BACKGROUND:Optical coherence tomography (OCT) enables in vivo assessment of retinal layers and is an emerging biomarker of neurodegeneration in multiple sclerosis (MS). In relapsing MS, peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness predict disease progression, but their role in primary progressive multiple sclerosis (PPMS) is unclear. OBJECTIVE:To determine whether pRNFL and GCIPL predict disability progression and retinal, brain, and spinal cord atrophy (SCA) in PPMS. METHODS:Retrospective longitudinal study of 69 PPMS patients with clinical, OCT, and magnetic resonance imaging (MRI) data. Patients stratified by pRNFL and GCIPL thickness tertiles (lower vs intermediate-upper). Annual thinning rates for pRNFL and GCIPL (aLpRNFL and aLGCIPL) estimated via linear regression. MRI assessed baseline and follow-up brain volumes, spinal cord area, and percentage of brain volume change (PBVC). Analyses included regression models, Kaplan-Meier, and Cox survival regression. RESULTS:pRNFL ⩽ 87 μm was associated with higher follow-up Expanded Disability Status Scale (EDSS) (6.0 (interquartile range (IQR) = 4.5-6.5) vs 4.0 (IQR = 3.0-6.0), p = 0.013). Risk of confirmed disability progression (CDP) increased 3.4-fold (95% confidence interval (CI) = 1.03-11.30, p = 0.044) over 2 years (IQR = 1.0-3.0), with median time to CDP of 1.84 vs 3.67 years (p = 0.027). Longitudinally, pRNFL ⩽87 μm showed faster retinal thinning (aLpRNFL = -1.66 vs -0.31 µm/year, p < 0.001), greater whole-brain atrophy (PBVC = -1.20%, p = 0.037), and greater SCA (B = 0.333, p = 0.008). CONCLUSION:In PPMS, pRNFL predicts disability progression and greater retinal, brain, and SCA, supporting its role as a surrogate marker of neurodegeneration in clinical trials.

OBJECTIVE:The objective of this study was to investigate the ability of patient-reported/administered outcomes to capture disability worsening and progression independent of relapse activity (PIRA) in multiple sclerosis (MS). METHODS:We included patients from the longitudinal multicenter MS PATHS cohort with ≥3 assessments and >6 months follow-up. PIRA was defined on the patient-determined disease steps (PDDS) and self-administered tests assessing walking speed, manual dexterity, and processing speed, in the absence of self-reported relapses. We assessed (i) prevalence of PDDS/self-administered test-based disability worsening and PIRA definitions; (ii) their concurrent validity, through the association with worsening and PIRA definitions based on the expanded disability status scale (EDSS; Barcelona subcohort); and (iii) their clinical meaningfulness, through the correlation with brain magnetic resonance imaging (MRI) and quality-of-life (QoL) data trajectories. RESULTS:We included 9,088 patients (73% female patients; age = 46.8 years; disease duration = 14.2 years). Over a 3-year follow-up, 4,066 (45%) patients worsened on ≥1 patient-reported/administered outcome, of which 2,357 (58%) developed PIRA. In the Barcelona subcohort (N = 279), 68 (24%) patients developed EDSS-based worsening, of which 30 (44%) developed EDSS-based PIRA; 99 of 279 (35%) worsened on ≥1 patient-reported/administered test, of which 78 of 99 (79%) had PIRA. Worsening (but not PIRA) on PDDS was associated with EDSS-based worsening (odds ratio = 3.03 [1.42; 6.43], p = 0.004). PDDS/self-administered-test-based worsening or PIRA strongly correlated with accelerated brain atrophy and T2 lesion volume increase compared to non-worseners (p < 0.05), and showed worse QoL (p < 0.05). INTERPRETATION:Despite only partial agreement with EDSS-based definitions, PDDS/self-administered test-based worsening and PIRA definitions were clinically meaningful, by identifying patients with greater brain damage and poorer QoL, supporting their use in clinical practice. ANN NEUROL 2026;100:525-546.

