Content and effects of balance training in people with diabetic peripheral neuropathy - a systematic review and meta-analysis.

BACKGROUND: Diabetic Peripheral Neuropathy (DPN) impairs balance due to sensory loss, proprioceptive deficits, muscle weakness, altered gait, and delayed reflexes. Targeted aerobic and balance training seem promising to mitigate these issues. However, the exact content of a recommended training regime is yet to be determined. OBJECTIVE: To delineate and synthesise balance training content and efficacy for people with DPN. METHODS: The literature search was conducted on PubMed and Embase in accordance with the PRISMA-checklist. Last search was performed on April 29, 2024. Inclusion criteria were established using the PICO-framework. Methodological quality was assessed using the TESTEX Scale. Meta-analyses were exclusively applied to studies featuring a passive control group. RESULTS: A total of 2007 articles were identified. Twelve studies were included in the qualitative synthesis. Seven studies were included in the meta-analyses. Two studies were of high quality. Most studies reported the frequency, session time, duration, and setting of balance training, while none reported the intensity. The meta-analyses showed a standardized mean difference in favor of balance training compared to passive control for One-Legged Stance (openeyes) (0.89[0.5,1.28]), One-Legged Stance (closed eyes) (1.48[0.36, 2.60]), Postural sway (-0.71[-1.04, -0,37]), Timed Up and Go(-0.94[-1.78, -0.10]), and Berg Balance Scale (2.26[0.48, 4.05]), respectively. CONCLUSION: Studies are few and generally of low methodological quality. The content of balance training interventions is minimally described, especially concerning the applied intensity. However, balance training does seem to improve balance outcomes in people with DPN, but given the methodological limitations, interpretation must be cautious.

Effects of Balance Exercise Interventions on Balance-Related Performance in People With Multiple Sclerosis: A Systematic Review and a Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Balance training covers a range of different modalities and complexity levels for people with multiple sclerosis (MS). When evaluating the effects of balance training across different kinds of interventions, determination of the specific intervention content that predict effects are needed. OBJECTIVE: To investigate the effects of balance training on gait and dynamic balance outcomes. METHODS: Four databases were systematically searched. Randomized controlled trials involving people with MS (Expanded Disability Status Scale [EDSS] score ≤7.5) where at least 50% of the intervention targeted balance control were included. Interventions were categorized based on training types. Risk-of-bias was assessed using the Tool for the Assessment of Study Quality and Reporting in Exercise (TESTEX). RESULTS: A total of 18 included studies involved 902 people with MS (EDSS range from 0 to 7.5). Interventions evaluated with a balance composite score or a mobility test showed a moderate effect size (ES = 0.46 [95% confidence interval (CI) = 0.18 to 0.74]; p < .01) and a small overall ES (ES = 0.19 [95% CI = 0.01-0.36]; p = .04), respectively, across different training types. Stepping and gait speed outcomes showed no effect. Cognitive dual-task training showed a significant effect (ES = 0.81 [95% CI = 0.24 to 1.37]) on subgroup level, when evaluated with a mobility outcome measure. The median TESTEX score on study quality and reporting was 11 (maximum score = 15). CONCLUSIONS: Improvements of balance were found across interventions when measured by balance composite scores and mobility tests, but not when measured by stepping or gait speed outcomes. Large training volume was positively associated with effect on balance. A definition of intensity in balance training is needed for evaluation of its impact on the effect of balance interventions.

Study protocol: effects of exercise booster sessions on preservation of exercise-induced adaptations in persons with multiple sclerosis, a multicentre randomised controlled trial-the MS BOOSTER trial.

INTRODUCTION: Multiple sclerosis (MS) causes a broad range of symptoms, with physical function being one of the most disabling consequences according to patients themselves. Exercise effectively improves lower extremity physical function. Nonetheless, it is unknown which exercise modality is most effective and it remains challenging to keep persons with MS adhering to exercise over a longer period. Therefore, the present study aims to investigate how exercise booster sessions (EBS) influence the sustainability of exercise-induced effects on physical function, and furthermore, to investigate which exercise modality (aerobic training or resistance training) is most effective in terms of improving physical function. MATERIALS AND METHODS: This study is a multi-arm, parallel-group, open-label multicentre randomised controlled trial investigating the effects of EBS. Participants (n=150) are initially randomised to 12 weeks of either resistance training+usual care, aerobic training+usual care or usual care. After 12 weeks of intervention, participants in the exercise groups will again be randomised to either EBS+usual care or usual care during a 40-week follow-up period. The primary outcome is physical function (composite score based on 6-min walk test and five-time sit to stand), and the secondary outcomes are fatigue, cognition, physical activity, symptoms of depression and quality of life. ETHICS AND DISSEMINATION: The study is approved by the Central Denmark Region Committees on Health Research Ethics (1-10-72-237-21) and is registered at the Danish Data Protection Agency (2016-051-000001) and at Clinicaltrials.gov (NCT04913012). All study findings will be published in scientific peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT04913012.

