Effects of a 6-Week Treadmill Training With and Without Virtual Reality on Frailty in People With Multiple Sclerosis.

OBJECTIVE: To examine the effects of a cognitive-motor rehabilitation program consisting of treadmill training (TT) augmented by virtual reality (TT+VR) on frailty in people with multiple sclerosis (pwMS). DESIGN: Secondary analysis from a multicenter randomized controlled trial investigating the effects of TT+VR, compared with TT only, on measures of mobility and cognitive function in pwMS. SETTING: Four university research laboratories in 3 countries. PARTICIPANTS: A total of 124 pwMS were randomized into the parent trial. Here, we studied a subset of n = 83 participants (mean age, 49.4±9.3y; 73.5% female; expanded disability status scale range, 2.0-6.0), who completed the intervention and had complete preintervention and postintervention frailty data. INTERVENTIONS: Participants were randomly allocated to TT+VR (n=44) or TT (n=39). Both groups trained 3 times a week for 6 weeks. MAIN OUTCOME MEASURES: Frailty was assessed using a 40-item frailty index (FI) through standard validated procedures and represented the primary study outcome. Two exploratory frailty indices were also computed by isolating health-related deficits involving the cognitive (FI-physical) or physical (FI-cognitive) domains from the main FI. The assessments were performed at baseline and after 6 weeks, upon intervention completion. RESULTS: The mean FI of study participants at baseline was 0.33±0.13, indicating a moderate average level of frailty. FI scores improved in both TT+VR and TT groups participants (pooled mean ΔFI, 0.024; 95% CI, 0.010-0.038; F=10.49; P=.002; ηp2=0.115), without any group-by-time interaction (F=0.82; P=.367; ηp2=0.010). However, a significant group-by-time interaction was found for pretraining and posttraining changes in FI-cognitive (F=5.74; P=.019; ηp2=0.066), suggesting a greater improvement for TT+VR group participants than for TT group participants. CONCLUSIONS: TT with or without virtual reality can reduce frailty levels in pwMS. While both TT and TT+VR had a positive effect on overall frailty, only TT+VR improved cognitive aspects of frailty and may represent an appropriate strategy for counteracting frailty in pwMS.

Modifying diet and exercise in multiple sclerosis (MoDEMS): A randomized controlled trial for behavioral weight loss in adults with multiple sclerosis and obesity.

BACKGROUND: Obesity is a risk factor for developing multiple sclerosis (MS) and MS-related disability. The efficacy of behavioral weight loss interventions among people with MS (pwMS) remains largely unknown. OBJECTIVE: Examine whether a group-based telehealth weight loss intervention produces clinically significant weight loss in pwMS and obesity. METHODS: Seventy-one pwMS were randomized to the weight loss intervention or treatment-as-usual (TAU). The 6-month program promoted established guidelines for calorie reduction and increased physical activity. Anthropometric measurements, mobility tasks, self-report questionnaires, and accelerometry were used to assess changes at follow-up. RESULTS: Mean percent weight loss in the treatment group was 8.6% compared to 0.7% in the TAU group (p < .001). Sixty-five percent of participants in the intervention achieved clinically meaningful weight loss (⩾ 5%). Participants in the treatment group engaged in 46.2 minutes/week more moderate-to-vigorous physical activity than TAU participants (p = .017) and showed improvements in quality of life (p = .012). Weight loss was associated with improved mobility (p = .003) and reduced fatiguability (p = .008). CONCLUSION: Findings demonstrate the efficacy of a behavioral intervention for pwMS and obesity, with clinically significant weight loss for two-thirds of participants in the treatment condition. Weight loss may also lead to improved mobility and quality of life.

Frailty and Falls in People Living With Multiple Sclerosis.

