Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis.

OBJECTIVE: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS). METHODS: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion. RESULTS: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively. INTERPRETATION: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis.

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-ß1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein-Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.

An electronic, unsupervised patient-reported Expanded Disability Status Scale for multiple sclerosis.

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.

Cognitive function influences cognitive-motor interference during dual task walking in multiple sclerosis.

BACKGROUND: Both physical and cognitive impairments are common in people with multiple sclerosis (PwMS). Performing a cognitive task while walking (i.e., dual-task walking) can introduce cognitive-motor interference (CMI), resulting in changes in walking performance. The association between the levels of cognitive impairment and of CMI in MS remains unclear. OBJECTIVES: To examine the association between cognitive functioning and differences in walking performance arise between single- and dual-task walking. METHODS: Ninety-five PwMS performed self-preferred pace walking and dual-task walking. The gait parameters recorded were used to compute dual task costs (DTC) as a metric of CMI. Cognitive functioning was assessed using Match, an unsupervised test developed based on the Symbol Digit Modalities Test. Participants were categorized as higher (HCF) and lower cognitive functioning (LCF) based on a Match z-score < -1.5. RESULTS: LCF group had elevated DTC for stride velocity, relative to the HCF group. Higher DTC for stride velocity was associated with lower cognition, as assessed by Match test. CONCLUSION: The findings support the hypothesis that CMI is associated with cognitive functioning in PwMS.

An autoantibody signature predictive for multiple sclerosis.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.

Capturing cognitive changes in multiple sclerosis by performance-based functional and virtual reality assessments.

Cognitive impairment (CI) has been recognized as one of the core multiple sclerosis (MS) symptoms that profoundly impact lives of people with MS (PwMS). Clinical trials have begun to focus on cognition as a primary or secondary outcome, but translating improvements in cognitive testing scores to functioning in the real world is difficult. Performance-based functional assessments and virtual reality (VR) assessments, which incorporate real-world challenges, have been proposed as a way to better assess functional cognition (i.e., cognitive performance and its impact on real-life cognitive functioning of PwMS) and could address the difficulty in evaluating the impact of a treatment on real-world functioning. In this narrative review, we identify and summarize some of the promising recent research applications of performance-based functional assessments and VR tools to assess functional cognition in MS. Overall, most of the studies suggest that functional and VR assessments can detect cognitive differences between people with and without MS and between PwMS with and without CI. Furthermore, performance on some of the functional and VR assessments was associated with performance on standard cognitive assessments. However, developing any guidelines on how to implement these assessments in clinical practice is difficult because of the relatively small sample size across these studies. Performance-based functional and VR assessments represent an innovative approach to increasing sensitivity of how cognitive impairments/abilities present in the daily life of PwMS. More studies, with a larger sample size, robust research methods, and pre- and post-treatment assessments, are warranted to validate relevant, accessible functional and VR assessments before implementing these assessment approaches in clinical practice.

Effects of transcranial alternating current stimulation on cognitive function in people with multiple sclerosis: A randomized controlled trial.

BACKGROUND: Cognitive impairment is a core symptom that profoundly impacts the lives of people with multiple sclerosis (PwMS). Since the existing disease modifying therapies can only stabilize, but not actively treat, cognition in PwMS, there is an unmet need to expand approaches to treat these cognitive symptoms. Transcranial alternating current stimulation (tACS) permits frequency-specific entrainment of neural oscillations intrinsic to cognitive activity. However, the effects of the tACS on cognitive function in PwMS have not yet been assessed. We aimed to evaluate the potential efficacy of applying frontal theta-tACS to improve information processing speed in PwMS. METHODS: 60 PwMS with cognitive complaints were enrolled in a double-blinded, randomized, controlled trial with three stimulation groups: 2 mA, 1 mA, or sham control. A single session of theta-tACS was applied while participants were engaged in a cognitive program which has shown to improve processing speed in PwMS. tACS effects were examined by the Symbol Digit Modalities Test (SDMT). Tolerability, side effects and acceptability were measured. RESULTS: 1 mA groups had a significantly higher SDMT score after stimulation compared to their pre-stimulation score, 2 mA group showed a marginally significant improvement of their SDMT score, while the SDMT score in the sham group did not change. Overall, 49% of the stimulation group participants showed a clinically meaningful SDMT improvement (4+-point increase). CONCLUSION: tACS is a well-tolerated, non-pharmacological intervention. Based on the positive effects observed in the current study of a single session of tACS applied during cognitive engagement, the effects of repeated tACS on cognitive function in PwMS merit further research. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466228.

