Search Results (183)

Background/Objectives: Metabolic dysregulation has emerged as a potential modifier of disease activity and disability in multiple sclerosis (MS). However, the relationship between glycemic status and clinical outcomes in patients with MS remains incompletely understood. This study aimed to investigate the associations of glycemic regulation with disease severity, relapse activity, inflammatory markers, and metabolic characteristics in patients with MS. Methods: In this retrospective single-center observational study, 455 patients with MS aged 18–65 years were included. Patients were categorized into normoglycemia (n = 241), prediabetes (n = 98), and diabetes (n = 116) according to American Diabetes Association criteria and documented diabetes diagnosis. Demographic characteristics, Expanded Disability Status Scale (EDSS) scores, annualized relapse rate (ARR), disease-modifying therapy (DMT), hematological indices, inflammatory markers, and metabolic parameters were retrieved from electronic medical records. Associations between glycemic status and clinical outcomes were evaluated using group comparisons, Spearman correlation analyses, and multivariable linear regression models. Results: Significant differences were observed among glycemic groups for age, disease duration, EDSS score, ARR, MS phenotype, platelet count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipid parameters, estimated glomerular filtration rate, alanine aminotransferase, gamma-glutamyl transferase, triglyceride–glucose (TyG) index, and atherogenic index of plasma (all p < 0.05). HbA1c, FPG, TyG index, lipid parameters, CRP, and ESR were positively correlated with EDSS scores (all p < 0.05). In contrast, these markers showed inverse correlations with ARR. However, after adjustment for demographic and clinical variables, including age, sex, disease duration, MS phenotype, and disease-modifying therapy (DMT), neither prediabetes nor diabetes remained independently associated with disability, as measured by the EDSS score, or with ARR. Progressive MS phenotype, older age, and longer disease duration were independently associated with higher disability, whereas age, disease duration, and progressive phenotype were independently associated with lower ARR. Conclusions: Impaired glycemic status is associated with greater disability, unfavorable metabolic profiles, and increased systemic inflammation in patients with MS. Nevertheless, glycemic status was not independently associated with disability or relapse activity after adjustment for major clinical confounders. These findings suggest that metabolic dysregulation accompanies more severe clinical characteristics but may not independently drive disease progression in MS. Full article

Background and Objectives: Circulating microRNAs (miRNAs) are emerging as accessible biomarkers for multiple sclerosis (MS). In experimental models, miR-221 and miR-222 have been linked to immune and Th17-related pathways, while interleukin-23 (IL-23) is a cytokine driving autoimmune inflammation. This observational study evaluated the expression of circulating miR-221/222 and serum IL-23 concentrations in treatment-naive adult patients with MS. Materials and Methods: This prospective, cross-sectional case–control study included 43 untreated adult patients with MS (36 with relapsing–remitting MS and 7 with primary progressive MS) and 37 healthy controls. Demographic features, Expanded Disability Status Scale (EDSS) scores, magnetic resonance imaging involvement, initial symptoms, serum IL-23 concentration, and miR-221/222 expression were recorded. Total RNA, including small RNAs, was isolated; complementary DNA was synthesized by reverse transcription from RNA templates; and reverse transcription–quantitative real-time PCR (RT-qPCR) was performed using RNU6-2 as the endogenous small RNA reference. Individual ΔΔCt values were specified as the primary inferential scale, while 2^−ΔΔCt fold-change was retained only for descriptive reporting. Results: The relative expression (2^−ΔΔCt) of miR-221 and miR-222 was higher in patients than in controls. Within the patient group, miR-221 and miR-222 relative expression did not differ by age, sex, EDSS, time since MS diagnosis, MRI involvement area, or initial symptoms. No statistically significant difference in IL-23 levels was observed between the patient and control groups. Conclusions: The presence of unaltered IL-23 levels alongside significantly elevated miR-221 and miR-222 expressions in treatment-naive MS patients during the remission phase suggests their potential utility as biomarkers for immune regulation. Given the cross-sectional design of this study, no causal or regulatory relationship between miR-221/222 and IL-23 can be inferred. Full article