BACKGROUND:Accelerated biological ageing has been proposed as a key mechanism influencing disease progression in multiple sclerosis. Anti-Müllerian hormone (AMH), a marker of ovarian reserve, may reflect biological ageing in women and could be associated with disability progression. We aim to evaluate the prognostic implications of AMH levels measured at the first demyelinating event (FDE) suggestive of multiple sclerosis (MS). METHODS:This retrospective study analysed prospectively collected data from three Spanish neuroimmunology centres (since 1994). It included 365 females aged 20-45 years with serum AMH measured within 2 years of onset. According to AMH tertiles (n, median ng/mL (range)), participants were classified as follows: high (n=121; 4.6 (3.2-17.4)), medium (n=122; 2.1 (1.3-3.2)) and low (n=121; 0.6 (0.01-1.3)). A total of 145 healthy females served as controls. Age-adjusted multivariable linear regression models assessed associations between AMH and baseline clinical, radiological and serum biomarkers. Cox regression models evaluated the risk of Expanded Disability Status Scale 3.0, second relapse, progression independent of relapse activity and relapse-associated worsening. RESULTS:At FDE, median (range) age was 32.9 (22.2-44.9) years, follow-up 6.5 years (0.01-29.4) and AMH 2.2 (0.01-17.4); 68% received disease-modifying treatment. AMH levels did not differ between patients and controls and were inversely correlated with chronological age (β -1.21 (95% CI -1.42 to -1.00), p<0.001). After adjustment for chronological age, AMH showed no independent association with clinical, radiological or biomarker measures, or long-term outcomes. CONCLUSIONS:AMH levels at the time of an FDE suggestive of MS were not associated with baseline activity or long-term outcomes related to relapses or disability. Our findings suggest that the apparent associations between AMH and disease characteristics are largely driven by chronological age, supporting the concept that ovarian reserve primarily reflects biological ageing rather than an independent determinant of MS progression.

OBJECTIVE:To determine the prevalence and clinical characteristics of patients with "low-positive" (LP) MOG-IgG (titres 1:160-1:320) among adults with a first demyelinating event (FDE) suggestive of multiple sclerosis (MS). METHODS:From the Barcelona CIS inception cohort, we included adult patients with serum collected ≤ 6 months from the FDE. MOG-IgG was assessed by a cell-based assay with flow cytometry (CBA-FC). Demographic, clinical, and paraclinical data were compared among seronegative, LP, and "clear-positive" (CP; ≥ 1:640) patients. Supporting MOGAD features and final diagnoses were retrospectively reviewed in seropositive cases. RESULTS:Of 613 patients, 42 (6.9%) were MOG-IgG positive (CP = 17; LP = 25). LP patients were indistinguishable from seronegative patients but differed from CP patients, who more frequently had optic neuritis, lacked cerebrospinal fluid-oligoclonal bands, and were less likely to meet the McDonald criteria (p < 0.05). At the last follow-up, 64% of LP versus 18% of CP patients were diagnosed with MS (p = 0.004). Only one LP patient fulfilled MOGAD criteria, compared with 14 CP patients (p < 0.001). INTERPRETATION:Lowering the CBA-FC positivity threshold to ≥ 1:160 had limited diagnostic yield in this MS-predominant cohort, as most LP cases were ultimately diagnosed with MS. These findings support cautious interpretation of LP MOG-IgG results in this clinical setting.

