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Abstract Background Multiple sclerosis (MS) is a leading cause of neurological disability among young and middle-aged adults worldwide, and disability is measured using a variety of approaches, including patient reported outcome measures (PROMs) such as the Patient Determined Disease Steps (PDDS) scale. There is limited evidence for the validity of inferences from the middle-range of scores on the PDDS (i.e., 3 “gait disability” – 6 “bilateral support”), but that range of scores seemingly represents moderate disability characterized by varying levels of walking dysfunction. Purpose The current study examined whether the middle-range of scores from the PDDS reflect varying levels of walking dysfunction among people with MS. Method Participants (N = 374) completed the Patient Determined Disease Steps (PDDS) scale, Multiple Sclerosis Walking Scale-12 (MSWS-12), timed 25-foot walk (T25FW), six-minute walk (6 MW), Modified Fatigue Impact Scale (MFIS), and Multiple Sclerosis Impact Scale-29 (MSIS-29), and underwent a neurological exam for generating an Expanded Disability Status Scale (EDSS) score as part of screening and baseline data collection for a clinical trial of exercise training in MS. We undertook a series of linear trend analyses that examined differences in the outcomes of EDSS, T25FW, 6 MW, MSWS-12, MFIS subscales, and MSIS-29 subscales across the 4 levels of PDDS scores (i.e., 3–6). Results There were statistically significant and strong linear trends for EDSS (F1,370 = 306.1, p

Abstract Objective Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2‐item scale polygenic score with anxiety in MS. Methods Using a case–control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview‐diagnosed, and lifetime self‐report physician‐diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome‐wide association study and was tested using regression. Results A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta‐analyses identified that in MS, each 1‐SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09–1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. Interpretation Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Background: Clinical efficacy of zilucoplan has been demonstrated in a 12-week, placebo-controlled, phase III study in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG). However, placebo-controlled zilucoplan data past 12 weeks are not available. Objectives: Predict the treatment effect of zilucoplan versus control (placebo or standard of care) in patients with gMG up to 24 weeks. Design: A model-informed analysis (MIA) within a Bayesian framework. Methods: Part 1 of the MIA comprised a control meta-regression using aggregate data on control response over time from randomised studies and a national myasthenia gravis (MG) registry. In Part 2, a combined Bayesian analysis of individual patient-level data from the phase II (NCT03315130), RAISE (NCT04115293) and RAISE-XT (NCT04225871) studies of zilucoplan was conducted using posterior distributions from Part 1 as informative priors. Population mean treatment effect in the change from baseline (CFB) at week 24 in MG-Activities of Daily Living (MG-ADL) and quantitative MG (QMG) scores for zilucoplan versus control were assessed. Results: At week 24, the predicted mean CFB in MG-ADL score was −4.55 (95% credible interval: −6.04, −3.13) with zilucoplan versus −2.00 (−3.35, −0.64) with control (difference: −2.55 [−3.76, −1.40]). The probability of a favourable treatment effect as measured by MG-ADL score at week 24 with zilucoplan versus control was >99.9%. There was an 82.8% probability that the difference in the predicted mean CFB in MG-ADL score at week 24 was greater than the clinically meaningful threshold (⩾2.0-point improvement). Comparable results were observed with QMG. Conclusion: This MIA demonstrates the maintenance of efficacy with zilucoplan versus control up to 24 weeks. Through combining real-world evidence with data from randomised studies, this novel method to estimate long-term treatment efficacy facilitated reduced exposure to placebo in the phase III RAISE study. This methodology could be used to reduce the length of future placebo-controlled studies.

Abstract Background Major depressive disorder (MDD) is prevalent, yet sub-optimally treated among persons with multiple sclerosis (MS). We propose that exercise training may be a promising approach for treating depression in persons with MS who have MDD. Our primary hypothesis predicts a reduction in depression severity immediately after an exercise training intervention compared with minimal change in an attention control condition, and the reduction will be maintained during a follow-up period. Methods This study involves a parallel-group, assessor-blinded RCT that examines the effect of a 4-month home-based exercise training intervention on depression severity in a sample of persons with MS who have MDD based on the MINI International Neuropsychiatric Interview. The primary outcomes of depression severity are the Patient Health Questionnaire-9 and Hamilton Depression Rating Scale. Participants (N = 146) will be recruited from within 200 miles of the University of Illinois at Chicago and randomized (1:1) into either a home-based exercise training condition or control condition with concealed allocation. The exercise training and social-contact, attention control (i.e., stretching) conditions will be delivered remotely over a 4-month period and supported through eight, 1:1 Zoom-based behavioral coaching sessions guided by social-cognitive theory and conducted by persons who are uninvolved in screening, recruitment, random assignment, and outcome assessment. We will collect outcome data at 0, 4 and 8 months using treatment-blinded assessors, and data analyses will involve intent-to-treat principles. Discussion If successful, the proposed study will provide the first Class I evidence supporting a home-based exercise training program for treating MDD in persons with MS. This is critical as exercise training would likely have positive secondary effects on symptoms, cognition, and quality of life, and provide a powerful, behavioral approach for managing the many negative outcomes of MDD in MS. The program in the proposed research is accessible and scalable for broad treatment of depression in MS, and provides the potential for integration in the clinical management of MS. Trial registration The trial was registered on September 10, 2021 at clinicaltrials.gov with the identifier NCT05051618. The registration occurred before we initiated recruitment on June 2, 2023