Objective: Axonal injury is a key determinant in irreversible disability in multiple sclerosis (MS). Reliable biomarkers of neuroaxonal damage are essential for improving diagnosis, monitoring disease progression, and evaluating treatment response. This study investigated the relationship between phosphorylated neurofilament heavy chain (pNF-H), clinical characteristics, and conventional cerebrospinal fluid (CSF) and serum biomarkers in Algerian patients with MS. Methods: A total of 102 participants were enrolled. Clinical, immunological, and biochemical parameters were assessed, including the Expanded Disability Status Scale (EDSS), oligoclonal bands (OCBs), IgG index, albumin quotient, and pNF-H concentrations in paired CSF and serum samples. Results: OCBs were detected in 85.5% of patients, and 65.21% exhibited intrathecal immunoglobulin synthesis, with a median IgG index of 0.87. Patients with progressive MS were significantly older and more disabled than those with relapsing–remitting MS (age: p = 0.01; EDSS: p = 0.0007). OCB-positive patients had significantly higher IgG index values (p = 0.0004), but OCB status was not associated with age, EDSS, or albumin quotient. EDSS correlated positively with age (p = 0.0007), albumin quotient (p = 0.01), and IgG index (p = 0.001). Both CSF and serum pNF-H levels were significantly elevated in MS patients compared with NSDs group (p < 0.001). Increased pNF-H concentrations were associated with progressive disease and greater disability (EDSS ≥ 5). Conclusions: Elevated pNF-H levels in CSF and serum are associated with disease severity and progressive MS, supporting their potential as complementary biomarkers of neuroaxonal damage and clinical disability in routine MS assessment. Full article

Background: Multiple sclerosis (MS) lacks a single invariant phenotypic core. Patients accumulate heterogeneous combinations of sensory, motor, cognitive, and autonomic impairments over time, reflecting lesions that are disseminated in time and space. Standard scales such as the Expanded Disability Status Scale (EDSS) distribute disability across functional systems, but do not explicitly represent MS phenotype as a mixture of latent symptom modules. Methods: We analyzed 4617 de-identified neurology progress notes from 577 patients with MS at a single academic medical center. A large language model (GPT-5.2) categorized each note with respect to 17 non-mutually-exclusive neurological phenotype features, and note-level features were aggregated to patient-level binary vectors. Non-negative matrix factorization (NMF) was applied to generate three-, four-, and five-module solutions. For each rank, we computed approximate variance captured, relative reconstruction error, and module-level feature loadings. In the preferred four-module solution, we derived patient-level module percentages, identified highly dominant (≥55%) and archetypal (≥70%) module profiles, and quantified admixture using Shannon entropy and the effective number of modules. Results: Three-, four-, and five-module NMF solutions showed similar approximate variance captured (52.7–54.3%) and reconstruction error (0.47–0.53), but the four-module solution provided the clearest clinical interpretation. The four latent modules were sensory-visual-pain, ataxic-spastic-falls, cognitive-psychologic-fatigue, and autonomic-bladder-bowel, aligning closely with established functional systems in MS. Most patients exhibited admixed phenotypes, with module entropies ranging from 0 (single-module dominance) to 1.386 (equal mixture) and effective modules spanning approximately 1 to 4. Using pre-specified thresholds, 154 patients (26.6%) were highly dominant in a single module and 72 (12.5%) were archetypal; these purer phenotypes were most often in the sensory-visual-pain module. Conclusions: MS phenotypic diversity in routine clinical practice can be parsimoniously represented as mixtures of four latent symptom modules rather than as positions along a single severity axis. Most patients show substantial admixture of sensory, motor, cognitive, and autonomic involvement, but a minority exhibit relatively pure or strongly dominant module patterns. This modular representation provides an interpretable framework for quantifying MS phenotype and for generating testable hypotheses about MS subtypes whose biological relevance remains to be established. Full article

