Background and Objectives Paramagnetic rim lesions (PRLs) in multiple sclerosis (MS) indicate chronic, innate immune-mediated inflammation contributing to disease progression. Rim disappearance or attenuation is interpreted as a treatment response; however, it remains uncertain whether reduced susceptibility signal-likely reflecting decreased iron within the rim compartment-represents true resolution of chronic inflammation, natural lesion aging, and/or advanced tissue degeneration. Cross-sectionally, PRLs show variable rim conspicuity, enabling classification as Definite or Probable. We used quantitative MRI (qMRI) to assess underlying tissue destruction in Definite vs Probable PRLs in people with progressive MS (PwPMS). Methods One hundred six PwPMS (34 primary progressive [PP], 72 secondary progressive; age 56 +/- 10 years; median Expanded Disability Status Scale [EDSS] 5.5; 44% on disease-modifying therapy) underwent 3D-EPI and multishell diffusion MRI. PRLs (N = 155) were classified as Definite (N = 114) or Probable (N = 41). Prior clinical MRI scans estimated lesion age using an accelerated failure time model accounting for censoring. Whole-lesion, rim, and core regions were segmented; lesion size, quantitative susceptibility mapping, diffusion tensor imaging, Neurite Orientation Dispersions Density Imaging metrics, and T1 signal intensity were compared after multiple comparison correction. Results In total, 52% of PwPMS had >= 1 PRL; only 33% had Definite PRLs. Probable PRLs were more frequent in secondary vs PP MS (24% vs 9%, p = 0.05). Higher PRL counts were associated with younger age (p < 0.001), and PRLs were more often Definite in younger PwPMS (p < 0.0004). Participants with only Definite PRLs had shorter disease duration than those with >= 1 Probable PRL or no PRLs, and Probable PRLs were significantly older. Definite PRLs showed higher rim susceptibility (22 vs 8 ppb, p < 0.001); Probable PRLs demonstrated greater tissue disruption at qMRI-higher mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and FISO and lower neurite density index (NDI), and larger lesion size (all p < 0.001). Discussion In progressive MS, PRLs with lower rim susceptibility are more likely classified as Probable but may represent older lesions with greater tissue damage. Because chronic active lesions do not require iron pathologically and rims can fade over time, rim disappearance at MRI cannot be interpreted unequivocally as resolving inflammation and may reflect natural lesion evolution. Rim persistence may be a more informative marker of ongoing compartmentalized inflammation than rim disappearance is of its resolution.
Background and Objectives Anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1E) is traditionally considered as limbic encephalitis, but emerging evidence characterizes LGI1E as a whole-brain disorder. Furthermore, most neuroimaging studies have relied on cross-sectional designs and purely volumetric measures. Here, we integrate volume and fractal dimensionality (FD), a novel measure of structural complexity, to investigate cross-sectional and longitudinal brain changes in LGI1E and their associations with clinical and cognitive outcomes.Methods This observational study included 3T MRI, clinical evaluations, and comprehensive cognitive assessments at Charit & eacute; - Universit & auml;tsmedizin Berlin. Patients with LGI1E underwent up to 3 study visits at median disease durations of 10, 46, and 58 months. Disease severity was rated using the modified Rankin Scale (mRS) and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). T1-weighted MRI was processed using FreeSurfer to extract volumetric data, alongside fractal analysis to estimate FD. Dominance analysis determined the relative importance of FD and volume. Longitudinal changes were examined using linear mixed-effects models in relation to age at onset, disease duration, and relapses.Results We studied 34 patients with LGI1E (median age: 67 years; 29% female; 52 study visits) and 34 age-matched and sex-matched healthy controls. Patients showed clinical improvement in both mRS and CASE scores from peak illness to first study visit. Morphological analyses revealed reduced FD in fronto-temporo-parietal cortices and reduced FD and volume in subcortical areas, with FD more frequently emerging as the more important measure in affected areas. Furthermore, reduced FD in the pallidum at the first study visit was associated with less mRS improvement since peak illness, while reduced accumbens volume was linked to less CASE improvement. Reductions in both FD and volume in frontotemporal cortices and subcortical areas were associated with impaired overall cognition, with FD more frequently emerging as the dominant measure in brain-cognition associations. Finally, longer disease duration and relapses were associated with longitudinal reductions in FD and volume in subcortical areas.Discussion LGI1E is characterized by widespread morphological brain alterations beyond the limbic system, with meaningful associations to clinical outcomes, cognitive function, and longitudinal disease course. FD emerged as the more comprehensive imaging marker, capturing unique morphological brain characteristics undetected by volumetry analyses.