Significant advancements have been achieved in delineating the progress of the Global PROMS (PROMS) Initiative. The PROMS Initiative, a collaborative endeavor by the European Charcot Foundation and the Multiple Sclerosis International Federation, strives to amplify the influence of patient input on MS care and establish a cohesive perspective on Patient-Reported Outcomes (PROs) for diverse stakeholders. This initiative has established an expansive, participatory governance framework launching four dedicated working groups that have made substantive contributions to research, clinical management, eHealth, and healthcare system reform. The initiative prioritizes the global integration of patient (For the purposes of the Global PROMS Initiative, the term “patient” refers to the people with the disease (aka People with Multiple Sclerosis – pwMS): any individual with lived experience of the disease. People affected by the disease/Multiple Sclerosis: any individual or group that is affected by the disease: E.g., family members, caregivers will be also engaged as the other stakeholders in the initiative). insights into the management of MS care. It merges subjective PROs with objective clinical metrics, thereby addressing the complex variability of disease presentation and progression. Following the completion of its second phase, the initiative aims to help increasing the uptake of eHealth tools and passive PROs within research and clinical settings, affirming its unwavering dedication to the progressive refinement of MS care. Looking forward, the initiative is poised to continue enhancing global surveys, rethinking to the relevant statistical approaches in clinical trials, and cultivating a unified stance among ‘industry’, regulatory bodies and health policy making regarding the application of PROs in MS healthcare strategies.

Murine research has revealed a significant role for antibody responses in protection against Chlamydia reinfection. To explore potential humoral immune markers of protection elicited by Chlamydia trachomatis (CT) antigens in humans in the context of presumed clinical correlates of protection, we used both an IgG1-based ELISA and a conventional total IgG ELISA to evaluate antibody responses. We evaluated responses to five CT outer membrane proteins (PmpE, PmpF, PmpG, PmpH, and MOMP), along with other promising CT antigens (Pgp3 and HSP60), negative control antigens (RecO and AtpE), and CT elementary bodies (EBs) in sera from a well-characterized cohort of 60 women with different CT infection outcomes, including two outcomes that are likely clinical correlates of protective immunity: spontaneous resolution of infection and absence of reinfection after treatment. Furthermore, we used a flow cytometry-based assay to measure antibody-mediated phagocytosis by neutrophils in these sera. Results demonstrated that IgG1 ELISA displayed higher sensitivity than conventional total IgG ELISA in assessing antibody responses to CT EBs and antigens. Pgp3 IgG1 ELISA exhibited the highest sensitivity compared to IgG1 ELISA incorporating CT EBs or other antigens, confirming Pgp3 IgG1 ELISA as an ideal assay for CT antibody detection. Most (95%) sera from women with CT infection outcomes exhibited antibody-mediated phagocytosis of CT EBs, which was significantly correlated with IgG1 antibody responses to MOMP, Pgp3, HSP60, and PmpF. However, neither IgG1 responses to CT antigens and EBs nor antibody-mediated phagocytosis were associated with clinical correlates of protection. These findings suggest that neither CT IgG1 antibody detection nor antibody-mediated phagocytosis will be useful as immune correlates of protection against CT infection in humans.

Abstract The mortality rates of individuals with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are currently unknown. This study aimed to assess the mortality rate in a large cohort of patients with MOGAD. Since none of the patients in our cohort died, we estimated the upper limit of a 95% confidence interval of the crude mortality rate in the cohort to be 2.1%. These data suggest that mortality in MOGAD is lower than that reported in other neuroinflammatory diseases and comparable to the age‐adjusted mortality rates of the general population in the United States. Additional studies are warranted to confirm this observation.