Background/Objectives: Visual evoked potential (VEP) P100 maximum latency is known to predict fatigue and cognition in multiple sclerosis (MS). However, the relationship between VEP and neurological (impairment)/neuropsychological status is not well understood in MS. Therefore, the aim of the present prospective cross-sectional study was to investigate associations among VEP, neurological impairment, and neuropsychological status in MS. Methods: The study included 25 subjects with primary progressive MS (PPMS), with a median EDSS score of 4.5, and 30 control subjects. Neurological status of PPMS subjects was evaluated with the Expanded Disability Status Scale (EDSS), while neuropsychological assessment included the Symbol Digit Modalities Test (SDMT), Nine-Hole Peg Test (9HPT), Fatigue Severity Scale (FSS), Depression, Anxiety and Stress Scale (DASS-21), and Multiple Sclerosis Impact Scale (MSIS-29). Statistical analysis included group comparisons, Spearman correlations, multivariable linear regression analyses, bidirectional stepwise selection, and a parsimonious multivariable model. Results: PPMS subjects had significantly prolonged P100 maximum latencies (p < 0.01) compared to control subjects, as well as significantly poorer performance on the 9HPT (p < 0.01) and higher fatigue scores (FSS; p < 0.01). In multivariable analyses within the PPMS group, disease duration was independently associated with the EDSS (p = 0.009), whereas neuropsychological measures were intercorrelated (ρ > 0.45) and associated with the EDSS at intermediate stages of model selection. P100 maximum latency showed a positive but non-significant association after adjustment for sex and disease duration in the parsimonious model, which explained approximately 49% of the variance in the EDSS. Conclusions: The findings provide insight into the complex interplay among neurophysiological (VEP), neuropsychological and neurological status in MS. Full article

Background and Objectives: Non-invasive biomarkers reflecting neurodegeneration are increasingly important in multiple sclerosis (MS). Optical coherence tomography (OCT) provides quantitative measures of retinal structure, most commonly peripapillary retinal nerve fiber layer (pRNFL) thickness. However, the potential clinical relevance of optic nerve head morphology, including cup-to-disc ratio (CDR), remains insufficiently explored. We investigated associations between OCT-derived parameters, subjective visual vertical (SVV), and disability in MS. Materials and Methods: In this retrospective study, 100 patients with MS were included. OCT parameters (pRNFL thickness and area-based CDR) were analyzed at baseline and follow-up. Clinical disability was assessed using the Expanded Disability Status Scale (EDSS). Detailed optic neuritis history was not consistently available in the retrospective clinical records and therefore could not be systematically accounted for in the analyses. SVV was evaluated in 37 patients using a virtual reality–based protocol. Associations were assessed using Spearman correlation and linear regression analyses. Multivariable regression models were adjusted for age, sex, and follow-up duration. Results: pRNFL thickness was not associated with baseline EDSS (rho = −0.06, p = 0.55) or annualized EDSS change. Baseline CDR correlated with both baseline EDSS (rho = 0.30, p = 0.0065) and follow-up EDSS (rho = 0.46, p < 0.0001). In univariable regression analysis, baseline CDR was associated with follow-up EDSS (B = 3.33, R² = 0.23, p < 0.0001), remaining significant after adjustment for age, sex, and follow-up duration (B = 2.59, 95% CI 1.26–3.92, p = 0.0002). No significant associations were observed between OCT parameters and SVV measures. Conclusions: Higher CDR values, but not pRNFL thickness, were associated with disability measures in this exploratory MS cohort. However, these findings should be interpreted cautiously because optic neuritis history could not be systematically accounted for and physiological optic disc variability may substantially influence CDR measurements. Full article

