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. 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. 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. 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. F Hoffmann-La Roche.
The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Multiple sclerosis remains under-recognized in Zambia and much of sub-Saharan Africa, often leading to misdiagnosis and delays. Understanding diagnostic pathways and barriers can inform strategies to improve multiple sclerosis recognition and care. This study explores the diagnostic journeys of adults with multiple sclerosis in Zambia, emphasizing the challenges encountered at each stage. We conducted a qualitative study using semi-structured interviews with adults diagnosed with multiple sclerosis in Zambia. Thematic analysis identified patterns in diagnostic experiences, enabling the mapping of common pathways and barriers, along with patient perspectives on the impact of diagnostic delays. Thirteen individuals with relapsing-remitting multiple sclerosis (mean age 34 ± 11 years; 70% female) were enrolled. Diagnostic pathways involved multiple healthcare visits, frequent misdiagnoses, and substantial delays. Key barriers included limited magnetic resonance imaging access, low multiple sclerosis awareness, and financial constraints. Thematic findings highlighted misinterpretation of symptoms, lack of specialists, and systemic health system limitations. Delayed diagnosis had a significantly negative impact on patients' lives. Multiple sclerosis diagnosis in Zambia is markedly delayed, adversely affecting patients. Greater awareness and policy reforms targeting diagnostic barriers are needed to promote earlier diagnosis and improve outcomes in Zambia and similar resource-limited settings.
Cognitive dysfunction involving working memory is common in multiple sclerosis (MS) but is often under-detected in clinical assessments. Noninvasive digital biomarkers like oculomotor metrics may enhance the detection of neurofunctional changes. Determine whether oculomotor metrics during a visuospatial N-back task reflect cognitive dysfunction and correspond with clinical measures in patients with MS. In a cross-sectional study, 38 patients completed an N-back working memory task with eye tracking to record gaze duration and task accuracy. Clinical measures included Symbol Digit Modalities Test (SDMT), retinal nerve fiber layer (RNFL), macular volume, Expanded Disability Status Scale (EDSS), and Nine-Hole Peg Test (9HPT). Linear regression models examined relationships between task accuracy, gaze duration, and clinical measures. Gaze duration and task accuracy were inversely correlated (r = -0.57, p < 0.001). Shorter gaze duration and higher task accuracy, indicators of better cognitive processing efficiency, were associated with better SDMT scores, greater RNFL thickness and macular volume, and better EDSS and 9HPT completion times. Oculomotor metrics recorded during a working memory task are associated with cognitive, retinal, and functional measures in pwMS, supporting their potential as noninvasive biomarkers to complement standard clinical assessments in detecting cognitive dysfunction.
Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system marked by inflammatory demyelination and progressive neurodegeneration. Although current immunomodulatory therapies can reduce relapse rates, they are often associated with limited long-term efficacy and adverse effects, highlighting the need for safer and more comprehensive complementary approaches. Dietary bioactive phytochemicals-notably, the polyphenols epigallocatechin-3-gallate (EGCG), curcumin, and resveratrol-have demonstrated potential to modulate the immune and inflammatory pathways implicated in MS pathogenesis. In addition to their immunomodulatory roles, emerging evidence suggests that these compounds also exert neuroprotective effects independent of immune modulation, including antioxidant activity, mitochondrial stabilization, and enhancement of neurotrophic signaling. Furthermore, recent studies identify the gut microbiota as a central mediator of MS pathophysiology and of how dietary phytochemicals are metabolized and exert their effects. This review examines experimental data evaluating the therapeutic potential of selected bioactive phytochemicals in MS, focusing on their mechanisms of action-including both immune-dependent and immune-independent neuroprotective effects-and interactions with the gut microbiota. Current limitations in translating findings from animal models to clinical settings are also discussed, and future directions for research in this evolving area are highlighted.
