Search Results (218)

Background: The diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) relies on sensitive serological detection of MOG-IgG. Fixed cell-based assays (CBAs) may yield low-positive or borderline results that complicate early clinical decision-making, whereas live CBAs—recommended as the reference method—preserve native antigen conformation and offer higher analytical sensitivity. Importantly, low-positive titres should not be confused with true seronegativity, as they may nevertheless be clinically meaningful. Case Presentation: A 14-year-old previously healthy male presented with left optic neuritis and perineuritis following an upper respiratory infection. Initial MOG-IgG testing on a fixed CBA was low-positive (1:10). He partially responded to intravenous methylprednisolone and required intravenous immunoglobulin (IVIG) for complete resolution. Over three years, he experienced sequential, steroid-dependent bilateral optic neuritis with perineuritis, relapsing on every steroid taper. Rituximab and subsequently mycophenolate mofetil failed to induce remission. Repeat testing with a live CBA at a reference laboratory yielded a high-positive MOG-IgG titre of 1:1000, confirming MOGAD. Tocilizumab (8 mg/kg every 4 weeks) was initiated and allowed complete corticosteroid withdrawal. At age 18, the patient remained asymptomatic, with an Expanded Disability Status Scale score of 0, best-corrected visual acuity of 20/20 in both eyes, and stable peripapillary retinal nerve fibre layer thickness on spectral-domain optical coherence tomography. Conclusions: In paediatric patients with recurrent optic neuritis with perineural involvement and borderline fixed-CBA results, confirmatory testing with a live CBA at a reference laboratory should be considered to avoid diagnostic delay and therapeutic misdirection. In refractory, steroid-dependent cases, IL-6 receptor blockade may represent a reasonable therapeutic option, in line with emerging evidence. Full article

Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease characterized by marked clinical heterogeneity. While the genetic architecture underlying disease susceptibility is well established, the role of genetic factors in shaping disease prognosis remains clearly defined. In this structured narrative review, we examine available evidence on genetic contribution to key MS prognostic domains. This includes clinical outcomes, such as age at onset, relapse rate, disability progression, neurological sequelae, and cognitive impairment. We also consider radiological measures like brain and spinal cord lesion burden, gadolinium-enhancing lesions, and atrophy, as well as laboratory biomarkers, such as oligoclonal bands and Immunoglobulin G (IgG) index. Overall, current evidence suggests that genetic influences on prognosis are modest and highly heterogeneous. Only a limited number of associations—primarily from genome-wide association studies (GWAS)—have shown consistent replication, whereas many reported findings come from small candidate-gene studies and remain unconfirmed. Among these, the largest GWAS on age-related Multiple Sclerosis Severity Score (MSSS) identified a locus in the DYSF–ZNF638 region reaching genome-wide significance. The strongest evidence from GWAS relates to relapse rate, magnetic resonance imaging (MRI) measures (e.g., thalamic atrophy) and intrathecal IgG synthesis, the latter also reaching genome-wide significance. Interpretation of genotype–phenotype associations is further limited by small sample sizes, limited replication, heterogeneity in study design with the predominance of candidate-gene approaches, variability in outcome definitions, treatment exposure, and population ancestry. These limitations currently preclude the routine use of genetic markers for prognostic stratification in clinical practice. Larger studies and collaborative genetic consortia efforts are needed to improve statistical power and reproducibility. Additionally, emerging epigenetic studies may provide valuable insights into prognosis and disease management. Understanding which genetic factors can predict diverse MS courses could enhance patient management and enable personalized treatment approaches. Full article

Background/Objectives: Gut microbiota (GM) dysbiosis has been implicated in multiple sclerosis (MS) pathogenesis, influencing inflammation and neurodegeneration, but findings remain inconsistent due to environmental and methodological variability. This study aimed to identify possible microbial biomarkers of MS status and disease severity by profiling gut microbiota and short-chain fatty acid (SCFA) patterns in people with relapsing–remitting MS (pwRRMS), using household-matched healthy controls (HC) to minimize environmental variability. Methods: Twenty-four pwRRMS and their respective household-matched healthy controls (HC) were enrolled, with dietary and lifestyle habits monitored. GM composition was assessed by 16S rRNA gene sequencing, and fecal SCFAs were quantified using gas chromatography–mass spectrometry. PwRRMS were stratified by Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS). Results: β-diversity did not differ between groups. However, α-diversity was significantly reduced in pwRRMS, particularly in those with greater disability. Reduced diversity was associated with lower abundance of butyrate-producing genera (Roseburia, Faecalibacterium, Coprococcus) and enrichment of Oscillibacter and UBA1819, alongside a downward trend in fecal butyrate and propionate levels. Conclusions: RRMS and greater disease severity are associated with gut microbial alterations characterized by reduced SCFA-producing bacteria. Despite limitations including small sample size and sex imbalance, the household-matched design strengthens internal validity. Our findings highlight the potential of targeting the gut microbiota, an accessible compartment within the gut–brain axis, for MS management. Full article

