Escalating to medium- versus high-efficacy disease modifying therapy after low-efficacy treatment in relapsing remitting multiple sclerosis.

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.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

BACKGROUND AND OBJECTIVES: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. METHODS: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. RESULTS: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). DISCUSSION: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Smartwatch-derived sleep and heart rate measures complement step counts in explaining established metrics of MS severity.

BACKGROUND: Passive remote monitoring of patients with MS (PwMS) with sensor-based wearable technologies promises near-continuous evaluation with high ecological validity. Step counts correlate strongly with traditional measures of MS severity. We hypothesized that remote monitoring of sleep and heart rate will yield complementary information. METHODS: We recruited 31 PwMS and 31 age- and sex-matched healthy volunteers (HV) as part of the dreaMS feasibility study (NCT04413032). Fitbit Versa 2 smartwatches were worn for 6 weeks and provided a total of 25 features for activity, heart rate, and sleep. Features were selected based on their pairwise intercorrelation (Pearson |r| < 0.6), test-retest reliability (intraclass correlation coefficient ≥ 0.6 or median coefficient of variation < 0.2) and group comparisons between HV and PwMS with moderate disability (expanded disability status scale (EDSS) ≥ 3.5) (rank-biserial |r| ≥ 0.5). These selected features were correlated with clinical reference tests (EDSS, timed 25-foot walk (T25FW), MS-walking scale (MSWS-12)) in PwMS, and multivariate models adjusted for age, sex, and disease duration were compared. RESULTS: We analyzed 28 PwMS (68% female, mean age 44 years, median EDSS 3.0) and 26 HV in our primary analysis. The objectively selected features discriminated well between HV and PwMS with moderate disability with rank-biserial r = 0.83 for Total number of steps, 0.51 for Deep sleep proportion, -0.51 for Median heart rate, 0.85 for Proportion very active, and 0.65 for Total number of floors. In PwMS they correlated strongly with the three clinical reference tests EDSS (strongest Spearman ρ = -0.75 for Proportion very active), T25FW (-0.75 for Total number of floors), and MSWS-12 (-0.72 for Total number of floors). Deep sleep proportion and Median heart rate complemented Total number of steps in explaining the variance of reference tests. CONCLUSIONS: Activity, deep sleep and heart rate measures can be derived reliably from smartwatches and contain independent clinically meaningful information about MS severity, highlighting their potential for continuous passive monitoring in both clinical trials and clinical care of PwMS.

Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis: A Systematic Review.

Importance: Emerging evidence suggests that progression independent of relapse activity (PIRA) is a substantial contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (RRMS). To date, there is no uniform agreed-upon definition of PIRA, limiting the comparability of published studies. Objective: To summarize the current evidence about PIRA based on a systematic review, to discuss the various terminologies used in the context of PIRA, and to propose a harmonized definition for PIRA for use in clinical practice and future trials. Evidence Review: A literature search was conducted using the search terms multiple sclerosis, PIRA, progression independent of relapse activity, silent progression, and progression unrelated to relapses in PubMed, Embase, Cochrane, and Web of Science, published between January 1990 and December 2022. Findings: Of 119 identified single records, 48 eligible studies were analyzed. PIRA was reported to occur in roughly 5% of all patients with RRMS per annum, causing at least 50% of all disability accrual events in typical RRMS. The proportion of PIRA vs relapse-associated worsening increased with age, longer disease duration, and, despite lower absolute event numbers, potent suppression of relapses by highly effective disease-modifying therapy. However, different studies used various definitions of PIRA, rendering the comparability of studies difficult. Conclusion and Relevance: PIRA is the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including clinically isolated syndrome and early RRMS. The harmonized definition suggested here may improve the comparability of results in current and future cohorts and data sets.