Limited correlation between physical performance and patient-reported outcomes at 1-year follow-up after anterior cruciate ligament reconstruction.

Purpose: The majority of anterior cruciate ligament reconstruction (ACLr) patients wish to return to sport. Clinical evaluations after ACLr often do not include physical testing, making it difficult to determine the patient's readiness to return to sport. Thus, it would be helpful to identify easily assessable factors associated with physical function in ACLr patients that could inform planning of patients' return to sport. This study sought to evaluate the associations between physical test performance in ACLr patients and known ACL injury risk factors, knee laxity and patient-reported outcomes at 1-year follow-up. Methods: The cohort included isolated primary ACLr patients operated between 2009 and 2014. Patients were invited to a 1-year visit to clarify their readiness to return to sport. A test battery was performed, including clinical evaluation, patient-reported outcomes and three physical tests, from which the Leg Symmetry Index (LSI) was calculated. Multivariate regression analyses were performed for each of the physical tests, including known risk factors, clinical outcomes and patient-reported outcomes. Laxity <3 mm, pivot shift = 0, Knee Injury and Osteoarthritis Outcome Score (KOOS) sport >75, International Knee Documentation Committee (IKDC) >75.9, and Single Assessment Numeric Evaluation (SANE) >92.7 were applied as cut-off values for good versus poor status. Results: A total of 480 ACLr patients were included in the study. Laxity <3 mm had a negative impact on the single-hop LSI, whereas a pivot shift = 0 or IKDC >75.9 had a positive impact on the single-hop LSI. Age <20, a pivot shift grade of 0 and KOOSsport >75 were positively associated with the triple-hop LSI. Finally, age <20 and IKDC >75.9 were positively associated with the leg extension strength LSI. Conclusions: Age, sagittal laxity, pivot shift and patient-reported outcomes were associated with physical test performance 1 year after ACLr. However, the associations were not completely uniform and strong, so information on age, sagittal laxity, pivot shift and patient-reported outcomes cannot replace a return-to-sport functional test battery in determining when it is safe to return to sport after ACLr. Level of Evidence: Level III.

First-line treatment for femoroacetabular impingement syndrome and hip-related quality of life: study protocol for a multicentre randomised controlled trial comparing a 6-month supervised strength exercise intervention to usual care (the Better Hip Trial).

INTRODUCTION: Femoroacetabular impingement syndrome (FAIS) is a motion-related and position-related clinical condition of the hip associated with pain, reduced physical function and hip-related quality of life (QoL). Interestingly, higher maximal muscle strength is associated with less pain, better physical function and improved QoL in people with FAIS. Furthermore, preliminary evidence suggests that a proportion of patients with FAIS respond positively to strength exercise as first-line treatment. Nonetheless, there is little evidence supporting a specific exercise intervention offered as a first-line treatment. We will conduct a randomised controlled trial investigating the clinical effectiveness and cost-effectiveness of a 6-month strength exercise intervention compared with usual care as first-line treatment in patients with FAIS. METHODS AND ANALYSIS: This is a multicentre randomised controlled trial that will be conducted at hospitals and physiotherapy clinics across Denmark and Australia. A total of 120 patients with FAIS will be randomised (1:1) to 6 months of supervised strength exercise or usual care. The primary outcome is the change in hip-related QoL measured using the International Hip and Outcome Tool 33 (iHOT-33) from baseline to the end of intervention. A health economic evaluation will be conducted from a societal and healthcare perspective based on the data collection over a 12-month period starting at baseline. The analysis will calculate incremental cost-effectiveness ratios using quality-adjusted life-years and iHOT-33 scores while estimating costs using microcosting and cost questionnaires. Secondary outcomes include objectively measured physical function at baseline and after 6 months and patient-reported outcomes measured at baseline, 3-month, 6-month and 12-month follow-up. ETHICS AND DISSEMINATION: The trial has been approved by the Committee on Health Research Ethics in the Central Denmark Region (journal no 1-10-72-45-23) and La Trobe University Human Ethics Committee (HEC24042) and is registered at the Central Denmark Region List of Research Projects (journal no 1-16-02-115-23). Informed consent will be obtained from each participant before randomisation. Results will be published in international peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT05927935.

Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial.

BACKGROUND: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings. METHODS: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task). RESULTS: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula. CONCLUSIONS: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements. TRIAL REGISTRATION NUMBER: NCT03679468.

Progressive Resistance Training or Neuromuscular Exercise for Hip Osteoarthritis : A Multicenter Cluster Randomized Controlled Trial.

BACKGROUND: Exercise is recommended as first-line treatment for patients with hip osteoarthritis (OA). However, randomized controlled trials providing evidence for the optimal exercise type are lacking. OBJECTIVE: To investigate whether progressive resistance training (PRT) is superior to neuromuscular exercise (NEMEX) for improving functional performance in patients with hip OA. DESIGN: Multicenter, cluster-randomized, controlled, parallel-group, assessor-blinded, superiority trial. (ClinicalTrials.gov: NCT04714047). SETTING: Hospitals and physiotherapy clinics. PARTICIPANTS: 160 participants with clinically diagnosed hip OA were enrolled from 18 January 2021 to 28 April 2023 and randomly assigned to PRT (n = 82) or NEMEX (n = 78). INTERVENTION: Twelve weeks of PRT or NEMEX with 2 supervised 60-minute group sessions each week. The PRT intervention consisted of 5 high-intensity resistance training exercises targeting muscles at the hip and knee joints. The NEMEX intervention included 10 exercises and emphasized sensorimotor control and functional stability. MEASUREMENTS: The primary outcome was change in the 30-second chair stand test (30s-CST). Key secondary outcomes were changes in scores on the pain and hip-related quality of life (QoL) subscales of the Hip Disability and Osteoarthritis Outcome Score (HOOS). RESULTS: The mean changes from baseline to 12-week follow-up in the 30s-CST were 1.5 (95% CI, 0.9 to 2.1) chair stands with PRT and 1.5 (CI, 0.9 to 2.1) chair stands with NEMEX (difference, 0.0 [CI, -0.8 to 0.8] chair stands). For the HOOS pain subscale, mean changes were 8.6 (CI, 5.3 to 11.8) points with PRT and 9.3 (CI, 5.9 to 12.6) points with NEMEX (difference, -0.7 [CI, -5.3 to 4.0] points). For the HOOS QoL subscale, mean changes were 8.0 (CI, 4.3 to 11.7) points with PRT and 5.7 (CI, 1.9 to 9.5) points with NEMEX (difference, 2.3 [CI, -3.0 to 7.6] points). LIMITATION: Participants and physiotherapists were not blinded. CONCLUSION: In patients with hip OA, PRT is not superior to NEMEX for improving functional performance, hip pain, or hip-related QoL. PRIMARY FUNDING SOURCE: Independent Research Fund Denmark.

Are physical activity levels, cardiorespiratory fitness and peak power associated with Parkinson's disease severity?

INTRODUCTION: Increased physical activity (PA) may slow Parkinson's disease (PD) progression. Associations between markers of PA and PD severity could justify further studies evaluating interventions increasing PA levels in PD. The objectives of the present study were to assess associations between PA, cardiorespiratory fitness (VO2-max), and muscle peak power and measures of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Parkinson's disease questionnaire-39 (PDQ-39), and the four PD hallmark motor symptoms (rigidity, bradykinesia, postural instability, and tremor). METHODS: Data from 105 people with PD were used. PA was measured for seven consecutive days using accelerometers. Peak power was measured with a linear encoder during a chair rise test, while VO2-max was directly assessed during a graded bicycle test. Analyses included simple and multiple linear regression and hurdle exponential regression. RESULTS: PA was weakly to moderately associated with MDS-UPDRS II + III, rigidity, bradykinesia, and postural instability, as well as PDQ-39 mobility and activities of daily living sub-scores. VO2-max and peak power were weakly to moderately associated with MDS-UPDRS III, bradykinesia, and postural instability, while peak power was further weakly associated with the MDS-UPDRS II. Lastly, VO2-max was associated with PDQ-39 mobility and activities of daily living sub-scores. CONCLUSION: PA, VO2-max, and peak power were associated with PD severity, thus highlighting the potential benefits of a physically active lifestyle. Furthermore, PA and VO2-max were associated with PDQ-39 sub-scores. This calls for confirmation of the potential effect of PA on quality of life in PD.