Background/Objectives: Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease affecting 2.9 million worldwide. Current immunosuppressive treatments offer limited neuroprotection and often cause adverse effects. Polyphenols with antioxidant and anti-inflammatory properties have been investigated as adjuncts in MS. Methods: On 19 June 2025, Embase, Medline, and ClinicalTrials.gov were systematically searched. Eligible clinical trials assessing polyphenol supplementation in MS were included. Outcomes of interest were Expanded Disability Status Scale (EDSS), annualised relapse rate (ARR), magnetic resonance imaging (MRI) changes, safety, and tolerability. Risk of bias was evaluated using the Cochrane tool, and certainty of evidence was appraised with Grading of Recommendations Assessment, Development, and Evaluation (GRADE). The protocol was registered with PROSPERO (CRD420251052042). Results: Of 870 records identified, 13 trials (n = 785) met inclusion. Nanocurcumin consistently improved EDSS in relapsing–remitting MS (3 trials, n = 150; p = 0.039–0.041), while epigallocatechin-3-gallate, silymarin (SM), cranberry extract, and bio-enhanced curcumin extract (BCM-95) curcumin showed no significant impact on disability, relapse rates, or MRI outcomes. Intervention adverse events were generally mild. SM showed potential hepatoprotective effects. Risk of bias was determined as low risk for seven of the trials and of some concern for five of the studies. Most often raising concerns because of selective reporting. Certainty of evidence, assessed using GRADE, was generally moderate, indicating some uncertainty regarding the outcomes. Meta-analysis was not possible due to the heterogeneity of included studies. Conclusions: Nanocurcumin may contribute to improvements in disability outcomes in Relapse Remitting Multiple Sclerosis (RRMS), whereas other polyphenols lack consistent efficacy. However, the evidence base remains limited by small sample sizes and methodological concerns. Larger, multicentre randomised controlled trials are required to establish optimal dosing, long-term safety, and therapeutic potential. Full article

Background/Objectives: Relapsing-remitting multiple sclerosis (RRMS) is frequently associated with anxiety and depressive symptoms, which significantly impact quality of life and clinical outcomes. The Hospital Anxiety and Depression Scale (HADS) is widely used to screen for psychological distress in medical populations. To perform a preliminary psychometric evaluation of the Romanian version of HADS in patients with RRMS, focusing on internal consistency and construct-related associations. Methods: This cross-sectional study included 60 RRMS patients. Internal consistency was assessed using Cronbach’s alpha and corrected item–total correlations. Construct-related evidence was explored through correlations with Expanded Disability Status Scale (EDSS) scores and disease duration, as well as known-groups comparisons based on disability level. Results: HADS demonstrated acceptable internal consistency (HADS-A α = 0.834; HADS-D α = 0.767). Depressive symptoms showed a moderate association with neurological disability (ρ = 0.456, p < 0.001), whereas no significant association was observed between anxiety symptoms and EDSS. Patients with higher disability had significantly higher HADS-D scores (p = 0.001), while HADS-A scores did not differ between groups. Conclusions: The Romanian version of HADS provides preliminary evidence of acceptable internal consistency and construct-related validity in RRMS. These findings support its potential use as a screening tool for psychological distress while highlighting the need for larger studies including factor analysis and test–retest reliability. Full article

Background and Objectives: Ocrelizumab significantly reduces inflammatory activity in relapsing-remitting multiple sclerosis (RRMS), but treatment-induced brain volume change and the specific contributions of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) compartments to global atrophy and pseudoatrophy remain unclear. We aim to characterize the longitudinal and infusion-related dynamics of brain compartments in ocrelizumab-treated RRMS patients and identify the clinical and time-dependent predictors of these changes. Methods: Fifty-one RRMS patients were enrolled in a four-year prospective study. Brain volumes, including WM, GM, peripheral GM (pGRAY), CSF, ventricular CSF (vCSF), total brain volume (TBV) and their respective fractions (WMF, GMF, BPF) were evaluated by absolute time points (baseline to 4 years) and infusion-based intervals (baseline to 8th infusion), before and after each ocrelizumab cycle. Correlations between brain volume measures and the Expanded Disability Status Scale (EDSS), as well as time-dependent variables such as age, age at onset and disease duration (DD) were examined. Results: Mean age was 41.62 ± 9.76 years, mean age at onset 28.17 ± 7.85, mean DD 12.89 ± 8.55 years and mean EDSS 3.26 ± 1.5, indicating moderate disability. During the study, vCSF and CSF significantly increased, whereas WM, WMF, TBV and BPF significantly decreased. Notably, these measures exhibited marked, non-linear, and transient changes during the first year of ocrelizumab treatment, consistent with pseudoatrophy, likely reflecting early resolution of inflammation rather than irreversible tissue loss. GM and pGRAY remained relatively stable, with minor early increases. Correlation analyses revealed that higher EDSS scores, older age, later age at onset and longer DD were associated with lower GM, pGRAY and TBV, emphasizing the interplay between disease progression and development of brain volumetric patterns. Conclusions: Ocrelizumab-induced pseudoatrophy is predominantly WM-driven and age-dependent, with WM shrinkage being the main contributor to parenchymal loss and secondary widening of CSF spaces. Age remains a powerful predictor of brain atrophy and neurological impairment. These findings provide mechanistic insights into the biological basis of this modulation in RRMS. Full article