Comparative analysis of dimethyl fumarate and teriflunomide in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: In relapsing-remitting multiple sclerosis (RRMS), analyses from observational studies comparing dimethyl fumarate (DMF) and teriflunomide showed conflicting results. We aimed to compare the effectiveness of DMF and teriflunomide in a real-world setting, where both drugs are licensed as first-line therapies for RRMS. METHODS: We included all patients who initiated DMF or teriflunomide between 2013 and 2022, listed in the Swiss National Treatment Registry. Coarsened exact matching was applied using age, gender, disease duration, baseline Expanded Disability Status Scale (EDSS) score, time since last relapse, and relapse rate in the previous year as matching variables. Time to relapse and time to 12-month confirmed EDSS worsening were compared using Cox proportional hazard models. RESULTS: In total, 2028 patients were included in this study, of whom 1498 were matched (DMF: n = 1090, 69.6% female, mean age 45.1 years, median EDSS score 2.0; teriflunomide: n = 408, 68.9% female, mean age 45.1 years, median EDSS score 2.0). Time to relapse and time to EDSS worsening was longer in the DMF than the teriflunomide group (hazard ratio 0.734, p = 0.026 and hazard ratio 0.576, p = 0.003, respectively). CONCLUSION: Analysis of real-world data showed that DMF treatment was associated with more favorable outcomes than teriflunomide treatment.

Wearable Sensor Technologies to Assess Motor Functions in People With Multiple Sclerosis: Systematic Scoping Review and Perspective.

BACKGROUND: Wearable sensor technologies have the potential to improve monitoring in people with multiple sclerosis (MS) and inform timely disease management decisions. Evidence of the utility of wearable sensor technologies in people with MS is accumulating but is generally limited to specific subgroups of patients, clinical or laboratory settings, and functional domains. OBJECTIVE: This review aims to provide a comprehensive overview of all studies that have used wearable sensors to assess, monitor, and quantify motor function in people with MS during daily activities or in a controlled laboratory setting and to shed light on the technological advances over the past decades. METHODS: We systematically reviewed studies on wearable sensors to assess the motor performance of people with MS. We scanned PubMed, Scopus, Embase, and Web of Science databases until December 31, 2022, considering search terms "multiple sclerosis" and those associated with wearable technologies and included all studies assessing motor functions. The types of results from relevant studies were systematically mapped into 9 predefined categories (association with clinical scores or other measures; test-retest reliability; group differences, 3 types; responsiveness to change or intervention; and acceptability to study participants), and the reporting quality was determined through 9 questions. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines. RESULTS: Of the 1251 identified publications, 308 were included: 176 (57.1%) in a real-world context, 107 (34.7%) in a laboratory context, and 25 (8.1%) in a mixed context. Most publications studied physical activity (196/308, 63.6%), followed by gait (81/308, 26.3%), dexterity or tremor (38/308, 12.3%), and balance (34/308, 11%). In the laboratory setting, outcome measures included (in addition to clinical severity scores) 2- and 6-minute walking tests, timed 25-foot walking test, timed up and go, stair climbing, balance tests, and finger-to-nose test, among others. The most popular anatomical landmarks for wearable placement were the waist, wrist, and lower back. Triaxial accelerometers were most commonly used (229/308, 74.4%). A surge in the number of sensors embedded in smartphones and smartwatches has been observed. Overall, the reporting quality was good. CONCLUSIONS: Continuous monitoring with wearable sensors could optimize the management of people with MS, but some hurdles still exist to full clinical adoption of digital monitoring. Despite a possible publication bias and vast heterogeneity in the outcomes reported, our review provides an overview of the current literature on wearable sensor technologies used for people with MS and highlights shortcomings, such as the lack of harmonization, transparency in reporting methods and results, and limited data availability for the research community. These limitations need to be addressed for the growing implementation of wearable sensor technologies in clinical routine and clinical trials, which is of utmost importance for further progress in clinical research and daily management of people with MS. TRIAL REGISTRATION: PROSPERO CRD42021243249; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=243249.

Recanalization Therapies for Large Vessel Occlusion Due to Cervical Artery Dissection: A Cohort Study of the EVA-TRISP Collaboration.