Importance:Live attenuated measles-mumps-rubella (MMR) and varicella vaccines are recommended for immunocompetent people with multiple sclerosis (MS) lacking immunity. However, concerns about postvaccination relapses may contribute to vaccine hesitancy, and robust data addressing this risk remain limited. Objective:To assess whether the risk of MS relapse within 1 year after MMR or varicella vaccination is not unacceptably worse than risk after no such vaccination based on a predefined noninferiority margin. Design, Setting, and Participants:This cohort study used prospectively collected data from July 2016 to October 2024 for people with MS at a tertiary MS center in Barcelona, Spain, who received at least 1 dose of live attenuated MMR and/or varicella vaccine due to serologic susceptibility. Vaccinated patients were matched 1:2 with unvaccinated control individuals with MS by sex, age, and epoch of first demyelinating event. Exposures:Live attenuated MMR and/or varicella vaccine. Main Outcomes and Measures:Primary outcomes were relapse count and time to first relapse within 1 year of time 0, analyzed using Poisson and Cox proportional hazards regression models with inverse probability weighting based on a propensity score including treatment category, Expanded Disability Status Scale score, and annualized relapse rate in the prior year. Noninferiority was predefined as an annualized relapse rate ratio with an upper bound of the 95% CI less than 1.4. Results:A total of 369 people with MS were included, of whom 123 were vaccinated (mean [SD] age, 28.75 [8.72] years; 85 females [69.1%]) and matched to 246 unvaccinated controls (mean [SD] age, 28.66 [8.60] years; 170 females [69.1%]). Overall, 36 relapse events were observed (15 [41.7%] among vaccinated patients and 21 [58.3%] among unvaccinated controls). In the weighted Poisson model, although relapse incidence was not significantly different between vaccinated and unvaccinated individuals (incidence rate ratio, 0.52; 95% CI, 0.23-1.06), the noninferiority criterion was met. Similarly, weighted Cox proportional hazards regression models showed no difference in hazard of relapse between groups (hazard ratio [HR], 0.55; 95% CI, 0.25-1.17) but the noninferiority criterion was met. Sensitivity and exploratory analyses, including time-dependent adjustment for postbaseline treatment exposure (HR, 0.60; 95% CI, 0.27-1.33), restriction to the high-risk period (n = 15 events), and comparisons of magnetic resonance imaging before (n = 43 events) and after (n = 21 events) exposure in vaccinated patients, revealed findings consistent with those of the primary analysis. Conclusions and Relevance:In this cohort study of nonimmunosuppressed people with MS, vaccination with live attenuated MMR or varicella vaccine was not associated with increased risk of postvaccination relapse. The results support the administration of these vaccines when indicated and may help reassure clinicians and patients, reducing vaccine hesitancy.

Multiple sclerosis (MS) is a potentially disabling disease that shows marked variability in its severity and underlying mechanisms. Early prediction of patients at risk of specific unfavourable outcomes may be key to treatment stratification and management. Here, we propose a prognostic framework, called the Spider-MS model, to predict a wide range of relevant outcomes at the individual level, at symptom onset. We included patients from the Barcelona first-attack cohort, i.e. with a first demyelinating attack suggestive of multiple sclerosis, younger than 50 years old at symptom onset and seen in the clinic within 3 months of the first attack, to build the Spider-MS model (original cohort). Patients with a first demyelinating attack from the Royal Melbourne Hospital were used to validate the model externally (validation cohort). All patients were prospectively assessed clinically, with the Expanded Disability Status Scale (EDSS) and relapse tracking, and through brain and, in some cases, spinal cord MRI. Spider-MS was built as a set of eight accelerated failure models with Weibull distribution, one for each outcome, including McDonald 2017 diagnosis, second attack, yearly rate of new T2 lesions > 2, relapse-associated worsening (RAW) at the first attack and at subsequent attacks, confirmed and sustained disability worsening, progression independent of relapse activity (PIRA) and EDSS 3.0. Model predictors included age, sex, first attack topography, brain and spinal cord lesions, CSF oligoclonal bands and percentage of time on high-/moderate-efficacy treatment before the outcome. We included 1180 patients from Barcelona (mean age 32.37 years, 810 females) and 108 from Melbourne (32.41 years, 78 females). Median follow-up times were 10.80 and 11.10 years, respectively. In the original cohort, 797/1180 (67.5%) fulfilled the McDonald criteria, 121/1180 (10.3%) developed RAW at subsequent relapses and 290/1180 (24.6%) developed PIRA over the follow-up period. The prediction models reached moderate-high accuracy levels (Harrell's C values: 0.653-0.823) and showed that older age, cord involvement at first attack, greater number of brain and cord lesions, presence of CSF oligoclonal bands and lower percentage of time on treatment predicted a greater risk of unfavourable outcomes, with varying effects depending on the outcome. When the Spider-MS model was applied to the external cohort, for all outcomes except for RAW at first or subsequent attacks, the prediction models reached moderate-high accuracy values (Harrell's C = 0.623-0.766). In general, patients with the highest predicted risks experienced acute inflammatory activity or disability earlier than lower-risk patients. In conclusion, our Spider-MS model can be considered a promising individual predictive tool with the potential to inform clinical practice.

