People with multiple sclerosis (PwMS) have an elevated risk of macrovascular disease that may be underestimated by vascular risk calculators (VRCs) validated in the general population. This study evaluated, recalibrated and externally validated five commonly used VRCs for PwMS using population-based data from England, 1987-2023. PwMS and matched controls were identified from Clinical Practice and Research Datalink (CPRD) GOLD (calibration) and CPRD Aurum (validation). Exposure variables included multiple sclerosis (MS) status and risk factors as defined in Atherosclerotic Cardiovascular Disease, Framingham Risk Score (FRS), FRS-BMI (body mass index), QRESEARCH risk estimator version 3 score and Systematic Coronary Risk Evaluation version 2 score (SCORE2). Model performance was assessed using Somers' D statistic, area under the receiver operating characteristic (ROC) curve and Hosmer-Lemeshow chi-square test. VRCs with ROC < 0.70 in PwMS were recalibrated using Cox regression, incorporating MS status. Ten-fold cross-validation was used to estimate Somers' D. Calibration: 9411 PwMS and 57,805 controls; validation: 45,934 PwMS and 278,452 controls. Discrimination declined with standard thresholds (e.g. SCORE2 sensitivity in PwMS, 30.0%). Only FRS-BMI retained all significant predictors and was successfully recalibrated, improving discrimination (Somers' D = 0.815 vs. 0.792; Δ = 0.023) and showing good calibration. External validation showed modest gain (Somers' D = 0.716; Δ = 0.003). These findings underscore the limitations of general-population VRCs in PwMS and support the development of MS-specific vascular risk models.
Little is known about the prodrome in pediatric-onset multiple sclerosis (POMS), especially potential age and sex differences. To compare annual hospitalization and physician visit rates overall, and for physician visits, examine sex- and age-group (<12, 12-15, 16 to <18 years) differences, up to 18 years pre-first demyelinating event (pre-index) in 451 POMS and 1420 matched non-multiple sclerosis (MS) individuals. Using Ontario administrative data (1991-2020), we estimated rate ratios (RRs) by visit-related diagnosis, sex, and age using over-dispersed-Poisson models. The POMS cohort showed elevated rates by year 1 pre-index ("year -1"), for ill-defined, other-health-contact, mental-, and respiratory-related hospitalizations (RRs ⩾ 3.6). Elevated physician visits began at year -14 for respiratory (RRs ⩾ 1.3), year -13 for endocrine (RRs ⩾ 2.4) and injury-related (RRs ⩾ 1.2), year -12 for ill-defined (RRs ⩾ 1.3), and year -11 for nervous system (RRs ⩾ 4.0) and mental-related (RRs ⩾ 2.0). Nervous system visits showed the largest sex-gap; males with (vs without) MS had elevated RRs from year -12 and females from year -6; both peaked the year pre-index (males: RR = 47.2; 95% confidence interval (CI): 17.3-128.3; females: RR = 17.0; 95% CI: 8.9-32.3). Among 12- to 15-year-olds, elevated rates were sustained for respiratory-related (from year -12, except year -5), injury-related, and ill-defined (from year -13); (all RR ⩾ 1.3), while findings were more sporadic in the other age groups. Findings suggest prolonged, organ-specific healthcare use pre-POMS, with some sex- and age-related differences indicating pre-onset disease heterogeneity.
Epstein-Barr virus (EBV) is a key environmental risk factor for multiple sclerosis (MS), and tonsils and adenoids serve as a primary viral reservoir. This study investigates the potential role of adenotonsillectomy in pediatric-onset multiple sclerosis (POMS) risk and relapse rate. POMS participants and controls were recruited from 16 pediatric MS clinics between 1 November 2011 and 1 July 2017. Clinical and demographic information, including history of adenotonsillectomy, EBV serostatus, and HLA-DRB1*15:01:01 status, were collected. Multivariable logistic regression assessed the association between adenotonsillectomy and MS risk. In addition, negative binomial regression offset by follow-up time was used to assess the relationship between adenotonsillectomy and relapse rate in POMS participants with available follow-up data. The case-control analysis included 359 POMS participants and 560 pediatric controls. Individuals with a history of adenotonsillectomy had a 63% increased odds of MS (adjusted odds ratio (OR) = 1.63, 95% confidence interval (CI) = 1.01-2.64, p = 0.046). Among the 239 POMS participants with available follow-up data, adenotonsillectomy was associated with a twofold increase in annualized relapse rate (adjusted incidence rate ratio (IRR) = 2.00, 95% CI = 1.15-3.48, p = 0.013). Prior adenotonsillectomy was associated with increased risk of MS and greater relapse rate in pediatric patients, suggesting a potential interplay between EBV, immune regulation, and MS pathogenesis.