Patients with multiple sclerosis (MS) have individual needs, preferences, and barriers to how they receive care; providers require an understanding of these to facilitate comprehensive clinical care. To determine MS clinic characteristics currently valued by or desired by adults with MS, their unmet support needs, and their barriers to care. An electronic cross-sectional survey was iteratively developed by a multidisciplinary team and distributed to adults with MS. Three hundred and eighty-seven participants completed the survey. The most desired characteristics in an MS clinic were the training or knowledge (55%) and compassion (54%) of providers, along with urgent appointment availability (48%). Appointment availability, transportation, and financial costs were barriers to accessing care (44%, 39%, and 30%). Support was requested most often for making lifestyle changes, including improving exercise (52%) and diet (45%). Opportunities for additional support included in-clinic rehabilitation therapies, mental health, and nutritionist services. Adults with MS report multiple desired clinic characteristics and support needs that are currently unmet. Opportunities for improving care and support include expanding in-clinic services, greater appointment availability, transportation, and education on exercise and diet. Future studies will benefit from assessing the effectiveness of expanded services or support programs in these areas.
Live attenuated measles-mumps-rubella (MMR) and varicella vaccines are recommended for immunocompetent people with multiple sclerosis (MS) lacking immunity. However, concerns about postvaccination relapses may contribute to vaccine hesitancy, and robust data addressing this risk remain limited. To assess whether the risk of MS relapse within 1 year after MMR or varicella vaccination is not unacceptably worse than risk after no such vaccination based on a predefined noninferiority margin. This cohort study used prospectively collected data from July 2016 to October 2024 for people with MS at a tertiary MS center in Barcelona, Spain, who received at least 1 dose of live attenuated MMR and/or varicella vaccine due to serologic susceptibility. Vaccinated patients were matched 1:2 with unvaccinated control individuals with MS by sex, age, and epoch of first demyelinating event. Live attenuated MMR and/or varicella vaccine. Primary outcomes were relapse count and time to first relapse within 1 year of time 0, analyzed using Poisson and Cox proportional hazards regression models with inverse probability weighting based on a propensity score including treatment category, Expanded Disability Status Scale score, and annualized relapse rate in the prior year. Noninferiority was predefined as an annualized relapse rate ratio with an upper bound of the 95% CI less than 1.4. A total of 369 people with MS were included, of whom 123 were vaccinated (mean [SD] age, 28.75 [8.72] years; 85 females [69.1%]) and matched to 246 unvaccinated controls (mean [SD] age, 28.66 [8.60] years; 170 females [69.1%]). Overall, 36 relapse events were observed (15 [41.7%] among vaccinated patients and 21 [58.3%] among unvaccinated controls). In the weighted Poisson model, although relapse incidence was not significantly different between vaccinated and unvaccinated individuals (incidence rate ratio, 0.52; 95% CI, 0.23-1.06), the noninferiority criterion was met. Similarly, weighted Cox proportional hazards regression models showed no difference in hazard of relapse between groups (hazard ratio [HR], 0.55; 95% CI, 0.25-1.17) but the noninferiority criterion was met. Sensitivity and exploratory analyses, including time-dependent adjustment for postbaseline treatment exposure (HR, 0.60; 95% CI, 0.27-1.33), restriction to the high-risk period (n = 15 events), and comparisons of magnetic resonance imaging before (n = 43 events) and after (n = 21 events) exposure in vaccinated patients, revealed findings consistent with those of the primary analysis. In this cohort study of nonimmunosuppressed people with MS, vaccination with live attenuated MMR or varicella vaccine was not associated with increased risk of postvaccination relapse. The results support the administration of these vaccines when indicated and may help reassure clinicians and patients, reducing vaccine hesitancy.
Myelin enables rapid action potential conduction and axonal support, and its disruption underlies diverse neurological disorders. Its assessment is essential for studying development, plasticity, and repair of the nervous system (NS), and for diagnosing demyelinating diseases and evaluating remyelination therapies. Multiple histological methods detect myelin, each with trade-offs in sensitivity, cost, and reproducibility. Among them, Eriochrome Cyanine R (EC-R) is a simple, affordable myelin stain widely used in thin sections, but remains poorly standardized, and underexplored in thick vibratome sections. Here we describe and validate a simple, inexpensive, solvent-free EC-R protocol for central and peripheral nervous system tissue across seven vertebrate species and multiple demyelinating conditions. The method replaces subjective microscopic differentiation with fixed, time-controlled incubations scaled to section thickness, improving reproducibility. Using perfusion and immersion-fixed samples, we show that the protocol yields homogeneous myelin labeling with sharp white/gray matter contrast in whole brains, cortical slabs, spinal cord, and peripheral nerves. Thick sections stained with EC-R preserve 3-dimensional tissue architecture, resolve single myelinated axons and intracortical bands, and can be combined with Nissl-like counterstains and immunohistochemistry. Developmental series in neonatal rats reveal expected PNS-CNS myelination gradients, while experimental demyelination models and naturally occurring diseases (canine distemper and human multiple sclerosis) illustrate the method's ability to delineate lesion cores, perilesional gradients, and associated glial and immune activation. This standardized EC-R approach provides a robust and versatile tool for comparative neuroanatomy, experimental neuropathology, and translational studies of myelination, demyelination, and remyelination, as well as for the clinical diagnosis of myelin-related disorders.