OBJECTIVE: To explore the association between frailty and history of falls in people living with multiple sclerosis (MS). DESIGN: Secondary analysis. SETTING: University research laboratories in the United States and Israel. PARTICIPANTS: A total of 118 people (N=118) with relapsing-remitting MS (mean age, 48.9±10.0 years; 74.6% female; Expanded Disability Status Scale [EDSS] range, 1.0-6.0) were studied in this cross-sectional analysis. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: A frailty index was calculated from 40 health deficits by following standard validated procedures. The number of falls (12-month history) was recorded. RESULTS: Overall, 33.9%, 29.7%, and 36.4% of participants were classified as nonfrail, moderately frail, and severely frail, respectively. The frailty index was significantly correlated (ρ=0.37, P<.001) with higher scores on the EDSS. In univariable negative binomial regression analysis, the frailty index was associated with a higher number of falls (incidence rate ratio [IRR]=3.33; 95% CI, 1.85-5.99; P<.001). After adjustment for age, sex, and EDSS, frailty remained strongly associated with history of falls (IRR=2.78; 95% CI, 1.51-5.10; P=.001). CONCLUSIONS: The current study identifies a significant relationship between frailty and history of falls in MS, independent of age, sex, and disease severity. These findings support the notion that frailty is a syndrome related to but independent of disability in MS.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Reasons for nonadherence and response to treatment in an adherence intervention trial for relapsing-remitting multiple sclerosis patients.

OBJECTIVES: To explore whether patients in an adherence trial who appeared not to take disease modifying therapy (DMT) for avoidance reasons could be reliably identified, by observational coding, for their main reason of not taking DMT. To determine whether reason groups could be distinguished by clinical and self-report psychological characteristics and intervention outcomes. METHOD: Participants were multiple sclerosis patients (N = 78, 88.5% female, mean age 45.64) demotivated to take DMT. Audio recordings of the sessions were coded for the main reason of not taking DMT. Reason groups were compared based on patient characteristics and intervention outcomes. RESULTS: Avoidance and three other reasons for not taking DMT (side effects, cost, and mild course) were reliably identified (κ = 0.88). Patient characteristics failed to distinguish participants in the Avoidance group, which also had poorer outcomes (X2 [2, n = 73] = 6.35, p = 0.036). CONCLUSIONS: Patients not taking DMT for avoidance reasons may need novel methods to identify them and encourage (re-)initiation.

Improved cognitive outcomes in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta: Results from the DECIDE study.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS), with cognitive processing speed being the most frequently affected domain. OBJECTIVE: Examine the effects of daclizumab beta versus intramuscular (IM) interferon (IFN) beta-1a on cognitive processing speed as assessed by Symbol Digit Modalities Test (SDMT). METHODS: In DECIDE, patients with relapsing-remitting multiple sclerosis (RRMS) (age: 18-55 years; Expanded Disability Status Scale (EDSS) score 0-5.0) were randomized to daclizumab beta ( n = 919) or IM IFN beta-1a ( n = 922) for 96-144 weeks. SDMT was administered at baseline and at 24-week intervals. RESULTS: At week 96, significantly greater mean improvement from baseline in SDMT was observed with daclizumab beta versus IM IFN beta-1a ( p = 0.0274). Significantly more patients treated with daclizumab beta showed clinically meaningful improvement in SDMT (increase from baseline of ⩾3 points ( p = 0.0153) or ⩾4 points ( p = 0.0366)), and significantly fewer patients showed clinically meaningful worsening (decrease from baseline of ⩾3 points ( p = 0.0103)). Odds representing risk of worsening versus stability or improvement on SDMT were significantly smaller for daclizumab beta ( p = 0.0088 (3-point threshold); p = 0.0267 (4-point threshold)). In patients completing 144 weeks of treatment, the effects of daclizumab beta were generally sustained. CONCLUSION: These results provide evidence for a benefit of daclizumab beta versus IM IFN beta-1a on cognitive processing speed in RRMS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01064401 (Efficacy and Safety of BIIB019 (Daclizumab High Yield Process) Versus Interferon ß 1a in Participants With Relapsing-Remitting Multiple Sclerosis (DECIDE)): https://clinicaltrials.gov/ct2/show/NCT01064401 .

In vivo evidence of oxidative stress in brains of patients with progressive multiple sclerosis.