The management of multiple sclerosis (MS) is shifting from a phenotype-based framework toward a biologically driven precision medicine model, as conventional magnetic resonance imaging (MRI) inadequately captures smoldering inflammation and progression independent of relapse activity (PIRA). This systematic review aimed to synthesize current evidence on the diagnostic and prognostic utility of fluid biomarkers in distinguishing acute inflammatory injury from chronic neurodegeneration. A comprehensive search of Web of Science, PubMed, and Scopus (January 2020–September 2025) identified 28 eligible studies including 7775 participants (6365 MS patients and 1410 controls). Biomarkers derived from serum, plasma, cerebrospinal fluid (CSF), and stool were evaluated in relation to clinical disability measured using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) outcomes. Neurofilament light chain (NfL) consistently predicted acute inflammatory activity, gadolinium-enhancing lesions, and relapse-associated worsening, but levels were reduced by high-efficacy therapies and did not reliably predict PIRA. In contrast, glial fibrillary acidic protein (GFAP) was associated with astrogliosis, disability progression, and retinal thinning, even in patients with low inflammatory activity. Additional CSF, metabolic, and immunologic markers correlated with neurodegeneration and disease severity. Nevertheless, broader clinical use will require greater assay standardization, improved consistency across cohorts, and validation in prospective longitudinal studies. These findings compel a shift toward a multi-biomarker model to guide personalized therapeutic strategies and develop targeted neuroprotective treatments for progressive multiple sclerosis. Full article

Background/Objectives: Real-world evidence on ofatumumab (OFA) beyond 12 months remains limited in relapsing–remitting multiple sclerosis (RRMS). We assessed 24-month effectiveness and safety, compared treatment-naïve and previously treated patients, and explored predictors of failure to achieve No Evidence of Disease Activity-3 (NEDA-3). Methods: This multicenter retrospective cohort study included adult RRMS patients treated with OFA in routine clinical practice. Effectiveness analyses were restricted to patients with complete 24-month follow-up and full clinical and magnetic resonance imaging (MRI) assessment (complete-case analysis). Outcomes included relapses, MRI activity, Expanded Disability Status Scale (EDSS) progression, NEDA-3, and adverse events (AEs). Exploratory multivariable logistic regression was used to assess baseline predictors of NEDA-3 non-achievement. Results: Of 258 patients who initiated OFA, 148 had completed 24-month clinical and MRI follow-up and were evaluable for effectiveness. Over 24 months, 71.5% achieved NEDA-3; relapses occurred in 15.5% of patients, MRI activity in 15.5%, gadolinium-enhancing lesions (GELs) in 4.7%, and EDSS progression in 17.6%. Disease activity was minimal during months 12–24, with relapses in 2.7%, MRI activity in 2.0%, and no GELs. In unadjusted analyses, no statistically significant differences were observed between treatment-naïve and previously treated patients. Higher baseline EDSS was associated with failure to achieve NEDA-3. In the 24-month safety subgroup, AEs were recorded in 28.4% of patients; infections occurred in 26.4% of patients (all grade 1–2), and no serious adverse events were observed. Conclusions: In this multicenter real-world cohort, OFA was associated with low inflammatory disease activity over 24 months in RRMS patients with complete follow-up. These findings should be interpreted cautiously because the effectiveness analysis was restricted to a complete-case cohort and safety data were collected retrospectively. Full article