Relapse prevention in multiple sclerosis (MS) is accomplished with disease-modifying therapy (DMT). Relapse rates typically decrease with age while DMT-associated risks increase, complicating treatment of older persons with MS (PwMS). This follow-up study aims to guide treatment decisions by evaluating clinical and patient-reported outcomes among older PwMS who discontinue DMT. This study included PwMS aged ≥60 evaluated at the Cleveland Clinic from 2010 to 2016, categorized as DMT continuers or discontinuers. Follow-up timeframe was February 2018-April 2024. Outcomes included relapses, magnetic resonance imaging (MRI) activity, and Neuro-QoL and MS Performance Test scores. Mixed-effects regression and survival models were used. In total, 600 PwMS were included. Median follow-up time was 10.5 years (interquartile range 7.7-13.4), 66.0% discontinued DMT, and 3.3% had ≥1 relapse. Relapse risk did not differ significantly between groups (hazard ratio for discontinuers vs. continuers, 1.80, 95% confidence interval 0.51-6.39, p = 0.365). T2 lesions developed in 37.5% of continuers and 36.6% of discontinuers. Gadolinium-enhancing lesions developed in 10.1% and 7.9%, respectively. Neuro-QoL Fatigue T-scores slightly worsened for discontinuers over time. Findings demonstrate low relapse risk among PwMS over age 60, however, MRI changes were common. DMT discontinuation may be considered in this population, though further studies are needed to better understand radiological disease activity.
Therapeutic inertia (TI) remains a critical barrier to optimizing outcomes in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSDs). We evaluated the proficiency of ChatGPT-4o in addressing complex neuro-immunological management challenges compared to practicing neurologists. We conducted a comparative analysis using 21 clinical vignettes derived from a multicenter research framework. Responses from 290 neurologists were benchmarked against ChatGPT-4o, both with and without Retrieval-Augmented Generation (RAG). The primary endpoint was guideline-adherent decision-making at the item level, with the prevalence of TI as a secondary clinical outcome. Scenarios included MS therapy escalation, aquaporin-4-IgG positive NMOSD management, and serum neurofilament light chain integration. ChatGPT-4o with RAG achieved significantly higher guideline adherence in decision-making than neurologists (80.5% vs. 66.5%; p = 0.001). Multivariable generalized estimating equation models identified ChatGPT-4o as an independent predictor of evidence-based decision-making (Odds ratio 3.17; 95% confidence interval: 2.05-4.88; p < 0.0001). While the model demonstrated a lower propensity for TI overall, performance parity occurred in emerging biomarker scenarios where clinical consensus is still evolving. ChatGPT-4o demonstrated superior guideline adherence and reduced TI compared to neurologists. Integrating Large Language Models as clinical decision-support tools may enhance the standardization of neuro-immunological care and serve as a valuable adjunct to mitigate human cognitive biases.
Bruton's tyrosine kinase (BTK) is an intracellular enzyme involved in a wide range of cellular functions. BTK inhibitors (BTKIs) are of interest in multiple sclerosis because they modulate various types of immune cells that have key roles in multiple sclerosis pathophysiological processes, including B cells and microglia. Moreover, because BTKIs are small molecules that might cross the blood-brain barrier and potentially modulate relevant cells within the CNS, there is added interest in their use in multiple sclerosis. In the past decade, there has been a flurry of drug development of BTKIs in multiple sclerosis. The BTKIs being evaluated in multiple sclerosis have differences in pharmacological properties that might result in meaningful differences in safety and efficacy. Recently reported phase 2 and phase 3 clinical trials have provided the field with renewed hope that some BTKIs could modulate progressive multiple sclerosis disease mechanisms that current disease-modifying treatments insufficiently address. However, meaningful differences in clinical outcomes and MRI findings have been reported. If the beneficial findings seen with some BTKIs are confirmed, these observations suggest the beginning of a new era of treatment in multiple sclerosis. The results of upcoming clinical trials, real-world studies, and regulatory approval decisions will guide a more nuanced approach to determining the patient populations that will benefit most from this treatment class.