IntroductionParkinson’s disease (PD) patients with REM sleep behavior disorder (RBD) are at greater risk for cognitive decline and RBD has been associated with alterations in sleep-related EEG oscillations. This study evaluates differences in sleep quantitative EEG (qEEG) and cognition in PD participants with (PD-RBD) and without RBD (PD-no-RBD).MethodsIn this cross-sectional study, polysomnography (PSG)-derived qEEG and a comprehensive level II neuropsychological assessment were compared between PD-RBD (n = 21) and PD-no-RBD (n = 31). Following artifact rejection, qEEG analysis was performed in the frontal and central leads. Measures included Scalp-slow wave (SW) density, spindle density, morphological properties of SW and sleep spindles, SW-spindle phase-amplitude coupling, and spectral power analysis in NREM and REM. The neurocognitive battery had at least two tests per domain, covering five cognitive domains as recommended by the Movement Disorders Society Task Force for PD-MCI diagnosis. Differences in qEEG features and cognitive performance were compared between the two groups. Stepwise linear regression was performed to evaluate predictors of cognitive performance. Multiple comparisons were corrected using the Benjamini-Hochberg method.ResultsSpindle density and SW-spindle co-occurrence percent were lower in participants with PD-RBD compared to PD-no-RBD. The PD-RBD group also demonstrated higher theta spectral power during REM. Sleep spindles and years of education, but not RBD, were predictors of cognitive performance.ConclusionPD participants with RBD have alterations in sleep-related qEEG compared to PD participants without RBD. Although PD-RBD participants had worse cognitive performance compared to PD-no-RBD, regression models suggest that lower sleep spindle density, rather than presence of RBD, predicts worse comprehensive cognitive score. Future studies should include longitudinal evaluation to determine whether sleep-related qEEG alterations are associated with more rapid cognitive decline in PD-RBD.

Aim: The presence of two or more publications that report on overlapping patient cohorts poses a challenge for quantitatively synthesizing real-world evidence (RWE) studies. Thus, we evaluated eight approaches for handling such related publications in network meta-analyses (NMA) of RWE studies. Methods: Bayesian NMAs were conducted to estimate the annualized relapse rate (ARR) of diseasemodifying therapies in multiple sclerosis. The NMA explored the impact of hierarchically selecting one pivotal study from related publications versus including all of them while adjusting for correlations. Results: When selecting one pivotal study from related publications, the ARR ratios were mostly similar regardless of the pivotal study selected. When including all related publications, there were shifts in the point estimates and the statistical significance. Conclusion: An a priori hierarchy should guide the selection among related publications in NMAs of RWE. Sensitivity analyses modifying the hierarchy should be considered for networks with few or small studies.

Abstract Background Microbial etiology for community-acquired pneumonia (CAP) is evolving with pathogens known for high CAP mortality e.g., Pseudomonas species. Chronic obstructive pulmonary disease (COPD) patients are at risk for hospitalization for CAP. Understanding regional patterns and risk factors for multidrug-resistant (MDR) Pseudomonas acquisition has implications for antimicrobial stewardship. Objectives To evaluate the regional epidemiology of MDR Pseudomonas CAP and its association with COPD. Methods We queried the electronic medical records of the University of Alabama at Birmingham Healthcare System to identify patients hospitalized for CAP with Pseudomonas positive respiratory samples between 01/01/2013–12/31/2019. Log binomial regression models were used to examine associations between COPD diagnosis and risk of Pseudomonas/MDR Pseudomonas CAP. Results Cohort consisted of 913 culture positive CAP cases aged 59-year (IQR:48–68), 61% (560) male, 60% (547) white, 65% (580) current/past smokers, and 42% (384) COPD. Prevalence of Pseudomonas CAP in culture positive CAP was 18% (167), MDR Pseudomonas CAP in Pseudomonas CAP was 22% (36), and yearly incidence of MDR Pseudomonas CAP was stable (p = 0.169). COPD was associated with Pseudomonas CAP (RR 1.39; 95% CI 1.01, 1.91; p = 0.041) but not with MDR Pseudomonas CAP (0.71; 95% CI 0.35, 1.45; p = 0.349). Stroke (RR 2.64; 95% CI 1.51, 4.61; p = 0.0006) and use of supplemental oxygen (RR 2.31; 95% CI 1.30, 4.12; p = 0.005) were associated with MDR Pseudomonas CAP. Conclusion Incidence of MDR Pseudomonas CAP was stable over time. COPD was associated with Pseudomonas CAP but not with MDR Pseudomonas CAP. Larger cohort studies are needed to confirm findings.

Abstract Identification of individuals at high risk for rapid progression of motor and cognitive signs in Parkinson disease (PD) is clinically significant. Postural instability and gait dysfunction (PIGD) are associated with greater motor and cognitive deterioration. We examined the relationship between baseline clinical factors and the development of postural instability using 5-year longitudinal de-novo idiopathic data (n = 301) from the Parkinson’s Progressive Markers Initiative (PPMI). Logistic regression analysis revealed baseline features associated with future postural instability, and we designated this cohort the emerging postural instability (ePI) phenotype. We evaluated the resulting ePI phenotype rating scale validity in two held-out populations which showed a significantly higher risk of postural instability. Emerging PI phenotype was identified before onset of postural instability in 289 of 301 paired comparisons, with a median progression time of 972 days. Baseline cognitive performance was similar but declined more rapidly in ePI phenotype. We provide an ePI phenotype rating scale (ePIRS) for evaluation of individual risk at baseline for progression to postural instability.