Prevalence and Associated Clinical Characteristics of Walking-Related Motor, Cognitive, and Fatigability in Progressive Multiple Sclerosis: Baseline Results From the CogEx Study.

BACKGROUND: People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task. OBJECTIVE: To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients. METHODS: PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment-Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue-Modified Fatigue Impact Scale (MFIS), MS impact-MSIS-29, and walking ability. RESULTS: Of 298 participants, 153 (51%) presented WF (DWI = -28.9 ± 22.1%) and 196 (66%) presented CF (-29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related. CONCLUSIONS: Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions. TRIAL REGISTRATION NUMBER: The "CogEx-study," www.clinicaltrial.gov identifier number: NCT03679468.

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.

Exercise as medicine in Parkinson's disease.

Parkinson's disease (PD) is an incurable and progressive neurological disorder leading to deleterious motor and non-motor consequences. Presently, no pharmacological agents can prevent PD evolution or progression, while pharmacological symptomatic treatments have limited effects in certain domains and cause side effects. Identification of interventions that prevent, slow, halt or mitigate the disease is therefore pivotal. Exercise is safe and represents a cornerstone in PD rehabilitation, but exercise may have even more fundamental benefits that could change clinical practice. In PD, the existing knowledge base supports exercise as (1) a protective lifestyle factor preventing the disease (ie, primary prevention), (2) a potential disease-modifying therapy (ie, secondary prevention) and (3) an effective symptomatic treatment (ie, tertiary prevention). Based on current evidence, a paradigm shift is proposed, stating that exercise should be individually prescribed as medicine to persons with PD at an early disease stage, alongside conventional medical treatment.

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.

Validity and reliability of linear encoder muscle power testing in persons with Parkinson's disease.

OBJECTIVE: To investigate the construct validity ON medication and the reliability both ON and OFF medication of linear encoder muscle power testing in persons with Parkinson's disease (pwPD). DESIGN: A study using baseline data from one randomized controlled trial (study 1) and one cohort study (study 2). SETTING: University exercise lab. PARTICIPANTS: Study 1: 35 healthy controls and 70 pwPD. Study 2: 20 pwPD. INTERVENTION: Study 1: baseline data. Study 2: 4 chair rise tests (2 ON and 2 OFF medication), in a randomized order, separated by 4 to 16 days. MAIN MEASURES: Linear encoder data were collected from a chair rise test. Known groups validity and convergent validity (i.e., construct validity) were assessed by comparing peak power between pwPD and healthy controls and associations between peak power and functional performance (i.e., 6-Min Walk Test, Timed Up and Go Test, Six-Spot Step Test), respectively. Reliability was assessed as day-to-day variation and by intraclass correlation coefficients. RESULTS: Peak power was comparable between pwPD and healthy controls (-7.2%, p = 0.17), but lower in moderately impaired pwPD compared to mildly impaired pwPD (-27%, p < 0.01) and healthy controls (-23%, p < 0.01). Moderate to strong associations were observed between peak power and functional performance (r2 = 0.44-0.51). Day-to-day variation ON and OFF medication were 1.0 and 1.3 W/kg, respectively, while intraclass correlation coefficients were 0.95 (0.87;0.98) and 0.93 (0.82;0.97), respectively. CONCLUSION: Linear encoder muscle power testing shows inconsistent known groups validity, acceptable convergent validity ON medication, and excellent day-to-day reliability ON and OFF medication in pwPD.

The six spot step test is superior in detecting walking capacity impairments compared to short- and long-distance walk tests in persons with multiple sclerosis.