Fatigue and cognitive impairment are common in people with multiple sclerosis (pwMS). This study evaluated the feasibility of a digital symptom management program integrated into the Finnish MS Registry targeting fatigue and cognitive symptoms. Forty pwMS with subjective fatigue and cognitive concerns enrolled in an eight-session eHealth program including symptom self-assessments, a mobile fatigue diary, individualized goal setting, and feedback from a neuropsychologist. Feasibility outcomes were completion rate, perceived usefulness, and technical functionality. Patient-reported outcome measures (PROMs) included the Goal Attainment Scale (GAS), Global Rating of Change (GRC), Fatigue Scale for Motor and Cognitive Functions, Multiple Sclerosis Neuropsychological Questionnaire, patient-reported Expanded Disability Status Scale, Visual Analogue Scales for neurological symptoms, and EQ-5D-5L. Twenty-three participants (58%) completed the program with follow-up. The program was rated useful by 65% and technically appropriate by 70%. The mean GAS T-score was 50 both postintervention and at follow-up. Mean GRC scores indicated slightly positive change in managing fatigue (+1.4), cognitive symptoms (+1.3), and overall effects (+1.8). Other PROM changes were minimal. The registry-integrated eHealth program showed potential to support the management of fatigue and cognitive symptoms in pwMS. Further development and evaluation of digital symptom management tools are warranted.
Cognitive disengagement syndrome (CDS) refers to a set of attentional symptoms comprising daydreaming, mental fogginess, and hypoactivity clearly distinguishable from ADHD-IN and other forms of psychopathological issues. The present study: (1) assessed CDS among adults with multiple sclerosis (MS) and healthy controls, and (2) investigated the associations between CDS and depression, insomnia, fatigue, and paresthesia in persons with MS. Two-hundred and seven adults with MS (mean age: 36.64 years; 72.5% females) and 213 healthy controls (mean age: 34.19 years; 54.5% females) provided self-ratings of CDS, insomnia, depression, fatigue, and paresthesia. Compared to healthy controls, adults with MS reported higher scores for CDS (t(418 = 4.29, p < 0.001, d = 0.42), depressive symptoms (t(41) = 2.21, p = 0.014, d = 0.22), and insomnia (t(418) = 1.66, p = 0.049). Among the MS sample, higher levels of CDS were associated with higher depression (r = 0.64), insomnia (r = 0.34), fatigue (r = 0.53), and paresthesia (r = 0.28). Further, higher scores for depression, insomnia, and fatigue were independently associated with higher CDS. Adults with MS experience greater CDS symptoms than healthy controls. Higher CDS scores were associated with depression, insomnia, fatigue, and paresthesia, which are typical of adults with MS. MS may contribute to or exacerbate CDS symptoms and be a potentially important target for further investigation.
Interpretation of cognitive impairment (CI) in persons with multiple sclerosis (PwMS) is limited by discrepancies between objective and subjective evaluation. Evaluate relationships between subjective and objective cognitive measures, accounting for contributors. Multiple Sclerosis Neuropsychological Questionnaire (MSNQ), patient-reported outcomes, Processing Speed Test (PST), Rey Auditory Verbal Learning (RAVLT), Visual Memory Test (VMT), Face Emotion Recognition (FER), Corsi, and Flanker test scores were collected. Spearman correlations, diagnostic metrics, and latent profile analysis assessed associations and cognitive phenotypes. In 83 PwMS, only 4.8-15.7% showed objective domain-specific CI, yet 42.2% reported significant CI. However, 51.8% had objective impairment in ≥1 domain. Compared with PwMS without objective or subjective CI, those with subjective but no objective CI had higher Hospital Anxiety Depression Scale-A (9.92 vs. 4.83) and D (8.23 vs. 2.88), and Fatigue Severity Scale (5.56 vs. 3.80) scores, p < 0.05. Latent profile analysis identified a performant cluster (C1, n = 36) and a less performant cluster (C2, n = 46) with higher mean z-scores on PST (0.46 vs. -0.70), VMT (0.32 vs. -0.54), RAVLT (0.99 vs. -0.06), and FER (0.57 vs. -0.80), p < 0.005, in C1. The MSNQ scores were similar between clusters. A discrepancy between subjective and objective CI is observed. Subjective CI is associated with anxiety, depression, and fatigue. Multidomain testing and assessment of contributors may help reconcile this discrepancy.
