Search Results (457)

Glatiramer acetate (GA) is a first-line disease-modifying therapy for multiple sclerosis (MS) with well-established moderate efficacy and high safety, yet its mechanisms of action remain incompletely understood. DNA methylation plays a significant role in MS development and is modulated by various environmental factors, including therapeutic drugs. In this pilot study, we report the first prospective analysis of genome-wide DNA methylation changes in peripheral blood mononuclear cells (PBMCs) from four female relapsing-remitting MS patients before GA initiation and after approximately four and eight months of therapy. We identified 365 loci that are characterized by differential methylation, distinguishing post-treatment time points from baseline, with significant enrichment in CpG islands, shores, and promoter regions. Two distinct temporal patterns emerged: (1) non-monotonic DNA methylation changes peaking at four months and associated with response to foreign antigenic stimuli, and monotonic changes progressively increasing by eight months and related to mTOR-associated pathways relevant to chronic inflammation and neurodegeneration. Integration of DNA methylation and transcriptomic data revealed significant methylation-expression correlations for eight genes, including HLA-DMA, PDE4A, and SMOX—genes with established roles in MS-associated antigen presentation, immunoregulation, and neuroinflammation. Cell composition of PBMCs remained stable throughout treatment. In general, GA therapy for MS appears to induce dynamic, locus-specific DNA methylation changes in PBMCs, with distinct temporal patterns suggesting a biphasic response of the immune system. However, given that none of the individual DMPs reached genome-wide significance, the results presented in this pilot study strongly require validation in larger independent cohorts. Nevertheless, we believe that our findings provide insights into the immunomodulatory effects of GA and lay the foundation for future hypothesis-driven studies to develop epigenetic biomarkers for therapeutic monitoring and generic GA product assessment. Full article

Background/Objectives: Multiple sclerosis (MS) remains challenging to diagnose due to clinical and radiological overlap with mimicking conditions. The 2024 revisions of the McDonald criteria have incorporated the central vein sign (CVS) and paramagnetic rim lesions (PRLs) as magnetic resonance imaging (MRI) biomarkers to improve diagnostic specificity. This study assessed the prevalence and anatomical distribution of CVS and PRLs in patients with relapsing–remitting MS (RRMS). Methods: This cross-sectional study included 91 patients with RRMS diagnosed according to the 2017 McDonald criteria. MRI scans were obtained using 3T scanners, and T2-FLAIR and susceptibility-weighted angiography (SWAN) sequences were analyzed. CVS and PRLs were identified using established criteria. Patients were stratified by lesion count (<5, 5–9, ≥10), and lesions were categorized by anatomical location. Descriptive statistics, chi-square tests, and multivariable logistic regression adjusted for covariates were performed. Results: CVS was present in 69.2% of patients, while PRLs were identified in 29.7%. Both markers were more frequent in patients with higher lesion burden in univariate analysis. CVS prevalence increased significantly with lesion count (p < 0.001) and remained an independent predictor in multivariable logistic regression. PRL presence was associated with lesion count in univariate analysis but not after adjustment. Most CVS- and PRL-positive lesions were supratentorial and predominantly periventricular. No significant association was observed between CVS and PRL presence. Conclusions: CVS is a highly prevalent MRI feature in RRMS and independently associated with lesion burden, supporting its role as a diagnostically relevant imaging marker. PRLs were less prevalent and showed weaker independent associations. Full article

The transition from relapsing–remitting multiple sclerosis (RRMS) to secondary-progressive multiple sclerosis (SPMS) represents an ambiguous transition period characterized by diagnostic delays and a shifting therapeutic window. While inflammatory relapses are well-managed, the underlying neurodegeneration often remains undetected until substantial disability has accrued. This review evaluated the shift from traditional metrics, such as the Expanded Disability Status Scale (EDSS), toward more sensitive, multimodal monitoring strategies. We described characteristic MRI findings in SPMS and addressed the impact of comorbidities that frequently confound the diagnosis of disease transition. Furthermore, we evaluated the predictive potential of emerging fluid biomarkers and gut microbial signatures in identifying the early RRMS-to-SPMS transition. Finally, we described the current therapeutic landscape and emerging immunomodulatory interventions. Diagnosing SPMS remains a clinical challenge due to comorbidities and the lack of a singular definitive marker. Moving toward high-sensitivity imaging and molecular biomarkers is essential for the early initiation of treatments and improved patient outcomes. Full article