Background: Circulating cytokines and their soluble receptors in body fluids have been implicated in the pathogenesis of multiple sclerosis (MS). Alterations in serum levels of pro- and anti-inflammatory cytokines and/or their soluble receptors can dysregulate central nervous system (CNS) signaling pathways and, therefore, may serve as potential biomarkers for the diagnosis of MS. Therefore, the primary end-point of this study is to investigate the utility of various cytokines and their soluble receptors as diagnostic biomarkers in MS. The secondary outcome is also to assess whether these cytokines are useful in differentiating the severity of MS. Methods: In this case–control study, we compared a panel of pro-inflammatory interleukins (ILs), including IL18 and tumor necrosis factor-alpha (TNFα), soluble IL receptors (sIL7Rα and sIL2Rα), and insulin-like growth factor-1 (IGF-1) in 45 MS patients and in 45 healthy control individuals matched for sex and age. Associations of these biomarkers with age, disease severity (Expanded Disability Status Scale [EDSS]), disease duration, and age at first MS symptom onset were also assessed. Results: Serum levels of cytokines and soluble IL receptors were elevated in MS patients compared to healthy controls. IGF-1 was lower (p < 0.001) in the MS patients than in the healthy individuals. The serum level of IGF-1 was higher (p < 0.01) in the remitting-relapsing phase compared to the primary progression and secondary progression stages. Similarly, only IGF-1 was more elevated (p < 0.01) in the mild stage compared to the moderate stage based on the EDSS score. Receiver operating characteristic (ROC) curve analysis demonstrated that IL18 had excellent discriminatory power for the diagnosis of MS (p < 0.001), with an area under the curve (AUC) of 0.96 ± 0.017, followed by IGF-1 (p < 0.001), which showed strong diagnostic performance (AUC = 0.873 ± 0.037). Soluble (s) IL2Rα exhibited fair diagnostic accuracy (p < 0.001; AUC = 0.717 ± 0.054). In contrast, sIL7Rα and TNFα showed poor discriminatory power despite statistical significance (p < 0.01), with AUC values of 0.675 ± 0.057 and 0.687 ± 0.056, respectively. Results of regression analysis revealed that EDSS, duration of disease, and use of any treatment had no impact on the cytokines. Similarly, no significant correlations were noted between these confounders and cytokines, except a moderate negative correlation (−0.418) between IGF-1 and EDSS. Conclusions: IL18 and IGF-1 have the potential to be used as biomarkers in distinguishing MS from healthy individuals. However, both biomarkers failed to demonstrate the discrimination between various phenotypic patterns of disease, limiting their utility for disease stratification. Future studies with larger, longitudinal cohorts and multi-marker panels are warranted to validate these results and to explore whether combining cytokines with imaging or genetic markers can improve prognostic precision. Full article

Background: There is a paucity of systematic investigations of the acceptability and preference of alternative oral drug formulations in multiple sclerosis (MS) patients. The use of appropriate oral dosage forms has the potential to circumvent challenges associated with the ingestion of tablets. Objective: This randomized, open, cross-over study aimed to investigate acceptability, swallowability, palatability, and preference of four oral placebo drug formulations of similar sizes/given volumes but different modes of ingestion (film-coated tablet, orodispersible tablet, orodispersible film, and gel) in MS patients. Methods: Acceptability was tested in two patient subgroups (32 participants each) of different MS disability levels (expanded disability status scale [EDSS] < 4 and ≥4). The primary endpoint was acceptability derived as a composite of swallowability (rated by investigator) and palatability (rated by participant). Results: The film-coated tablet showed the highest acceptability rates for EDSS < 4 and EDSS ≥ 4 (100.0%, 93.8%), followed by gel (81.3%, 68.8%). Acceptability rates for all formulations were consistently higher for EDSS < 4 compared to EDSS ≥ 4. Concerning the subjective assessment of palatability, the gel received the highest rate of positive ratings, but also was frequently judged as ‘Unpleasant’. Furthermore, the gel was ranked as the first or second choice as the most-preferred formulation, followed by the film-coated tablet. All formulations were considered safe in the study population. Conclusions: Film-coated tablets are well-suited for use in MS patients and gels may represent an interesting alternative for a certain subgroup of MS patients. Full article