Abstract Background Hospitalized patients with SARS-CoV2 develop acute kidney injury (AKI) frequently, yet gaps remain in understanding why adults seem to have higher rates compared to children. Our objectives were to evaluate the epidemiology of SARS-CoV2-related AKI across the age spectrum and determine if known risk factors such as illness severity contribute to its pattern. Methods Secondary analysis of ongoing prospective international cohort registry. AKI was defined by KDIGO-creatinine only criteria. Log-linear, logistic and generalized estimating equations assessed odds ratios (OR), risk differences (RD), and 95% confidence intervals (CIs) for AKI and mortality adjusting for sex, pre-existing comorbidities, race/ethnicity, illness severity, and clustering within centers. Sensitivity analyses assessed different baseline creatinine estimators. Results Overall, among 6874 hospitalized patients, 39.6% (n = 2719) developed AKI. There was a bimodal distribution of AKI by age with peaks in older age (≥60 years) and middle childhood (5–15 years), which persisted despite controlling for illness severity, pre-existing comorbidities, or different baseline creatinine estimators. For example, the adjusted OR of developing AKI among hospitalized patients with SARS-CoV2 was 2.74 (95% CI 1.66–4.56) for 10–15-year-olds compared to 30–35-year-olds and similarly was 2.31 (95% CI 1.71–3.12) for 70–75-year-olds, while adjusted OR dropped to 1.39 (95% CI 0.97–2.00) for 40–45-year-olds compared to 30–35-year-olds. Conclusions SARS-CoV2-related AKI is common with a bimodal age distribution that is not fully explained by known risk factors or confounders. As the pandemic turns to disproportionately impacting younger individuals, this deserves further investigation as the presence of AKI and SARS-CoV2 infection increases hospital mortality risk.

Summary: Background: Inebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770). Methods: Peripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up ≥2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed. Findings: Inebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with ≤4 cells/μL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024–0.04] vs 0.086 [0.056–0.12]; p = 0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43–0.56] vs 1.36 [1.12–1.61]; p

BackgroundIn a randomized, controlled trial, we showed that high-intensity rehabilitation, combining resistance training and body-weight interval training, improves sleep efficiency in Parkinson's disease (PD). Quantitative sleep EEG (sleep qEEG) features, including sleep spindles, are altered in aging and in neurodegenerative disease.ObjectiveThe objective of this post-hoc analysis was to determine the effects of exercise, in comparison to a sleep hygiene, no-exercise control group, on the quantitative characteristics of sleep spindle morphology in PD.MethodsWe conducted an exploratory post-hoc analysis of 24 PD participants who were randomized to exercise (supervised 3 times/week for 16 weeks) versus 26 PD participants who were assigned to a sleep hygiene, no-exercise control group. At baseline and post-intervention, all participants completed memory testing and underwent polysomnography (PSG). PSG-derived sleep EEG central leads (C3 and C4) were manually inspected, with rejection of movement and electrical artifacts. Sleep spindle events were detected based on the following parameters: (1) frequency filter = 11–16 Hz, (2) event duration = 0.5–3 s, and (3) amplitude threshold 75% percentile. We then calculated spindle morphological features, including density and amplitude. These characteristics were computed and averaged over non-rapid eye movement (NREM) sleep stages N2 and N3 for the full night and separately for the first and second halves of the recording. Intervention effects on these features were analyzed using general linear models with group x time interaction. Significant interaction effects were evaluated for correlations with changes in performance in the memory domain.ResultsA significant group x time interaction effect was observed for changes in sleep spindle density due to exercise compared to sleep hygiene control during N2 and N3 during the first half of the night, with a moderate effect size. This change in spindle density was positively correlated with changes in performance on memory testing in the exercise group.ConclusionsThis study is the first to demonstrate that high-intensity exercise rehabilitation has a potential role in improving sleep spindle density in PD and leading to better cognitive performance in the memory domain. These findings represent a promising advance in the search for non-pharmacological treatments for this common and debilitating non-motor symptom.

There is increasing evidence suggesting that Epstein-Barr virus infection is a causative factor of multiple sclerosis (MS). Epstein-Barr virus (EBV) is a human herpesvirus, Human Gammaherpesvirus 4. EBV infection shows two peaks: firstly, during early childhood and, secondly during the teenage years. Approximately, 90–95% of adults have been infected with EBV and for many this will have been a subclinical event. EBV infection can be associated with significant morbidity and mortality; for example, primary infection in older children or adults is the leading cause of infectious mononucleosis (IM). A disrupted immune response either iatrogenically induced or through genetic defects can result in lymphoproliferative disease. Finally, EBV is oncogenic and is associated with several malignancies. For these reasons, vaccination to prevent the damaging aspects of EBV infection is an attractive intervention. No EBV vaccines have been licensed and the prophylactic vaccine furthest along in clinical trials contains the major virus glycoprotein gp350. In a phase 2 study, the vaccine reduced the rate of IM by 78% but did not prevent EBV infection. An EBV vaccine to prevent IM in adolescence or young adulthood is the most likely population-based vaccine strategy to be tested and adopted. National registry studies will need to be done to track the incidence of MS in EBV-vaccinated and unvaccinated people to see an effect of the vaccine on MS. Assessment of vaccine efficacy with MS being a delayed consequence of EBV infection with the average age of onset being approximately 30 years of age represents multiple challenges.