BACKGROUND: The oxidative stress hypothesis links neurodegeneration in the later, progressive stages of multiple sclerosis (MS) to the loss of a major brain antioxidant, glutathione (GSH). OBJECTIVE: We measured GSH concentrations among major MS subtypes and examined the relationships with other indices of disease status including physical disability and magnetic resonance imaging (MRI) measures. METHODS: GSH mapping was performed on the fronto-parietal region of patients with relapsing-remitting multiple sclerosis (RRMS, n = 21), primary progressive multiple sclerosis (PPMS, n = 20), secondary progressive multiple sclerosis (SPMS, n = 20), and controls ( n = 28) using GSH chemical shift imaging. Between-group comparisons were performed on all variables (GSH, T2-lesion, atrophy, Expanded Disability Status Scale (EDSS)). RESULTS: Patients with MS had substantially lower GSH concentrations than controls, and GSH was lower in progressive MS (PPMS and SPMS) compared with RRMS. GSH concentrations were not significantly different between PPMS and SPMS, or between RRMS and controls. Brain atrophy was significant in both RRMS and progressive MS compared with controls. CONCLUSION: Markedly lower GSH in progressive MS than RRMS indicates more prominent involvement of oxidative stress in the progressive stage of MS than the inflammatory stage. The association between GSH and brain atrophy suggests the important role of oxidative stress contributing to neurodegeneration in progressive MS, as suggested in other neurodegenerative diseases.

Dynamic Balance Is Related to Physiological Impairments in Persons With Multiple Sclerosis.

OBJECTIVES: To compare physiological impairments between persons with multiple sclerosis (MS) with a history of falls and persons with MS without a history of falls, and to investigate the association between physiological impairments and dynamic balance. DESIGN: Cross-sectional study. SETTING: University motion analysis laboratory. PARTICIPANTS: Persons with MS (N=55; 27 recurrent fallers and 28 nonfallers). Participants were classified as fallers if they self-reported ≥2 falls in the previous 6 months. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Physiological impairment was assessed with sensorimotor delays, spasticity, plantar cutaneous sensation, and the sensory, cerebellar, and pyramidal subscales of the Expanded Disability Status Scale (EDSS). Dynamic balance was assessed using the average and variability of margin of stability and variability of trunk accelerations. RESULTS: Compared with nonfallers, fallers had lower plantar sensation, longer sensorimotor delays, more spasticity, and more impairment in the pyramidal and cerebellar subscales of the EDSS. Additionally, these impairments were all moderately to strongly correlated with worse dynamic balance. CONCLUSIONS: This study highlights the multifactorial nature of instability in persons with MS. A better understanding of the physiological mechanisms of dynamic instability in persons with MS can be used to improve methods of monitoring disease progression, identifying which impairments to target through interventions, and appropriately evaluating intervention efficacy.

Longitudinal changes of cerebral glutathione (GSH) levels associated with the clinical course of disease progression in patients with secondary progressive multiple sclerosis.

BACKGROUND: Increased oxidative stress leads to loss of glutathione (GSH). We have reported lower cerebral GSH in patients with secondary progressive multiple sclerosis (SPMS), indicating the involvement of oxidative stress in multiple sclerosis (MS) pathophysiology. OBJECTIVE: This study expanded upon our earlier work by examining longitudinal changes in cerebral GSH in patients with SPMS in relation to their clinical status. METHODS: A total of 13 patients with SPMS (Expanded Disability Status Scale (EDSS) = 4.0-6.5; MS duration = 21.2 ± 8.7 years) and 12 controls were studied over 3-5 years. GSH mapping was acquired from frontal and parietal regions using a multiple quantum chemical shift imaging technique at 3 T. Clinical assessments of the patient's disability included EDSS, gait, motor strength, ataxia, tremor, brainstem function and vision changes. RESULTS: Brain GSH concentrations in patients were lower than those in controls for both baseline and 3- to 5-year follow-ups. Longitudinal GSH changes of patients were associated with their neurologist's blinded appraisal of their clinical progression. Patients judged to have worsening clinical status had significantly greater declines in frontal GSH concentrations than those with stable clinical status. CONCLUSION: GSH provides a distinct measure associated with the disease progression in SPMS, possibly due to its dynamic alignment with pathogenic processes of MS related to oxidative stress.

Instrumented balance and walking assessments in persons with multiple sclerosis show strong test-retest reliability.