Background and Objectives: Employment is a major determinant of quality of life in people with multiple sclerosis (pwMS). This multicenter cross-sectional study aimed to identify which commonly studied demographic, disease-related, clinical, cognitive, and psychological variables, alongside the presence of lower urinary tract symptoms (LUTS), predict employment status in pwMS. Materials and Methods: Seventy-eight pwMS were classified as either full-time employed (n = 41) or non-employed (n = 37). Participants underwent clinical and neuropsychological assessment including disability status (Expanded Disability Status Scale; EDSS), fatigue (Modified Fatigue Impact Scale; MFIS), information processing speed (Symbol Digit Modalities Test; SDMT), depressive symptoms (Hospital Anxiety and Depression Scale-Depression; HADS-D), and LUTS status (presence/absence), alongside demographic and disease-related variables (sex, age, education level, relationship status, and disease duration). Results: Hierarchical binary logistic regression indicated that higher information processing speed was associated with higher odds of employment (OR = 1.11, p = 0.008), whereas the presence of LUTS was associated with lower odds of employment (OR = 0.13, p = 0.026). Disability severity, fatigue, depressive symptoms, demographic characteristics, and disease duration did not contribute in the final model (p > 0.05). Conclusions: Information processing speed and urinary dysfunction were associated with employment status in pwMS. Within the present sample, the multivariable model including these variables showed good discrimination between employed and non-employed participants. The findings should be interpreted as exploratory, and they require further confirmation in independent cohorts before any potential application is considered. Full article

Background/Objectives: Walking impairment and fatigue are common in multiple sclerosis (MS) and contribute to reduced physical function and quality of life (QoL). This study evaluated the feasibility, safety, and pre–post changes associated with a 12-week treadmill walking training (TWT) programme on walking performance, physical function, fatigue, and QoL in people with MS. Methods: Single-arm pilot study with pre–post assessments (T1–T2). Eleven adults with MS (Expanded Disability Status Scale [EDSS] ≤ 6) completed supervised TWT for 12 weeks (two 25 min sessions/week) at the Complejo Asistencial Universitario de Soria (Spain). Outcomes included SF-36, Timed Up and Go (TUG), 4 m gait speed, Short Physical Performance Battery (SPPB), and Modified Fatigue Impact Scale (MFIS). Within-participant changes were analysed using paired t-tests or Wilcoxon signed-rank tests as appropriate; effect sizes were reported as appropriate for the statistical test. Results: SF-36 total score did not change significantly (p = 0.160), while general health (p = 0.039) and vitality (p = 0.043) improved. Walking performance improved (TUG, p = 0.007; 4 m gait speed, p < 0.001), and physical function increased (SPPB, p = 0.003). Fatigue impact decreased (MFIS total, p = 0.015; physical, p = 0.007; psychosocial, p = 0.026), whereas the cognitive subscale did not change significantly (p = 0.094). Adherence was 91.7%, and no adverse events were reported. Conclusions: In this pilot sample, a 12-week TWT programme was feasible and safe and was associated with improvements in walking performance, physical function, and fatigue, with QoL changes limited to specific SF-36 domains. These findings support proceeding to a randomised controlled trial to establish efficacy. These findings should be interpreted as preliminary and exploratory, given the single-arm pre–post study design. Full article

Background/Objectives: Response heterogeneity limits the implementation of dry needling for spasticity in multiple sclerosis (MS). This secondary analysis aimed to identify early responders and explore predictors of response. Methods: We conducted a responder analysis of a pilot randomized, double-blind, sham-controlled trial (NCT05956119) including 18 ambulatory MS patients with spasticity, randomized to a single session of dry needling (n = 9) or sham (n = 9). Sensitive responder criteria were defined as improvement ≥ 2.0 s in Timed Up-and-Go, ≥5 points in MSQOL-54 physical component, or ≥10% in 25-Foot Walk Test at 4 weeks. Results: Using these criteria, 33.3% (3/9) of dry needling recipients were classified as responders versus 0% (0/9) in the sham group (p = 0.214). Responders were more frequently observed among participants with relapsing–remitting MS (100% vs. 40%, p = 0.090) and lower baseline disability (Expanded Disability Status Scale 3.4 vs. 4.4). A positive association was observed between baseline pyramidal subscore and physical quality-of-life change, although this did not reach statistical significance (r = 0.52, p = 0.150) in the active group. Conclusions: Approximately one-third of participants met predefined responder criteria following dry needling; however, these findings should be interpreted as preliminary signals derived from an exploratory, underpowered pilot analysis. These results are hypothesis-generating and require confirmation in adequately powered trials. Full article