A virtual reality program to assess cognitive function in multiple sclerosis: A pilot study.

Introduction: Cognitive impairment is a debilitating symptom in people with multiple sclerosis (MS). Most of the neuropsychological tasks have little resemblance to everyday life. There is a need for ecologically valid tools for assessing cognition in real-life functional contexts in MS. One potential solution would involve the use of virtual reality (VR) to exert finer control over the task presentation environment; however, VR studies in the MS population are scarce. Objectives: To explore the utility and feasibility of a VR program for cognitive assessment in MS. Methods: A VR classroom embedded with a continuous performance task (CPT) was assessed in 10 non-MS adults and 10 people with MS with low cognitive functioning. Participants performed the CPT with distractors (i.e., WD) and without distractors (i.e., ND). The Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II), and a feedback survey on the VR program was administered. Results: People with MS exhibited greater reaction time variability (RTV) compared to non-MS participants, and greater RTV in both WD and ND conditions was associated with lower SDMT. Conclusions: VR tools warrant further research to determine their value as an ecologically valid platform for assessing cognition and everyday functioning in people with MS.

A Predictive Autoantibody Signature in Multiple Sclerosis.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster of PwMS that share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active prodromal period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid (CSF) and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically- or radiologically-isolated neuroinflammatory syndromes.

Effect of gender on late-onset multiple sclerosis.

OBJECTIVES: We aimed to examine the incidence and disease course of late-onset multiple sclerosis (LOMS) compared with adult-onset MS (AOMS) in our clinic cohort, stratified based on gender and race, since both have been reported as important modifiers of disease outcomes in MS. METHODS: Patients with LOMS and AOMS were compared in terms of demographic characteristics and disease course characteristics. Combined effects were investigated with a logistic regression model. Time from disease onset to sustained Expanded Disability Status Scale (EDSS) score of 6 was investigated using an extension of log-rank test appropriate for interval-censored data. RESULTS: Some 7.96% of 4273 patients studied had an onset of MS after the age of 50 years (LOMS), and 1.33% experienced an onset after age 60. Progressive onset was more common in LOMS relative to AOMS. The proportion of women with progressive-onset disease was similar in AOMS and LOMS. Time to EDSS 6 was delayed in AOMS females compared with males; however, it was similar between males and females in the LOMS group. CONCLUSIONS: Women with LOMS have a different trajectory in terms of disease progression than women with AOMS. The effect of menopause combined with race/ethnicity on the MS disease course requires further investigation.

The pattern and pace of hyperacute hemorrhage expansion.

BACKGROUND: Intracerebral hemorrhage (ICH) expansion is common during the first 24 h after onset, but the pattern and pace of hyperacute hemorrhage growth have not been described because serial imaging is typically performed over the course of hours and days, not minutes. The purpose of this study is to elucidate the spatial and temporal characteristics of hyperacute hemorrhage expansion within minutes of ICH onset. METHODS: An 86-year-old man with probable cerebral amyloid angiopathy developed an ICH while in the MRI scanner. Hyperacute hemorrhage growth was captured at three time points over a 14-min interval of MRI data acquisition and at fourth time point with CT 22 h later. MRI and CT datasets were spatially coregistered, and three-dimensional models of ICH expansion were generated. RESULTS: Longitudinal analysis revealed that the spatial pattern of ICH growth was asymmetric at each time point. Maximal expansion occurred along the anterior-posterior plane during the first 4 min but along the superior-inferior plane during the next 10 min. The temporal pace of ICH expansion was also non-uniform, as growth along the anterior-posterior plane outpaced medial-lateral growth during the first 4 min (2.8 vs. 2.5 cm), but medial-lateral growth outpaced anterior-posterior growth over the next 10 min (1.0 vs. 0.2 cm). CONCLUSIONS: We provide evidence for asymmetric, non-uniform expansion of a hyperacute hemorrhage. These serial imaging observations suggest that hemorrhage expansion may be caused by local cascades of secondary vessel rupture as opposed to ongoing bleeding from a single ruptured vessel.

Pregnancy Management in Multiple Sclerosis and Other Demyelinating Diseases.

