Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 13 appraisals
BMJ open
Potential benefits of music-based therapies on rehabilitation outcomes in people with multiple sclerosis: a systematic review
OBJECTIVES: To assess the evidence for a benefit of music-based therapies (MBTs) on rehabilitation outcomes in adults with multiple sclerosis (MS). SETTING: Scholarly literature (published in English) from any country. This systematic review received no specific funding and was registered on PROSPERO as CRD420251083656. DATA SOURCES: Six bibliographic databases: AMED (Ebsco), APA PsycINFO (Ovid), CINAHL (Ebsco), Cochrane CENTRAL, EMBASE (Ovid) and MEDLINE (Ovid), plus supplementary searches and citation chasing (search date July 2025). PRIMARY AND SECONDARY OUTCOME MEASURES: Eligible studies used a clinical trial or controlled quantitative observational study design to assess the benefit of MBTs on rehabilitation outcomes in adults with MS. Risk of bias was assessed using Critical Appraisal Skills Programme checklists. Data were synthesised using narrative synthesis. RESULTS: 23 studies were included (955 participants, of whom 880 people had MS and 691 received MBTs). The most frequently assessed outcome was motor function (16 studies), followed by quality of life (12 studies). Evidence suggests potential benefits for MBTs, particularly rhythmic auditory stimulation and music-cued motor imagery, on gait and mobility outcomes, including walking speed, walking distance, cadence, stride length and gait symmetry. Findings for other outcomes were less clear. CONCLUSIONS: MBTs may benefit people with MS, with the most consistent evidence observed for gait and mobility outcomes. However, heterogeneity in intervention type, study design and outcome measurement limits the strength of conclusions. Higher-quality, adequately powered trials with standardised outcomes and direct comparisons between MBTs are needed to clarify effectiveness and inform clinical implementation. PROSPERO REGISTRATION NUMBER: CRD420251083656.
24 July 2026
Read appraisal →Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Effects of transcranial direct current stimulation on motor function in patients with multiple sclerosis: a systematic review and meta-analysis
OBJECTIVE: To assess the effectiveness of transcranial direct current stimulation (tDCS) in enhancing motor function recovery in the upper and lower extremities of individuals with multiple sclerosis. DATA SOURCES: PubMed, Embase, Web of Science, Cochrane Library, and China Knowledge Network (CNKI) databases from inception until December 28, 2025. STUDY SELECTION: Randomized controlled trials that investigated transcranial direct current stimulation and tDCS combined with physical training on motor function in the upper and lower limbs of individuals with MS. DATA EXTRACTION: Two reviewers extracted the data and assessed the risk of bias. Standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated using a random-effects model based on heterogeneity. The analysis included 10 articles with a total of 299 subjects. DATA SYNTHESIS: The Meta-analysis shows tDCS significantly improves lower limb motor function in MS patients (SMD = 0.31, 95% CI: 0.16 - 0.46, p < 0.0001). Subgroup analyses found significant increases in walking distance (p = 0.0005) and static balance (Berg Balance Score, p = 0.0002), but no significant improvements were observed in walking speed and dynamic balance. For upper limb motor function, no statistically significant difference was found in hand dexterity (9-HPT) (p = 0.11). Notably, subgroup analyses of stimulation parameters showed that high intensity (2.0-2.5 mA, p = 0.007) and a 20-minute duration (p = 0.03) yielded significant effects, whereas low intensity (1.0-1.5 mA) and 15-minute duration showed no significant benefits. CONCLUSIONS: Transcranial direct current stimulation is effective in enhancing lower limb motor function in patients with MS. However, the efficacy of tDCS in improving upper limb fine motor skills remains unclear. Evidence suggests that stimulation at 2.0-2.5 mA for 20 min may be the optimal protocol for clinical intervention.
