Low-intensity repetitive transcranial magnetic stimulation is safe and well tolerated by people living with MS - outcomes of the phase I randomised controlled trial (TAURUS).

Background: Low-intensity repetitive transcranial magnetic stimulation (rTMS), delivered as a daily intermittent theta burst stimulation (iTBS) for four consecutive weeks, increased the number of new oligodendrocytes in the adult mouse brain. Therefore, rTMS holds potential as a remyelinating intervention for people with multiple sclerosis (MS). Objective: Primarily to determine the safety and tolerability of our rTMS protocol in people with MS. Secondary objectives include feasibility, blinding and an exploration of changes in magnetic resonance imaging (MRI) metrics, patient-reported outcome measures (PROMs) and cognitive or motor performance. Methods: A randomised (2:1), placebo controlled, single blind, parallel group, phase 1 trial of 20 rTMS sessions (600 iTBS pulses per hemisphere; 25% maximum stimulator output), delivered over 4-5 weeks. Twenty participants were randomly assigned to 'sham' (n = 7) or active rTMS (n = 13), with the coil positioned at 90° or 0°, respectively. Results: Five adverse events (AEs) including one serious AE reported. None were related to treatment. Protocol compliance was high (85%) and blinding successful. Within participant MRI metrics, PROMs and cognitive or motor performance were unchanged over time. Conclusion: Twenty sessions of rTMS is safe and well tolerated in a small group of people with MS. The study protocol and procedures are feasible. Improvement of sham is warranted before further investigating safety and efficacy.

Diet and omega-3 and vitamin D supplement use predict five-year fatigue and disability trajectories in people with multiple sclerosis.

BACKGROUND: Fatigue and disability are indicators of disease progression experienced by many people with multiple sclerosis (pwMS). Understanding trajectories of these outcomes, and their predictors, may provide insight to potential interventions for MS management. METHODS: Survey data from 839 pwMS from the Health Outcomes and Lifestyle in pwMS study were analysed. Fatigue was defined as mean Fatigue Severity Scale >5, and severe disability as Patient Determined Disease Steps >5. Group-based trajectory modelling was used to identify fatigue and disability trajectories over five-years. Dietary predictors associated with outcome trajectory group membership were assessed using log-binomial regression. Demographic and clinical characteristics were considered in multivariable models. RESULTS: Distinct trajectories for fatigue and disability were identified. For fatigue, 58 % of pwMS were assigned to low-, and 42 % to high-, fatigue trajectory groups. For disability, 85 % of pwMS were assigned to low-, and 15 % to high-, disability groups. Baseline high-quality diet, and omega-3 and vitamin D supplement use, were associated with reduced risk of being in high-fatigue and high-disability trajectories, while meat and dairy consumption were associated with increased risk. CONCLUSIONS: A high-quality diet, avoiding meat and dairy, and omega-3 and vitamin D supplement use, individually predict better fatigue and disability trajectories. Dietary modifications should be considered in MS management.

Changes in employment status over time in multiple sclerosis following a first episode of central nervous system demyelination, a Markov multistate model study.

BACKGROUND AND PURPOSE: Understanding predictors of changes in employment status among people living with multiple sclerosis (MS) can assist health care providers to develop appropriate work retention/rehabilitation programs. We aimed to model longitudinal transitions of employment status in MS and estimate the probabilities of retaining employment status or losing or gaining employment over time in individuals with a first clinical diagnosis of central nervous system demyelination (FCD). METHODS: This prospective cohort study comprised adults (aged 18-59 years) diagnosed with FCD (n = 237) who were followed for more than 11 years. At each review, participants were assigned to one of three states: unemployed, part-time, or full-time employed. A Markov multistate model was used to examine the rate of state-to-state transitions. RESULTS: At the time of FCD, participants with full-time employment had an 89% chance of being in the same state over a 1-year period, but this decreased to 42% over the 10-year follow-up period. For unemployed participants, there was a 92% likelihood of remaining unemployed after 1 year, but this probability decreased to 53% over 10 years. Females, those who progressed to clinically definite MS, those with a higher relapse count, and those with a greater level of disability were at increased risk of transitioning to a deteriorated employment state. In addition, those who experienced clinically significant fatigue over the follow-up period were less likely to gain employment after being unemployed. CONCLUSIONS: In our FCD cohort, we found a considerable rate of employment transition during the early years post-diagnosis. Over more than a decade of follow-up post-FCD, we found that females and individuals with a greater disability and a higher relapse count are at higher risk of losing employment.

