Helmut Butzkueven

The choroid plexus (CP) is increasingly recognised as a contributor to chronic inflammation in multiple sclerosis (MS). While CP enlargement is reported in early MS, its role in secondary progressive MS (SPMS) is poorly understood. We aimed to quantify CP volume in SPMS and compare it to relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS), and to assess associations with disease severity and progression. CP volumes were manually segmented and normalised to intracranial volume. Age correction was applied using a healthy control cohort. Cross-sectional and longitudinal analyses evaluated relationships with ventricular volume, lesion burden, and brain atrophy. CP volume increased significantly across MS phenotypes: SPMS patients showed 26% higher CP volume than CIS (p=0.010) and 17% higher than RRMS (p=0.034). CP enlargement in SPMS was independent of ventricular size, indicating distinct underlying mechanisms. While lesion burden was the primary determinant of brain atrophy in SPMS, longitudinal data revealed significant associations between CP volume, chronic lesion expansion (r2=0.31), and brain volume loss (r2=0.52). CP enlargement is a progressive feature of MS, not driven by ventricular expansion. In SPMS, it may reflect ongoing inflammation contributing to tissue damage, supporting its role as a biomarker.

Objective: Rituximab is an anti-CD20 monoclonal antibody used in patients with anti-NMDAR antibody (Ab)-mediated encephalitis as both an acute escalation therapy and a longer term relapse risk-reduction treatment. The potential long-term benefit of a single course administered during the acute disease phase on future relapse risk is uncertain. Moreover, the optimal dosing duration to reduce relapse risk is unknown. The aim of this study was to evaluate the effect of a single course of rituximab on relapse incidence. We also studied the duration of effect of a course of rituximab in adult patients with anti-NMDAR Ab-mediated encephalitis. Methods: We recruited 67 patients with anti-NMDAR Ab-mediated encephalitis from 10 Australian hospitals. Rituximab exposure was quantified as a time-varying covariate in Cox proportional hazard models. Results: A single course of rituximab was associated with longer time to first relapse (hazard ratio [HR] 0.11, 95% CI 0.02-0.70, p = 0.02). For patients in whom redosing is considered, rituximab was associated with longer time to first relapse at 6 months after the last infusion, after adjusting for concurrent immunotherapies and the presence of ovarian teratoma at disease onset (HR 0.05, 95% CI 0.00-0.48, p = 0.005). The treatment effect did not persist out to 12 months after a given course (HR 0.60, 95% CI 0.15-2.44, p = 0.47). Conclusions: A single course of rituximab reduces the risk of relapse of anti-NMDAR antibody-mediated encephalitis. In select patients for whom redosing of rituximab is considered, administration at 6 months delays relapses. Methods: This study provides Class IV evidence that rituximab delays relapses in patients with anti-NMDAR antibody-mediated encephalitis.

Progression independent of relapse activity (PIRA) is a significant contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (MS). Prior studies have used varying PIRA definitions, hampering the comparability of study results. To compare various definitions of PIRA. This cohort study involved a retrospective analysis of prospectively collected data from the MSBase registry from July 2004 to July 2023. The participants were patients with MS from 186 centers across 43 countries who had clinically definite relapsing-remitting MS, a complete minimal dataset, and 3 or more documented Expanded Disability Status Scale (EDSS) assessments. Three-hundred sixty definitions of PIRA as combinations of the following criteria: baseline disability (fixed baseline with re-baselining after PIRA, or plus re-baselining after relapses, or plus re-baselining after improvements), minimum confirmation period (6, 12, or 24 months), confirmation magnitude (EDSS score at/above worsening score or at/above threshold compared with baseline), freedom from relapse at EDSS score worsening (90 days prior, 90 days prior and 30 days after, 180 days prior and after, since previous EDSS assessment, or since baseline), and freedom from relapse at confirmation (30 days prior, 90 days prior, 30 days before and after, or between worsening and confirmation). For each definition, we quantified PIRA incidence and persistence (ie, absence of a 3-month confirmed EDSS improvement over ≥5 years). Among 87 239 patients with MS, 33 303 patients fulfilled the inclusion criteria; 24 152 (72.5%) were female and 9151 (27.5%) were male. At the first visits, the mean (SD) age was 36.4 (10.9) years; 28 052 patients (84.2%) had relapsing-remitting MS, and the median (IQR) EDSS score was 2.0 (1.0-3.0). Participants had a mean (SD) 15.1 (11.9) visits over 8.9 (5.2) years. PIRA incidence ranged from 0.141 to 0.658 events per decade and persistence from 0.753 to 0.919, depending on the definition. In particular, the baseline and confirmation period influenced PIRA detection. The following definition yielded balanced incidence and persistence: a significant disability worsening compared with a baseline (reset after each PIRA event, relapse, and EDSS score improvement), in absence of relapses since the last EDSS assessment, confirmed with EDSS scores (not preceded by relapses within 30 days) that remained above the worsening threshold for at least 12 months. Incidence and persistence of PIRA are determined by the definition used. The proposed standardized definition aims to enhance comparability among studies.

Background: Monitoring of cognition in multiple sclerosis (MS) is critical. Traditional cognitive testing is resource intensive and insensitive to subtle changes. Digital tests could address this need; however, their long-term usability remains unexplored. Objective: To determine the long-term acceptability and feasibility of digital cognitive measures in MS. Methods: Participants with relapsing or secondary progressive MS were prospectively enrolled. MSReactor, a web-based test evaluating processing speed, attention and working memory, was performed 6-monthly for up to 36 months. Patient acceptability, anxiety, depression and quality of life were collected concurrently. Correlations between test acceptability, psychosocial measures, physical disability and cognition were analysed using Spearman's correlation. Results: This study included participants with complete data at 12 (n = 601), 24 (n = 280) and 36 (n = 317) months. Attrition after 12 months was low (3.5%). Acceptability of MSReactor was high, although interest and enjoyment decreased slightly. Minor correlations were observed between reduced acceptability and increased anxiety, depression and disability and lower quality of life. Conclusions: Long-term cognitive monitoring was highly acceptable. We identified characteristics, such as increased anxiety, that were associated with reduced acceptability. Patients with these characteristics may benefit from support to maintain monitoring. These findings underscore the potential for integrating such tools into MS care.