13 July 2026
Read appraisal →PloS one
Motherhood choice in multiple sclerosis (MoMS) - Pilot trial of web-based decision support
BACKGROUD: Uncertainty concerning motherhood is common among women with multiple sclerosis (wwMS). Therefore, we developed and pre-tested a patient decision aid (PtDA) and a nurse-led decision coaching intervention (DC) to support motherhood choice. The DC includes the PtDA, a decision guide on motherhood choice, and decision coaching. METHODS: We conducted a randomised pilot trial across Germany to test feasibility, with decisional conflict (Decisional Conflict Scale, DCS) as an exploratory endpoint. Initially, we planned a 3:1 randomisation ratio (planned; PtDA = 48, DC = 16). Due to recruitment difficulties, we switched to a 1:1 randomisation ratio to ensure an appropriate sample size (PtDA > 20, DC > 10). Women between 18 and 45 years old with relapsing-remitting MS or clinically isolated syndrome, and who had not yet decided about motherhood, were eligible. We recruited two nurses for our decision coaching training course. We used questionnaires to measure decisional conflict, programme feasibility, knowledge, and worries regarding pregnancy in MS. Interviews were conducted to gain in-depth information on the potential feasibility of the programmes. Interviews were analysed thematically and questionnaires descriptively. We conducted explorative group comparisons and merged findings using joint display analysis. RESULTS: We trained two decision coaches in the DC group and recruited 35 wwMS (PtDA = 22; DC = 13) over five months. Median DCS scores in the DC group were 49 at baseline and 15 at follow-up (range 0-100; higher scores indicate greater decisional conflict). In the PtDA group, scores were 54 (baseline) and 31 (follow-up). Explorative group comparison indicated lower decisional conflict at follow-up in the DC group than in the PtDA group (p = 0.035). Interviewees (PtDA = 5; DC = 6; nurses = 2) described both interventions as helpful for decision-making. Qualitative findings indicate greater satisfaction levels in the DC group. CONCLUSION: Both interventions appear useful for wwMS in making motherhood choices. The DC programme seems more promising in supporting decision-making. TRIAL REGISTRATION: German Clinical Trials Register (DRKS); DRKS00038534.
14 June 2026
Read appraisal →Lancet (London, England)
Efficacy and safety of a bodyweight-adjusted higher dose of ocrelizumab in relapsing (MUSETTE) and primary progressive (GAVOTTE) multiple sclerosis: two multicentre, randomised, double-blind, parallel-group phase 3b trials.
BACKGROUND: Ocrelizumab is a humanised anti-CD20 monoclonal antibody approved for people with relapsing (RMS) or primary progressive multiple sclerosis (PPMS). In a post-hoc analysis of phase 3 trials in RMS and PPMS using a 600 mg dose, higher exposure to ocrelizumab was associated with greater B-cell depletion and lower risk of confirmed disability progression. Here, we prospectively assessed the efficacy and safety of a high dose of ocrelizumab in patients with RMS or PPMS. METHODS: Two multicentre, double-blind, phase 3 controlled trials were conducted to compare high-dose ocrelizumab with the approved 600 mg dose of the drug in patients with RMS (MUSETTE) and PPMS (GAVOTTE) aged 18-56 years. MUSETTE involved 122 centres in 21 countries and GAVOTTE involved 149 centres in 22 countries. Participants were randomly assigned 2:1, with a permuted-block randomisation method, to high-dose ocrelizumab (1200 mg or 1800 mg for baseline body weight <75 kg or ≥75 kg, respectively) or 600 mg ocrelizumab. Patients, investigators, and the sponsor were blinded to treatment allocation. Patients received ocrelizumab infusions every 24 weeks for a minimum 120 weeks and until a prespecified minimum number of confirmed disability events (MUSETTE, 205; GAVOTTE, 357) had occurred. In both trials, the primary endpoint was time to onset of 12-week composite confirmed disability progression (cCDP), assessed by prespecified increases in Expanded Disability Status Scale, Timed 25-Foot Walk Test, or 9-Hole Peg Test scores. Efficacy endpoints were evaluated in all randomised participants and safety endpoints were evaluated in participants who received at least one ocrelizumab infusion. These studies are registered with ClinicalTrials.gov: MUSETTE, NCT04544436; GAVOTTE, NCT04548999. FINDINGS: Participants