Instruments measuring change in cognitive function in multiple sclerosis: A systematic review.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating/neurodegenerative disease associated with change in cognitive function (CF) over time. This systematic review aims to describe the instruments used to measure change in CF over time in people with MS (PwMS). METHODS: PubMed, OVID, Web of Science, and Scopus databases were searched in English until May 2021. Articles were included if they had at least 100 participants and at least a 1-year interval between baseline and last follow-up measurement of CF. Results were quantitatively synthesized, presented in tables and risk of bias was assessed with the Newcastle-Ottawa Scale. RESULTS: Fifty-seven articles met the inclusion criteria (41,623 PwMS and 1105 controls). An intervention (drug/rehabilitation) was assessed in 22 articles. In the studies that used a test battery, Visual and verbal learning and memory were the most frequently measured domains, but when studies that used test battery or a single test are combined, Information processing speed was the most measured. The Symbol Digit Modalities Test (SDMT) was the most frequently used test as a single test and in a test battery combined. Most studied assessed "change in CF" as cognitive decline defined as 1 or more tests measured as ≥ 1.5 SD from the study control or normative mean in a test battery at baseline and follow-up. Meta-analysis of change in SDMT scores with seven articles indicated a nonstatistically significant -0.03 (95% CI -0.14, 0.09) decrease in mean SDMT score per year. CONCLUSION: This study highlights the slow rate of measured change in cognition in PwMS and emphasizes the lack of a gold standard test and consistency in measuring cognitive change at the population level. More sensitive testing utilizing multiple domains and longer follow-up may define subgroups where CF change follows different trajectories thus allowing targeted interventions to directly support those where CF is at greatest risk of becoming a clinically meaningful issue.

Ensemble machine learning identifies genetic loci associated with future worsening of disability in people with multiple sclerosis.

Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci (rs7731626: HR 0.92, P = 2.4 × 10-5; rs12211604: HR 1.16, P = 3.2 × 10-7; rs55858457: HR 0.93, P = 3.7 × 10-7; rs10271373: HR 0.90, P = 1.1 × 10-7; rs11256593: HR 1.13, P = 5.1 × 10-57; rs12588969: HR = 1.10, P = 2.1 × 10-10; rs1465697: HR 1.09, P = 1.7 × 10-128) associated with risk worsening of disability; most of which were located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles produced a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.

Safety of low-intensity repetitive transcranial magneTic brAin stimUlation foR people living with mUltiple Sclerosis (TAURUS): study protocol for a randomised controlled trial.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease, characterised by oligodendrocyte death and demyelination. Oligodendrocyte progenitor cells can differentiate into new replacement oligodendrocytes; however, remyelination is insufficient to protect neurons from degeneration in people with MS. We previously reported that 4 weeks of daily low-intensity repetitive transcranial magnetic stimulation (rTMS) in an intermittent theta-burst stimulation (iTBS) pattern increased the number of new myelinating oligodendrocytes in healthy adult mice. This study translates this rTMS protocol and aims to determine its safety and tolerability for people living with MS. We will also perform magnetic resonance imaging (MRI) and symptom assessments as preliminary indicators of myelin addition following rTMS. METHODS: Participants (N = 30, aged 18-65 years) will have a diagnosis of relapsing-remitting or secondary progressive MS. ≤2 weeks before the intervention, eligible, consenting participants will complete a physical exam, baseline brain MRI scan and participant-reported MS symptom assessments [questionnaires: Fatigue Severity Scale, Quality of Life (AQoL-8D), Hospital Anxiety and Depression Scale; and smartphone-based measures of cognition (electronic symbol digit modalities test), manual dexterity (pinching test, draw a shape test) and gait (U-Turn test)]. Participants will be pseudo-randomly allocated to rTMS (n=20) or sham (placebo; n=10), stratified by sex. rTMS or sham will be delivered 5 days per week for 4 consecutive weeks (20 sessions, 6 min per day). rTMS will be applied using a 90-mm circular coil at low-intensity (25% maximum stimulator output) in an iTBS pattern. For sham, the coil will be oriented 90° to the scalp, preventing the magnetic field from stimulating the brain. Adverse events will be recorded daily. We will evaluate participant blinding after the first, 10th and final session. After the final session, participants will repeat symptom assessments and brain MRI, for comparison with baseline. Participant-reported assessments will be repeated at 4-month post-allocation follow-up. DISCUSSION: This study will determine whether this rTMS protocol is safe and tolerable for people with MS. MRI and participant-reported symptom assessments will serve as preliminary indications of rTMS efficacy for myelin addition to inform further studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001196134 . Registered on 27 August 2019.