Metabolic dysregulations have been reported in multiple sclerosis (MS), but it is unclear whether metabolic profiles at disease onset predict long-term outcomes. We evaluated whether baseline metabolic profiles at MS onset could predict disease activity/progression over 5 years. This prospective study included 468 patients enrolled in the BENEFIT trial at first clinical episode who completed 5 years of follow-up. Untargeted metabolomic profiling of 545 metabolites was performed at baseline using liquid chromatography-mass spectrometry. Associations with clinical and radiological outcomes were assessed using regression models, and machine learning was applied to identify metabolic signatures of worse outcomes. Models were adjusted for demographic, clinical, and lifestyle covariates. Distinct metabolomic signatures were associated with worse 5-year outcomes, including relapses, lesion volume, brain atrophy, and disability (Expanded Disability Status Scale (EDSS), multiple sclerosis functional composite (MSFC)). These signatures modestly improved outcome prediction beyond established predictors, with the largest gain for brain volume loss (area under the curve (AUC) = 0.68-0.86). Pathway analysis showed enrichment of nicotinate/nicotinamide, histidine, and arginine metabolism across several outcomes, with unsaturated fatty acid biosynthesis specifically with relapses. Metabolic profiles in early MS modestly improve the prediction of 5-year outcomes beyond clinical factors. Consistent enrichment across some pathways suggests potential biological relevance, warranting further investigation of individual metabolites.
Mucosal-associated invariant T (MAIT) cells recognize microbial vitamin B2 and B9 metabolites via MR1 and have been implicated in multiple sclerosis (MS). How patient-specific gut microbiota shape human MAIT-cell pathogenicity at the clonal level remains unknown. We generated 62 MAIT-cell clones from relapsing-remitting multiple sclerosis (RRMS) patients and 50 from healthy controls (HCs). Clones were stimulated with riboflavin- or folate-pathway metabolites, paraformaldehyde-fixed patient-matched gut bacterial isolates, or interleukin (IL)-12/IL-18. Activation markers, cytokine secretion, cytotoxicity, and competitive MR1-ligand inhibition were assessed. Intestinal permeability was evaluated using I-FABP, LBP, GLP-2, and fecal α-1-antitrypsin. MS-derived MAIT clones showed markedly enhanced activation, increased interferon-gamma (IFN-γ), IL-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion, and greater cytotoxicity compared with HCs when stimulated with riboflavin-producing taxa isolated from the same patients. Importantly, several responses diverged from predictions based on murine models and genomic inference, including mixed cytokine profiles and graded competitive inhibition by folate-derived ligands. These findings highlight species-specific differences in MR1 ligand handling and MAIT-cell activation. Activation required uptake of intact bacteria and acid-dependent MR1 loading. MS patients exhibited significant intestinal barrier dysfunction, linking dysbiosis to systemic MAIT-cell hyperactivation. At clonal resolution, this study demonstrates that patient-specific microbial metabolism, MR1-ligand competition, and epithelial barrier disruption cooperate to amplify MAIT-cell pathogenicity in MS, revealing human-specific mechanisms not predicted by animal models.
Little is known about glucagon-like peptide-1 receptor agonists (GLP1RAs) use in multiple sclerosis. We described the frequency and characteristics associated with use. A cross-sectional survey of NARCOMS Registry participants captured use of GLP1RAs semaglutide and tirzepatide. Multivariable logistic regression explored factors associated with use. Among 4181 eligible participants, 7.4% had ever and 5.5% currently used these GLP1RAs. Ever users were younger and had more cardiometabolic conditions. 37.3% of never users had an indication for GLP1RAs. Despite 40% having an indication for taking GLP1RAs, a small percentage of surveyed persons with multiple sclerosis used them.
