Effects of power training in older patients with multiple sclerosis on neurodegeneration, neuromuscular function, and physical function. A study protocol for the "power training in older multiple sclerosis patients (PoTOMS) randomized control trial.

Introduction: Approximately one-third of all persons with multiple sclerosis (pwMS) are older, i.e., having an age ≥60 years. Whilst ageing and MS separately elicit deteriorating effects on brain morphology, neuromuscular function, and physical function, the combination of ageing and MS may pose a particular challenge. To counteract such detrimental changes, power training (i.e., a type of resistance exercise focusing on moderate-to-high loading at maximal intended movement velocity) presents itself as a viable and highly effective solution. Power training is known to positively impact physical function, neuromuscular function, as well as brain morphology. Existing evidence is promising but limited to young and middle-aged pwMS, with the effects of power training remaining to be elucidated in older pwMS. Methods: The presented 'Power Training in Older MS patients (PoTOMS)' trial is a national, multi-center, parallel-group, randomized controlled trial. The trial compares 24 weeks of usual care(n = 30) to 24 weeks of usual care and power training (n = 30). The primary outcome is whole brain atrophy rate. The secondary outcomes include changes in brain micro and macro structures, neuromuscular function, physical function, cognitive function, bone health, and patient-reported outcomes. Ethics and dissemination: The presented study is approved by The Regional Ethics Committee (reference number 1-10-72-222-20) and registered at the Danish Data Protection Agency (reference number 2016-051-000001). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences independent of the results. The www.clinicaltrials.gov identifier is NCT04762342.

Effects of walking interventions in persons with multiple sclerosis-A systematic review.

OBJECTIVE: The aim of the present systematic review was to investigate the effects of voluntary walking interventions in persons with multiple sclerosis (pwMS). For this purpose, we developed a framework to describe the components of walking interventions. DATA SOURCES: Two databases (MEDLINE/PubMed and EMBASE) were searched in January 2023. STUDY SELECTION: Included studies enrolled pwMS and evaluated walking interventions with a duration of 2 weeks or longer. Further, they evaluated at least one walking-related outcome. Both RCTs and non-controlled studies were enrolled. DATA EXTRACTION: Data were extracted using a customized spreadsheet, which included detailed information on patient characteristics, interventions, outcomes, and results. Based on the extracted results, the effect sizes (ES, Hedge's g) of the walking interventions were calculated if possible. The methodological quality of the included studies and their reporting was determined using the TESTEX evaluation tool. DATA SYNTHESIS: Data from a total of n = 200 pwMS was included from N = 7 RCT´s (from 3 we used within-group data) and N = 5 single-group studies. On average 91.7 ± 9.9 % of the planned walking sessions were attended, 8.7 ± 10.5 % of the participants dropped out, and very few adverse events occurred. Walking interventions improved walking performance during short distance walk tests (ES ranging from -0.21 to -0.72, "walking time") and long distance walk tests (ES ranging from 0.27 to 0.72, "walking distance"). CONCLUSIONS: Voluntary walking interventions appear to be safe and effective at improving walking performance in pwMS. However, well-powered walking intervention studies are needed to confirm these promising effects. The simplicity of walking interventions makes them highly relevant for ambulatory pwMS.

The combined deleterious effects of multiple sclerosis and ageing on neuromuscular function.

BACKGROUND: The prevalence of older (>60 years) people with multiple sclerosis (pwMS) is increasing. This introduces numerous challenges, as both MS and ageing independently contribute to the deterioration of neuromuscular function. AIM: The aim was to compare the neuromuscular function in pwMS and healthy controls (HC) across three age groups: young, middle-aged, and old. METHODS: Using a cross-sectional study design, the maximal muscle strength (Fmax) and rate of force development (RFD) of the knee extensors (KE) and plantar flexors (PF) were assessed using an isokinetic dynamometer. In addition, voluntary activation (VA) and resting twitch (RT) were measured using the interpolated twitch technique. RESULTS: The Fmax, RFD, and VA of the KE were reduced in pwMS compared to HC across age groups. In pwMS, reductions were observed in PF Fmax, RFD, and RT, predominantly in the middle-aged and old age groups. Reductions increased with age in KE for both groups (except for VA) but in PF only for pwMS. The "trajectory" differed between pwMS and HC, as pwMS showed reductions from young to middle age, while HC showed reductions from middle to old age in KE. CONCLUSION: The combined negative effects of MS and ageing on neuromuscular function were especially present in the PF but also substantial in the KE. RFD showed large deficits for pwMS compared to HC across age groups. The findings can partly be explained by a reduction in VA and RT, but further investigations of neural regulation are needed to explain large RFD deficits.

Neuromuscular rate of force development discriminates fallers in ambulatory persons with multiple sclerosis - an exploratory study.