BACKGROUND: There is a need for objective movement assessment for clinical research trials aimed at improving gait and balance in persons with multiple sclerosis (PwMS). Wireless inertial sensors can accurately measure numerous walking and balance parameters but these measures require evaluation of reliability in PwMS. The current study determined the test-retest reliability of wireless inertial sensor measures obtained during an instrumented standing balance test and an instrumented Timed Up and Go test in PwMS. METHODS: Fifteen PwMS and 15 healthy control subjects (HC) performed an instrumented standing balance and instrumented Timed Up and Go (TUG) test on two separate days. Ten instrumented standing balance measures and 18 instrumented TUG measures were computed from the wireless sensor data. Intraclass correlation coefficients (ICC) were calculated to determine test-retest reliability of all instrumented standing balance and instrumented TUG measures. Correlations were evaluated between the instrumented standing balance and instrumented TUG measures and self-reported walking and balance performance, fall history, and clinical disability. RESULTS: For both groups, ICCs for instrumented standing balance measures were best for spatio-temporal measures, while frequency measures were less reliable. All instrumented TUG measures exhibited good to excellent (ICCs > 0.60) test-retest reliability in PwMS and in HC. There were no correlations between self-report walking and balance scores and instrumented TUG or instrumented standing balance metrics, but there were correlations between instrumented TUG and instrumented standing balance metrics and fall history and clinical disability status. CONCLUSIONS: Measures from the instrumented standing balance and instrumented TUG tests exhibit good to excellent reliability, demonstrating their potential as objective assessments for clinical trials. A subset of the most reliable measures is recommended for measuring walking and balance in clinical settings.

Aspirin and multiple sclerosis.

Aspirin is widely used to lessen the risks of cardiovascular events. Some studies suggest that patients with multiple sclerosis have an increased risk for some cardiovascular events, for example, venous thromboembolism and perhaps ischemic strokes, raising the possibility that aspirin could lessen these increased risks in this population or subgroups (patients with limited mobility and/or antiphospholipid antibodies). However, aspirin causes a small increased risk of hemorrhagic stroke, which is a concern as it could potentially worsen a compromised blood-brain barrier. Aspirin has the potential to ameliorate the disease process in multiple sclerosis (for example, by limiting some components of inflammation), but aspirin also has the potential to inhibit mitochondrial complex I activity, which is already reduced in multiple sclerosis. In an experimental setting of a cerebral ischemic lesion, aspirin promoted the proliferation and/or differentiation of oligodendrocyte precursors, raising the possibility that aspirin could facilitate remyelination efforts in multiple sclerosis. Other actions by aspirin may lead to small improvements of some symptoms (for example, lessening fatigue). Here we consider potential benefits and risks of aspirin usage by patients with multiple sclerosis.

Investigating the Impact of Polypharmacy and Anticholinergic Medication Burden on Objective Cognitive Performance in Adults With Multiple Sclerosis.

BACKGROUND: Polypharmacy, or the use of 5 or more daily medications, is common in adults with multiple sclerosis (MS), and is often due to various physical, cognitive, and emotional symptoms. However, research regarding the association between polypharmacy and cognitive outcomes in MS is sparse. Furthermore, individuals with MS often use medications with anticholinergic properties, which are commonly associated with cognitive impairment and other central nervous system adverse effects. Currently, the utility of scales measuring anticholinergic burden in MS is unknown. This study aims to investigate the relationship between polypharmacy, anticholinergic burden, and objective cognitive performance in MS. METHODS: We recruited 90 individuals with MS during routine visits at an MS specialty clinic in Kansas City. Participants completed a brief, virtual cognitive assessment and answered questions about their health. Participants provided their medication lists from which we determined polypharmacy and scores on several anticholinergic burden scales. Statistical analyses included Spearman correlations and linear regression models. RESULTS: Approximately 44% of the individuals surveyed met the criteria for polypharmacy. The number of daily medications was negatively correlated with cognitive performance (rs = -0.45, P < .001). Further, the Drug Burden Index accounted for additional variance in cognitive performance beyond that explained by age, education, MS disease duration, and comorbidities [ΔR2 = .12, F(5, 84) = 7.84, P < .001.]. CONCLUSIONS: Clinicians should consider the possible negative consequences of polypharmacy when addressing cognitive concerns in MS. Anticholinergic burden scales may be valuable in this regard. Future investigations could explore behavioral and pharmacological interventions aimed at reducing polypharmacy in MS.

Multimodal exercise training to reduce frailty in people with multiple sclerosis: study protocol for a pilot randomized controlled trial.