Little is known about the long-term health-related quality of life (HRQOL) of adults with pediatric-onset MS (POMS) nor the factors that may modify HRQOL in this population. We sought to define symptom burden and HRQOL among adults with POMS and to interrogate the potential relationship of adverse childhood experiences (ACEs) with HRQOL. In this cross-sectional study, 98 adults with POMS were recruited through the North American Research Committee on Multiple Sclerosis Registry, Nationwide Children's Hospital, and Ohio State University. Participants completed demographics, Multiple Sclerosis Quality of Life-54 (MSQoL-54), SymptoMScreen, Patient-Determined Disease Steps (PDDS), MS Resiliency Scale (MSRS), and ACEs questionnaires. The Pearson correlations were computed between ACE, MSQoL-54, PDDS, and SymptoMScreen scores. Multivariable linear regression was performed for MSQoL-54 outcomes using ACE and MSRS scores. Participants were 90% female with a mean age of 53 years. A higher number of ACEs was associated with poorer physical and mental HRQOL (p = 0.003 and p = 0.01, respectively) and SymptoMScreen (p = 0.002). Higher resiliency scores (MSRS) were associated with greater physical and mental HRQOL (both p < 0.001). ACEs may have a long-standing impact on the lived experience of POMS patients into adulthood. Future work should explore the role of resiliency in mitigating these effects.
Few studies assessed drug dispensations for periods >5 years pre-multiple sclerosis (MS) onset or examined the time pre-MS symptom onset. The objective of this study was to examine prescription drug dispensations up to 15 years pre-MS symptom onset. Matched cohort study linking prescription, clinical and administrative data, 1996-2018. Among 1243/6212 MS/non-MS persons, those with MS had higher dispensation rate ratios (RRs) pre-onset for systemic antibacterials up to 15 years (RR (range) = 1.15-1.30; q-values (range) = 0.11-0.31), airway drugs up to 8 years (RR (range) = 1.49-1.71; q-values (range) = 0.26-0.35), sex hormones (females only) up to 7 years (RR (range) = 1.19-1.46; q-values (range) = 0.26-0.39) and psychoanaleptics up to 6 years (RR (range) = 1.36-1.59; q-values (range) = 0.09-0.31), but lower beta-blockers (years 13-14 pre-onset, RRs = 0.10; q-values (range) = <0.00001-0.31). After multiple-comparison adjustment, beta-blockers remained significant. Drug dispensations differed up to 15 years pre-MS onset and may reflect early disease.
Postpartum depression (PPD) is a common mental health concern, but its occurrence among mothers with multiple sclerosis (MS) is not well established. Understanding this risk is important for guiding perinatal care. To investigate the risk of treatment-requiring PPD among mothers with MS compared to mothers without MS. We conducted a nationwide cohort study including all live births in Denmark from 1997 to 2023, using Danish national health registers. Treatment-requiring PPD was defined as redeemed prescriptions for antidepressants within 12 months postpartum, identified in the Danish National Prescription Register. Logistic regression models estimated crude and adjusted odds ratios (aORs), adjusting for maternal age, parity, preterm birth, multifetal gestation, and antidepressant use within 6 months before conception. Analyses were clustered by mother. Within 12 months postpartum, 236 of 2850 deliveries in women with MS (8.3%) and 58,778 of 1,532,959 deliveries of women without MS (3.8%) redeemed antidepressant prescriptions. Mothers with MS had higher odds of antidepressant use with aOR 1.9 (95% confidence interval (CI): 1.6-2.3). Mothers with MS have an elevated risk of treatment-requiring PPD. Enhanced monitoring and tailored mental health support during the perinatal period may be warranted.