in MUSETTE were enrolled between Nov 26, 2020, and Aug 30, 2022; participants in GAVOTTE were enrolled between Dec 3, 2020, and May 15, 2023. In MUSETTE, 860 patients were randomly assigned (high-dose ocrelizumab, n=577; 600 mg ocrelizumab, n=283) and had median overall treatment duration of 184·4 weeks. In GAVOTTE, 753 patients were randomly assigned (high-dose ocrelizumab, n=500; 600 mg ocrelizumab, n=253) and had median overall treatment duration of 174·1 weeks. In MUSETTE, the percentage of patients with 12-week cCDP was 34% (198 of 577) with high-dose ocrelizumab versus 37% (104 of 283) with 600 mg ocrelizumab (hazard ratio [HR] 0·93 [95% CI 0·73-1·18]; p=0·53). In GAVOTTE, the percentage of patients with 12-week cCDP was 47% (235 of 500) with high-dose ocrelizumab versus 49% (124 of 253) with 600 mg ocrelizumab (HR 0·95 [95% CI 0·76-1·18]; p=0·64). Safety profiles were similar for the high-dose ocrelizumab and 600 mg ocrelizumab; in MUSETTE, rates of adverse events (552 [96%] of 577 and 267 [94%] of 283), serious adverse events (77 [13%] of 577 and 34 [12%] of 283), and fatalities (four [1%] of 577 and one [<1%] of 283) were comparable, as were rates of adverse events (447 [90%] of 499 and 230 [91%] of 254), serious adverse events (61 [12%] of 499 and 29 [11%] of 254), and fatalities (two [<1%] of 499 and three [1%] of 254) in GAVOTTE. INTERPRETATION: In both studies, high-dose ocrelizumab did not further improve control of disability progression in either RMS or PPMS, and no new safety concerns were identified. FUNDING: F Hoffmann-La Roche.
1 June 2026
Read appraisal →Lancet (London, England)
Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis, including older patients and those with more advanced disease (ORATORIO-HAND): a multicentre, double-blind, randomised, placebo-controlled, phase 3b study
BACKGROUND: The ORATORIO trial showed that ocrelizumab reduced the risk of disability progression versus placebo in patients with primary progressive multiple sclerosis (PPMS). We aimed to elucidate the effect of ocrelizumab in older and more disabled patients with PPMS, particularly regarding hand function preservation. METHODS: ORATORIO-HAND was a multicentre, double-blind, randomised, placebo-controlled, phase 3b study with 138 sites across 22 countries. Patients with PPMS aged 18-65 years and Expanded Disability Status Scale (EDSS) score of 3·0-8·0 were randomly assigned 1:1 to intravenous ocrelizumab 600 mg or placebo every 6 months for 144 weeks or until a prespecified number of progression events occurred. Masking was achieved by use of a placebo solution administered in the same manner as ocrelizumab. Double-blinding across all periods was maintained through separation of investigators responsible for efficacy and safety assessments. MRI scans were evaluated by a masked central reader, and laboratory parameters that could reveal treatment allocation were masked to site personnel until the primary analysis. Two coprimary estimands were defined, with the endpoint of time to onset of 12-week composite confirmed disability progression (12W-cCDP) in 9-Hole Peg Test or EDSS evaluated in all randomly assigned patients, and the same endpoint evaluated in a subset of patients with MRI activity at baseline. This study is registered with ClinicalTrials.gov, NCT04035005 and is ongoing and not recruiting. FINDINGS: Between Aug 12, 2019, and Dec 10, 2024, of 1360 patients assessed for eligibility, 1013 were randomly assigned (ocrelizumab [n=505]; placebo [n=508]). The proportion of patients with 12W-cCDP was 165 (33%) of 505 with ocrelizumab and 205 (40%) of 508 with placebo (hazard ratio, 95% CI 0·70 0·57-0·86; relative risk reduction=30%; p=0·0007). In the MRI-active subgroup, a significant risk reduction was also observed in 12W-cCDP (risk reduction=55%; p<0·0001). The overall safety profile was similar in both groups. More infections (245 [48%] of 506 vs 226 [45%] of 506) were observed with ocrelizumab, but not after COVID-19 was excluded (38% vs 37%). Rates of serious adverse events and serious infections were similar between groups. INTERPRETATION: Ocrelizumab was superior to placebo in delaying disability progression, with stronger effect on hand function, in a broad PPMS population including older patients and those with more advanced disease, while maintaining a manageable safety profile. FUNDING: F Hoffmann-La Roche.
