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.
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.
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.
Motor rehabilitation effectiveness in progressive multiple sclerosis (PMS) remains uncertain. We assessed whether task-oriented (TO) rehabilitation, with or without non-immersive virtual reality, improves upper limb function in PMS and evaluated magnetic resonance imaging (MRI) changes related to motor performance. Eighty-one progressive multiple sclerosis patients on B-cell depleting therapy were randomized to task-oriented rehabilitation with virtual reality (TO-VR), TO rehabilitation, or passive mobilization (CG) for 8 weeks. Upper extremity performance was measured with the Nine-Hole Peg Test (9-HPT), Action Research Arm Test (ARAT), AbilHand Test (ABILHAND), and Manual Ability Measure-36 (MAM-36). Upper limb function, neurological status, and MRI were evaluated at baseline, after rehabilitation, and at 3 months. Seventy-nine patients completed the study. No difference was observed in 9-HPT, but in the whole sample, ABILHAND improved post-treatment (p < 0.001), and ARAT improved on the left side (p = 0.014, false discovery rate adjusted p = 0.084). Additional gains appeared in several neurological tests. Brain volumes, morphometry, and diffusion indices were unchanged, while functional MRI showed increased connectivity post-treatment in TO-VR and TO groups, but not in CG. Connectivity changes were correlated, in particular, with clinical amelioration (ABILHAND) in both TO-VR (r = 0.54, p = 0.013) and TO groups (r = 0.50, p = 0.035). In PMS treated with high-efficacy therapy, TO rehabilitation, particularly when combined with VR, can improve motor function, inducing functional gains and plasticity in cerebral networks.
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.
Smokers with multiple sclerosis (MS) experience worse disease, yet underlying mechanisms remain unknown. Smoking disrupts bile acid and tryptophan metabolism in non-MS populations; both pathways involve host-microbiome co-metabolism and have been linked to MS. Determine whether smoking perturbs these metabolic pathways in MS and whether such alterations statistically mediate smoking's effect on MS severity. We analyzed serum bile acid, tryptophan, and tobacco-related metabolites across four independent MS cohorts (N = 266) using discovery-replication analyses. Mixed-effects regression assessed replicating associations with current smoking and nicotine exposure. Mediation analyses tested if replicating metabolites were potential mediators between smoking and MS severity. Hypothesis-generating metagenomic analyses explored smoking-associated gut-microbial shifts and metabolite correlations. Current smokers and nicotine-exposed MS subjects had reductions in bile acids and tryptophan metabolites, notably indolepropionate, a neuroprotective, anti-inflammatory gut-microbial metabolite. Lower indolepropionate statistically mediated ~20% of smoking's adverse effect on MS severity. Metagenomic analyses identified potential smoking-enriched MS-linked taxa, and that indolepropionate broadly co-occurs with microbial networks (e.g. Lachnoclostridium appeared inversely associated with indolepropionate in smokers with MS). Tobacco exposure disrupts host-microbiome tryptophan and bile acid metabolism in persons with multiple sclerosis, with indolepropionate depletion partially mediating disease severity, highlighting a potential mechanistic pathway warranting further investigation in MS smokers.
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.