Early initiation of high-efficacy therapies (HETs) has been associated with improved disease control in pediatric-onset multiple sclerosis (POMS). However, some children remain clinically stable on low-/moderate-efficacy therapies (METs), highlighting the need for decision-support tools. To develop a Therapeutic Escalation Score (TES) to identify children at low risk of early escalation after initiating MET. We analyzed treatment-naïve children with POMS who initiated MET between 2010 and 2024 in the French MS registry (Observatoire Français de la Sclérose en Plaques (OFSEP)). TES was derived using Cox regression modeling based on baseline clinical and magnetic resonance imaging (MRI) variables, with internal validation in OFSEP and external validation in the Italian MS registry Registro Italiano Sclerosi Multipla (RISM). We included 455 children from OFSEP (training n = 303; validation n = 152) and 573 from RISM. TES incorporated age, year of treatment initiation, Expanded Disability Status Scale score, prior-year relapses, brain lesion location, and T2 spinal cord lesions. A TES threshold of 1.34 stratified patients by 1-year escalation risk. In OFSEP, low-risk patients had a 1-year escalation probability of 3.6% (negative predictive value: 97.0%). In RISM, discrimination was similar (area under the curve (AUC): 72.8%-73.8%). TES is a baseline-only prognostic tool using routine clinical and MRI data to identify children with POMS unlikely to require early escalation after MET initiation.
Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. Likert-type assessment performed by neuroradiologist ratings demonstrated superior generalization of the model compared to existing contrast-specific pipelines (p < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. The proposed model can achieve accurate and reliable spinal cord MS lesion segmentation across heterogeneous MRI data, addressing a key barrier to clinical translation. The model is available in the Spinal Cord Toolbox v7.2 and higher.Code repository: https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast.
Observational studies suggest an association between immune responses to Epstein-Barr virus nuclear antigen 1 (EBNA1) and multiple sclerosis (MS) risk. Nevertheless, a causal effect cannot be established, as confounding and reverse causation cannot be excluded. We performed a bidirectional two-sample Mendelian randomization (MR) to test whether higher anti-EBNA1 IgG levels causally influence MS risk, or vice versa. Genetic associations for anti-EBNA1 IgG were obtained from 7972 UK Biobank participants, and for MS from 115,803 individuals in the International MS Genetics Consortium. Given that most anti-EBNA1 IgG instruments lie in the pleiotropic major histocompatibility complex, we applied a robust cis-MR framework, sensitivity analyses, and external validation using genetic association from anti-EBNA1 IgG levels obtained from 914 French individuals. A one standard deviation increase in genetically predicted anti-EBNA1 IgG levels was causally associated with a 69% higher MS risk (OR = 1.69 [95% CI: 1.28; 2.23], p < 0.001). Results were consistent across sensitivity analyses and showed no directional pleiotropy. External validation supported these findings. Reverse MR provided no evidence that MS influences anti-EBNA1 IgG levels (p > 0.05). These results support a unidirectional causal effect of elevated anti-EBNA1 IgG levels on MS risk, reinforcing the role of EBV-related immune responses in MS pathogenesis.
Fatigue is common in multiple sclerosis and may be influenced by cardiovascular comorbidities. To test whether cardiovascular comorbidity burden relates to fatigue at baseline and over time, and to assess dose response. We analyzed prospectively collected data from MS PATHS across 10 centers. Fatigue was measured with Neuro-QoL Fatigue T-scores. Cardiovascular comorbidity was defined as a composite (any vs none) and as a count of hypertension, diabetes, and dyslipidemia. Cross-sectional associations and longitudinal trajectories were modeled using multivariable regression. Extended models also included depression, anxiety, and sleep disturbance. Among 5507 participants, 49% had no cardiovascular comorbidity, 32% had one, 16% had two, and 3% had three. In minimally adjusted cross‑sectional models, any comorbidity was associated with higher fatigue (beta = 0.85; 95% CI, 0.18 to 1.53), with attenuation after adjustment for depression, anxiety, and sleep (beta = 0.20; 95% CI, -0.09 to 0.49). A graded dose response was evident across 0-3 conditions. In longitudinal analyses, effect sizes were larger and remained positive after adjustment (Any vs None: beta = 1.06 in minimal models; beta = 0.39 after adjustment), consistent with a greater comorbidity burden associated with higher fatigue over time. Cardiovascular comorbidity burden is associated with greater fatigue, with a dose response over time.
Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system that often affects women of reproductive age. The impact of MS on obstetric and neonatal outcomes remains unclear, particularly in women of advanced maternal age. We aimed to evaluate obstetric and neonatal outcomes in women with MS using data extracted from the National Health Screening Examination (NHSE) and the National Health Screening Program for Infants and Children (NHSPIC) in Korea. Women with singleton live births between 2011 and 2020 who underwent the NHSE within 4 years before pregnancy were identified. Women with MS (n = 481) were matched 1:10 to women without MS (n = 4810) based on age and comorbidity indices. Outcomes were compared using multivariate logistic regression considering maternal age. Women with MS had a higher risk of preterm birth (odds ratio [OR] = 2.50; 95% confidence interval [CI] = 1.38-4.52) and placenta previa (OR = 1.83; 95% CI = 1.05-3.20) compared with controls. The association between MS and preterm birth was particularly pronounced in women of advanced age. Other obstetric outcomes did not differ significantly according to MS status, and neonatal outcomes were similar between the two groups. Most obstetric and neonatal outcomes were comparable between women with and without MS. However, for pregnant women with MS, age ⩾ 35 years was associated with an increased risk of preterm birth, highlighting the importance of careful prenatal monitoring in this population. Further studies are warranted to elucidate the mechanisms underlying this risk.
Optical coherence tomography (OCT) enables evaluation of inter-eye differences (IEDs) in peri-papillary retinal nerve fiber layer (pRNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thicknesses to identify unilateral optic nerve involvement (UONI), included in the 2024 revised McDonald diagnostic criteria for multiple sclerosis (MS). To evaluate pRNFL and GCIPL thickness test-retest reliability in scans fulfilling (SFO) versus not fulfilling (SNFO) OSCAR-IB criteria in people with MS using Spectralis SD-OCT. From 164 participants, two scans per eye per protocol (optic nerve head: pRNFL; macular volume: GCIPL) were obtained with Spectralis SD-OCT and classified as SFO or SNFO. Intra-visit intraclass correlation coefficients (ICCs) and coefficients of variation (COVs) quantified reproducibility. pRNFL thicknesses from SNFO exhibited lower reliability (n = 72, ICC = 0.827, COV = 3.38%), than from SFO (n = 216, ICC = 0.991, COV = 1.14%). GCIPL thicknesses demonstrated excellent reliability from both SFO (n = 199, ICC = 0.997, COV = 0.53%) and SNFO (n = 97, ICC = 0.990, COV = 0.83%). Algorithm failure and low signal strength most affected pRNFL (COV = 7.72%) and GCIPL (COV = 3.34%) reproducibility, respectively. OSCAR-IB violations negligibly affected GCIPL reliability, although reduced pRNFL reliability, supporting quality control to avoid erroneous UONI, and suggesting that GCIPL measures may be more robust than pRNFL measures with Spectralis SD-OCT, in contrast to prior Cirrus HD-OCT studies.
Progression independent of relapse and MRI activity (PIRMA) is a major contributor to long-term disability in relapsing-remitting multiple sclerosis (RRMS). In Latin America, limited access to high-efficacy disease-modifying therapies (DMTs) may influence PIRMA risk, but real-world evidence is scarce. We aimed to estimate the causal effect of DMT efficacy on PIRMA in an Argentine cohort. We conducted a retrospective observational study including 264 adults with RRMS meeting predefined disability follow-up criteria. Treatment exposure was modeled as a time-varying variable (low-efficacy vs moderate-/high-efficacy), applying a 60-day pharmacological lag after treatment switches. To address time-dependent confounding, we used a marginal structural model with overlap weighting and a weighted Cox proportional hazards model. Median age at treatment initiation was 31.5 years, 62.1% were female, and median baseline EDSS was 1.0. Over a median follow-up of 7 years, 26 PIRMA events occurred. Exposure to low- or moderate-efficacy DMTs was associated with a significantly higher risk of PIRMA compared with high-efficacy therapies (HR 7.05; 95% CI 1.15-43.35). Exposure to low-/moderate-efficacy disease-modifying therapies was associated with a substantially higher risk of PIRMA compared with high-efficacy treatments, supporting the potential benefit of early access to high-efficacy therapies in RRMS.