31 May 2026
Read appraisal →Neurology
Intrathecal Mesenchymal Stem Cells in Progressive Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial (SMART-MS)
BACKGROUND AND OBJECTIVES: There is an unmet need for neuroregenerative therapies in multiple sclerosis (MS). Mesenchymal stem cells (MSCs) have shown immunomodulatory and regenerative effects in preclinical models and early clinical studies. Intrathecal administration may enhance therapeutic potential by direct delivery to the CNS. However, randomized, placebo-controlled trials are needed to establish safety and efficacy. The objective of this trial was to assess whether a single intrathecal administration of autologous MSCs could provide evidence of a neuroregenerative effect in progressive MS. METHODS: In this randomized, double-blind, placebo-controlled phase I/II trial (NCT04749667), patients with progressive MS enrolled at 4 Norwegian tertiary hospitals received a single intrathecal injection of autologous bone marrow-derived MSCs (1 × 106 cells/kg) in a crossover design. The primary end point was the change in latency of combined evoked potentials at 6 months. Secondary end points included safety, brain MRI measures, functional and ophthalmologic assessments, and serum biomarkers at 6 and 12 months. Exploratory analyses comprised proteomic profiling of CSF. Outcomes were analyzed using baseline-adjusted regression models. RESULTS: A total of 18 patients were included (mean age 46.7 years; 55.6% female). No significant between-group difference was observed for the primary end point (β = -0.31, 95% CI -1.84 to 1.22, p = 0.668). At 6 months, patients in the MSC group showed reduced cerebral atrophy on MRI (β = 9.37, 95% CI 0.29 to 18.45, p = 0.044) and lower serum glial fibrillary acidic protein levels (β = -16.3 pg/mL, 95% CI -33.0 to 0.3, p = 0.054), but neither were sustained at 12 months. Exploratory CSF proteomics revealed reductions in multiple inflammation-related proteins at 6 months. One serious adverse event was deemed probably related to MSC treatment. Common adverse events included fever (n = 9) and low back pain (n = 10) after MSC administration, and spinal MRI abnormalities with fluid loculations and nerve root clumping (n = 7) at 6 months. One patient developed chronic coccygeal pain attributed to arachnoiditis. DISCUSSION: A neuroregenerative effect was not detected, although interpretation may be limited by the small sample size. Adverse events suggest an acute localized inflammatory reaction after MSC administration. Our findings suggest that intrathecal administration of MSCs in progressive MS should be approached with caution in future studies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, in patients with progressive multiple sclerosis, treatment with a single intrathecal administration of autologous mesenchymal stem cells does not provide neuroregenerative effect, as assessed by a composite evoked potential score. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04749667); registered February 8, 2021; first patient enrolled August 9, 2021.