PURPOSE OF REVIEW: Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSDs) are chronic autoimmune demyelinating conditions of the central nervous system often diagnosed in women of childbearing age. Therefore, safe family planning, pregnancy, and postpartum management are important considerations for many patients with MS or NMOSD. RECENT FINDINGS: Many patients with MS can safely become pregnant and remain well throughout pregnancy and the postpartum period with guidance from specialists on treatment planning. During pregnancy, women with NMOSD may face some increased risk of both neurologic and obstetric complications. Recent attention has focused on evaluating the safety of pharmacologic agents during pregnancy and breastfeeding. Unfortunately, care disparities remain common in both MS and NMOSD, and recovery of function is often not optimally managed in the postpartum period. SUMMARY: This article reviews the current state of knowledge on peripartum management in these neurologic conditions and offers practical considerations and case studies. When caring for women with MS and NMOSD of childbearing potential, treatment planning is important to optimize outcomes in both patient and newborn.

Accessibility to Telerehabilitation Services for People With Multiple Sclerosis: Analysis of Barriers and Limitations.

BACKGROUND: In multiple sclerosis (MS), telemedicine improves access to specialized medical care; however, barriers remain, including universal access and effective implementation. Focusing on telerehabilitation, ie, remotely delivered physical therapy, our goal was to identify barriers to telerehabilitation implementation and factors associated with patients completing telerehabilitation physical therapy treatment. METHODS: Quantitative data included a review of electronic health records of patients with MS treated at the University of California San Francisco Physical Therapy Faculty Practice. We extracted demographic, clinical, and transit-related factors. For patients who scheduled an initial evaluation, we recorded the number of follow-ups, cancellations, completed physical therapy goals, and discharges. Qualitative data included interviews with 3 board-certified neurologic physical therapists and patients' perspectives recorded in the subjective portion of physical therapy notes. RESULTS: We identified 111 patients with at least 1 visit (in-person or telerehabilitation) to physical therapy (82 women; mean ± SD age, 54.2 ± 12.7 years). Patients with no disability (Expanded Disability Status Scale [EDSS] score, 0) were 73% less likely to schedule a follow-up appointment (in-person or telerehabilitation) than those with some disability (EDSS score, >0) (odds ratio, 0.27; 95% CI, 0.09-0.75; P = .012). Neurologic physical therapists identified reduced travel burden and scheduling flexibility as benefits of telerehabilitation vs in-person visits. Barriers to telerehabilitation included low technological literacy, cognitive impairment, and fall risk. Patients described scheduling conflicts and pain/illness as barriers to telerehabilitation. CONCLUSIONS: Patients with no disability were least likely to complete physical therapy treatment via telerehabilitation. Although both benefits and barriers to completing physical therapy via telerehabilitation are present, the neurologic physical therapists were supportive of a hybrid model for physical therapy.

Transitioning From S1P Receptor Modulators to B Cell-Depleting Therapies in Multiple Sclerosis: Clinical, Radiographic, and Laboratory Data.

BACKGROUND AND OBJECTIVES: Patients with multiple sclerosis (MS) transition from oral sphingosine-1-receptor (S1P) modulators to anti-CD20 therapies for several circumstances. Optimal timing of this transition is uncertain, given competing concerns of rebound disease activity and ensuring immune reconstitution. The objective of this study was to evaluate the relationship between inflammatory activity and the transition period from fingolimod to anti-CD20 therapies in a real-world MS cohort. METHODS: Medical records were reviewed for all patients at our center transitioning from fingolimod to rituximab or ocrelizumab between 2010 and October 2020. Time periods reviewed were the following: before fingolimod discontinuation, interval between fingolimod and anti-CD20 treatments, and after the first anti-CD20 infusion. The primary outcome was clinical relapses; MRI activity, time to absolute lymphocyte count (ALC) recovery, and infections were secondary. Clinical and demographic factors significant in univariable analyses were included in multivariable analyses. RESULTS: Transition data were available for 108 patients (68.5% women, 68.5% relapsing-remitting MS, mean age 44.6 years). The median (interquartile range) interval between fingolimod and anti-CD20 therapy was 28 (1-115.2) days. Six of 51 patients (11.8%) with intervals >1 month and 0/57 patients with shorter intervals experienced a relapse (MRI confirmed) within 6 months of fingolimod discontinuation. In the year following anti-CD20 initiation, 4/108 patients (3.7%) experienced a relapse (median 214.5 days after infusion). An additional 7% of those undergoing contrast-enhanced MRIs developed Gd+ lesions. ALC normalized following treatment switch in 89/92; the interval between treatments was unrelated to ALC recovery or infection. DISCUSSION: Delaying anti-CD20 start to monitor ALC after S1P modulator discontinuation may not be necessary and could increase rebound risk. ALC monitoring could instead occur after a rapid switch to anti-CD20 treatment.