BACKGROUND AND OBJECTIVES:Serum neurofilament light chain (sNfL) reflects inflammatory axonal damage in relapsing multiple sclerosis (RMS). Longitudinal sNfL dynamics may aid treatment response assessment, although data on expected changes under disease-modifying treatments remain limited, particularly in real-world practice. This study evaluated whether on-treatment changes in sNfL were associated with subsequent evidence of disease activity (EDA) and whether they provided complementary information to established treatment response scoring systems (TRSS). METHODS:This prospective, real-world cohort study was conducted at the Multiple Sclerosis Center of Catalonia (Cemcat). Adult RMS patients initiating disease-modifying treatments (DMTs) with serum samples at treatment initiation (baseline) and after 1 year (Y1) were included. The primary exposure was change in sNfL z-scores (ΔzNfL = zNfLY1 - zNfL-baseline) analyzed using data-derived thresholds (ΔzNfL ≥0 and <0.5-point reduction). At Y1, Expanded Disability Status Scale progression, clinical/radiologic activity, and TRSS (Rio [RS], modified Rio [mRS], and MAGNIMS) were assessed. The primary outcome was EDA between years 1 and 2 (EDA-Y2). Multivariable logistic regression models evaluated associations between ΔzNfL and EDA-Y2, as well as the added value of ΔzNfL across TRSS strata. RESULTS:A total of 329 patients (66.3% female; median age 39 years) initiated 352 DMTs; 342 remained on treatment for ≥1 year and 182 had complete EDA-Y2 data. Mean (SD) ΔzNfL at Y1 was -0.62 (1.2), with greater reductions in monoclonal antibody-treated and treatment-naïve patients. Lack of zNfL reduction over the first year (ΔzNfL ≥0) was associated with higher odds of EDA-Y2 in the overall cohort (OR [95% CI], p: 3.07 [1.47-6.39], 0.003), in treatment-naïve cases (14.04 [2.47-79.93], 0.003), and in those achieving No Evidence of Disease Activity (NEDA-3) at Y1 (4.54 [1.26-16.30], 0.02). Similar associations were observed for <0.5-point reductions. Adding ΔzNfL to TRSS showed persistent associations with EDA-Y2 despite otherwise favorable scores [e.g., RS: 2.26 (1.12-4.59), 0.024]. DISCUSSION:Failure to reduce zNfL levels after 1 year of treatment was associated with subsequent disease activity, even in patients otherwise considered stable, providing complementary information to clinical and MRI-based monitoring. Limitations include incomplete follow-up and the modest discriminative performance of ΔzNfL, supporting a complementary rather than stand-alone role for zNfL dynamics.

BACKGROUND AND OBJECTIVES:Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria. METHODS:In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up. RESULTS:We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [p = 0.002], DIS and DIT vs noDIS and noDIT [p < 0.001], and DIS and noDIT vs noDIS and noDIT [p = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]). DISCUSSION:These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.

BACKGROUND:Radiologically isolated syndrome (RIS) represents a subclinical period of multiple sclerosis (MS). OBJECTIVES:We aimed to characterize and identify risk factors for developing MS in an RIS cohort and to assess various proposed RIS definitions for their predictive value in MS development. METHODS:This cohort study included all patients with at least one typical inflammatory-demyelinating lesion suggestive of MS on brain and/or spinal cord magnetic resonance imaging (MRI). The development of MS symptoms and new T2 lesions were the primary and secondary outcomes, respectively. Cox regression was used to identify risk factors, and diagnostic performance was assessed. RESULTS:Eighty-eight patients were included, with 25.0% developing MS symptoms over a mean 55.1-month follow-up. Younger age and spinal cord and cortico-/juxtacortical lesions were associated with worse outcomes. The 2017 McDonald dissemination in space (DIS) criteria and 2023 Lebrun RIS definition, which correspond to either the 2005 McDonald DIS criteria or one brain inflammatory-demyelinating lesion associated with two among oligoclonal bands, a spinal cord lesion and dissemination in time during radiological follow-up, showed high sensitivity (0.82 and 0.94, respectively). However, the sensitivity decreased (0.79) when only the baseline characteristics of the 2023 Lebrun RIS definition were considered. Combining the 2017 McDonald DIS criteria with positivity for oligoclonal bands or contrast-enhancing lesions on baseline MRI, which are the current McDonald MS criteria, improved the specificity (to 0.64 and 0.90, respectively). CONCLUSIONS:Our findings support the utility of the current DIS component of the 2017 McDonald MS criteria for RIS patients.