10 May 2026
Read appraisal →Clinical chemistry and laboratory medicine
Serum GFAP as a biomarker for progression in multiple sclerosis: assay comparison and a large reference database of healthy controls
OBJECTIVES: Compare Elecsys (Roche) and Simoa (Quanterix) immunoassays for serum glial fibrillary acidic protein (GFAP) using our reference database and Z scores, and evaluate their prognostic value for progression independent of relapse activity (PIRA) in multiple sclerosis (MS). METHODS: Platform correlation was assessed in 612 samples from healthy controls (n=188; median [interquartile range, IQR] age 45.1 [36.4-61.7] years) and people with MS (n=424; 45.3 [35.2-53.9] years). Elecsys values were converted to Z scores via Passing-Bablok-derived regression and validated in fingolimod (n=414), and B-cell depleting therapy (BCDT; n=353) cohorts. Z scores and hazard ratios (HRs) for time-to-PIRA were compared using Cox regression. RESULTS: GFAPSimoa and GFAPElecsys measurements were correlated (r=0.94), with Elecsys values ∼54 % lower (GFAPElecsys, ng/L=2.847 [95 % confidence interval, CI: 1.335 - 4.98] + 0.457 [0.434 - 0.478] * GFAPSimoa, ng/L). In univariable Cox models, GFAPSimoa and GFAPElecsys Z scores were associated with time-to-PIRA in both validation cohorts. In multivariable Cox models, higher GFAPSimoa Z scores were associated with shorter time-to-PIRA in fingolimod cohort (HR: 1.27 [95 % CI 1.08 - 1.50], p=0.0031) and trended toward significance in BCDT (1.18 [0.99 - 1.41, p=0.0693). In contrast, GFAPElecsys Z scores were associated with time-to-PIRA in both cohorts (fingolimod: 1.27 [1.09 - 1.48], p=0.0023; BCDT: (1.19 [1.00 - 1.40], p=0.0487). CONCLUSIONS: Serum GFAP measured by Elecsys shows a comparable association with time-to-PIRA as Simoa, and GFAPSimoa Z scores can be successfully bridged to GFAPElecsys Z scores, supporting Elecsys`s potential for clinical implementation.
25 Apr 2026
Read appraisal →Antonie van Leeuwenhoek
Faecalibacterium prausnitzii and Akkermansia muciniphila: driving the multiple sclerosis-a systematic review
The gut microbiota (GM) is a complex microbial ecosystem, and its alteration contributes to the development of several diseases including multiple sclerosis (MS). Progressive research concerning neurodegenerative diseases and GM reveals that GM dysbiosis has been linked to fostering the development and progression of MS. Among existing bacteria, F.prausnitzii and A.muciniphila are key species implicated in this disease. Thus, the present study systematically reviewed and synthesized the research on the involvement of F. prausnitzii and A. muciniphila in MS patients versus healthy individuals. We systematically searched PubMed, MEDLINE, EMBASE, and Web of Science databases for relevant published articles from January 2010 till January 2023. Out of 400 articles, 16 met the required criteria. The included research investigations originated from the US, Germany, Norway, Egypt, Iran, Brazil, China, the UK, and Romania. Most publications reported decreased levels of F. prausnitzii and increased levels of A. muciniphila in MS patients compared to controls. This review underscored the importance of the F. prausnitzii and A. muciniphila in MS, which could explain the chronic inflammation that characterizes this disease and not only help in understanding its etiology and progression but also open new avenues for the treatment strategies focusing on gut health. Moreover, understanding the role of F. prausnitzii and A. muciniphila could lead to novel biomarkers for early detection and progression monitoring MS.
25 Apr 2026
Read appraisal →Journal of neurology
Efficacy and safety of monoclonal antibodies in the treatment of relapsing remitting multiple sclerosis: a systematic review
INTRODUCTION: In relapsing-remitting multiple sclerosis (RRMS), conventional immunomodulatory and immunosuppressive therapies are widely used. However, in many cases, optimal control of inflammatory activity and disease progression is not achieved, which has led to the use of biological drugs such as monoclonal antibodies that act specifically on key components of the immune system. The aim was to evaluate the efficacy and safety of monoclonal antibodies compared to other drugs or placebo in adult patients with RRMS. METHODS: A systematic review was performed based on randomized, double-blind, phase III controlled clinical trials published between 2012 and 2025 in the PubMed, Cochrane Library, and Web of Science databases, assessing efficacy and safety in adult patients with RRMS. The review was carried out following the PICO methodology and PRISMA guidelines. RESULTS: A total of 11 studies were included, evaluating 5 monoclonal antibodies: alemtuzumab, daclizumab, ocrelizumab, ofatumumab, and ublituximab. These therapies showed superior efficacy compared to conventional treatments in reducing the annual relapse rate, MRI inflammatory activity and MRI activity, particularly in patients with highly active disease. However, effects on disability progression were heterogeneous across trials and not consistently significant. In addition, decreases in biomarkers of axonal damage were observed. Nevertheless, relevant adverse effects were identified, including infections, autoimmune reactions, hepatic and cutaneous toxicity, whose incidence varies depending on the drug, requiring close clinical monitoring. CONCLUSIONS: Monoclonal antibodies are an effective option in RRMS, with clinical and radiological benefits superior to those of conventional treatments. Their use requires individualized assessment and close follow-up due to the risk of adverse effects, especially in high-risk patients.