Background: Walking capacity is important not only to persons with multiple sclerosis but also to clinical practice and research. The present study aims to compare the extent of impairments (relative to healthy controls) across three commonly used walking capacity outcomes in persons with multiple sclerosis. Methods: In a two-hospital cross-sectional study, walking capacity was assessed using the timed-25-footwalk-test (timed 25-ft walk test; 'walking speed'), the six-minute-walk-test ('walking endurance') and the six-spot-step-test ('walking balance and coordination'). Data were compared to normative reference data in healthy controls. Results: A total of 228 persons with multiple sclerosis (68% females) were involved in the study: age 53.7 ± 11.6 y (range 26-81 y); patient-determined-disease-steps 3 [IQR; 1; 4] (range 0-7); time since diagnosis 12.6 ± 9.9 y (range 0-49 y); MS-phenotype (relapse remitting MS, secondary progressive MS, primary progressive MS) 146/39/41; and co-morbidity n = 80 (35%). Compared to healthy controls, deficits were observed across all walking capacity outcomes (p < 0.001): timed 25-foot walk test -26 [-30; -23]%, 6 minute-walk-test -36 [-39; -32]% and six-spot-step-test -44 [-47; -40]%. Deficits differed across walking capacity outcomes (p < 0.001). Conclusion: Altogether, persons with multiple sclerosis performed substantially worse than healthy controls across all three walking capacity outcomes. The results showed that the six-spot-step-test was superior to the timed 25-foot walk test and the 6 minute-walk-test in detecting walking capacity impairments in persons with multiple sclerosis.

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.

The MoXFo initiative - study design: Considerations related to study design and methodology in exercise research for people with multiple sclerosis.

BACKGROUND: Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleiotropic effects, but continued progression of the field requires better future designs and methodologies. OBJECTIVES: This paper outlines the work of the 'Study design and methodology' group of the MoXFo (moving exercise research forward) initiative, and addresses critical aspects and future directions when defining the research question of interest, and subsequently, designing the study and exercise intervention in MS patients. METHODS: The work is based on the formation of an international expert panel formed within the MoXFo initiative. We provide a structured and concise synthesis of exercise-specific MS research challenges and considerations when designing randomized controlled trials (RCTs). RESULTS: Challenges and considerations are presented using the Patient population, Intervention, Comparator, Outcomes, Timing, Setting (PICOTS) framework, thereby forming a new and specific MS exercise PICOTS framework. CONCLUSION: We propose that researchers should carefully consider and align all elements of this MS exercise PICOTS framework when developing future research questions and study designs, ultimately improving the quality of new exercise studies in people with MS.

Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis (CogEx): a randomised, blinded, sham-controlled trial.

BACKGROUND: Cognitive dysfunction in people with relapsing-remitting multiple sclerosis can improve with cognitive rehabilitation or exercise. Similar effects have not been clearly shown in people with progressive multiple sclerosis. We aimed to investigate the individual and synergistic effects of cognitive rehabilitation and exercise in patients with progressive multiple sclerosis. METHODS: CogEx was a randomised, sham-controlled trial completed in 11 hospital clinics, universities, and rehabilitation centres in Belgium, Canada, Denmark, Italy, UK, and USA. Patients with progressive multiple sclerosis were eligible for inclusion if they were aged 25-65 years and had an Expanded Disability Status Scale (EDSS) score of less than 7. All had impaired processing speed defined as a performance of 1·282 SD or greater below normative data on the Symbol Digit modalities Tests (SDMT). Participants were randomly assigned (1:1:1:1), using an interactive web-response system accessed online from each centre, to cognitive rehabilitation plus exercise, cognitive rehabilitation plus sham exercise, exercise plus sham cognitive rehabilitation, or sham exercise plus sham cognitive rehabilitation. The study statistician created the randomisation sequence that was stratified by centre. Participants, outcome assessors, and investigators were blinded to group allocation. The study statistician was masked to treatment during analysis only. Interventions were conducted two times per week for 12 weeks: cognitive rehabilitation used an individualised, computer-based, incremental approach to improve processing speed; sham cognitive rehabilitation consisted of internet training provided individually; the exercise intervention involved individualised aerobic training using a recumbent arm-leg stepper; and the sham exercise involved stretching and balance tasks without inducing cardiovascular strain. The primary outcome measure was processing speed measured by SDMT at 12 weeks; least squares mean differences were compared between groups using linear mixed model in all participants who had a 12-week assessment. The trial is registered with ClinicalTrials.gov, NCT03679468, and is completed. FINDINGS: Between Dec 14, 2018, and April 2, 2022, 311 people with progressive multiple sclerosis were enrolled and 284 (91%) completed the 12-week assessment (117/311 [38%] male and 194/311 [62%] female). The least squares mean group differences in SDMT at 12 weeks did not differ between groups (p=0·85). Compared with the sham cognitive rehabilitation and sham exercise group (n=67), differences were -1·30 (95% CI -3·75 to 1·16) for the cognitive rehabilitation plus exercise group (n=70); -2·78 (-5·23 to -0·33) for the sham cognitive rehabilitation plus exercise group (n=71); and -0·71 (-3·11 to 1·70) for the cognitive rehabilitation plus sham exercise group (n=76). 11 adverse events possibly related to the interventions occurred, six in the exercise plus sham cognitive rehabilitation group (pain, dizziness, and falls), two in the cognitive rehabilitation plus sham exercise group (headache and pain), two in the cognitive rehabilitation and exercise group (increased fatigue and pain), and one in the dual sham group (fall). INTERPRETATION: Combined cognitive rehabilitation plus exercise does not seem to improve processing speed in people with progressive multiple sclerosis. However, our sham interventions were not inactive. Studies comparing interventions with a non-intervention group are needed to investigate whether clinically meaningful improvements in processing speed might be attainable in people with progressive multiple sclerosis. FUNDING: MS Canada.