Progression independent of relapse activity is the main cause of irreversible disability in multiple sclerosis and is strongly associated with older age at symptom onset. Early and accurate prediction, at symptom onset, of which patients are at highest risk of progression independent of relapses, is an unmet need. This study aimed to develop a deep learning survival model using only routine MRI acquired at the first demyelinating attack to predict the risk of progression independent of relapses, and assess its ability to improve classical age-adjusted predictions. We analysed a prospective cohort of patients under 50, clinically assessed within three months of symptom onset, with available MRI (T1- and T2-Fluid-Attenuated Inversion Recovery sequences). An independent early multiple sclerosis cohort (≤1 year from symptom onset) from the Multiple Sclerosis Partners Advancing Technology and Health Solutions database (N = 32) was used for external validation. Patients were assessed for progression independent of relapse activity, defined as a 6-month confirmed increase in the Expanded Disability Status Scale without relapses. Our deep learning model used EfficientNet to estimate the cumulative probability of progression independent of relapses at 1-year intervals. We employed 5-fold cross-validation for model training and testing, assessing performance with the time-dependent concordance index. We also investigated the optimal cumulative probability threshold for binary risk stratification. The model's ability to improve a classical Cox regression model was evaluated. Additionally, we identified brain regions most relevant to deep learning-based progression independent of relapse activity predictions using an interpretability algorithm. A total of 259 patients were evaluated, 58 (22%) of whom experienced at least one event of progression independent of relapse activity over a median follow-up of 4.2 years. The deep learning model demonstrated high performance (time-dependent concordance index = 0.72) with an accuracy of 78% in the original cohort and 72% in the external cohort for predicting the risk of progression independent of relapse activity. Incorporating the deep learning-derived cumulative probability of progression independent of relapses significantly improved an age-adjusted Cox regression model, raising Harrell's C index from 0.62 to 0.74. Interpretability revealed the frontoparietal cortex as a key region in predicting progression independent of relapse activity. In conclusion, our deep learning survival model, based on routine MRI at the first demyelinating attack, can accurately identify patients at high risk of progression independent of relapses and may serve as a valuable tool in clinical practice.

BACKGROUND:GG homozygosity for the risk gene variant rs7665090 has been reported to enhance nuclear factor kappa B (NFκB) activity in T cells from multiple sclerosis (MS) patients. Here, we investigated the association between this polymorphism and the response to different disease-modifying therapies in MS. METHODS:The rs7665090 polymorphism was genotyped in 558 MS patients treated with injectable therapies [IFNβ (n = 213) and glatiramer acetate (n = 55)], oral therapies [dimethylfumarate (n = 97), teriflunomide (n = 41), and fingolimod (n = 37)], and natalizumab (n = 115). Treatment response was assessed after 1 year for injectable therapies using the Rio Score, which considers relapses, EDSS progression, and radiological activity on MRI. For oral therapies and natalizumab, response was evaluated after 2 years based on clinical and radiological disease activity. Univariable and multivariable logistic regression analyses were performed to assess treatment response for each therapy independently. RESULTS:GG homozygosity was associated with a favorable response outcome in patients treated with IFNβ in the multivariable analysis after adjusting for age and EDSS at treatment onset [OR 0.42 (0.18-0.94); p = 0.037]. This finding was restricted to MS patients carrying the GG risk genotype and seemed specific for IFNβ treatment, since the rs7665090 polymorphism did not influence the response to the other MS therapies. CONCLUSION:The polymorphism rs7665090 is associated with a favorable response to IFNβ. This study illustrates how genotyping this polymorphism could serve as a useful biomarker in clinical practice to help identify MS patients who are likely to respond favorably to treatment, and encourages further replication in larger cohorts.