BACKGROUND: Falls as well as fall-related injuries (e.g., bone fractures) are common in persons with multiple sclerosis (pwMS). Whilst some studies have identified lower extremity maximal muscle strength (Fmax) as one among several risk factors, no previous studies have investigated the association between rate of force development (RFD; ability to generate a rapid rise in muscle force) and falls in pwMS. Not only is RFD substantially compromised (and more so than Fmax) in pwMS, studies involving other neurodegenerative populations have shown that RFD - to a greater extent than Fmax - is crucial for counteracting unexpected perturbations and avoiding falling. OBJECTIVE: To explore whether knee extensor RFD (and Fmax) can discriminate fallers from non-fallers in pwMS. METHODS: Knee extensor neuromuscular function (comprising RFD50ms and RFD200ms (force developed in the interval 0-50 ms and 0-200 ms, respectively) as well as Fmax) of the weaker leg was assessed by isokinetic dynamometry. Falls were determined by 1-year patient recall, with pwMS subsequently being classified as non-fallers (0 falls), fallers (1-2 falls), or recurrent fallers (≥3 falls). RESULTS: A total of n=53 pwMS were enrolled in the study, with n=24 classified as non-fallers (63% females, 48 years, EDSS 2.2), n=16 as fallers (88% females, 57 years, EDSS 3.3), and n=13 as recurrent fallers (46% females, 60 years, EDSS 4.2). Compared with non-fallers, neuromuscular function was reduced in both fallers (RFD50 -4.42 [-7.47;-1.37] Nm.s-1.kg-1, -48%; RFD200 -1.45 [-2.98;0.07] Nm.s-1.kg-1, -24%; Fmax -0.42 [-0.81;-0.03] Nm.kg-1, -21%) and recurrent fallers (RFD50 -5.69 [-8.94;-2.43] Nm.s-1.kg-1, -62%; RFD200 -2.26 [-3.89;-0.63] Nm.s-1.kg-1, -38%; Fmax -0.38 [-0.80;0.03] Nm.kg-1, -19%). Across all participants, associations were observed between RFD50ms and falls (rs = -0.46 [-0.67;-0.24], between RFD200ms and falls (rs = -0.34 [-0.59;-0.09]), and between Fmax and falls (rs = -0.24 [-0.48;0.01]). CONCLUSION: In this exploratory study, knee extensor neuromuscular function was able to discriminate fallers from non-fallers in pwMS, with RFD being superior to Fmax. Routine assessment of lower extremity neuromuscular function (RFD50ms in particular) may be a helpful tool in identifying pwMS at future risk of falling.

Participant characteristics of existing exercise studies in persons with multiple sclerosis - A systematic review identifying literature gaps.

BACKGROUND: Exercise is a cornerstone in rehabilitation of persons with multiple sclerosis (pwMS), which is known to elicit beneficial effects on various symptoms and to have a potential disease-modifying effect. However, it remains to be elucidated if the existing MS exercise literature covers the full age and disability span of pwMS. OBJECTIVE: To systematically review MS exercise studies and provide a detailed mapping of the demographic and clinical characteristics of the included pwMS. METHODS: A systematic review of MS exercise studies were performed using MEDLINE and EMBASE. From the resulting MS exercise studies, mean sample characteristics were extracted. RESULTS: 4576 records were identified, from which 202 studies were included. Of these, 166 studies (82.2%) enrolled pwMS aged 35-54 years, 10.9% enrolled pwMS <35 years, and 6.9% enrolled pwMS ≥55 years (only 1.5% enrolled pwMS ≥60 years). A total of 118 studies (58.4%) reported Expanded Disability Status Scale (EDSS), with 88.1% of included pwMS having an EDSS between 2.0 and 6.5, while only one study enrolled pwMS with an EDSS ≥7.0. Finally, 80% of the studies included pwMS having a disease duration of 5-14.5 years. CONCLUSION: Exercise studies in pwMS included primarily middle-aged (35-54 years) pwMS having an EDSS of 2.0-6.5 and a disease duration of 5-14.5 years. Few exercise studies were identified in young and older pwMS, in pwMS with mild disability and severe disability, and in pwMS having shorter or longer disease durations. These findings highlight the need for further investigation of exercise in these specific subgroups of pwMS as benefits of exercise might not generalize across subpopulations.

Investigating the potential disease-modifying and neuroprotective efficacy of exercise therapy early in the disease course of multiple sclerosis: The Early Multiple Sclerosis Exercise Study (EMSES).

BACKGROUND: Potential supplemental disease-modifying and neuroprotective treatment strategies are warranted in multiple sclerosis (MS). Exercise is a promising non-pharmacological approach, and an uninvestigated 'window of opportunity' exists early in the disease course. OBJECTIVE: To investigate the effect of early exercise on relapse rate, global brain atrophy and secondary magnetic resonance imaging (MRI) outcomes. METHODS: This randomized controlled trial (n = 84, disease duration <2 years) included 48 weeks of supervised aerobic exercise or control condition. Population-based control data (Danish MS Registry) was included (n = 850, disease duration <2 years). Relapse rates were obtained from medical records, and patients underwent structural and diffusion-kurtosis MRI at baseline, 24 and 48 weeks. RESULTS: No between-group differences were observed for primary outcomes, relapse rate (incidence-rate-ratio exercise relative to control: (0.49 (0.15; 1.66), p = 0.25) and global brain atrophy rate (-0.04 (-0.48; 0.40)%, p = 0.87), or secondary measures of lesion load. Aerobic fitness increased in favour of the exercise group. Microstructural integrity was higher in four of eight a priori defined motor-related tracts and nuclei in the exercise group compared with the control (thalamus, corticospinal tract, globus pallidus, cingulate gyrus) at 48 weeks. CONCLUSION: Early supervised aerobic exercise did not reduce relapse rate or global brain atrophy, but does positively affect the microstructural integrity of important motor-related tracts and nuclei.