Background/Objectives: SARS-CoV-2 infection may exacerbate neuroinflammation in patients with multiple sclerosis (MS) and thus accelerate MS progression. Previous studies have reported an increased risk of disability and lesion burden among those infected with SARS-CoV-2 while others reported no differences compared to COVID− controls. We aimed to determine whether COVID-19 is associated with accelerated radiological progression of MS. Methods: This single-center, retrospective longitudinal study included patients with pre-existing relapsing-remitting MS. We identified 34 SARS-CoV-2–positive MS patients (COVID+) who had at least one brain MRI prior to, and one after, their first positive PCR test. These patients were matched 2:1 by index date to 67 SARS-CoV-2–negative MS patients (COVID−). Baseline demographics and comorbidities were comparable between groups. Two radiologists independently scored pre- and post-index MRIs for new or enlarging T2 lesions, T1 gadolinium-enhancing lesions, and parenchymal brain volume loss. Logistic regression analyses evaluated group differences, adjusting for demographic and clinical covariates. Results: Across an average imaging interval of approximately two years, no significant differences were observed between COVID+ and COVID− patients in new lesions (8.8% vs. 9.0%), enlarging lesions (2.9% vs. 6.0%), T1-enhancing lesions (5.9% vs. 1.5%), or brain volume loss (35.3% vs. 47.8%; all p > 0.05). Conclusions: There was no detectable association between SARS-CoV-2 infection and accelerated radiological progression in patients with MS over an average two-year follow-up. Longer-term investigations are warranted to clarify whether certain subgroups or more severe COVID-19 cases might be at heightened risk. Full article

Background/Objectives: Uric acid (UA), a major circulating antioxidant, has been consistently reported at lower levels in multiple sclerosis (MS) patients, yet long-term UA trajectories stratified by disease-modifying therapy (DMT) efficacy remain unexplored. This study aimed to evaluate the 5-year longitudinal evolution of serum UA levels in relapsing-remitting MS (RRMS), comparing high-efficacy (HE-DMT) and moderate-efficacy (ME-DMT) treatment groups. Methods: This retrospective longitudinal cohort study included adult RRMS patients who initiated or switched DMTs between January 2020 and June 2025. Serum UA was measured at treatment initiation (T0) and annually for up to 5 years (T1–T5). Linear mixed-effects models adjusted for sex, age, and EDSS were used to examine longitudinal UA trajectories. Results: A total of 222 patients were included and followed for up to 5 years across HE-DMT and ME-DMT treatment groups. Groups were comparable at baseline regarding serum UA levels despite significant differences in age, EDSS, and therapy status. Linear mixed-effects modeling demonstrated that serum UA levels changed significantly over time (F(5, 307.04) = 11.03, p < 0.01), with a significant main effect of treatment type (F(1, 378.31) = 5.25, p = 0.02) and a significant time × treatment interaction (F(5, 307.05) = 2.42, p = 0.04), indicating that UA trajectories differed between groups across the follow-up period. In the HE-DMT group, UA levels increased progressively from 4.27 mg/dL at baseline to 5.58 mg/dL at year 4, whereas the ME-DMT group showed an initial decline at year 1 followed by a more gradual increase from 4.19 mg/dL to 5.04 mg/dL at year 4. Sex was a significant independent predictor of UA levels (p < 0.01), whereas age and EDSS were not. Conclusions: HE-DMTs were associated with an earlier and more pronounced increase in serum UA levels over 5 years compared with ME-DMTs, with distinct trajectories depending on treatment efficacy. These findings suggest that longitudinal UA assessment may serve as a complementary exploratory indicator of the metabolic context associated with DMT efficacy. Full article

Multiple sclerosis (MS) is a chronic, progressive, inflammatory neurodegenerative disease. Oxidative stress and ferroptosis are implicated in MS pathology, contributing to both inflammation and neurodegeneration. Potentially functional variants in genes related to antioxidant defense and ferroptosis were chosen through an extensive selection process to investigate their possible association with the progressive form of MS. The study included 845 MS patients (604 relapsing–remitting (RRMS) and 241 progressive (PMS)). The selected gene variants—GCLC rs572496, GCLM rs2273406, GPX4 rs713041, NQO1 rs1800566 and CAT rs2420388—were genotyped using TaqMan^® technology. mRNA expression levels of the corresponding genes in PBMCs were previously determined by targeted RNA sequencing. Circulatory molecular indicators of antioxidant defense and ferroptosis were quantified using ELISA and colorimetric enzymatic recycling assays. The findings indicate that the GCLC rs572496 variant was significantly associated with MS disease severity and had a significant effect on GCLC mRNA levels. Additionally, the NQO1 rs1800566 variant had a significant effect on NQO1 mRNA expression in PBMCs of MS patients overall. The results suggest further analysis of antioxidant defense and ferroptosis-related gene variants with MS severity and validation of the gained results in larger study groups. Full article