PurposeIn this cross-sectional, proof-of-concept study, we propose that using the more pathologically-specific neurite orientation dispersion and density imaging (NODDI) method, in conjunction with high-resolution probabilistic tractography, white matter tract templates can improve the assessment of regional axonal injury and its association with disability of people with multiple sclerosis (pwMS).MethodsParametric maps of the neurite density index, orientation dispersion index, and the apparent isotropic volume fraction (IVF) were estimated in 18 pwMS and nine matched healthy controls (HCs). Tract-specific values were measured in transcallosal (TC) fibers from the paracentral lobules and TC and corticospinal fibers from the ventral and dorsal premotor areas, presupplementary and supplementary motor areas, and primary motor cortex. The nonparametric Mann–Whitney U test assessed group differences in the NODDI-derived metrics; the Spearman's rank correlation analyses measured associations between the NODDI metrics and other clinical or radiological variables.ResultsIVF values of the TC fiber bundles from the paracentral, presupplementary, and supplementary motor areas were both higher in pwMS than in HCs (p ≤ 0.045) and in pwMS with motor disability compared to those without motor disability (p ≤ 0.049). IVF in several TC tracts was associated with the Expanded Disability Status Scale score (p ≤ 0.047), while regional and overall lesion burden correlated with the Timed 25-Foot Walking Test (p ≤ 0.049).ConclusionIVF alterations are present in pwMS even when the other NODDI metrics are still mostly preserved. Changes in IVF are biologically non-specific and may not necessarily drive irreversible functional loss. However, by possibly preceding downstream pathologies that are strongly associated with disability accretion, IVF changes are indicators of, otherwise, occult prelesional tissue injury.

Abstract Background Myasthenia gravis (MG), a chronic neuromuscular disorder, can adversely affect patients’ health-related quality of life (HRQoL), especially in women. The study aimed to evaluate the difference in HRQoL of women and men MG patients and explore the factors that mediate the relationship between gender and HRQoL. Methods A cross-sectional study was conducted among 1815 patients with MG in China. The revised 15-item MG quality of life scale (MG-QOL15r) was used to access patients’ HRQoL in overall, physical, social and emotional domains. Socio-demographic information, diagnosis and treatment history, comorbidities, social support, active lifestyle and the MG activities of daily living scale (MG-ADL) were recorded and compared between women and men using the Student’s t-test and Pearson’s Chi-square test. Multivariable regression analyses were conducted to identify independent contributors to HRQoL, especially those affecting different gender. Results On average, female patients with MG reported a lower MG-QOL15r score than the males (44.49 ± 29.10 vs 49.32 ± 29.18). The association between gender and patients’ HRQoL interacted with the number of comorbidities across the overall, physical and social domains of patients. As the number of comorbidities increased, the scores of HRQoL decreased and it was faster among females than the males (p

Abstract Background Cognitive dysfunction affects up to 70% of people with progressive MS (PMS). It can exert a deleterious effect on activities of daily living, employment and relationships. Preliminary evidence suggests that performance can improve with cognitive rehabilitation (CR) and aerobic exercise (EX), but existing data are predominantly from people with relapsing-remitting MS without cognitive impairment. There is therefore a need to investigate whether this is also the case in people with progressive forms of the disease who have objectively identified cognitive impairment. It is hypothesized that CR and EX are effective treatments for people with PMS who have cognitive impairment, in particular processing speed (PS) deficits, and that a combination of these two treatments is more effective than each individual treatment given alone. We further hypothesize that improvements in PS will be associated with modifications of functional and/or structural plasticity within specific brain networks/regions involved in PS measured with advanced MRI techniques. Methods This study is a multisite, randomized, double-blinded, sham controlled clinical trial of CR and aerobic exercise. Three hundred and sixty subjects from 11 sites will be randomly assigned into one of four groups: CR plus aerobic exercise; CR plus sham exercise; CR sham plus aerobic exercise and CR sham plus sham exercise. Subjects will participate in the assigned treatments for 12 weeks, twice a week. All subjects will have a cognitive and physical assessment at baseline, 12 weeks and 24 weeks. In an embedded sub-study, approximately 30% of subjects will undergo structural and functional MRI to investigate the neural mechanisms underlying the behavioral response. The primary outcome is the Symbol Digit Modalities Test (SDMT) measuring PS. Secondary outcome measures include: indices of verbal and non-verbal memory, depression, walking speed and a dual cognitive-motor task and MRI. Discussion The study is being undertaken in 6 countries (11 centres) in multiple languages (English, Italian, Danish, Dutch); with testing material validated and standardized in these languages. The rationale for this approach is to obtain a robustly powered sample size and to demonstrate that these two interventions can be given effectively in multiple countries and in different languages. Trial registration The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468 . Registration was performed before recruitment was initiated.