Multiple Sclerosis (MS) is a neuroinflammatory disorder in which genetic and environmental factors contribute to disease onset. Evidence implicates the inflammasome pathway in MS pathophysiology. However, the interaction between inflammasome-related genetic variants and 25-OH-vitamin D₃ (25(OH)D₃) levels remains unclear. 105 MS patients and 109 healthy controls were enrolled. Genotyping of NLRP3 (rs10754558, rs3806265) and NLRC4 (rs479333) polymorphisms was performed using real-time PCR. Serum 25(OH)D₃ levels were measured by high-performance liquid chromatography. Clinical severity was assessed using the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Score (MSSS), annualized relapse rate (ARR), and age at onset. MS patients showed significantly lower serum 25(OH)D₃ levels than controls. Genotype distributions did not differ significantly under an additive model; however, the NLRP3 rs10754558 GG genotype was more frequent in MS patients under a recessive model and was significantly associated with disease status after adjustment for sex. Subjects carrying the GG genotype also had significantly lower serum 25(OH)D₃ levels than CC/CG carriers, independently of sex. No significant associations were observed for NLRP3 rs3806265 or NLRC4 rs479333, and none of the investigated variants was associated with EDSS, MSSS, ARR, or age at onset. The NLRP3 rs10754558 polymorphism may be associated with MS susceptibility and reduced circulating vitamin D levels, suggesting a potential link between inflammasome-related genetic variability and immunometabolic regulation in MS. 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 and Objectives: Multiple sclerosis (MS) is characterized by progressive disability and a spectrum of motor and cognitive impairments. Exergames and virtual reality (VR) are proposed as motivating exercise tools, potentially useful for improving adherence and expanding access to rehabilitation. The objectives are to explore the feasibility and safety of a supervised rehabilitation program based on a high-intensity exercise program with immersive virtual reality (IVR) in people with MS and to describe its effects on physical, cognitive, and functional domains, as well as on the serum biomarker neurofilament light chain (sNfL). Materials and Methods: Pre–post exploratory study in five volunteers from a local MS Association [Vigo, Spain]. Intervention: 8 weeks, two sessions/week, 10 min/session of an IVR boxing-based exergame combined with usual rehabilitation, supervised by a physiotherapist. The variables studied were safety (Simulator Sickness Questionnaire [SSQ]), usability (System Usability Scale [SUS]), disability (Expanded Disability Status Scale [EDSS]), gait (25-Foot Walk Test [25FWT]), manual dexterity (9 Hole Peg Test [9HPT]), cognition (Symbol Digit Modalities Test [SDMT]), and axonal damage biomarker (sNfL). Results: The intervention could be feasible and safe (100% adherence, no adverse events (without SSQ symptoms), 95% usability [SUS]). There were positive changes in all variables studied (mean ± SD): EDSS −0.5 ± 0.9; 25FWT −4.9 ± 9.8 s; right 9HPT −3.3 ± 0.9 s; sNfL −4.4 ± 4.5 pg/mL, except for left 9HPT +0.5 ± 5.0 s and cognition (SDMT −2.4 ± 1.3 points). Conclusions: A brief, supervised exercise program combing an IVR exergame with standard rehabilitation was feasible and safe in people with MS. Although the results seem promising with the proposed design, the clinical and biological changes are merely exploratory, and it is not possible to infer their efficacy. Our findings open the door to future controlled studies including perceived high-intensity exercise programs and larger sample sizes to explore efficacy and estimate clinically relevant effect sizes. Full article