BACKGROUND: Frailty, a syndrome characterized by decreased reserve and resistance to stressors across multiple physiologic systems, is highly prevalent in people living with multiple sclerosis (pwMS), independent of age or disability level. Frailty in MS is strongly associated with adverse clinical outcomes, such as falls, and may aggravate MS-related symptoms. Consequently, there is a pressing necessity to explore and evaluate strategies to reduce frailty levels in pwMS. The purpose of this pilot randomized controlled trial (RCT) will be to examine the feasibility and preliminary efficacy of a multimodal exercise training program to reduce frailty in pwMS. METHODS: A total of 24 participants will be randomly assigned to 6 weeks of multimodal exercise or to a waitlist control group with a 1:1 allocation. PwMS aged 40-65 years and living with frailty will be eligible. The multimodal exercise program will consist of cognitive-motor rehabilitation (i.e., virtual reality treadmill training) combined with progressive, evidence-based resistance training. At baseline and post-intervention, participants will complete the Evaluative Frailty Index for Physical Activity (EFIP), measures of fall risk, and quality of life. Frailty-related biomarkers will also be assessed. In addition, the feasibility of the multimodal exercise program will be systematically and multidimensionally evaluated. DISCUSSION: To date, no RCT has yet been conducted to evaluate whether targeted exercise interventions can minimize frailty in MS. The current study will provide novel data on the feasibility and preliminary efficacy of multimodal exercise training as a strategy for counteracting frailty in pwMS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06042244 (registered in September 2023).

Difficulties in planning among patients with multiple sclerosis: a relative consequence of deficits in information processing speed.

Previous studies show that MS patients take longer than healthy controls to plan their solutions to Tower of London (TOL) problems but yield conflicting results regarding the quality of their solutions. The present study evaluated performance under untimed or timed conditions to assess the possibility that differences in planning ability only occur when restrictions in solution times are imposed. MS patients (n = 39) and healthy controls (n = 43) completed a computerized version of the TOL under one of two conditions. In the untimed condition, participants were allowed as much time as needed on each problem. In the timed condition, limits were imposed on solution times and time remaining was displayed with each problem. Patients exhibited longer planning times than controls, and the disparity between groups increased with problem difficulty. Planning performance depended upon condition. In the untimed condition, patients and controls performed equally well. When solution times were restricted, however, patients solved fewer problems than controls. MS patients' planning ability is intact when permitted sufficient time to formulate the required plan. Deficiencies in planning are only evident when time is restricted, and, therefore, are more accurately considered a relative consequence of disease-related problems in information processing speed.

Longitudinal Olfactory Patterns in Multiple Sclerosis: A Scoping Review and Implication for Use in Management of Disease.

BACKGROUND: Although studies regarding multiple sclerosis (MS) and olfactory dysfunction (OD) have been previously described and summarized, there is not a sole review of longitudinal studies regarding the matter. This review examines the existing literature investigating MS and its effect on olfaction. In addition, the role of OD in the diagnosis and prognosis of MS is explored. METHODS: A scoping review of the literature was performed covering longitudinal studies investigating MS and OD. Systematic searches of PubMed, Google Scholar, Web of Science, Embase, PsycInfo, Cumulative Index to Nursing and Allied Health Literature, AgeLine, and MEDLINE were performed using terms that encompassed MS and olfaction. The aim of this review was to build on the existing literature by summarizing only findings that were demonstrated longitudinally. RESULTS: Of 6938 articles identified from the search, 9 met the inclusion criteria: longitudinal observation of relapsing-remitting or progressive MS. Olfaction was measured and scored using various testing arrays, and these scores were then correlated with a multitude of clinical markers. Across all studies, patients with MS demonstrated increased OD. Longitudinally, 2 contrasting patterns were identified: (1) clinical markers of acute inflammation correlated with an increased odor threshold and (2) clinical markers of neurodegeneration, or progression of disease, correlated with a decreased ability to discriminate and identify odors. CONCLUSIONS: These studies suggest that olfaction is a dynamic, dependent variable of neurodegeneration, correlating with inflammation and clinical markers. This opens the door for future exploration of olfaction's relationship with MS diagnosis, characterization, and therapeutic response.

A pilot study evaluating the prefeasibility of a behavioral weight loss program in people with multiple sclerosis.