Intermediate outcomes for clinical trials of multiple sclerosis rehabilitation interventions: Conceptual and practical considerations.

BACKGROUND: Rehabilitation is an essential health care service and a critical component of comprehensive multiple sclerosis (MS) care. OBJECTIVE: As part of a 2-day meeting hosted by the International Advisory Committee on Clinical Trials in MS in December 2022, a panel initiated a discussion on the conceptual and practical issues related to selecting intermediate outcomes for clinical trials of MS rehabilitation interventions. RESULTS: The overarching goal of rehabilitation - optimal functioning - was acknowledged as a complex biopsychosocial phenomenon that varies with patient priorities and environmental context. This complexity means that multiple causal pathways and potential intermediate outcomes must be carefully considered during the design of clinical trials in MS rehabilitation that aim to improve functioning. In addition, practical issues must be considered such as psychometric properties of outcome measures, measure type, and characteristics of the target population, including severity of dysfunction. CONCLUSION: This article uses the International Classification of Functioning, Disability and Health as a foundation for determining relevant intermediate outcomes for clinical trials of MS rehabilitation interventions.

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.

Muscle Strength, Oxygen Saturation and Physical Activity in Patients with Chronic Exertional Compartment Syndrome Compared to Asymptomatic Controls.

Background: One of the most common causes of exercise-induced pain in the lower leg is chronic exertional compartment syndrome (CECS). Research is limited on muscle strength, oxygen saturation and physical activity in patients with CECS. Purpose: To compare muscle strength, oxygen saturation, and daily physical activity between patients with CECS and matched asymptomatic controls. A secondary purpose was to investigate the association between oxygen saturation and lower leg pain in patients with CECS. Study Design: Case-control study. Method: Maximal isometric muscle strength of the ankle plantar and dorsiflexors was tested in patients with CECS and sex- and age-matched controls using an isokinetic dynamometer and oxygen saturation (StO2) during running was tested by near infrared spectroscopy. Perceived pain and exertion were measured during the test using the Numeric Rating Scale and Borg Rating of Perceived Exertion scale and the exercise-induced leg pain questionnaire. Physical activity was assessed by accelerometry. Results: Twenty-four patients with CECS and 24 controls were included. There were no differences in maximal isometric plantar or dorsiflexion muscle strength between patients and controls. Baseline StO2 was 4.5pp (95% CI: 0.7;8.3) lower for patients with CECS than for controls, whereas no difference existed when they experienced pain or reached exhaustion. No differences were found in daily physical activities, except that on average, patients with CECS spent less time cycling daily. During the StO2 measurement, patients experienced pain or reached exhaustion while running significantly earlier than the controls (p<0.001). StO2 was not associated with leg pain. Conclusion: Patients with CECS have similar leg muscle strength, oxygen saturation and physical activity levels as asymptomatic controls. However, patients with CECS experienced significantly higher levels of lower leg pain than the controls during running, daily activities and at rest. Oxygen saturation and lower leg pain were not associated. Level of Evidence: Level 3b.