opgenomen mag worden in een bestand heeft overigens geen betekenis. Het werk is uitgevoerd in opdracht van (en betaald door) Rijkswaterstaat als publieke opdrachtgever, dus Rijkswaterstaat mag er mee doen wat ze willen. Wel hebben IV-Infra en DHV het copyright. Dat betekent dat je de informatie uit deze rapporten niet commercieel mag doorverkopen als “eigen werk”. Het is dus aan Rijkswaterstaat om te besluiten wat er mee mag gebeuren, waarbij Rijkswaterstaat als overheid wel gebonden is aan de Wet Openbaarheid van Bestuur, dus niet zonder reden een bepaald rapport vertrouwelijk mag houden. Het is mij niet meer, Sluis IJmuiden