Abstract Cognitive problems are common in children with neurofibromatosis type 1, representing a significant source of lifelong morbidity. Assessment of cognitive function has been challenging in the setting of clinical trials. Spatial learning deficits may be an important target for cognitive interventions. We leveraged a large, international cognitive study in affected children with NF1 treated with lovastatin to assess spatial learning using the “Arena Maze”, a portable, computerized task that allows for retesting in the same environment. As with the parent study, spatial learning assessed with this task did not improve with lovastatin treatment.

Abstract Objective Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism‐based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test‐retest reliability of the measures and the application of data reduction techniques to improve reproducibility. Methods Data were analyzed from the STARS clinical trial (n = 146), a multi‐center double‐blind placebo‐controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra‐class correlation coefficients were generated between pre‐ and post‐performances (16‐week interval) on neuropsychological endpoints in the placebo group to determine test‐retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. Results Test‐retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test‐retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. Interpretation These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test‐retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

Background Multiple sclerosis (MS) is an autoimmune disease leading to physical, emotional and cognitive disability. High body mass index (BMI) may impact cognitive function and brain volume in MS. Yet, there is paucity of evidence addressing the impact of BMI on cognitive function and brain volume in MS. Objectives The purpose of this study was to examine the effects of BMI on normal appearing brain volume and cognitive function in patients with relapsing–remitting MS. Methods A secondary data analysis of the NIH CombiRx study was conducted. Multivariate regression and mixed model analyses were executed to analyze the effect of BMI on brain volume and cognitive function. Results The mean baseline age of the 768 participants was 38.2(SD = 9.4) years. 73% were female and 88.8% were Caucasian. The mean BMI was 28.8 kg/m 2 (SD = 6.7). The multivariate regression and mixed model analyses failed to show a clinical effect of BMI on brain volume and cognitive function. Conclusion BMI did not show an effect on cognitive function and brain volume among MS patients. Although there is increased interest in the effects of modifiable factors on the course of MS, the effects of BMI on brain volume and cognitive function are debatable and warrant further research. ClinicalTrials.gov NCT00211887

Background Since 2014, the USA has documented three outbreaks of acute flaccid myelitis (AFM). Unique features and treatment responses of this myelitis variant have not been prospectively studied. This study prospectively measured outcomes in paediatric myelitis patients relative to treatments.Methods This was a prospective, multicentre, non-randomised, observational cohort study. The study duration was 5 years and the length of follow-up was 1 year. This study collected data from children and families in North America. Patients were enrolled at academic centres with expertise in myelitis or online via a web portal. Paediatric patients diagnosed with myelitis were eligible for enrolment in the study within 6 months of onset of symptoms. Patients were characterised as transverse myelitis (TM) or the AFM variant based on clinical and radiographic findings.Results The cohort of 90 patients included patients with AFM and TM. Of the 51 patients with AFM there was evidence of two clinically relevant patterns. This included a grey matter restricted form of AFM and a cohort with concomitant white matter that could explain lower extremity motor deficits in patients with lesions restricted to the cervical spine. The improvement in deficits with the use of corticosteroids was similar to what was observed in the TM cohort (p=0.97).Conclusions Clinicians should consider on a case by case basis the approach to therapy for AFM patients. Prospective controlled studies of long-term outcomes would be useful in this growing patient population.