BACKGROUND AND PURPOSE: This study aimed to investigate the effect of endovascular treatment (EVT, with or without intravenous thrombolysis [IVT]) versus IVT alone on outcomes in patients with acute ischemic stroke (AIS) and intracranial large vessel occlusion (LVO) attributable to cervical artery dissection (CeAD). METHODS: This multinational cohort study was conducted based on prospectively collected data from the EVA-TRISP (EndoVAscular treatment and ThRombolysis for Ischemic Stroke Patients) collaboration. Consecutive patients (2015-2019) with AIS-LVO attributable to CeAD treated with EVT and/or IVT were included. Primary outcome measures were (1) favorable 3-month outcome (modified Rankin Scale score 0-2) and (2) complete recanalization (thrombolysis in cerebral infarction scale 2b/3). Odds ratios with 95% confidence intervals (OR [95% CI]) from logistic regression models were calculated (unadjusted, adjusted). Secondary analyses were performed in the patients with LVO in the anterior circulation (LVOant) including propensity score matching. RESULTS: Among 290 patients, 222 (76.6%) had EVT and 68 (23.4%) IVT alone. EVT-treated patients had more severe strokes (National Institutes of Health Stroke Scale score, median [interquartile range]: 14 [10-19] vs. 4 [2-7], P<0.001). The frequency of favorable 3-month outcome did not differ significantly between both groups (EVT: 64.0% vs. IVT: 86.8%; ORadjusted 0.56 [0.24-1.32]). EVT was associated with higher rates of recanalization (80.5% vs. 40.7%; ORadjusted 8.85 [4.28-18.29]) compared to IVT. All secondary analyses showed higher recanalization rates in the EVT-group, which however never translated into better functional outcome rates compared to the IVT-group. CONCLUSION: We observed no signal of superiority of EVT over IVT regarding functional outcome in CeAD-patients with AIS and LVO despite higher rates of complete recanalization with EVT. Whether pathophysiological CeAD-characteristics or their younger age might explain this observation deserves further research.

Assessment of cognitive performance in multiple sclerosis using smartphone-based training games: a feasibility study.

BACKGROUND: Cognitive impairment occurs in up to 70% of people with MS (pwMS) and has a large impact on quality of life and working capacity. As part of the development of a smartphone-app (dreaMS) for monitoring MS disease activity and progression, we assessed the feasibility and acceptance of using cognitive games as assessment tools for cognitive domains. METHODS: We integrated ten cognitive games in the dreaMS app. Participants were asked to play these games twice a week for 5 weeks. All subjects underwent a battery of established neuropsychological tests. User feedback on acceptance was obtained via a five-point Likert-scale questionnaire. We correlated game performance measures with predetermined reference tests (Spearman's rho) and analyzed differences between pwMS and Healthy Controls (rank biserial correlation). RESULTS: We included 31 pwMS (mean age 43.4 ± 12.0 years; 68% females; median Expanded Disability Status Scale score 3.0, range 1.0-6.0) and 31 age- and sex-matched HC. All but one game showed moderate-strong correlations with their reference tests, (|rs|= 0.34-0.77). Performance improved in both groups over the 5 weeks. Average ratings for overall impression and meaningfulness were 4.6 (range 4.2-4.9) and 4.7 (range 4.5-4.8), respectively. CONCLUSION: Moderate-strong correlations with reference tests suggest that adaptive cognitive games may be used as measures of cognitive domains. The practice effects observed suggest that game-derived measures may capture change over time. All games were perceived as enjoyable and meaningful, features crucial for long-term adherence. Our results encourage further validation of adaptive cognitive games as monitoring tools for cognition in larger studies of longer duration. STUDY REGISTER: ClinicalTrials.gov: NCT04413032.

Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis.

Importance: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). Objective: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression. Design, Setting, and Participants: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab). Exposures: Patients received standard immunotherapies or were untreated. Main Outcomes and Measures: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally. Results: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001). Conclusions and Relevance: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Synthesizing cross-design evidence and cross-format data using network meta-regression.

In network meta-analysis (NMA), we synthesize all relevant evidence about health outcomes with competing treatments. The evidence may come from randomized clinical trials (RCT) or non-randomized studies (NRS) as individual participant data (IPD) or as aggregate data (AD). We present a suite of Bayesian NMA and network meta-regression (NMR) models allowing for cross-design and cross-format synthesis. The models integrate a three-level hierarchical model for synthesizing IPD and AD into four approaches. The four approaches account for differences in the design and risk of bias (RoB) in the RCT and NRS evidence. These four approaches variously ignoring differences in RoB, using NRS to construct penalized treatment effect priors and bias-adjustment models that control the contribution of information from high RoB studies in two different ways. We illustrate the methods in a network of three pharmacological interventions and placebo for patients with relapsing-remitting multiple sclerosis. The estimated relative treatment effects do not change much when we accounted for differences in design and RoB. Conducting network meta-regression showed that intervention efficacy decreases with increasing participant age. We also re-analysed a network of 431 RCT comparing 21 antidepressants, and we did not observe material changes in intervention efficacy when adjusting for studies' high RoB. We re-analysed both case studies accounting for different study RoB. In summary, the described suite of NMA/NMR models enables the inclusion of all relevant evidence while incorporating information on the within-study bias in both observational and experimental data and enabling estimation of individualized treatment effects through the inclusion of participant characteristics.