Long-term trajectories of employment status, workhours and disability support pension status, after a first episode of CNS demyelination.

BACKGROUND: People with multiple sclerosis face significant employment-related challenges, with little known of the drivers of these outcomes. OBJECTIVE: We examined prospective trajectories of employment-related outcomes up to 11 years following a first episode of central nervous system (CNS) demyelination (FCD). METHODS: Participants were aged 18-59 years, at FCD, with at least two observations and were employed at study entry or anytime during follow-up (n = 207). Outcomes were employment status (full-time, part-time and unemployed), average workhours per week and disability support pension (DSP; receiving/not receiving). We used group-based trajectory modelling to identify groups with common trajectories. Factors associated with trajectory membership were explored using log-multinomial regression. RESULTS: Distinct trajectories were identified for employment (4), workhours (4) and DSP (2). Compared with stable full-time, female sex was strongly associated with being in the stable part-time trajectory (risk ratio (RR): 5.35; 95% confidence interval (CI) = 2.56-11.20; p < 0.001). A greater level of disability at 5-year review (RR: 1.35; 95% CI = 1.19-1.53) and having more than two comorbidities at baseline (RR: 2.77; 95% CI = 1.37-5.64) were associated with being in early and late deteriorated employment trajectories, respectively. Compared with the increased part-time trajectory, every additional relapse during the 5 years post-FCD was associated with a 10% increased risk of being in the reduced part-time trajectory (RR = 1.10; 95%CI = 1.00-1.22). For every additional EDSS point at 5-year review, the risk of being in the DSP trajectory increased (RR = 1.21; 95% CI = 1.05-1.41). CONCLUSION: These trajectories indicate substantial heterogeneity and the complex impact of MS on employment from its earliest timepoints. Understanding these trends could enable better targeting of interventions to facilitate workforce retention, particularly for females, those with a higher number of comorbidities, more frequent relapses and greater rate of disability accrual.

Psychological impacts of COVID-19 pandemic on individuals living with multiple sclerosis: A rapid systematic review.