Background: Although the aggregate of data among patients with multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY), most studies have not assessed long-term worsening of disability. We compared long-term disability worsening over 5 years, as assessed by the Patient-Determined Disease Steps (PDDS), among participants with MS treated with DMF or FTY. Methods: We identified individuals in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry who had relapsing-remitting MS (RRMS), residing in the United States (Spring 2011 to Spring 2018), who initiated treatment with DMF ( n = 689) or FTY ( n = 565) and had ⩾1 year follow-up on index treatment. Participants receiving DMF who were previously treated with FTY and those on FTY previously treated with DMF were excluded. Propensity score matching at baseline was used to match FTY-treated to DMF-treated participants. Time to 6-month confirmed disability worsening (⩾1-point increase on PDDS, sustained for ⩾6 months) was estimated using Cox regression. A sensitivity analysis was conducted to account for differences in the duration of index exposure between DMF and FTY groups. Results: After propensity score matching, 468 DMF-treated participants were matched with 468 FTY-treated participants. Median treatment duration was 3.0 years for DMF and 4.0 years for FTY. At 5 years, 68.3% [95% confidence interval (CI): 62.4–73.5] of DMF-treated participants and 63.3% (95% CI: 59.6–70.1) treated with FTY were free from 6-month confirmed PDDS worsening [hazard ratio (HR) 1.01 (95% CI: 0.79–1.28); p = 0.95]. Results were similar in the sensitivity analysis: 70.5% (95% CI: 61.8–77.6) of DMF-treated participants and 72.7% (95% CI: 65.4–78.6) of FTY-treated participants were free from 6-month confirmed PDDS worsening [HR: 1.04 (95% CI: 0.71–1.51); p = 0.84]. Conclusions: In participants with MS from the NARCOMS registry, there was no significant difference in confirmed disability (PDDS) worsening over 5 years between those treated with DMF versus FTY.

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for the treatment of disease activity and are effective in reducing relapses and new magnetic resonance imaging (MRI) lesions. However, disease activity generally subsides with time, and age-dependent changes in DMT efficacy are not well-established. We aimed to investigate whether age impacts the efficacy of DMTs in treating disease activity in patients with relapsing–remitting MS (RRMS). Methods: DMT efficacy related to age was assessed through a meta-analysis of clinical trials that evaluated the efficacy of DMTs in RRMS patients as measured by reductions in the annualized relapse rate (ARR), new T2 lesions, and gadolinium-enhanced lesions on MRI. Using the mean baseline patient age from each trial, a weighted linear regression was fitted to determine whether age was associated with treatment efficacy on a group level. Results: Group-level data from a total of 28,082 patients from 26 trials of 14 different DMTs were included in the meta-analysis. There were no statistically significant associations between age and reductions in ARR, new T2 lesions, and gadolinium-enhanced lesions of the treatment group compared with placebo. Conclusion: DMTs for RRMS show efficacy in treating disease activity independent of age as demonstrated by group-level data from DMT clinical trials. Nevertheless, clinical trials select for patients with baseline disease activity regardless of age, thereby not representing real-world patients with RRMS, where disease activity declines with age.

Background: Diet quality has not been distinctively examined in wheelchair users with multiple sclerosis (MS). Methods: This cross-sectional study examined the Diet History Questionnaire (DHQ) III and the Automated Self-Administered 24-h (ASA24) Dietary Assessment Tool in 128 wheelchair users with MS. Participants were prompted to complete the DHQ-III and 3 ASA24 recalls during a seven-day data collection period. Healthy Eating Index (HEI)-2015 scores were calculated for DHQ-III and ASA24, and scores were compared with normative values. Spearman’s correlation analyses (rs) estimated the associations between DHQ-III and ASA24 HEI-2015 total and component scores with supportive paired sample t-tests. Results: HEI-2015 scores for DHQ-III and ASA24 were significantly higher than normative values for total score, total protein foods, and added sugar. Correlations between HEI-2015 scores generated using ASA24 and DHQ-III were all statistically significant (range rs = 0.23–0.69); however, significant differences between ASA24 and DHQ-III values were noted for HEI-2015 total score, total fruits, whole fruit, total vegetable, greens and beans, whole grains, seafood and plant protein, refined grains, and saturated fats. Conclusion: This study provided a novel description of diet quality in wheelchair users with MS for guiding future research promoting healthy eating in this population.

Clinical trials of new treatments in multiple sclerosis (MS) currently require large sample sizes and long durations in order to yield reliable results. The differential responses of an already heterogeneous population of MS patients to individual disease-modifying therapies (DMTs) will further complicate future trials. MS trials with smaller samples and faster outcomes are conceivable through the substitution of current clinical and MRI outcomes with objectively measureable genomic and proteomic biomarkers. Currently, biomarkers that could be utilized for diagnosis and monitoring of MS disease activity are in the early validation phase. The power of single biomarkers or multiple correlated biomarkers to predict prognosis and response to treatment could initially be compared with currently accepted methods. These prospectively validated disease biomarkers could then be used to subcategorize the spectrum of MS patients into a finite number of endophenotypes with demonstrable different molecular pathogeneses and DMT response profiles. Newly developed DMT could potentially be assessed within specific endophenotypes and compared with pharmacogenomically relevant active comparator DMT. This approach may increase the efficiency of MS trials through homogenization of patient population and minimization of nonresponders in study groups, providing the potential for the development of targeted therapies.