To evaluate the feasibility and potential efficacy of percutaneous spinal stimulation (epidural stimulation, ES) combined with task-specific training to reduce spasticity and improve gait and balance in individuals with progressive multiple sclerosis (MS). Two men with progressive MS (EDSS 6.5) underwent ES lead implantation targeting the lower spinal cord, followed by one month of rehabilitation involving 12 ES-assisted training sessions. Assessments included instrumented gait analysis, Modified Ashworth Scale (MAS), pendulum test, and static balance testing performed at baseline, and at end of the study with ES-Off and ES-On conditions. Participant 1, with spastic hemiparetic gait, demonstrated improved lower extremity joint kinematics and muscle activation during gait, reduced knee extensor spasticity, and enhanced functional movement patterns with ES-On. Participant 2, with significant paraparesis and minimal spasticity, showed limited gait changes but experienced marked improvements in static balance, particularly under eyes-closed conditions. No adverse events were reported. This pilot study demonstrates the feasibility and tolerability of ES paired with task-specific training in progressive MS. Participant-specific responses were observed, including improvements in gait kinematics, neuromuscular activation, spasticity, or balance; however, spatiotemporal gait parameters did not improve. These preliminary findings highlight response heterogeneity and the need for individualized ES parameter tuning. Trial registry name and URL: https://clinicaltrials.gov/study/NCT06019611.
Multiple sclerosis (MS) is a progressive disease that may affect respiratory muscle function. Pulmonary dysfunction may be subclinical, and posture changes can reduce lung volumes, especially in the presence of respiratory muscle weakness. To determine whether lung function differs between sitting and supine positions in individuals with moderate MS, and to explore associations with respiratory muscle strength and disability. Forty-eight participants with moderate MS (13 men, 35 women; median Expanded Disability Status Scale (EDSS) 4.5, range: 4.0-6.5) underwent spirometry (VC, FVC, FEV1, PEF) in sitting and supine positions. Respiratory muscle strength was assessed using maximal inspiratory (MIP) and expiratory pressures (MEP). VC and FVC did not differ significantly between positions. FEV1 and PEF were slightly reduced in the supine position (p ≤ 0.001), with median relative decreases of -6% and -10%, respectively. These changes did not correlate with EDSS, MIP, or MEP. No sex-related differences were observed. FEV1 and PEF are reduced in the supine position in individuals with moderate MS, indicating early positional respiratory changes. These alterations appear independent of disability level or respiratory muscle strength. However, it remains uncertain whether these changes differ from those of healthy individuals. Controlled studies are warranted to clarify their clinical significance.
People with multiple sclerosis (pwMS) often face complex challenges leading to work-related barriers, reduced employment and impaired health-related quality of life (HRQOL). Explore status for and associations between disability, employment, work barriers and HRQOL in pwMS. Cross-sectional survey, 252 pwMS (49.2% of the 512 invited) aged ≥18 in Nordland County, Norway. Demographics, Expanded Disability Status Scale (EDSS), employment status, MS Work Difficulties Questionnaire-23(MSWDQ-23), and MS Quality of Life-54(MSQOL-54). Descriptive statistics, ANOVA and Pearson's correlation in IBM SPSS-27/28. Participants had mean EDSS 2.8 [SD2.2], age 52.3 years [SD12.9], 43.7% were currently working, 22.6% held full positions. The mean preferred work percentage in a tailored job was 81.9% [SD24.9] (employed) and 32.3% (non-employed). Disability benefits started early, mean 43.85 years [SD10.65]. Associations were weak between EDSS and work-percentage (r = -0.286), work-related barriers (r = 0.34) and MSQOL-54 Mental Health Composite Score (HCS) (r = -0.27), while moderate for Physical HCS (r = 0.53) and between Physical HCS and work percentage (r = 0.45). Unemployment occurred at all disability levels. While physical problems increased over time, mental factors impacted employment at any disability level. However, both employed and unemployed want to work more, indicating possibilities for sustained employment if the job is individually adjusted.