INTRODUCTION: The global spread of COVID-19 has raised concerns about its possible impact on mental health. People living with multiple sclerosis (PwMS) are considered potentially vulnerable to the mental health effects of the pandemic, as they may be subject to increased social isolation. AIM: To systematically review the current evidence on the impact of the COVID-19 pandemic on mental health outcomes among PwMS. METHOD: We searched four major databases (Medline, EMBASE, PsychInfo and Scopus) and the WHO Global Health COVID-19 research database. We included peer-reviewed primary research studies using validated health-related quality of life (HRQOL) and psychometric screening tools to evaluate mental health outcomes among PwMS during the COVID-19 pandemic. Studies reporting data on the prevalence of mental health disorders, severity of psychological symptoms and contributing demographic and clinical factors for PwMS during the COVID-19 pandemic were included. RESULTS: Our initial search yielded 268 records; 19 studies (13 cross-sectional, 6 longitudinal) were included. Most were conducted during a peak in the pandemic in the host country via an online platform. The main mental health outcomes were depression, anxiety, stress, sleep quality and HRQOL. The included studies used a variety of outcome assessment tools and study designs. The prevalence of mental health issues such as depression, anxiety and stress were high among PwMS during the pandemic. In addition, compared to control populations, PwMS experienced more severe symptoms of depression and stress during the COVID-19 outbreak. However, results from longitudinal studies demonstrate that the severity of mental health symptoms among PwMS during the pandemic were not significantly different compared with the pre-pandemic period. CONCLUSION: Although mental health issues such as anxiety and depression were common among PwMS during the pandemic, current evidence suggests that mental health among PwMS has not been significantly affected by pandemic-related restrictive measures. Instead, the observed differences may be the result of pre-pandemic differences in prevalence and severity. Where possible, future studies should seek to address the methodological issues identified in the included studies to ensure that data collected during the pandemic can be synthesized into recommendations for policy and practice.

Role of environmental factors in multiple sclerosis.

INTRODUCTION: Environmental factors play a significant role in the pathogenesis and progression of multiple sclerosis (MS), either acting alone or by interacting with other environmental or genetic factors. This cumulative exposure to external risk factors is highly complex and highly variable between individuals. AREAS COVERED: We narratively review the current evidence on the role of environment-specific risk factors in MS onset and progression, as well as the effect of gene-environment interactions and the timing of exposure We have reviewed the latest literature, by Ovid Medline, retrieving the most recently published systematic reviews and/or meta-analyses and more recent studies not previously included in meta-analyses or systematic reviews. EXPERT OPINION: There is some good evidence supporting the impact of some environmental risk factors in increasing the risk of developing MS. Tobacco smoking, low vitamin D levels and/or low sun exposure, Epstein Barr Virus (EBV) seropositivity and a history of infectious mononucleosis may increase the risk of developing MS. Additionally, there is some evidence that gene-smoking, gene-EBV, and smoking-EBV interactions additively affect the risk of MS onset. However, the evidence for a role of other environmental factors in MS progression is limited. Finally, there is some evidence that tobacco smoking, insufficient vitamin D levels and/or sun exposure have impacts on MS phenotypes and various markers of disease activity including relapse, disability progression and MRI findings. Clearly the effect of environmental factors on MS disease course is an area that requires significantly more research.

The effect of lamotrigine on learning in mice using the passive avoidance model.

INTRODUCTION: Lamotrigine (LTG) is an antiepileptic drug that inhibits the release of glutamate by blocking sodium channels. The present study was conducted to evaluate the effect of LTG in different stages of memory using a passive avoidance learning task in mice. METHODS: Male albino mice in the weight range 20-25g were used. They were divided into four groups (control group and three groups receiving various doses of LTG). LTG was given in three doses of 10, 25, and 50mg/kg as intraperitoneal (IP) injections. The doses of LTG were used in three injection groups: before acquisition, after consolidation, and before retrieval at 24h. The retention latency times in each group were recorded using a step-through passive avoidance task 24h and one week after consolidation. RESULTS: Retention latency in the group receiving a high dose of LTG (25mg/kg) after one week was significantly increased in comparison to the group receiving a low dose of LTG (10mg/kg) (267±49.96 vs. 198.87±57.22, P=0.015). With injection of LTG after consolidation, the retention latency times were increased in all doses after a one-week retrieval compared to the control (P=0.023). Kaplan-Mayer surveillance analysis also showed significant differences in the latencies of the LTG-receiving group after 24h and one week's retrieval (P=0.041). Administration of LTG before retrieval at 24h showed a significant difference in retention latency time, which was increased for two doses of LTG (10 and 50mg/kg) after one week (203.5±63.67 vs. 270.25±19.78, P=0.024). CONCLUSION: LTG at higher doses may facilitate the learning process in mice and appears to improve memory function at different stages.