Epiretinal membranes (ERMs) consist of glial and fibrocellular tissue, potentially arising from pathologic microgliosis, macrogliosis, and/or retinal pigment epithelium (RPE) cell migration. The clinical relevance of ERMs in people with multiple sclerosis (PwMS) remains largely unstudied. To investigate ERM prevalence and their associations with retinal layer thicknesses and disability measures in PwMS. PwMS exhibiting ERMs (ERM+) were matched 1:1 with PwMS without ERMs (ERM-) by optic neuritis (ON) history, multiple sclerosis (MS) subtype, age, sex, and race. Disability assessments included high-contrast/low-contrast letter acuity (HC-/LCLA), Expanded Disability Status Scale (EDSS), walking speed test (WST), manual dexterity test (MDT), and processing speed test (PST) scores. Among 1264 participants screened (1120 PwMS and 144 healthy controls [HCs]), ERMs were observed in 206 PwMS (18.4%) and 17 HCs (11.8%). ERM+ PwMS exhibited higher EDSS (1.0 ± 0.3, p = 0.002), longer WST (0.8 ± 0.2 seconds, p < 0.001), longer MDT (2.2 ± 0.5 seconds, p < 0.001), lower PST (-3.0 ± 1.4, p = 0.08), lower LCLA (-4.2 ± 1.1 letters, p < 0.001), and lower ganglion cell-inner plexiform layer (-1.8 ± 0.8 µm, p = 0.03), inner nuclear layer (-0.8 ± 0.3 µm, p = 0.01), outer nuclear layer (-1.6 ± 0.6 µm, p = 0.01), and RPE (-0.5 ± 0.1 µm, p < 0.001) thicknesses. Higher ERM stage correlated with greater disability. ERMs may identify a distinct MS phenotype, potentially characterized by pathological microglial and/or macroglial activity. ERMs may be a marker of similar global processes throughout the central nervous system that potentially contribute to greater overall disability.
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.
Advanced magnetic resonance imaging (MRI) of the cerebellum remains underutilized to detect early microstructural abnormalities associated with multiple sclerosis (MS) clinical disability. To examine associations between cerebellar magnetization transfer ratio (MTR) and clinical measures in people with radiologically isolated syndrome (RIS), early relapsing-remitting MS (RRMS), and primary progressive MS (PPMS). MTR data were acquired at 3.0 T across four sites in 53 RIS, 202 RRMS, 46 PPMS, and 42 control participants, as part of the Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo). Multiple linear regression analyses evaluated associations between cerebellar MTR and clinical measures. Across MS subtypes, lower cerebellar MTR was associated with greater motor disability, most notably with impaired manual dexterity (β = -1.04 to -0.67). After the false discovery rate correction, two associations remained statistically significant (p < 0.01): lower MTR in the inferior cerebellar peduncles was associated with worse cerebellar function in RRMS, and lower MTR in the anterior lobe was associated with worse manual dexterity in PPMS. This large, multi-center, hypothesis-generating study identified two statistically significant associations between cerebellar MTR and clinical disability, alongside several exploratory findings. These results suggest that cerebellar MTR may capture clinically relevant microstructural abnormalities in early MS.
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.
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.
Left-truncation is an unrecorded interval between multiple sclerosis (MS) onset and initial data in observational studies. This delay may bias estimates of disease-modifying therapy (DMT) effectiveness, especially when determined by patient or disease characteristics. To examine whether causal effect estimates of DMTs over the full disease course can be reliably derived from left-truncated registry data. We analysed data from MSBase (144 centres, 41 countries) to assess the impact of left-truncation on causal treatment effect estimates. Cox marginal structural models (MSMs) estimated hazard ratios (HRs) for relapses, disability worsening and improvement, considering left-truncation at random and not-at-random. Fixed-time truncation and multivariable adjustment were applied to remediate bias. The study included 5588 patients tracked from true MS onset. The null model, without left-truncation, estimated the DMT effect on relapse risk (HR = 0.64; 95% confidence interval (CI) = 0.54-0.77). Left-truncation inflated this estimate. Shorter random truncation (1 year) produced greater bias (HR = 0.34), decreasing with longer durations (3-year HR = 0.48). Truncation not-at-random biased relapse estimates (HR = 0.37). Disability outcomes were less sensitive. MSMs can reliably estimate DMT effectiveness in left-truncated MS registry data, although accuracy depends on truncation mechanism and duration. Both random and not-at-random truncation impact relapse estimates. Disability outcomes appear less sensitive. Fixed-time truncation and covariate adjustment mitigated bias.