Background:In multiple sclerosis (MS), predicting at symptom onset who will develop early and severe disability is an unmet need with significant therapeutic implications. Here we propose the Barcelona-Baseline Risk Score (BRS) model to predict long-term disease outcomes in a flexible and generalisable manner. Methods:Using prospectively acquired data from the Barcelona first-attack cohort, we created the Barcelona-BRS model as a set of six Weibull survival models of time to an Expanded Disability Status Scale score of 3.0, built with flexible combinations of predictors, including sex, age at first attack, and number and topography of T2 lesions, among others, adaptable to data availability. Data-driven risk groups were identified and compared in terms of long-term clinical and MRI outcomes, including relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), conversion to secondary progressive MS (SPMS), lesional and brain volumetric data, and patient-reported/administered clinical scores, through Kaplan-Meier and mixed-effects models. Finally, we externally validated our model in a completely unseen cohort. Findings:We included 1074 patients (737 [69%] female, mean age: 31.7 years) with a first demyelinating attack. Over a median follow-up of 11.9 years, 375 (35%), 298 (28%), and 94 (8.8%) developed RAW, PIRA, and SPMS, respectively. Weibull models included age at first attack, number of brain T2 lesions, and disability at first visit as main predictors. Four data-driven groups of increasing risk of unfavourable outcomes were created: Light-Green-BRS (N = 258), Dark-Green-BRS (N = 319), Orange-BRS (N = 321), and Red-BRS (N = 176), which, over time, behaved significantly differently across disability, quality of life, and MRI measures, being the Red-BRS the group with worst outcomes (p < 0.01). The results in the external validation cohort (N = 139, 100 female [72%], 34 years) mirrored those of the original one. Interpretation:The robustness, flexibility, and generalisability of the Barcelona-BRS model support its consideration as a ready-to-use tool for clinical practice. Funding:None.

BACKGROUND:It is essential to exclude alternative diagnoses to diagnose multiple sclerosis (MS). However, detailed descriptions of alternative diagnoses in patients with suspected MS presenting with clinically isolated syndrome (CIS) are limited. OBJECTIVES:To describe alternative diagnoses in patients presenting with CIS suggestive of MS. METHODS:We conducted a descriptive analysis of patients from the Barcelona CIS cohort including subjects under 50 years of age with a CIS suggestive of MS but later diagnosed with conditions other than MS. We collected clinical, biological, and radiological data, and described the alternative etiologies identified. RESULTS:Among 1468 patients in the Barcelona CIS cohort, 100 (6.8%) were diagnosed with an alternative condition. The most common neurological syndrome was optic neuritis (43.0%). Four patients (4.0%) had inflammatory-demyelinating lesions in at least two typical MS topographies on baseline magnetic resonance imaging (MRI), and 2 (2.0%) met the 2017 McDonald MS criteria. The most common etiologies were immune-mediated diseases (42.0%), especially MOGAD, followed by functional neurological disorders (15.0%) and vascular disease (10.0%). CONCLUSION:The range of alternative diagnoses encountered during the MS diagnostic process highlights the need to rule out better explanations than MS. However, current MS diagnostic criteria effectively identify patients without MS in this context.

BACKGROUND:Predicting treatment response and disease progression in multiple sclerosis (MS) is challenging. Treatment Response Scoring Systems (TRSS) are potentially useful, but their utility in patients receiving high-efficacy therapies and very high-efficacy therapies (HET/vHET) remains unclear. OBJECTIVE:This study aimed to evaluate the performance of TRSS in patients treated with HET/vHET. METHODS:We retrospectively studied MS patients treated with HET/vHET in an MS specialized centre. TRSS, including the Rio Score, modified Rio Score and MAGNIMS score, were applied to assess response to treatment. We evaluated the predictive value of the TRSS on disease activity and disability progression. RESULTS:TRSS effectively predicted disease activity and progression of disability in patients treated with HET/vHET. Patients with high TRSS scores at 12 months post-HET/vHET initiation had a significantly increased risk of relapses, new lesions on magnetic resonance imaging (MRI) scans and progression of disability at 4 years. DISCUSSION:Our findings highlight the importance of personalized treatment strategies in MS. TRSS are valuable tools for monitoring treatment response, guiding clinical decision-making and optimizing patient care.