Background/Objectives: Cognitive impairment and sleep disturbances are highly prevalent in individuals with multiple sclerosis (MS), particularly during middle age, and negatively affect functional independence and quality of life. Although physical exercise has demonstrated cognitive and sleep-related benefits in MS, tolerance to high-intensity training is often limited. Blood flow restriction (BFR) training, which combines low-load resistance exercise with partial vascular occlusion, has emerged as a feasible alternative. This study aimed to evaluate the effects of a 12-week BFR training program on performance in specific cognitive domains and sleep quality in middle-aged adults with MS. Methods: A randomized controlled trial was conducted in 65 adults with relapsing–remitting multiple sclerosis (RRMS) aged 40–65 years and an Expanded Disability Status Scale score below 7. Participants were randomly assigned to a BFR training group or a usual-care control group. The intervention consisted of supervised low-load resistance training with BFR performed twice weekly for 12 weeks. Outcomes assessed before and after the intervention included processing speed (Symbol Digit Modalities Test), executive function (Trail Making Test A and B), verbal fluency (Isaacs Set Test), and self-reported sleep quality (Pittsburgh Sleep Quality Index). Results: Compared with controls, participants in the BFR group showed significant improvements in specific cognitive domains, including processing speed, executive function, and verbal fluency. Significant reductions were also observed in self-reported global sleep disturbance and daytime dysfunction. No adverse events were reported. Conclusions: A 12-week BFR training program improved performance in key cognitive domains and self-reported sleep quality in middle-aged adults with MS, supporting its feasibility and potential clinical relevance as an exercise-based intervention. Full article

Background and Objectives: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system with rising prevalence in the Middle East. Real-world comparative data on disease-modifying therapies from this region remain limited. This retrospective study compared the clinical outcomes and tolerability of fingolimod and interferon beta-1a (IFN-β1a) among patients with relapsing–remitting multiple sclerosis treated at a large public referral hospital in Jordan. Materials and Methods: All eligible RRMS patients received fingolimod or IFN-β1a at a single tertiary hospital. The annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and adverse effect frequencies were analyzed using descriptive and inferential statistics. A full-cohort inclusion approach was applied instead of sample-size calculation, as all available cases at Al-Basheer Hospital (Amman, Jordan) were included. Results: Fingolimod-treated patients showed a significantly higher ARR than those on IFN-β1a (0.51 vs. 0.26, p = 0.016), an association likely influenced by treatment sequencing and baseline disease activity. EDSS distributions were similar between treatment groups, with most patients demonstrating mild disability (EDSS ≤ 3.5). IFN-β1a was linked to injection site reactions, while fingolimod was better tolerated. Conclusions: The higher observed relapse rate among fingolimod-treated patients possibly reflects treatment sequencing and underlying disease severity rather than pharmacologic efficacy, as fingolimod was commonly prescribed as an escalation therapy. These findings highlight the importance of individualized treatment selection and underscore the need for prospective studies incorporating standardized baseline disease activity measures to better inform multiple sclerosis care in Jordan and the wider Middle Eastern region. Full article

Purpose: To investigate associations between lipid oxidation biomarkers (oxylipins), antioxidant micronutrients, lipoprotein particles, and apolipoproteins in multiple sclerosis (MS). Methods: Blood and neurological assessments were collected from 30 healthy controls, 68 relapsing remitting MS subjects, and 37 progressive MS subjects. Hydroxy (H) and hydroperoxy lipid peroxidation products of the polyunsaturated fatty acids (PUFAs) arachidonic (20:4, ω-6), linoleic (octadecadienoic acid or ODE, 18:2, ω-6), eicosapentaenoic (20:5, ω-3), and α-linolenic (18:3, ω-3) acids were measured using liquid chromatography–mass spectrometry. Antioxidant micronutrients, including β-cryptoxanthin and lutein/zeaxanthin, were quantified by high-performance liquid chromatography. Lipoprotein and metabolite profiles were obtained using nuclear magnetic resonance spectroscopy. Regression models were adjusted for age, sex, body mass index, and disease status. Results: The 9-hydroxy octadecadienoic acid to 13-hydroxy octadecadienoic acid ratio (9-HODE/13-HODE ratio), which reflects autoxidative versus enzymatic oxidation, was associated with MS status (p = 0.002) and disability on the Expanded Disability Status Scale (p = 0.004). Lutein/zeaxanthin (p = 0.023) and β-cryptoxanthin (p = 0.028) were negatively associated with the 9-HODE/13-HODE ratio. Apolipoprotein-CII, a marker of liver-X-receptor (LXR) signaling, was associated with 9-HODE/13-HODE ratio and other oxylipins. Octadecadienoic fatty acid-derived oxylipins were negatively associated with LC3A, a mitophagy marker, and positively correlated with 7-ketocholesterol, a cholesterol autoxidation product. Conclusions: Autoxidation of PUFAs is associated with greater disability in MS. Higher β-cryptoxanthin and lutein/zeaxanthin were associated with reduced auto-oxidation. Lipid peroxidation shows associations with LXR signaling, mitophagy, inflammation, and cholesterol autoxidation. Full article