Comparison Between Isometric and Concentric Motor Fatigability in Persons With Multiple Sclerosis and Healthy Controls - exploring central and peripheral contributions of motor fatigability.

BACKGROUND: Motor fatigability (i.e. contraction-induced reduction in muscle strength) from a concentric task associate stronger to walking and perception of fatigue in persons with multiple sclerosis (pwMS), compared with an isometric task. However, the central and peripheral contributions of motor fatigability between these tasks have not been investigated. OBJECTIVE: Compare the central and peripheral contributions of motor fatigability in the knee extensors in a sustained isometric fatigability protocol versus a concentric fatigability protocol and in pwMS versus healthy controls (HCs). METHODS: Participants (n=31 pwMS; n=15 HCs) underwent neuromuscular testing before and immediately after two knee extensor fatigability tasks (sustained isometric and concentric) in an isokinetic dynamometer. Neuromuscular testing of fatigability consisted of maximal voluntary contraction, voluntary activation (central/neural contributor), and resting twitch (peripheral/muscular contributor) determined by the interpolated twitch technique. RESULTS: Sustained isometric and concentric fatigability protocols resulted in motor fatigability for both pwMS and HCs, with no between-protocols differences for either group. Regression analysis showed that motor fatigability variance in pwMS was mainly attributed to central fatigability in the sustained isometric protocol and to both central and peripheral fatigability in the concentric protocol. In HCs, the variance in sustained isometric and concentric fatigability were attributed to both peripheral and central fatigability. CONCLUSION: Central and peripheral contributions of motor fatigability differed between sustained isometric and concentric protocols as well as between pwMS and HCs. These between-protocol differences in pwMS provide a neuromuscular dimension to the reported difference in the strength of associations of concentric and isometric tasks to walking and perception of fatigue in pwMS.

Personalised inpatient multidisciplinary rehabilitation elicits clinically relevant improvements in physical function in patients with multiple sclerosis - The Danish MS Hospitals Rehabilitation Study.

PURPOSE: Evidence of the effects of inpatient multidisciplinary rehabilitation (MDR) on physical function in patients with multiple sclerosis (MS) is limited, particularly whether clinically relevant improvements can be achieved. The aim of this study, therefore, was to investigate the effects of personalised inpatient MDR on the physical function of MS patients. METHODS: Embedded in the Danish MS Hospitals Rehabilitation Study, a pragmatic study was performed in MS patients undergoing four weeks of inpatient MDR specifically targeting physical function. Outcomes were assessed at baseline (n = 142), at discharge (n = 137) and at six months follow-up (n = 126) using the six-minute walk test (6MWT), six-spot step test (SSST), five times sit to stand test (5STS), nine-hole peg test (NHPT), dynamic gait index (DGI) and 12-item MS walking scale (MSWS). RESULTS: From Baseline-to-Discharge, significant and clinically relevant improvements were found in all measures of walking capacity (6MWT, SSST, 5STS, DGI and MSWS; p < 0.05) along with significant (but not clinically relevant) improvements in upper extremity function (NHPT; p < 0.05). Whilst comparable improvements were observed within subgroups of MS phenotype (relapsing-remitting [RR] vs. secondary + primary progressive [SP + PP]), disease severity (moderate [EDSS2.5-5.5] vs. severe [EDSS6.0-7.5]) and age (young/middle-aged [Age24-59] vs. old [Age60-65]), an attenuated adaptation was nevertheless observed for 6MWT in the most affected and vulnerable subgroups (i.e. SP + PP, EDSS6.0-7.5 and Age60-65). The significant improvements in walking capacity and upper extremity function persisted at six months follow-up but did not exceed anymore the thresholds regarded as clinically relevant. CONCLUSION: The results provide novel evidence that personalised inpatient MDR targeting physical function in MS patients elicits significant and clinically relevant improvements in physical function.

Predicting long walking capacity from the timed 25-foot walk test in persons with multiple sclerosis - a potential simple aid to assist ambulation scoring?

BACKGROUND: In people with multiple sclerosis (pwMS), no formula exists to predict long walking capacity. OBJECTIVE: To examine the accuracy of the timed 25-foot walk (T25FW) to predict long walking in pwMS with various degrees of walking dysfunction. METHODS: A linear regression was made between the T25FW and the 6-minute walk test (6MWT) using data from 498 pwMS. RESULTS: Prediction showed an excellent agreement between actual and predicted 6MWT distances, with an acceptable error of 10%, which increased as walking dysfunction increased. CONCLUSIONS: The T25WT provided acceptable prediction of the 6MWT in pwMS, although less accurate at higher degrees of dysfunction.