Objective To evaluate the effectiveness of fampridine on gait performance in patients with multiple sclerosis (MS) and to identify clinical predictors of therapeutic response. Methods Prospective observational study of 197 MS consecutive patients with walking impairment (EDSS 4.0—7.00) treated with fampridine between 2018 and 2024. Gait was assessed using the Timed 25-Foot Walk (T25FW), 2-Minute Walk Test (2MWT), and the 12-item Multiple Sclerosis Walking Scale (MSWS-12) at five timepoints over a 12-month follow-up. Responders were defined as those with ≥20% improvement in T25FW or ≥6-point reduction in MSWS-12. A multivariable logistic regression was performed to identify independent predictors of response. Results Significant improvements were observed across all gait measures (p<0.001) in the follow-up visits. Male sex (OR=2.375; p=0.018) and higher baseline MSWS-12 scores (OR=1.141; p=0.001) were associated with increased likelihood of response. Older age (OR=0.962; p=0.028) and higher baseline EDSS (OR=0.356; p<0.001) were associated with reduced probability of response. Fampridine was well tolerated, with a 33% discontinuation rate at the end of follow-up, mainly due to perceived lack of benefit. Conclusion Fampridine significantly improves gait performance in MS patients in real-world settings. Simple clinical variables such as age, sex, EDSS, and subjective walking impairment (MSWS-12) may help identify individuals most likely to benefit from treatment.

BACKGROUND AND OBJECTIVES:Emerging concepts in the early detection of multiple sclerosis (MS) progression reveal that disability accumulation can start early in the disease course. Aging in MS is increasingly recognized as a key factor for disease progression and disability accrual. We evaluate the prognostic impact of age in a cohort of patients experiencing a first demyelinating event (FDE), using a variety of disability outcomes, including some not previously assessed in age-specific studies. METHODS:Patients aged 18-50 years, assessed within 3 months from the FDE, were prospectively included since 1994 and categorized into 3 age groups: 18-29, 30-39, and 40-50 years. Relapse-associated worsening (RAW) at FDE, annualized relapse rate, and EDSS trajectories during follow-up were compared across age groups. Cox regression analyses adjusted for sex, comorbidities, and time exposed to very high-efficacy drugs were performed to assess the risk of achieving the following outcomes: time to reach McDonald 2017 criteria, first relapse, recurrent RAW, >2 new T2 brain lesions/year, first progression independent of relapse activity (PIRA), confirmed disability accumulation (CDA), and confirmed EDSS score 3.0. Patient-reported outcome measures were also analyzed. RESULTS:A total of 1,170 patients were included (median age 32 years; 69% female). The 40-50 group had a higher proportion of RAW at FDE (34% vs 25% and 29%; p = 0.031) and less time exposed to very high-efficacy treatments (p < 0.001) than the 30-39 and 18-29 groups, respectively. EDSS trajectories in the 40-50 group displayed a greater annual increase in the EDSS score compared with the 18-29 group (β 0.019 [95% CI 0.0001; 0.0387]). Cox analyses (HR; 95% CI) showed that the 40-50 group was at lower risk to reach McDonald 2017 criteria (0.80; 0.67-0.96), first relapse (0.59; 0.47-0.74), recurrent RAW (0.51; 0.31-0.86), or >2 new T2 brain lesions/year (0.39; 0.30-0.52), but at a higher risk of CDA (1.49; 1.16-1.97), PIRA (2.48; 1.88-3.27), and EDSS score 3.0 (1.50; 1.05-2.12), than the 18-29 group. Different functional and well-being variables were more affected in the 40-50 group, compared with 30-39 and 18-29 groups (p values< 0.05). DISCUSSION:Patients with a FDE at 40-50 years exhibit less inflammatory outcomes compared with younger patients and reach outcomes more closely related to neurodegeneration despite the lower disease activity.