Reliability and acceptance of dreaMS, a software application for people with multiple sclerosis: a feasibility study.

BACKGROUND: There is an unmet need for reliable and sensitive measures for better monitoring people with multiple sclerosis (PwMS) to detect disease progression early and adapt therapeutic measures accordingly. OBJECTIVE: To assess reliability of extracted features and meaningfulness of 11 tests applied through a smartphone application ("dreaMS"). METHODS: PwMS (age 18-70 and EDSS ≤ 6.5) and matched healthy volunteers (HV) were asked to perform tests installed on their smartphone once or twice weekly for 5 weeks. Primary outcomes were test-retest reliability of test features (target: intraclass correlation [ICC] ≥ 0.6 or median coefficient of variation [mCV] < 0.2) and reported meaningfulness of the tests by PwMS. Meaningfulness was self-assessed for each test on a 5-point Likert scale (target: mean score of > 3) and by a structured interview. CLINICALTRIALS: gov Identifier: NCT04413032. RESULTS: We included 31 PwMS (21 [68%] female, mean age 43.4 ± 12.0 years, median EDSS 3.0 [range 1.0-6.0]) and 31 age- and sex-matched healthy volunteers. Out of 133 features extracted from 11 tests, 89 met the preset reliability criteria. All 11 tests were perceived as highly meaningful to PwMS. CONCLUSION: The dreaMS app reliably assessed features reflecting key functional domains meaningful to PwMS. More studies with longer follow-up are needed to prove validity of these measures as digital biomarkers in PwMS.

Recurrent disability progression endpoints in multiple sclerosis clinical trials.

BACKGROUND: The current standard endpoint to assess disability accumulation in multiple sclerosis (MS) clinical trials is the time to the first confirmed disability progression, which excludes subsequent progression events. Including recurrent progression events may permit a more comprehensive assessment of treatment effects on disability progression. OBJECTIVE: To propose a definition of recurrent disability progression events and to compare time-to-first and recurrent event analysis. METHODS: Recurrent disability progression events were defined by expanding the recommended first event definition. Marginal recurrent event methods (negative binomial model, Lin-Wei-Yang-Ying model) were compared with Cox regression in data from three randomized controlled trials in relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), and in simulated randomized controlled trial data. RESULTS: The recurrent event analyses included a substantially larger number of progression events compared with the time-to-first-event analyses (+7.5% and +9.9% in the RMS trials and +22.7% in the PPMS trial). The increase in the number of events resulted in more precise treatment effect estimates and a corresponding gain in statistical power. CONCLUSION: Our results support the use of recurrent event data analysis, especially in progressive MS trials, to improve estimates of treatment effects, increase statistical power, and better capture the clinically meaningful long-term disability progression experience.

Heterogeneity on long-term disability trajectories in patients with secondary progressive MS: a latent class analysis from Big MS Data network.

BACKGROUND: Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time. METHODS: All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3-4. RESULTS: A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria. CONCLUSIONS: Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.

Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis.

Importance: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. Objective: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. Design, Setting, and Participants: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. Exposures: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Main Outcomes and Measures: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Results: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Conclusions and Relevance: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

Endovascular Treatment for Acute Ischemic Stroke With or Without General Anesthesia: A Matched Comparison.