The conventional classification of multiple sclerosis (MS) into relapsing–remitting, secondary progressive, and primary progressive phenotypes has long guided diagnosis, prognosis, and therapeutic decision-making. However, accumulating evidence indicates that disability accumulation frequently occurs independently of clinical relapses, challenging relapse-centric and phenotype-based models of disease evolution. The concept of progression independent of relapse activity (PIRA) has emerged as a clinically relevant framework capturing this phenomenon across MS phenotypes. In this state-of-the-art narrative review, we propose a spectrum-based reinterpretation of MS, integrating PIRA with concepts of smouldering-associated worsening and neurologic reserve. We highlight the heterogeneity of relapse-independent worsening, distinguishing transient from persistent PIRA, and discuss how ageing-related decline in compensatory capacity contributes to the clinical unmasking of progression over time. Within this framework, secondary progressive MS is redefined as the clinically recognizable accumulation of persistent relapse-independent worsening, while primary progressive MS is conceptualized as early predominance of clinically manifest progression due to limited reserve rather than a distinct disease entity. Finally, we examine diagnostic and therapeutic implications of a spectrum-based model in the contemporary era, emphasizing the limitations of relapse-centric treatment strategies and unmet needs in addressing progression-related biology. By reframing MS as a dynamic continuum shaped by the interaction between ongoing pathology and evolving neurologic reserve, this review aims to support earlier recognition of clinically meaningful progression and to inform more biology-aware approaches to disease monitoring and therapy. Full article

Background/Objectives: Cytokine-mediated immune dysregulation contributes to the heterogeneity of multiple sclerosis (MS). Interleukin-18 (IL-18) and interleukin-8 (IL-8) are involved in distinct inflammatory pathways; however, their genetic contributions to disease susceptibility and radiological activity remain incompletely defined. Methods: In this study, 98 relapsing–remitting MS (RRMS) patients and 98 healthy controls were genotyped for IL-18 and IL-8 variations using PCR-based methods. Clinical data and MRI findings were analyzed in the MS cohort. Associations with disease susceptibility, clinical severity (EDSS), and MRI activity were evaluated using regression analyses. Results: IL-18 (−137 G/C) and IL-8 variations were significantly associated with MS susceptibility. The G allele of IL-18 (−137), the T allele of IL-8 (−251), and the C allele of IL-8 (+781) were more frequent in MS patients. No significant associations were observed between cytokine variations and clinical severity measures. However, IL-18 (−137) variation was significantly associated with higher baseline MRI lesion burden, with C allele carriers showing increased lesion counts. In addition, IL-8 (−251 AA genotype) was independently associated with increased annual lesion development. These findings were confirmed in multivariable regression analyses. Conclusions: IL-18 and IL-8 gene variations contribute to MS through distinct but complementary mechanisms. IL-18 appears to be primarily involved in disease susceptibility and baseline inflammatory burden, whereas IL-8 is more closely associated with ongoing radiological activity. These results highlight the importance of integrating genetic and imaging biomarkers to better understand disease heterogeneity in MS. Full article

Background/Objectives: Multiple sclerosis (MS) is a chronic, demyelinating and neurodegenerative disease frequently associated with dysphagia, nutritional imbalances, and alterations in body composition. This study aims to describe the anthropometric profile and body composition in people with MS, estimate the risk and type of dysphagia, analyse dietary intake and habits, and evaluate the evolution of these parameters over six months. Methods: This descriptive analytical longitudinal study included 30 patients with MS (20 women, 10 men), with a median age of 53.3 years at baseline and 54.0 years at final assessment. The prevalence of dysphagia risk was determined, dietary patterns and body composition were characterised, and their interactions were explored through two assessments conducted six months apart. Results: Overall, 90% of the sample had relapsing–remitting MS (RRMS). At both the initial and final assessments, the median BMI was above 25 kg/m² and a high prevalence of dysphagia risk (63.3% and 76.7%), particularly for liquids. Frequent inadequacies were observed in the intake of certain macronutrients and micronutrients, including energy, fibre, potassium and magnesium. Likewise, the analysis by food groups revealed low adherence to recommendations, particularly for fruits, cereals, legumes, fish and lean meats. No significant differences were detected between the two time points. Conclusions: Dysphagia, dietary intake, habits, and body composition are interconnected dimensions in MS; systematically integrating nutritional assessment and dysphagia screening into clinical practice would contribute to a more comprehensive management and to improvements in swallowing disorders and nutritional status in people with MS. Full article