Background and Objectives Late-onset neutropenia (LON) is a rare, transient reduction in absolute neutrophil count (ANC) associated with anti-CD20 therapies. In multiple sclerosis (MS), data regarding severity, infectious outcomes, and predictors remain limited. We aimed to determine the incidence, characteristics, and predictors of LON in rituximab-treated people with MS (pwMS). Methods We conducted a registry-based retrospective multicenter cohort study of pwMS in Sweden exposed to rituximab between 2008 and 2024. Any LON was defined as ANC <1,500 cells/EL occurring at least 30 days after rituximab initiation. Grades 3-4 LON was defined as ANC <1,000 cells/EL, recording infectious complications for these events. Incidence rates (IRs) were calculated per 1,000 person-years, and event times were summarized as medians (interquartile range [IQR]). Predictors of LON events were evaluated using Cox regression with time-varying covariates and binary logistic regression. Results Among 2,686 rituximab-exposed pwMS, 6.2% (n = 165) experienced >= 1 LON event during a median follow-up of 7.8 years (IQR 5.7-9.8). The IR for any LON (grades 2-4) was 10.1/ 1,000 person-years (95% CI 8.6-11.8); the median time-to-first event was 360 days (IQR 112-1,017). Most events were mild, 5.3% (grade 2, n = 142). Grades 3-4 LON occurred for 1% (23 individuals; 36 events) and IR 2.1/1,000 person-years (95% CI 1.4-2.9). Ten infections occurred among LON grades 3-4 events, classifying 8 as severe. All individuals with infectious LON grades 3-4 events (48%) recovered after hospitalization, antibiotics/antivirals, and/or granulocyte colony-stimulating factor. Rituximab was rechallenged in 89% (32/36) of grades 3-4 events: 14 recurred and 2 complicated by infections. In time-dependent Cox models, higher accumulated rituximab exposure (HR 0.87, 95% CI 0.81-0.93) and prior injectable therapy (HR 0.66, 95% CI 0.45-0.96) were associated with a lower hazard of any LON. Exploratory binary analyses of LON grades 3-4 showed associations with prior natalizumab (odds ratio [OR] 2.8) and higher body mass index (OR 0.87), not confirmed in time-to-event models. Discussion In this large real-world cohort, high-grade LON (grades 3-4) events were rare and frequently complicated by infections. Mild (grade 2) LON events were often fluctuating and generally clinically uneventful. Rechallenge with rituximab was rarely complicated by serious adverse events. Prediction of LON remains challenging, highlighting the relevance of infection vigilance during anti-CD20 therapy.
Background and Objectives Antibodies against LGI1 and CASPR2 (LGI1/CASPR2-IgG) associate with forms of autoimmune encephalitis (AE) that improve with immunotherapy but often show long-term residual disability. We aimed to investigate whether autoantibody effector functions contribute to pathogenic mechanisms and might act as prognostic biomarkers in patients with LGI1/CASPR2-AE. Methods We included patients with LGI1/CASPR2-AE, sufficient clinical information, and 1 serum sample available. We assessed the functional profile of LGI1/CASPR2-IgG using in vitro cell-based assays for complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC). Outcome was measured using the modified Rankin Scale (mRS) and the Clinical Assessment Scale in AE. Results We enrolled 55 patients (LGI1 = 31 and CASPR2 = 24). Coexistent ADCC and ADCP (ADCC+/ADCP+) were found in 28/55 patients (10/31 with LGI1 and 18/24 with CASPR2), while an isolated ADCP (ADCC-/ADCP+) was detected in 15 patients (12 with LGI1-IgG and 3 with CASPR2-IgG), and an isolated ADCC (ADCC+/ADCP-) was detected in 2 LGI1-IgG-positive patients. Because most patients (84%) showed a combination of IgG1/IgG3 and IgG4 subclass, no specific functional profiles could be identified according to the predominant subclass. Quantitative ADCP levels showed only a moderate correlation with CASPR2/LGI1-IgG titers (rho = 0.35, p = 0.02), while ADCC showed a moderate/strong correlation (rho = 0.54, p = 0.002). None of the patients showed CDC activation. In a multivariate logistic regression model (including functional profile, rituximab treatment, relapsing course, and cognitive impairment at onset), the ADCC+/ADCP + profile was the only predictor of poor outcome (mRS > 1, OR: 10.97 [95% CI 1.96-106.9]; p = 0.014). Discussion ADCC and ADCP, but not CDC, are common effector functions of LGI1/CASPR2-IgG, and their presence correlates with long-term poor outcome, suggesting that they might represent a useful prognostic biomarker and suggest additional pathogenic mechanisms. We provide the proof- of principle for a framework that could be applied to other autoantibody-mediated disorders.
Background and Objectives A proportion of patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) experience relapses, but biomarkers predicting which patients are likely to relapse are not yet widely available. The MOG alpha 1 isoform is the most commonly used in diagnostic MOG antibody assays, while the clinical relevance of antibodies against other MOG isoforms remains unclear. Methods This study used a stepwise approach using international multicenter serum samples collected prospectively. First, diagnostic accuracy of the MOG alpha 1 and beta 1 isoforms was compared using 748 consecutive sera from Korean patients suspected of having demyelinating disease of the CNS. Next, the predictive values of antibodies against each of 7 MOG isoforms for relapses were assessed on sera from Korean patients with MOGAD (derivation cohort). Finally, the association between MOG isoform antibody with relapses was validated in 2 independent cohorts: a Korean validation cohort (n = 49) and a UK validation cohort (n = 56). Results Both MOG alpha 1 antibody and MOG beta 1 antibody assays had comparable diagnostic accuracy. Among patients with MOGAD, the presence of MOG alpha 3 antibody was associated with a higher risk of relapse, with a hazard ratio of 4.3 in the derivation cohort (log-rank p < 0.001). This finding was also confirmed in an independent smaller Korean validation cohort (log-rank p = 0.009) and in a subgroup of UK validation cohort (log-rank p = 0.048). Discussion The presence of MOG alpha 3-IgG in patients with MOGAD may be associated with an increased risk of relapse, indicating that early preventive treatment strategies may be appropriate in these individuals. MOG beta 1-IgG demonstrated diagnostic accuracy similar to MOG alpha 1-IgG.Classification of Evidence This study provides Class II evidence that MOG alpha 1 antibody and MOG beta 1 antibody assays have comparable diagnostic accuracy for MOGAD.