BACKGROUND: Endovascular treatment in large artery occlusion stroke reduces disability. However, the impact of anesthesia type on clinical outcomes remains uncertain. METHODS: We compared consecutive patients in the Swiss Stroke Registry with anterior circulation stroke receiving endovascular treatment with or without general anesthesia (GA). The primary outcome was disability on the modified Rankin Scale after 3 months, analyzed with ordered logistic regression. Secondary outcomes included dependency or death (modified Rankin Scale score ≥3), National Institutes of Health Stroke Scale after 24 hours, symptomatic intracranial hemorrhage with ≥4 points worsening on National Institutes of Health Stroke Scale within 7 days, and mortality. Coarsened exact matching and propensity score matching were performed to adjust for indication bias. RESULTS: One thousand two hundred eighty-four patients (GA: n=851, non-GA: n=433) from 8 Stroke Centers were included. Patients treated with GA had higher modified Rankin Scale scores after 3 months than patients treated without GA, in the unmatched (odds ratio [OR], 1.75 [1.42-2.16]; P<0.001), the coarsened exact matching (n=332-524, using multiple imputations of missing values; OR, 1.60 [1.08-2.36]; P=0.020), and the propensity score matching analysis (n=568; OR, 1.61 [1.20-2.15]; P=0.001). In the coarsened exact matching analysis, there were no significant differences in National Institutes of Health Stroke Scale after 1 day (estimated coefficient 2.61 [0.59-4.64]), symptomatic intracranial hemorrhage (OR, 1.06 [0.30-3.75]), dependency or death (OR, 1.42 [0.91-2.23]), or mortality (OR, 1.65 [0.94-2.89]). In the propensity score matching analysis, National Institutes of Health Stroke Scale after 24 hours (estimated coefficient, 3.40 [1.76-5.04]), dependency or death (OR, 1.49 [1.07-2.07]), and mortality (OR, 1.65 [1.11-2.45]) were higher in the GA group, whereas symptomatic intracranial hemorrhage did not differ significantly (OR, 1.77 [0.73-4.29]). CONCLUSIONS: This large study showed worse functional outcome after endovascular treatment of anterior circulation stroke with GA than without GA in a real-world setting. This finding appears to be independent of known differences in patient characteristics between groups.

Practice Effects of Mobile Tests of Cognition, Dexterity, and Mobility on Patients With Multiple Sclerosis: Data Analysis of a Smartphone-Based Observational Study.

BACKGROUND: Smartphones and their built-in sensors allow for measuring functions in disease-related domains through mobile tests. This could improve disease characterization and monitoring, and could potentially support treatment decisions for multiple sclerosis (MS), a multifaceted chronic neurological disease with highly variable clinical manifestations. Practice effects can complicate the interpretation of both improvement over time by potentially exaggerating treatment effects and stability by masking deterioration. OBJECTIVE: The aim of this study is to identify short-term learning and long-term practice effects in 6 active tests for cognition, dexterity, and mobility in user-scheduled, high-frequency smartphone-based testing. METHODS: We analyzed data from 264 people with self-declared MS with a minimum of 5 weeks of follow-up and at least 5 repetitions per test in the Floodlight Open study, a self-enrollment study accessible by smartphone owners from 16 countries. The collected data are openly available to scientists. Using regression and bounded growth mixed models, we characterized practice effects for the following tests: electronic Symbol Digit Modalities Test (e-SDMT) for cognition; Finger Pinching and Draw a Shape for dexterity; and Two Minute Walk, U-Turn, and Static Balance for mobility. RESULTS: Strong practice effects were found for e-SDMT (n=4824 trials), Finger Pinching (n=19,650), and Draw a Shape (n=19,019) with modeled boundary improvements of 40.8% (39.9%-41.6%), 86.2% (83.6%-88.7%), and 23.1% (20.9%-25.2%) over baseline, respectively. Half of the practice effect was reached after 11 repetitions for e-SDMT, 28 repetitions for Finger Pinching, and 17 repetitions for Draw a Shape; 90% was reached after 35, 94, and 56 repetitions, respectively. Although baseline performance levels were highly variable across participants, no significant differences between the short-term learning effects in low performers (5th and 25th percentile), median performers, and high performers (75th and 95th percentile) were found for e-SDMT up to the fifth trial (ß=1.50-2.00). Only small differences were observed for Finger Pinching (ß=1.25-2.5). For U-Turn (n=15,051) and Static Balance (n=16,797), only short-term learning effects could be observed, which ceased after a maximum of 5 trials. For Two Minute Walk (n=14,393), neither short-term learning nor long-term practice effects were observed. CONCLUSIONS: Smartphone-based tests are promising for monitoring the disease trajectories of MS and other chronic neurological diseases. Our findings suggest that strong long-term practice effects in cognitive and dexterity functions have to be accounted for to identify disease-related changes in these domains, especially in the context of personalized health and in studies without a comparator arm. In contrast, changes in mobility may be more easily interpreted because of the absence of long-term practice effects, even though short-term learning effects might have to be considered.