25 Apr 2026
Read appraisal →Journal of neurology
Predicting disease progression in multiple sclerosis with clinically accessible information and technology
BACKGROUND: Predicting disease progression at the individual level is essential for personalized medicine. We previously developed machine-learning tools to estimate 5-year progression risk in people with multiple sclerosis (PwMS). Such models should account for disease-modifying therapy (DMT) and objective outcome definitions. METHODS: In a retrospective multicenter case-control study, we evaluated adults with relapsing-remitting multiple sclerosis (RRMS) at baseline. Using machine-learning, we developed two complementary tools for individualized 5-year risk estimation: DAAE-M, optimized for transparency, software-neutral use, and mitigation of indication bias, and ELIE, optimized for dynamic landmark-based modeling, complex treatment histories, and mitigation of immortal-time bias. Disease progression was defined using both a clinical outcome (RRMS-to-progressive MS) and an objective outcome (late-stage confirmed progression independent of relapse activity). RESULTS: Among 34,510 people with RRMS (72.6% female, mean age = 37.1, mean disease duration = 5.8), 9.8% and 21% met clinical and objective progression criteria, respectively, over five years. Both models demonstrated good calibration across risk-groups (Brier scores 0.06-0.16). DAAE-M provided patient-level risk estimates with monotonic risk escalation across risk-groups for clinical (3.1%/11.2%/22.6%/33.0%) and objective (8.4%/14.5%/23.3%/38.8%) progression. For DAAE-M, high-efficacy DMT was associated with approximately half the progression risk compared with low-efficacy DMT (risk-ratios: 0.42-0.59; p < 0.01). ELIE also showed good calibration across risk deciles with increasing incidence for both clinical (0.3%/1.2%/1.7%/2.5%/3.7%/5.5%/7.2%/10.2%/14.3%/21.5%) and objective (0.9%/1.6%/2.5%/4.0%/5.8%/7.8%/10.2%/15.3%/20.9%/32.5%) outcomes. CONCLUSION: We developed two well-calibrated machine-learning-based tools for individualized 5-year prediction of clinically- and objectively-defined MS progression, each with distinct strengths in usability, bias handling, and treatment modeling. These findings support future tool use in personalized risk stratification and secondary prevention.
21 Apr 2026
Read appraisal →Journal of neurology
Iron accumulation in multiple sclerosis and implications for cognitive and clinical progression: a systematic review of advanced neuroimaging studies
BACKGROUND AND AIMS: Iron-related alterations are frequently implicated in multiple sclerosis (MS) neurodegeneration, but its relationship with clinical symptoms and cognitive impairment remains unclear. We systematically reviewed evidence linking iron-sensitive susceptibility-based magnetic resonance imaging (MRI) metrics to cognitive outcomes, in order to evaluate their potential role as diagnostic and prognostic biomarkers of cognitive decline in MS. MATERIALS AND METHODS: A systematic review was conducted using the PRISMA guidelines. 600 studies were identified by searching PubMed, Scopus, Web of Science, and Embase in October 2025. After screening, 12 studies fulfilled the eligibility criteria and were included. RESULTS: Two main patterns emerged: (i) higher basal ganglia susceptibility/iron-related metrics are consistently linked to worse cognitive performance, particularly information processing speed and executive control; and (ii) thalamic findings are more variable in direction and clinical meaning, with susceptibility often capturing a mixed signal that overlaps with thalamic atrophy. CONCLUSIONS: Iron-sensitive quantitative MRI captures clinically relevant deep gray matter (DGM) pathology associated with cognitive impairment in MS, with basal ganglia measures showing the strongest linkage with cognitive and clinical outcomes. Future studies should include harmonized methodology and a longitudinal component.