Effects of Transcranial Direct Current Stimulation on Cognition, Mood, Pain, and Fatigue in Multiple Sclerosis: A Systematic Review and Meta-Analysis.

Background: The study aimed to evaluate the effects of transcranial direct current stimulation (tDCS) on cognition, mood disturbance, pain, and fatigue in people with multiple sclerosis (PwMS). Methods: A literature search was performed on articles published between January 1990 and May 2020 in Pubmed, Medline, and Web of Science using the following keywords and their abbreviation in combinations: multiple sclerosis and transcranial direct current stimulation. Mean effect size (ES) and 95% confidence interval were calculated for each domain of interest. Results: Seventeen articles with a total of 383 PwMS were included in this analysis. For cognition, a strong effect size was found for the trial administering the Symbol Digit Modalities Test (ES: 1.15), whereas trials applying the Attention Network Test showed a negative effect size of -0.49. Moderate to strong effect sizes were observed for mood disturbance (mean ES: 0.92), pain (mean ES: 0.59), and fatigue (mean ES: 0.60). Further subgroup analyses for MS-related fatigue showed that both high and low intensities of stimulation lead to nearly the same degree of favorable effects. More pronounced effects were observed in studies administering the Fatigue Severity Scale compared with studies using other fatigue measures such as the Modified Fatigue Impact Scale. Conclusion: These results provide preliminary evidence that tDCS has a favorable effect on cognitive processing speed, mood disturbance, pain, and fatigue in MS. However, the effects on cognition and fatigue vary based on the specific assessment used.

Effects of melatonin on sleep disturbances in multiple sclerosis: A randomized, controlled pilot study.

BACKGROUND: Sleep disturbances are commonly reported by people with multiple sclerosis (PwMS). However, optimal management of sleep disturbances is uncertain, and objective studies of sleep quality in PwMS are scarce. OBJECTIVES: To determine the effect of exogenous melatonin on sleep quality and sleep disturbances in PwMS. METHODS: Thirty adult PwMS reporting sleep difficulties were recruited in a randomized, controlled, double-blind cross-over study. They took either melatonin or placebo for 2 weeks, and the opposite for the following 2 weeks. During weeks 2 and 4, an actigraph was used to capture mean total sleep time and sleep efficiency. Patient-reported outcomes (PROs) were collected at weeks 0, 2 and 4. RESULTS: Melatonin use significantly improved mean total sleep time (p = 0.03), with a trend towards higher sleep efficiency (p = 0.06). No PROs were significantly different; there was a trend for melatonin use to decrease mean Insomnia Severity Index score (p = 0.07), improve Pittsburgh Sleep Quality Index sleep quality component (p = 0.07), and improve NeuroQoL-Fatigue (p = 0.06). No other PROs showed differences between melatonin and placebo; nor did step count measured by actigraphy (all p > 0.45). CONCLUSION: These results provide preliminary evidence that melatonin, a low-cost, over-the-counter supplement, could improve objective measures of sleep quality in PwMS.

American Academy of Neurology Telehealth Position Statement.

Telehealth services complement in-person neurologic care. The American Academy of Neurology supports patient access to telehealth services regardless of location, coverage for telehealth services by all subscriber benefits and insurance, equitable provider reimbursement, simplified state licensing requirements easing access to virtual care, and expanding telehealth research and quality initiatives. The roles and responsibilities of providers should be clearly delineated in telehealth service models.

Navigating monoclonal antibody use in breastfeeding women: Do no harm or do little good?

Many neurologic diseases disproportionately affect women, particularly during their reproductive years. For many of these diseases, monoclonal antibodies (mAbs) are becoming widely available as a treatment option, for example, in migraine, multiple sclerosis, and myasthenia gravis. Yet, despite how common pregnancy is (latest estimates suggest that 86% of US women ages 40-44 have given birth), there is a paucity of research on the safety of prescription medications, including mAbs, during the peripartum period. In this article, we focus on the safety of mAbs during breastfeeding. We summarize how pregnancy affects the trajectory of these diseases and explore the benefit derived from mAb therapies. We posit that as neurologists, we are uniquely poised to lead the study of peripartum safety for the mAbs now on the market and provide a framework for their future study.