Background: The clinical–radiological paradox in multiple sclerosis (MS) underscores the need for biomarkers that better reflect neurodegenerative pathology. Serum neurofilament light chain (sNfL) is a dynamic marker of neuroaxonal injury, while brain volumetry provides structural assessment of disease impact. However, the precise link between sNfL and regional atrophy patterns, as well as their combined utility for patient stratification and prediction, remains underexplored. Objective: This study aimed to establish a multimodal biomarker framework by integrating sNfL with comprehensive volumetric MRI to define neurodegenerative endophenotypes and predict neuroaxonal injury using Bayesian inference and machine learning. Methods: In a cohort of 57 MS patients, sNfL levels were measured using single-molecule array (Simoa) technology. Brain volumes for 42 regions were quantified via automated deep learning segmentation (mdbrain software). We employed (1) Bayesian correlation to quantify evidence for sNfL–volumetric associations; (2) mediation analysis to test whether grey matter atrophy mediates the EDSS–sNfL (Expanded Disability Status Scale) relationship; (3) unsupervised K-means clustering to identify patient subtypes based on combined sNfL–volumetric profiles; and (4) supervised machine learning (Elastic Net and Random Forest regression) to predict sNfL from volumetric features. Results: Bayesian analysis revealed strong evidence linking sNfL to total grey matter volume (r = −0.449, BF₁₀ = 0.022) and lateral ventricular volume (r = 0.349, BF₁₀ = 0.285). Mediation confirmed that grey matter atrophy significantly mediates the relationship between EDSS and sNfL (indirect effect = 0.45, 95% CI [0.20, 0.75]). Unsupervised clustering identified three distinct endophenotypes: “High Neurodegeneration” (elevated sNfL, severe atrophy, high disability), “Moderate Injury,” and “Benign Volumetry” (low sNfL, preserved volumes, mild disability). Supervised models predicted sNfL with high accuracy (R² = 0.65), identifying total grey matter volume, ventricular volume, and age as top predictors. Conclusions: This integrative multi-method analysis demonstrates that sNfL is robustly associated with global grey matter and ventricular volumes, and that these measures define clinically meaningful neurodegenerative subtypes in MS. Machine learning confirms that a concise set of volumetric features can effectively predict neuroaxonal injury. These findings advance a pathobiology-driven subtyping framework and provide a validated model for using routine MRI volumetry to assess neuroaxonal health, with implications for prognosis and personalised therapeutic strategies. Full article

Background: Physical function, muscle strength, and fatigue are often impaired in patients with multiple sclerosis (MS). This study aimed to assess these parameters and their associations. Methods: This cross-sectional study included patients with relapsing-remitting MS. Physical function was assessed using the dynamic gait index (DGI), two-minute walk test (2MWT), and Expanded Disability Status Scale (EDSS). Muscle strength and fatigue were assessed using a load cell (measured in kgf). Generalized linear models (GLMs) with log link and gamma distribution examined the associations between MS and physical function, muscle strength, and fatigue. In the MS group, GLMs explored links between fatigue, muscle strength, and physical function. Results: Forty-seven individuals participated (18 MS; 27 controls). Patients with MS showed reduced physical function and muscle strength, and higher fatigue. Knee extension fatigue was associated with DGI (Exp β = 0.23; p = 0.03), 2MWT (Exp β = 0.11; p = 0.02), and EDSS (Exp β = 17.17; p < 0.0001); knee flexion fatigue was associated with EDSS (Exp β = 2.45; p = 0.006). Knee flexion and extension strength were also associated with EDSS. Conclusions: Patients with MS show reduced physical function and strength, increased fatigue, and knee muscle performance. The associations between strength, fatigue, and functional outcomes varied in magnitude, with knee-related measures, especially knee extension fatigue, showing the most consistent relationships. Full article