Background and Objectives: Visual evoked potentials (VEPs) are a simple, noninvasive method for detecting subclinical visual pathway involvement in multiple sclerosis. This study investigated the frequency of VEP abnormalities and their associations with baseline clinical, radiological, and cerebrospinal fluid (CSF) features in treatment-naïve patients with clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) without prior optic neuritis. Materials and Methods: We retrospectively reviewed newly diagnosed, treatment-naïve CIS/early RRMS patients evaluated between January 2022 and July 2024 who underwent CSF analysis. Pattern-reversal VEPs were recorded under standardized conditions. VEP abnormalities were analyzed as any or bilateral, and associations were assessed using group comparisons and multivariable logistic regression. Results: In 101 patients (mean age 31.8 ± 9.7 years; 72% female; median EDSS 1.0), latency prolongation occurred in 69 (42 any,27 bilateral) and amplitude reduction in 33 (22 any, 11 bilateral). Among patients with latency prolongation, both the number of OCB bands and the IgG index were higher (bilateral p = 0.032; any p = 0.007). In multivariable analysis, male sex (p = 0.032) and pyramidal/brainstem-onset presentation (p = 0.006) were independently associated with any amplitude reduction; neither was associated with latency abnormalities. Conclusions: VEP abnormalities are common early in the disease, even without a history of optic neuritis. Male sex and pyramidal/brainstem-onset presentation were associated with reduced amplitude, suggesting that amplitude decrease may reflect early tissue dysfunction and may be related to adverse baseline clinical features. Associations between intrathecal immune activation and prolonged latency may indicate subclinical demyelination of the visual pathways related to inflammatory activity. Larger longitudinal studies are needed to clarify the clinical significance of VEP abnormalities in early RRMS. 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

Background: Serum neurofilament light chain (sNfL) is an established biomarker of neuroaxonal damage in multiple sclerosis (MS). Despite its prognostic utility, patient awareness of its clinical application remains poorly characterized. The objective of this study was to assess the acceptance of sNfL monitoring among patients with early-stage relapsing–remitting MS (RRMS) and identify factors predicting their willingness to adopt this tool. Methods: This non-interventional, cross-sectional study was conducted across 16 neuroimmunology clinics. We included RRMS patients with a disease duration of ≤3 years receiving disease-modifying therapy. Acceptance was assessed following a standardized educational tutorial. Multivariable logistic regression was employed to identify predictors of patient acceptance. Results: The study included 144 patients (mean age 37.6 [SD 10.3] years, 69.4% female). Only 19.4% (n = 28) had prior awareness of sNfL. However, after the tutorial, 84.0% (n = 121) expressed willingness to adopt sNfL testing. Furthermore, 62.5% (n = 90) indicated that normal sNfL levels would provide emotional reassurance between clinical visits. Patients willing to undergo testing showed higher disease knowledge, less treatment regret, and better physical quality of life and cognitive performance. In the multivariable analysis, higher disease knowledge (OR = 1.52, 95%CI 1.16–1.99; p = 0.002) and lower symptom burden (OR = 0.96, 95%CI 0.93–0.99; p = 0.038) were associated with greater acceptance. Conclusions: Patients demonstrate high receptivity to sNfL monitoring when provided with adequate clinical context. Because disease knowledge is a primary driver of acceptance, personalized educational initiatives may be a complementary strategy to facilitate the integration of precision biomarkers into MS management. 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/Objectives: Multiple Sclerosis (MS) is a chronic immune-mediated disorder characterized by neuroinflammation and neurodegeneration. Increasing evidence implies the kynurenine pathway (KP) in the MS pathophysiology; however, data from Mexican populations are lacking. This exploratory study aimed to characterize central and circulating KP metabolites in Mexican patients with MS and to investigate potential genetic variants in KP-related genes. Methods: Serum concentrations of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK), as well as cerebrospinal fluid (CSF) levels of KYNA, quinolinic acid (QUIN), interleukin-4 (IL-4), and interleukin-6 (IL-6), were determined in treatment-naïve relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and treated PMS patients. Serum levels were compared with those of healthy controls, and CSF findings contrasted with those of non-MS neurological patients and individuals with neurocysticercosis (NCC). Public whole-exome datasets were analyzed for variants in KP-related genes, and target exome sequencing was performed in three Mexican patients with MS. Results: Serum concentrations of KYNA and 3-HK were decreased in MS patients compared with healthy controls. CSF KYNA and QUIN levels did not differ significantly among MS subtypes or the non-MS neurological group, but they were lower than those observed in NCC. IL-4 and IL-6 were detectable in MS CSF samples, supporting the presence of intrathecal inflammation. Genetic and bioinformatic analyses identified variants in genes encoding KP enzymes in both public MS datasets and in Mexican patients with MS. Conclusions: These findings indicate an altered KP metabolism in Mexican MS patients, particularly during the relapse phase, and suggest a possible contribution of genetic variability. Further large-scale studies are needed to confirm these observations and to determine the functional implications of KP-related genetic variants in MS. 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