Background The combination of anatomical MRI and deep learning‐based methods such as convolutional neural networks (CNNs) is a promising strategy to build predictive models of multiple sclerosis (MS) prognosis. However, studies assessing the effect of different input strategies on model's performance are lacking. Purpose To compare whole‐brain input sampling strategies and regional/specific‐tissue strategies, which focus on a priori known relevant areas for disability accrual, to stratify MS patients based on their disability level. Study Type Retrospective. Subjects Three hundred nineteen MS patients (382 brain MRI scans) with clinical assessment of disability level performed within the following 6 months (~70% training/~15% validation/~15% inference in‐house dataset) and 440 MS patients from multiple centers (independent external validation cohort). Field Strength/Sequence Single vendor 1.5 T or 3.0 T. Magnetization‐Prepared Rapid Gradient‐Echo and Fluid‐Attenuated Inversion Recovery sequences. Assessment A 7‐fold patient cross validation strategy was used to train a 3D‐CNN to classify patients into two groups, Expanded Disability Status Scale score (EDSS) ≥ 3.0 or EDSS < 3.0. Two strategies were investigated: 1) a global approach, taking the whole brain volume as input and 2) regional approaches using five different regions‐of‐interest: white matter, gray matter, subcortical gray matter, ventricles, and brainstem structures. The performance of the models was assessed in the in‐house and the independent external cohorts. Statistical Tests Balanced accuracy, sensitivity, specificity, area under receiver operating characteristic (ROC) curve (AUC). Results With the in‐house dataset, the gray matter regional model showed the highest stratification accuracy (81%), followed by the global approach (79%). In the external dataset, without any further retraining, an accuracy of 72% was achieved for the white matter model and 71% for the global approach. Data Conclusion The global approach offered the best trade‐off between internal performance and external validation to stratify MS patients based on accumulated disability. Evidence Level 4 Technical Efficacy Stage 2

Importance Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay. Objective To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment. Design, Setting, and Participants This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023. Exposures Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (<= 1 year) or long-term (>1 year). Main Outcomes and Measures Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed. Results Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment. Conclusions and Relevance The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.

Background and Objectives We aimed to assess the presence of retinal neurodegeneration independent of optic neuritis (ON) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to investigate the development of trans-synaptic anterograde degeneration in these patients after ON. Methods Cross-sectional, retrospective study of 34 adult patients with MOGAD and 23 healthy controls (HC). Clinical, optical coherence tomography (OCT), and MRI data were collected. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell inner plexiform layer (GCIPL) were obtained using Heidelberg Spectralis. FreeSurfer7 was used to obtain the lateral geniculate nucleus (LGN), occipital volume fractions (to total estimated intracranial volume), and occipital cortical thickness. For the anterior visual pathway, the analysis was conducted using eyes, classified based on the history of ON (Eye-ON and Eye-NON) and compared with Eye-HC. The analysis of OCT and brain volumetric measures was conducted comparing MOGAD-ON, MOGAD-NON, and HC groups. The analysis of covariance with a Bonferroni-adjusted post hoc test was used to test differences between groups and linear regression analysis to evaluate OCT/MRI associations; age and sex were considered as covariates. Results 24 (70.5%) patients had a prior ON. Median pRNFL and GCIPL thickness (um) was significantly reduced in Eye-ON vs EyeNON and HC (pRNFL: 69.4 (17.3), 89.6 (13.7), 98.2 (11.7), p < 0.001; GCIPL: 55.8 (8.7), 67.39 (8.7), 72.6 (4.5), p < 0.001). pRNFL and GCIPL thickness had a negative correlation with the number of ON episodes (p = 0.025 and p = 0.031, respectively). LGN volume fraction was significantly lower in patients with MOGAD-ON than in HC (0.33 (0.05) vs 0.39 (0.04), p = 0.002). The occipital cortical thickness was lower in MOGAD-ON compared with MOGAD-NON and HC (p = 0.010). In patients with MOGAD-ON, pRNFL correlated with LGN volume (p = 0.006), occipital thickness (p = 0.002), and the medial occipital cortex (p = 0.002), but not the lateral occipital lobe. Discussion Compared with HC, MOGAD-ON exhibits reduced retinal thickness, primarily influenced by the presence and the number of prior ON episodes. Moreover, MOGAD-ON demonstrates significant atrophy in the retinal, subcortical, and cortical regions of the visual pathway, distinguishing them from MOGAD-NON and HC. These findings suggest that in patients with MOGAD neurodegeneration is tightly correlated with damage to the involved pathway.