Clinical trials have advanced the treatment of multiple sclerosis (MS) by demonstrating the safety and efficacy of disease-modifying therapies (DMTs). This review discusses major changes to MS clinical trials in the era of DMTs. As treatment options for MS continue to increase, patients in modern MS trials present earlier and with milder disease compared with historic MS populations. While placebo-controlled trials for some questions may still be relevant, DMT trials in relapsing–remitting MS (RRMS) are no longer ethical. The replacement of the placebo arm by an active comparator arm in trials have raised the cost of trials by requiring larger sample sizes to detect on-study changes in treatment effects. Efforts to improve trial efficiency in RRMS have focused on exploring adaptive designs and relying on sensitive magnetic resonance imaging measures of disease activity. In trials for progressive forms of MS (PMS), the lack of sensitive outcome measures that can be used in shorter-term trials have delayed the development of effective treatments. Recent shifting of the focus to advancing trials in PMS has identified paraclinical outcome measurements with improved potential, and the testing of agents for neuroprotection and remyelination is in progress.

The achievements in multiple sclerosis (MS) therapeutics are founded on the outcomes of clinical trials that demonstrate quantifiable results in treating a disease with an unpredictable course. Much has changed since the early trials in MS from the mid-20th century that compared a potential therapeutic agent with a placebo and measured outcomes based on patients’ subjective reports. Advancements over the past decades have simplified diagnosis of the disease and allowed for more quantitative monitoring of its progression alongside support from paraclinical studies. Further collaborative efforts have led to pivotal meetings that steered the direction of future trials and the creation of patient databases that provided important epidemiologic information on trial subjects. These innovations and changes have improved MS clinical trials but challenge future trials to create more efficient designs lest the pace of progress necessarily slows because of the increased time to conduct such studies. As treatment options for MS broaden, clinical trials will continue to incorporate new strategies to identify novel therapies and pathways of intervention.

BACKGROUND: Information on causes of death (CODs) for patients with multiple sclerosis (MS) in the United States is sparse and limited by standard categorizations of underlying and immediate CODs on death certificates. Prior research indicated that excess mortality among MS patients was largely due to greater mortality from infectious, cardiovascular, or pulmonary causes. OBJECTIVE: To analyze disease categories in order to gain insight to pathways, which lead directly to death in MS patients. METHODS: Commercially insured MS patients enrolled in the OptumInsight Research database between 1996 and 2009 were matched to non-MS comparators on age/residence at index year and sex. The cause most-directly leading to death from the death certificate, referred to as the "principal" COD, was determined using an algorithm to minimize the selection of either MS or cardiac/pulmonary arrest as the COD. Principal CODs were categorized into MS, cancer, cardiovascular, infectious, suicide, accidental, pulmonary, other, or unknown. Infectious, cardiovascular, and pulmonary CODs were further subcategorized. RESULTS: 30,402 MS patients were matched to 89,818 controls, with mortality rates of 899 and 446 deaths/100,000 person-years, respectively. Excluding MS, differences in mortality rate between MS patients and non-MS comparators were largely attributable to infections, cardiovascular causes, and pulmonary problems. Of the 95 excessive deaths (per 100,000 person-years) related to infectious causes, 41 (43.2%) were due to pulmonary infections and 45 (47.4%) were attributed to sepsis. Of the 46 excessive deaths (per 100,000 person-years) related to pulmonary causes, 27 (58.7%) were due to aspiration. No single diagnostic entity predominated for the 60 excessive deaths (per 100,000 person-years) attributable to cardiac CODs. CONCLUSIONS: The principal COD algorithm improved on other methods of determining COD in MS patients from death certificates. A greater awareness of the common CODs in MS patients will allow physicians to anticipate potential problems and, thereby, improve the care that they provide.

BackgroundChronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients.Methodology/principal findingsThis study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, pConclusions/significanceThe lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS.

Background: Mycophenolate mofetil (MMF, CellCept ® ) has been utilized as an antirejection agent in transplant recipients and in patients with myriad autoimmune disorders including multiple sclerosis (MS). Objective: To investigate radiographic and clinical safety involving monotherapy use of daily oral MMF (1 g b.i.d.) versus weekly intramuscular interferon beta 1a (Avonex ® at 30 mcg) in relapsing-remitting MS (RRMS). Methods: We organized a randomized, serial, 6-monthly, MRI-blinded, parallel-group multicenter pilot study to determine the safety of MMF versus interferon beta monotherapy in 35 untreated patients with RRMS, all of whom exhibited evidence of gadolinium (Gd) enhancement on a screening MRI of the brain. The primary outcome was the reduction in the cumulative mean number of combined active lesions (CAL), new Gd-enhancing lesions, and new T2 lesions on MRI analyses. Results: Both interferon beta and MMF appeared safe and well tolerated in the majority of patients. There was no difference between MMF therapy and the standard regimen of interferon beta therapy on the primary safety MRI endpoints of the study. However, the MMF group showed a trend toward a lower accumulation of combined active lesions, CAL, Gd and T2 lesions when compared with interferon beta treated patients. Conclusions: The results from this pilot study suggest that the application of MMF monotherapy in MS deserves further exploration.