Natalizumab is effective for relapsing MS but may trigger anti-natalizumab antibodies (ANZ) that neutralise drug activity and increase reactions. Trials report persistent antibodies in ∼6% and overall prevalence between 4% and 14%, but real-world burden and optimal testing remain uncertain. We assessed ANZ prevalence, timing, and correlates, comparing systematic with indication-driven testing. Single-centre retrospective cohort of natalizumab-treated patients with ≥1 ANZ test. Testing followed routine care: systematic screening at months 6/12/18 or testing triggered by suspected inefficacy or infusion reactions. Clinical/MRI data were abstracted; time to positivity was used in Kaplan-Meier; predictors were assessed using multivariable logistic regression. Among 182 patients (348 tests), ANZ were detected in nine (4.9%; four persistent and five transient), all within the first 12 infusions. Positivity differed by indication (p = 0.005): suspected inefficacy 10.5% (4/38), systematic screening 1.6% (5/304), post-reaction testing 0% (0/6). Within suspected inefficacy, MRI activity was more strongly associated with positivity than symptoms alone (p = 0.04). In multivariable models, suspected inefficacy was the only independent predictor; adding indication improved discrimination (AUC 0.74 vs. 0.56). In routine care, ANZ positivity is uncommon and occurs early. Indication-driven testing - especially when prompted by new MRI lesions - yields greater diagnostic value than routine screening of clinically stable patients, supporting a selective, context-driven approach to ANZ monitoring.
Multiple sclerosis (MS) is characterized by progressive mitochondrial dysfunction affecting complexes I, III, and IV of the electron transport chain, contributing to axonal energy failure and neurodegeneration. This review examines the potential of combining β-hydroxybutyrate (βHB), epigallocatechin-3-gallate (EGCG), and ellagic acid (EA) as a multi-target therapeutic strategy to restore mitochondrial function in patients with MS. Experimental and clinical studies demonstrate that each compound exerts complementary mechanisms. Ketone bodies provide an alternative energy substrate and restore complex I activity via sirtuin-dependent pathways. EGCG acts predominantly at the peripheral level by reducing systemic inflammation and oxidative stress. EA-derived urolithins effectively cross the blood-brain barrier to directly enhance mitochondrial biogenesis and respiratory chain function in the central nervous system. Clinical trials have reported improvements in fatigue, cognition, mood, and muscle function following supplementation with these compounds. The convergence of their actions on energy restoration, reactive oxygen species reduction, and epigenetic modulation of protective pathways suggests their synergistic potential. Optimized delivery strategies, including exogenous ketone salts, liposomal EGCG, and microencapsulated EA, may overcome bioavailability limitations and interindividual variability in the gut microbiota metabolism.
The Patient-Determined Disease Steps (PDDS) and Neuro-QoL Lower Extremity Function-Short Form (Neuro-QoL LEF-SF) are patient-reported outcome measures used to monitor mobility symptoms in multiple sclerosis (MS). To develop and validate a crosswalk between the PDDS and Neuro-QoL LEF-SF. Using equipercentile equating, we created a crosswalk from a training sample of 619 MS patients (mean PDDS = 2.4 ± 2.3; mean Neuro-QoL LEF-SF = 33.0 ± 8.3). Validation was performed in a separate sample of 147 MS patients (mean PDDS = 0.6 ± 1.2; mean Neuro-QoL LEF-SF = 38.9 ± 2.8). Agreement between original and converted scores was evaluated using paired t-tests and concordance correlation coefficients. PDDS and Neuro-QoL LEF-SF scores were strongly correlated in both training (r = -0.89) and validity (r = -0.76) samples. No significant differences in change scores were observed. Concordance coefficients of original and converted scores supported good to very good agreement. We developed a crosswalk for the conversion of scores between the PDDS and the Neuro-QoL LEF-SF for patients with MS. Evidence for the preliminary validity of this crosswalk was demonstrated with both the initial training sample and a separate validity sample. This crosswalk facilitates score comparisons and data harmonization across studies and clinical registries using either measure.