Objective Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow‐up. Notably, “no evidence of disease activity” at 2 years did not predict long‐term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long‐term disability accumulation. Methods Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0–5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA‐DRB1*15:01 as covariates. Results Relapses were associated with a transient increase in disability over 1‐year intervals ( p = 0.012) but not with confirmed disability progression ( p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable ( p < 0.05). Interpretation Long‐term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing–remitting MS. Ann Neurol 2019;85:653–666

Importance Disability measures in multiple sclerosis (MS) fail to capture potentially important variability in walking behavior. More sensitive and ecologically valid outcome measures are needed to advance MS research. Objectives To assess continuous step count activity remotely among individuals with MS for 1 year and determine how average daily step count is associated with other measures of MS disability. Design, Setting, and Participants In a prospective longitudinal observational cohort study, 95 adults with relapsing or progressive MS who were able to walk more than 2 minutes with or without an assistive device were recruited between June 15, 2015, and August 8, 2016, and remotely monitored in their natural environment for 1 year. Patients were excluded if they had a clinical relapse within 30 days or comorbidity contributing to ambulatory impairment. Longitudinal analysis was performed from October 2017 to March 2018. Revised analysis was performed in December 2018. Intervention Activity monitoring of step count using a wrist-worn accelerometer. Main Outcomes and Measures Average daily step count compared with in-clinic assessments and patient-reported outcomes. Results Of the 95 participants recruited (59 women and 36 men; mean [SD] age, 49.6 [13.6] years [range, 22.0-74.0 years]), 35 (37%) had progressive MS, and the median baseline Expanded Disability Status Scale score was 4.0 (range, 0-6.5). At 1 year, 79 participants completed follow-up (83% retention). There was a modest reduction in accelerometer use during the 1 year of the study. A decreasing average daily step count during the study was associated with worsening of clinic-based outcomes (Timed 25-Foot Walk, β = −13.09; P < .001; Timed-Up-and-Go, β = −9.25; P < .001) and patient-reported outcomes (12-item Multiple Sclerosis Walking Scale, β = −17.96; P < .001). A decreasing average daily step count occurred even when the Expanded Disability Status Scale score remained stable, and 12 of 25 participants (48%) with a significant decrease in average daily step count during the study did not have a reduction on other standard clinic-based metrics. Participants with a baseline average daily step count below 4766 (cohort median) had higher odds of clinically meaningful disability (Expanded Disability Status Scale score) worsening at 1 year, adjusting for age, sex, and disease duration (odds ratio, 4.01; 95% CI, 1.17-13.78; P = .03). Conclusions and Relevance Continuous remote activity monitoring of individuals with MS for 1 year appears to be feasible. In this study, a decreasing average daily step count during a 1-year period was associated with worsening of standard ambulatory measures but could also occur even when traditional disability measures remained sta...

Purpose of review This review discusses concepts for diagnosing neuromyelitis optica spectrum disorders (NMOSD), distinguishing NMOSD from other inflammatory diseases of the central nervous system, and highlights recent and forthcoming data on acute and maintenance therapy of NMOSD. Recent findings The neurologic manifestations of NMOSD are heterogenous, extending beyond classic presentations of optic neuritis and longitudinally extensive transverse myelitis. NMOSD may be comorbid with rheumatologic diseases, such as systemic lupus erythematosus, but is recognized as a distinct entity. Recent studies of acute treatment of NMOSD support early use of plasmapheresis. Relapse prevention is essential, as relapses can be disabling and patients may have only partial recovery. Current practice generally recommends at least 5 years of maintenance treatment. Recent randomized data demonstrates superiority of rituximab over azathioprine. Phase 3 trials have recently been completed or are underway studying novel therapies employing B-cell depletion, complement inhibition, and cell-based mechanisms (among other mechanisms) for maintenance therapy of NMOSD. Summary NMOSD is a heterogeneous but well-defined clinical entity, distinct from other neurologic and systemic inflammatory diseases, and treatment is poised for expansion.

Background: Objective tools for prognosis and disease progression monitoring in multiple sclerosis (MS) are lacking. The visuomotor system could be used to track motor dysfunction at the micron scale through the monitoring of fixational microsaccades. Aims: The aim of this study was to evaluate whether microsaccades are correlated with standard MS disability metrics and to assess whether these methods play a predictive role in MS disability. Method: We used a custom-built retinal eye tracker, the tracking scanning laser ophthalmoscope (TSLO), to record fixation in 111 participants with MS and 100 unaffected controls. Results: In MS participants, a greater number of microsaccades showed significant association with higher Expanded Disability Status Scale score (EDSS, p < 0.001), nine-hole peg test (non-dominant: p = 0.006), Symbol Digit Modalities Test (SMDT, p = 0.014), and Functional Systems Scores (FSS) including brainstem ( p = 0.005), cerebellar ( p = 0.011), and pyramidal ( p = 0.009). Both brainstem FSS and patient-reported fatigue showed significant associations with microsaccade number, amplitude, and peak acceleration. Participants with MS showed a statistically different average number ( p = 0.020), peak vertical acceleration ( p = 0.003), and vertical amplitude ( p < 0.001) versus controls. Logistic regression models for MS disability were created using TSLO microsaccade metrics and paraclinical tests with ⩾80% accuracy. Conclusion: Microsaccades provide objective measurements of MS disability level and disease worsening.

Background: In persons with multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) is the criterion standard for assessing disability, but its in-person nature constrains patient participation in research and clinical assessments. Objective: The aim of this study was to develop and validate a scalable, electronic, unsupervised patient-reported EDSS (ePR-EDSS) that would capture MS-related disability across the spectrum of severity. Methods: We enrolled 136 adult MS patients, split into a preliminary testing Cohort 1 ( n = 50), and a validation Cohort 2 ( n = 86), which was evenly distributed across EDSS groups. Each patient completed an ePR-EDSS either immediately before or after a MS clinician’s Neurostatus EDSS evaluation. Results: In Cohort 2, mean age was 50.6 years (range = 26–80) and median EDSS was 3.5 (interquartile range (IQR) = [1.5, 5.5]). The ePR-EDSS and EDSS agreed within 1-point for 86% of examinations; kappa for agreement within 1-point was 0.85 ( p < 0.001). The correlation coefficient between the two measures was 0.91 (<0.001). Discussion: The ePR-EDSS was highly correlated with EDSS, with good agreement even at lower EDSS levels. For clinical care, the ePR-EDSS could enable the longitudinal monitoring of a patient’s disability. For research, it provides a valid and rapid measure across the entire spectrum of disability and permits broader participation with fewer in-person assessments.