The therapeutic landscape of multiple sclerosis (MS) has evolved substantially with earlier diagnosis and increasing use of highly effective disease-modifying therapies, leading to marked reductions in relapse activity and delayed disability progression. Despite these advances, cognitive impairment remains highly prevalent. This topical review summarises current evidence on cognitive impairment in MS, from the earliest and preclinical stages to paediatric and ageing populations. Particular emphasis is placed on emerging data-driven cognitive phenotypes, which capture the multidimensional nature of cognitive dysfunction and link distinct cognitive profiles to specific neuroimaging substrates. The review also discusses key neurobiological mechanisms underlying cognitive decline, including grey matter pathology, network dysfunction and synaptic alterations, as well as cognitive progression independent of relapse activity. Cognitive impairment represents a major source of disability. Implications for cognitive monitoring and management are considered, highlighting cognition as a core outcome and therapeutic target in contemporary MS care.
Comparative studies in paediatric-onset multiple sclerosis (PoMS) that also include highly effective monoclonal antibody therapies are rare. To compare treatment persistence, as a proxy of effectiveness and tolerability, across disease-modifying therapies (DMTs). Nationwide cohort study using Swedish MS Registry data on individuals with MS onset before age 18 from 2000 to 2024. Treatment persistence was analysed using Kaplan-Meier and Cox models, adjusted for demographics and treatment epoch. We included 383 individuals (69.2% female; median onset age 15.8 and 17.2 years at first DMT start), observed for a median 10.1 years (interquartile range (IQR): 5.5-15.5), yielding 934 treatment episodes: rituximab (272), injectables (263), natalizumab (248), fingolimod (86) and dimethyl fumarate (65). Median age at any treatment initiation, regardless of treatment sequence, was 18.9 years, with a median Expanded Disability Status Scale (EDSS) score of 1.5 (IQR: 0.0-2.0). Treatment persistence never dropped below 50% for rituximab, while median persistence was 35.6 months for natalizumab (95% confidence interval (CI): 28.8-44.9), 34.7 for dimethyl fumarate (95% CI: 21.7-56.9), 32.0 for fingolimod (95% CI: 21.1-48.1) and 17.6 for injectables (95% CI: 14.4-20.8). Compared to injectables, adjusted hazard ratios (HRs) for discontinuation were significantly lower for rituximab (0.09; 95% CI: 0.07-0.12), natalizumab (0.39; 95% CI: 0.31-0.48), fingolimod (0.41; 95% CI: 0.30-0.55) and dimethyl fumarate (0.49; 95% CI: 0.36-0.68). Rituximab displayed the highest treatment persistence, supporting B-cell depletion as a first-line option in PoMS.
Recent research has suggested that rituximab is not non-inferior to ocrelizumab in the treatment of relapsing multiple sclerosis (RMS). We compared the effectiveness of rituximab versus ocrelizumab in RMS. Individuals with RMS treated with rituximab or ocrelizumab with ⩾12 months of clinical follow-up and/or post-rebaseline magnetic resonance imaging (MRI) data were propensity-scored matched 1:1 and included. Primary outcomes were annualized relapse rate (ARR), ARR ratio and cumulative hazard of relapses. The secondary outcome was the proportion of each group demonstrating post-rebaseline radiological activity. In total, 538 individuals were included in the primary (clinical) outcome analysis and 350 individuals were included in the secondary (radiologic) outcome analysis. Over a median 2-year follow-up, very low ARR was observed in both groups (rituximab: 0.05 (95% CI: 0.03-0.08) versus ocrelizumab: 0.03 (95% CI: 0.02-0.05)). The adjusted ARR ratio for rituximab compared with ocrelizumab was elevated at 1.76 (95% CI: 0.70-4.59), and the adjusted cumulative hazard of relapses was also elevated for rituximab-treated individuals (HR = 2.17 (95% CI: 0.91-5.1)). Although our results suggest that rituximab may be inferior to ocrelizumab for relapse suppression, the rarity of relapses underpowered comparisons, and no definitive conclusions could be drawn.