Weight loss interventions seldom include individuals with neurologic disease. The aims of the present study were to: 1) develop and assess the prefeasibility of a 6-month telehealth behavioral weight loss program for people with multiple sclerosis (MS) and obesity and 2) examine changes in weight loss (primary outcome), physical activity, and fruit/vegetable consumption at follow-up. Participants with obesity and MS engaged in a 24-week weight loss program. Participants followed established diet, exercise, and self-monitoring guidelines and attended weekly online group meetings. Median percentage weight loss was 10.54 % (SD = 7.19). Participants who adhered more closely to the self-monitoring guidelines (r = 0.81, p =.02), and who averaged higher weekly active minutes (r = 0.91, p =.002) achieved greater percentage weight loss. Six of the eight pilot participants achieved clinically meaningful weight loss (>5%) after 6-months.

Association Between Frailty and Free-Living Walking Performance in People With Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to examine the association between frailty and the quantity and quality of free-living walking and the mediating effect of frailty on the relationship between disability and walking performance in people with multiple sclerosis (MS). METHODS: Ninety-nine people with relapsing-remitting MS (mean age = 49.3 [SD = 9.8] years; 73.7% women; Expanded Disability Status Scale [EDSS] score range = 2.0-6.0) wore a triaxial accelerometer for 7 days. Recorded measures reflected the quantity (daily step counts, number of 30-second walking bouts, and signal vector magnitude [SVM]) and quality (gait speed, step cadence, step and stride regularity, and sample entropy) of walking. For each walking quality measure, the typical (median), best (90th percentile), and worst (10th percentile) values were calculated. Frailty was evaluated through a 38-item frailty index. RESULTS: Participants were classified as not frail (n = 31), moderately frail (n = 34), and severely frail (n = 34) on the basis of established procedures. Patients who were moderately and severely frail exhibited poorer performance in all measures of walking quantity and quality, except for sample entropy, than individuals who were not frail. No differences in free-living walking performance were observed between the moderately and severely frail groups. Frailty did not mediate the relationship between disability (EDSS) and measures of walking quality. Conversely, frailty had a significant mediating effect on the relationship between disability and measures of walking quantity, such as daily step counts (indirect effect: b = -220.42, 95% CI = -452.03 to -19.65) and SVM (indirect effect: b = -1.00, 95% CI = -1.86 to -0.30). CONCLUSION: Frailty is associated with poorer free-living walking performance in people with MS. The study findings suggest that frailty, rather than disability, may be primarily responsible for the lower amount of physical activity performed by people with MS in the real world. IMPACT: The observation that frailty and disability are differently related to measures of walking quality and quantity underscores the importance of a targeted approach to rehabilitation in people with MS.

Treadmill training with virtual reality to enhance gait and cognitive function among people with multiple sclerosis: a randomized controlled trial.

BACKGROUND: Motor and cognitive impairments impact the everyday functioning of people with MS (pwMS). The present randomized controlled trial (RCT) evaluated the benefits of a combined motor-cognitive virtual reality training program on key motor and cognitive symptoms and related outcomes in pwMS. METHODS: In a single-blinded, two-arm RCT, 124 pwMS were randomized into a treadmill training with virtual reality (TT + VR) group or a treadmill training alone (TT) (active-control) group. Both groups received three training sessions per week for 6 weeks. Dual-tasking gait speed and cognitive processing speed (Symbol Digit Modalities Test, SDMT, score) were the primary outcomes. Secondary outcomes included additional tests of cognitive function, mobility, and patient-reported questionnaires. These were measured before, after, and 3 months after training. RESULTS: Gait speed improved (p < 0.005) in both groups, similarly, by about 10 cm/s. The TT + VR group (n = 53 analyzed per-protocol) showed a clinically meaningful improvement of 4.4 points (95% CI 1.9-6.8, p = 0.001) in SDMT, compared to an improvement of only 0.8 points in the TT (n = 51 analyzed per-protocol) group (95% CI 0.9-2.5 points, p = 0.358) (group X time interaction effect p = 0.027). Furthermore, TT + VR group-specific improvements were seen in depressive symptoms (lowered by 31%, p = 0.003), attention (17%, p < 0.001), and verbal fluency (11.6% increase, p = 0.002). DISCUSSION: These findings suggest that both TT and TT + VR improve usual and dual-task gait in pwMS. Nonetheless, a multi-modal approach based on VR positively impacts multiple aspects of cognitive function and mental health, more than seen after treadmill-treading alone. Trial registered at ClinicalTrials.Gov NCT02427997.

Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. METHODS: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. FINDINGS: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. INTERPRETATION: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers. FUNDING: National Multiple Sclerosis Society (USA).