19 Apr 2026
Read appraisal →PloS one
A pilot randomized controlled trial of neuromodulation-augmented balance training in people with multiple sclerosis: STIM-Balance Protocol
BACKGROUND: Impairments in balance control and falls are common problems for people with multiple sclerosis (PwMS), resulting in mobility limitations and reduced participation. Non-invasive neuromodulation techniques such as functional electrical stimulation (FES) and transcutaneous spinal stimulation (TSS) have revealed promising results in improving motor functions in other neurological populations; however, their effects during task-specific balance training have not been investigated in PwMS. OBJECTIVE: To evaluate the feasibility, acceptability, safety, and preliminary clinical efficacy of neuromodulation-augmented balance training programs on balance, mobility, and neuroplasticity in PwMS (ClinicalTrials.gov Identifier: NCT07174973). METHODS: Twenty-four ambulatory PwMS will be randomly assigned into three groups: (1) visual feedback balance training (VFBT) with sham stimulation, (2) VFBT with active (closed-loop) FES for the ankle muscles and sham TSS, and (3) VFBT with active FES and active (open-loop sub-motor-threshold) TSS at the lumbosacral enlargement. Participants in each group will complete 12 training sessions over six weeks. Feasibility, safety, and acceptability will be assessed through recruitment and adherence metrics, adverse-event monitoring, and semi-structured interviews guided by the Technology Acceptance Model questionnaire-2. Performance-based measures of balance, mobility, and walking speed, as well as patient-reported outcomes of balance confidence, walking ability, and fear of falling will be recorded to assess the preliminary efficacy. Modulation in neural pathways excitability will be quantified by recording motor evoked potentials and spinal motor evoked potentials. CONCLUSION: Findings will help to determine whether neuromodulation-augmented balance training is feasible, safe, and acceptable for PwMS and will guide the design of a future fully powered RCT.
17 Apr 2026
Read appraisal →Journal of neurology, neurosurgery, and psychiatry
Breaking the PROMISE: poor association between brain volume loss and clinical disability worsening over 2 years of follow-up in primary progressive multiple sclerosis.
BACKGROUND: Phase 2 clinical trials in primary progressive multiple sclerosis (PPMS) often use MRI brain volume measures as their primary endpoint. Here, we investigate the longitudinal association between change in MRI outcomes and change in disability over 2 years of follow-up in a large and well-characterised PPMS trial dataset. METHODS: Using the dataset from PROMISE (n=943, mean age of 58.0 years, mean Expanded Disability Status Scale (EDSS) 5.0, and mean disease duration of 10.5 years at baseline), a phase 3 trial of glatiramer acetate in PPMS, we described the change in MRI and disability measures during follow-up and used multivariable logistic regression models to investigate whether change in four MRI outcomes (grey matter volume, white matter volume, brain fraction and total burden of disease) was associated with seven measures of clinical disability worsening (including the EDSS, Timed 25 Foot Walk, Nine-Hole Peg Test and Paced Auditory Serial Addition Test). RESULTS: We found only weak and inconsistent associations between change in MRI and physical and cognitive outcome measures over 2 years of follow-up. Change in MRI measures in year 1 of the trial did not predict change in physical nor cognitive disability in year 2. DISCUSSION: The association of the investigated volumetric MRI measures and clinical disability outcomes was noticeably weak and inconsistent. Our findings question the suitability of brain volume loss and lesion burden accumulation as functionally relevant trial endpoints in PPMS and inform the design and interpretation of clinical trials in PPMS.
17 Apr 2026
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