Acute Polyradiculomyelitis With Spinal Cord Gray Matter Lesions: A Report of Two Cases.

Objective: Inflammatory polyradiculomyelitis belongs to a rare group of immune-mediated diseases affecting both the central and peripheral nervous system. We aimed to describe an unusual presentation of acute polyradiculomyelitis with marked spinal cord lesions restricted to the gray matter. Methods: Thorough examination of two case reports including clinical, MRI, serologic, electrophysiologic and CSF examinations as well as short-term follow-up. Results: We present two adult patients with acute polyradiculomyelitis and unusual spinal cord lesions restricted to the gray matter on MRI. The clinical presentation, serologic, electrophysiologic and CSF features of the two patients varied, whereas both patients demonstrated severe, asymmetrical, predominantly distal, motor deficits of the lower extremities as well as bladder and bowel dysfunction. Both patients only partially responded to anti-inflammatory treatment. Severe motor impairment and bladder dysfunction persisted even months after symptom onset. Conclusions: To our best of knowledge, these are the first reports of acute polyradiculomyelitis with distinct involvement of the lower thoracic spinal cord gray matter. Currently, it remains unclear whether gray matter lesions reflect a separate pathophysiologic mechanism or an exceedingly rare presentation of spinal cord involvement in acute polyradiculomyelitis.

Disability progression in relapse-free multiple sclerosis patients on fingolimod versus interferon-beta/glatiramer acetate.

BACKGROUND: Disability progression independent of relapses (PIRA) has been described as a frequent phenomenon in relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To compare the occurrence of disability progression in relapse-free RRMS patients on interferon-beta/glatiramer acetate (IFN/GA) versus fingolimod. METHODS: This study is based on data from the Swiss association for joint tasks of health insurers. Time to relapse and 12-month confirmed disability progression were compared between treatment groups using multivariable Cox regression analysis with confounder adjustment. Inverse-probability weighting was applied to correct for the bias that patients on fingolimod have a higher chance to remain relapse-free than patients on IFN/GA. RESULTS: We included 1640 patients (64% IFN/GA, 36% fingolimod, median total follow-up time = 4-5 years). Disease-modifying treatment (DMT) groups were well balanced with regard to potential confounders. Disability progression was observed in 155 patients (8.8%) on IFN/GA and 51 (7.6%) on fingolimod, of which 44 and 23 were relapse-free during the initial DMT, respectively. Adjusted standard regression analysis on all patients indicated that those on fingolimod experience less frequently disability progression compared with IFN/GA (hazard ratio = 0.53 (95% confidence interval = 0.37-0.76)). After bias correction, this was also true for patients without relapses (hazard ratio=0.56 (95% confidence interval = 0.32-0.98). CONCLUSION: Our analysis indicates that fingolimod is superior to IFN/GA in preventing disability progression in both relapsing and relapse-free, young, newly diagnosed RRMS patients.

Accurate classification of secondary progression in multiple sclerosis using a decision tree.

BACKGROUND: The absence of reliable imaging or biological markers of phenotype transition in multiple sclerosis (MS) makes assignment of current phenotype status difficult. OBJECTIVE: The authors sought to determine whether clinical information can be used to accurately assign current disease phenotypes. METHODS: Data from the clinical visits of 14,387 MS patients in Sweden were collected. Classifying algorithms based on several demographic and clinical factors were examined. Results obtained from the best classifier when predicting neurologist recorded disease classification were replicated in an independent cohort from British Columbia and were compared to a previously published algorithm and clinical judgment of three neurologists. RESULTS: A decision tree (the classifier) containing only most recently available expanded disability scale status score and age obtained 89.3% (95% confidence intervals (CIs): 88.8-89.8) classification accuracy, defined as concordance with the latest reported status. Validation in the independent cohort resulted in 82.0% (95% CI: 81.0-83.1) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95% CI: 77.1-78.4) accuracy. With complete patient history of 100 patients, three neurologists obtained 84.3% accuracy compared with 85% for the classifier using the same data. CONCLUSION: The classifier can be used to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information.