Multiple sclerosis (MS) is a chronic neurological disorder characterized by autoimmune-mediated inflammation and neurodegeneration. Despite major advances in disease-modifying therapies, many people with MS continue to face significant challenges. This topical review summarizes clinical studies over the past two decades examining transcranial magnetic stimulation (TMS) as a therapeutic approach for MS symptoms, including fatigue, motor dysfunction, spasticity, and cognitive impairment. Available evidence suggests potential symptomatic benefits, particularly for motor/spasticity-related outcomes, and indicates that neuroplasticity remains at least partially preserved in MS, providing a plausible substrate for neuromodulation-based interventions. Moreover, TMS appears generally well-tolerated; however, findings are heterogeneous, and the evidence base includes few adequately powered sham-controlled trials across symptom domains. Overall, current findings support further controlled trials to clarify efficacy, durability, and patient-level predictors, and to inform stepwise clinical translation of TMS-based interventions as a complementary strategy to leverage residual neuroplasticity and reduce symptom burden in individuals with MS.
The spinal cord plays a central role in the pathophysiology and clinical manifestations of multiple sclerosis (MS), yet remains under-studied compared with the brain. This review summarizes key insights from the 2025 North American Imaging in MS Spinal Cord Imaging Workshop, highlighting recent advances, ongoing challenges, and future opportunities in MS spinal cord imaging. We review pathological studies and outline the clinical relevance of spinal cord lesions and atrophy for diagnosis, prognosis, and disease monitoring, highlighting emerging biomarkers of progression independent of relapse activity. Correlations between magnetic resonance imaging, histopathology, and clinical outcomes support the validation and translational potential of advanced spinal cord imaging techniques. Finally, we discuss spinal cord-specific processing pipelines and reproducibility challenges. Collectively, these insights underscore the need to integrate advanced and quantitative spinal cord imaging into clinical trials, research studies, and-when feasible-clinical care, to fully capture the extent of MS pathology, and ultimately improve patient outcomes.
Neurological care and disease-modifying therapies (DMTs) are central to multiple sclerosis (MS) management, but how comorbidities like cancer affect them remains unclear. We assessed the impact of cancer on MS-related healthcare and DMT use. This cohort study accessed population-based data from France (2009-2021) and British Columbia, Canada (1991-2020). Cases were individuals with MS diagnosed with an incident cancer. The 4-year study period encompassed the 2 years before and after the cancer diagnosis. Each case was matched to two cancer-free individuals with MS (i.e. controls). Outcomes were neurologist visit rates, MS hospitalization rates, and percentage of DMT users. Mixed-effects models were used with a knot at cancer diagnosis. Incidence rate ratios (IRRs) were estimated pre- and post-cancer (cases vs. controls) and compared using a slope ratio (SR). In total, 6902 cases were matched to 13,804 controls. There was a negative effect of cancer on DMT use (SR = 0.36 [0.19-0.70]), especially among those on chemotherapy (SR = 0.24 [0.14-0.40]). Neurologist visit IRRs did not differ pre- and post-cancer (SR = 0.96 [0.91-1.005]). Similarly, MS hospitalization IRRs did not differ (SR = 1.06 [0.84-1.33]). Following cancer, DMT use declined sharply. However, there was no evidence of a strong impact of cancer on neurologist visits and MS hospitalizations.
Understanding sex differences in relapsing-remitting multiple sclerosis (RRMS) and initiation of disease-modifying treatments (DMTs) is crucial for tailored approaches. The objective of this study is to analyze sex-specific differences in early RRMS. We analyzed data of therapy-naïve adults from the German NationMS cohort to describe first symptoms, onset relapse treatment, disability evolution, and DMT exposure separated by sex to investigate previously described sex differences. Relapse presentation and treatment were similar (p = n.s.). Time to Expanded Disability Status Scale (EDSS) ⩾3.0 was comparable between sexes (adjusted hazard ratio, 95% confidence interval (95% CI): 1.32 (0.95-1.81)). DMT exposure did not differ (p = 0.60). Around 5.0% of both sexes received initial high-efficacy (HE) DMT. Younger age (odds ratio (OR) (95% CI): 0.95 (0.92-0.98); p = 0.000847), higher baseline EDSS (1.79 (1.40-2.27); p = 0.00000218), and RRMS diagnosis (2.26 (1.28-4.17), p = 0.006703) were associated with initial HE-DMT, but not sex (0.99 (0.57-1.77), p = 0.943166). We did not observe major sex differences in early MS as described earlier regarding initial presentation and disability evolution suggesting a change of MS course. The decision for initial HE-DMT was influenced by younger age and higher EDSS, but not sex suggesting a lower sex bias regarding the initial treatment decision, yet only investigated in specialized academic MS centers.