Natalizumab (NTZ) effectively suppresses clinical and radiologic disease activity in paediatric patients with multiple sclerosis (MS), however, it is unclear whether serum neurofilament light chain (sNfL), a biomarker of neuronal injury, normalizes. To evaluate sNfL response to NTZ in the paediatric setting. sNfL was measured (single-molecule array) in 66 paediatric patients on NTZ for highly active MS in a single-centre between 2007 and 2023. sNfL levels were converted to age-adjusted z-scores for longitudinal assessment. sNfL declined significantly on NTZ, however, not all patients achieved normalized levels. Percentage of patients with sNfL < 90th percentile of healthy aged-matched individuals increased from 6.8% initially to 50%, 65% and 75% within 12, 24 and 36 treatment-months, respectively. Higher on-treatment levels were associated with higher baseline levels (B = 0.791, p < 0.001) and John Cunningham virus (JCV) seropositivity (B = 0.286, p < 0.001). sNfL > 97th percentile at 12 treatment-months indicated greater likelihood of disease activity in following year. NTZ treatment resulted in a significant reduction in sNfL levels, correlating with its clinical efficacy in paediatric MS. However, higher baseline sNfL concentrations were associated with a prolonged time to normalization. In addition, JCV seropositivity was linked to elevated NfL levels during treatment.
Limited evidence exists on how to use kappa free light chains (κFLCs) and oligoclonal bands (OCBs) in diagnosing intrathecal immunoglobulin synthesis (IgS). To compare different algorithms to define IgS. A retrospective analysis of the 2022 French cohort study was conducted. Patients were considered to have IgS if (1) the κFLC index was ⩾6.1, (2) OCB was positive, (3) the κFLC index was ⩾6.1 or OCB was positive, (4) the κFLC index was ⩾20 or OCB was positive, regardless of the κFLC index value, or (5) the κFLC index was ⩾20 or OCB was positive (with OCB tested only when the κFLC index was between 3.5 and 20). People with multiple sclerosis (MS) were compared with controls and with a subgroup of age- and sex-matched MS-mimicking disorders. Of 1531 patients, 675 had MS and 856 were controls (133 MS mimics). Agreement between OCB and κFLC index (⩾6.1) was high (89%). All tested algorithms demonstrated high accuracy in separating groups. Using the sequential approach (5) achieves higher specificity and a significant reduction in OCB testing. Using a simple cut-off point of 6.1 for routine screening is accurate, but testing for OCB when the κFLC index is between 3.5 and 20 increases specificity and should be prospectively studied in challenging cases.
Monitoring radiologic disease activity (RDA) is standard of care in multiple sclerosis (MS) because new lesions on magnetic resonance imaging (MRI) are associated with adverse outcomes and frequently prompt treatment reassessment and optimization. Coregistration-fusion comparison (CF) is more sensitive than conventional side-by-side comparison (CS) for detecting new lesions. To apply CF to identify CS-missed RDA on brain MRIs originally reported as "stable" and to evaluate whether CS-missed RDA predicts future disease activity. This retrospective cohort included 314 people with MS (pwMS) with three consecutive brain MRIs: previous MRI (t1), index MRI (t2; reported "stable" on CS), and subsequent MRI (t3). CF was applied to three-dimensional Fluid-Attenuated Inversion Recovery (FLAIR) to identify CS-missed new lesions on t2 versus t1. Future RDA was defined as ⩾1 new lesion on t3 versus t2. Clinical disease activity (CDA) was defined as clinical relapse and/or confirmed disability progression during follow-up after t2. CF identified 183 CS-missed new lesions in 65/314 pwMS (20.7%). Future RDA (70.8% vs. 16.1%; p < 0.001) and CDA (20.0% vs. 10.0%; p = 0.028) were more frequent in the CS-missed lesion group. Relapse and disability progression, when analyzed separately, did not differ between groups. CS-missed RDA independently predicted future RDA (adjusted odds ratio (aOR) = 10.43; 95% confidence interval (CI) = 5.31-20.46, p < 0.001) and CDA (aOR = 2.49; 95% CI = 1.10-5.65, p = 0.029). Each additional missed lesion at t2 was associated with more new lesions at t3 (incidence rate ratio (IRR) = 1.205; 95% CI = 1.184-1.226, p < 0.001). CF reclassified one in five pwMS reported as "stable" on CS as having CS-missed RDA, which predicted future disease activity.