Background and Objectives: The goal of this study was to evaluate the associations between peripapillary retinal nerve fibre layer (pRNFL) thickness, disability-related clinical measures, including the Expanded Disability Status Scale (EDSS), and report-based magnetic resonance imaging (MRI) findings in patients with multiple sclerosis (MS), and to explore potential longitudinal relationships between pRNFL changes and disability progression. Materials and Methods: A retrospective single-centre study was conducted in patients with MS diagnosed according to the 2010/2017 McDonald criteria at the Neurology Clinic of the Hospital of Lithuanian University of Health Sciences Kauno Klinikos. The study included 84 patients. pRNFL thickness was measured using optical coherence tomography (OCT) at baseline (defined as the time of diagnosis) and, for some patients, follow-up. Associations between pRNFL measures and clinical as well as MRI-derived variables were assessed using Spearman correlation and multivariable linear and ordinal regression analyses. Results: In cross-sectional analyses, lower baseline pRNFL thickness was associated with higher baseline disability (ρ = −0.257, p = 0.019) and greater worsening of EDSS over time (ρ = −0.268, p = 0.013). Significant associations were also observed between thinner pRNFL and pyramidal system impairment and bowel/bladder dysfunction. In adjusted linear regression models, each 20 µm reduction in pRNFL was associated with a 0.46-point increase in EDSS (B = −0.023, SE = 0.009) and a 0.32-point rise in cerebellar functional system score (B = −0.016, SE = 0.006). Among the 45 patients with repeat OCT, exploratory longitudinal pRNFL thinning showed directional trends toward increasing disability; however, these associations were not consistently significant after adjustment. Baseline pRNFL thickness showed a modest association with a composite MRI regional lesion score derived from report-based binary variables. Conclusions: In this real-world retrospective cohort, thinner pRNFL was associated with greater disability in cross-sectional analyses. Associations with individual MRI regions and radiological activity were limited and inconsistent. These findings should be interpreted as preliminary and hypothesis-generating. Further prospective studies are needed to clarify the potential role of OCT-derived pRNFL measurements. Full article

Background and Objectives: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that progressively leads to brain atrophy and the accumulation of disability over time. In this study, we used FreeSurfer to compare subcortical volumes and cortical surface areas between patients with MS and healthy controls and to investigate how regional atrophy relates to both disease lasting and clinical disability. Materials and Methods: We included 80 participants in this study, 40 patients with clinically definite MS and 40 age- and sex-matched healthy controls, all imaged on a Philips Ingenia 3.0T MRI scanner. High-resolution 3D T1-weighted MPRAGE sequences of the brain were processed using FreeSurfer 7.3.3. MS patients were stratified by disease lasting into two subgroups: ≤5 years (n = 17) and >5 years (n = 23). Subcortical volumes were normalised to estimated total intracranial volume (eTIV). Between-group differences were assessed using Welch’s t-test with Benjamini–Hochberg false discovery rate (FDR) correction. Multiple linear regression models controlled for age, sex, and the Expanded Disability Status Scale (EDSS). Results: We found statistically significant volume reductions in 48 of the 52 normalised regions examined. Thalamic volume showed the most severe reduction (mean—21.6% bilaterally) in MS patients. The corpus callosum, hippocampus, and amygdala were also prominently affected. Receiver operating characteristic (ROC) analysis of mean bilateral thalamic volume yielded an area under the curve (AUC) of 0.822 (95% CI: 0.731–0.913). Cortical surface area did not survive FDR correction in the primary comparison, though nominal reductions emerged in longer-lasting MS patients. EDSS correlated with both thalamic and hippocampal volumes in regression models. Conclusions: FreeSurfer-based volumetric analysis detected widespread grey and white matter volume differences in MS patients relative to matched controls, with changes already present in patients within the first five years of diagnosis. The high proportion of significant regions is consistent with a combined pattern of generalised and regionally accentuated atrophy. Among the regions examined, thalamic volume showed the strongest cross-sectional discrimination (AUC = 0.822; sensitivity 65%, specificity 90%) and the most consistent associations with EDSS; these findings support further evaluation of thalamic volume as a candidate imaging biomarker of neurodegeneration, although its diagnostic performance is moderate and requires external longitudinal validation before clinical deployment. 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