Massimiliano Calabrese

Background and Objectives: Gait impairment is a common and disabling manifestation of multiple sclerosis, affecting mobility, independence, and quality of life. However, gait differences between people with multiple sclerosis and healthy individuals have not been well characterized within corresponding age strata. Methods: This exploratory cross-sectional study included 23 participants with relapsing–remitting multiple sclerosis and 50 healthy individuals aged 20–69 years. Participants underwent instrumented gait analysis at self-selected walking speed using a Vicon motion-capture system synchronized with force plates. Spatiotemporal parameters, lower-limb and pelvic kinematics, and ground reaction forces were assessed. Between-group comparisons were performed within predefined age strata (20–39, 40–49, 50–59, and 60–69 years) using one-dimensional Statistical Parametric Mapping and non-parametric analyses. Results: Across age strata, participants with relapsing–remitting multiple sclerosis generally showed slower walking and shorter stride-related measures, together with phase-specific multi-joint kinematic and ground reaction force deviations. Estimated gait-speed and stride-length differences were largest in the youngest stratum, whereas mean stride width was 0.04 m greater in both the youngest and oldest strata; however, confidence intervals were wide, and no between-stratum contrast was tested. Exploratory threshold crossings were not interpreted as evidence that the underlying effects differed among strata. Conclusions: The age-stratified, participant-level analysis identified recurrent differences in forward progression, lower-limb and pelvic kinematics, and loading and propulsion. These findings provide a quantitative description that may support individualized gait assessment and hypothesis generation for adequately powered studies. They do not establish an independent effect of age or an age-by-disease interaction.

Cortical lesions have evolved from a largely overlooked pathological feature to a central component of multiple sclerosis pathophysiology, yet their biology, clinical relevance and response to treatment remain incompletely understood. In this Review, we trace how pathological studies established the frequency and heterogeneity of cortical demyelination, with particular attention to subpial lesions and inflammation at the brain–cerebrospinal fluid interface. We examine the neuropathological and imaging evidence linking cortical pathology to meningeal inflammation, neuroaxonal injury and progression independent of relapse activity, and assess how emerging magnetic resonance imaging approaches for detecting and monitoring cortical lesions contribute to diagnosis and prognosis across the multiple sclerosis spectrum. Last, we discuss the sensitivity limits of imaging, the effects of disease-modifying therapies on this compartmentalized damage, and how quantitative magnetic resonance imaging, fluid biomarkers and artificial intelligence could help define biologically meaningful cortical endotypes and guide future therapeutic development.

Objective: To determine whether myelin‐sensitive quantitative MRI reveals microstructural abnormalities in normal‐appearing cortex (NACtx) in myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), indicating that conventional MRI underestimates remission residual cortical injury. Methods: Forty‐two patients with MOGAD in remission and 42 age‐ and sex‐matched healthy controls (HCs) underwent cognitive testing (Rao Brief Repeatable Battery), disability rating (Expanded Disability Status Scale) and 3‐T MRI, including three‐dimensional T1‐weighted, T2‐weighted and double‐inversion‐recovery sequences to identify cortical lesions and delineate NACtx. T1‐ to T2‐weighted ratio z‐scores (T1/T2r), magnetisation transfer ratio (MTR) and magnetisation transfer saturation (MTsat) were derived in global and lobar NACtx; MT imaging was available in 22 patients and 24 controls. Linear mixed‐effects models compared MOGAD with HCs and cortical (history of at least one acute cortical attack) with non‐cortical phenotypes, adjusting for age, sex, site and cortical thickness with false‐discovery‐rate correction. Results: Sixteen of 42 MOGAD patients had a cortical phenotype; cortical lesions at remission were present in 4 of 42 (9.5%), all with a cortical phenotype. MTsat metric, but not T1/T2r or MTR, detected NACtx alterations in the MOGAD cohort compared with HCs. Cortical MOGAD phenotype showed reduced MTsat in global, frontal, temporal, limbic, hippocampal and insular NACtx regions vs. HCs, whereas non‐cortical MOGAD was similar to HCs. Exploratory analyses suggested lower MTsat in temporal, limbic, hippocampal and insular NACtx regions in cortical MOGAD with cognitive impairment than in cognitively preserved MOGAD. Interpretation: Myelin‐sensitive MTsat reveals persistent, regionally specific abnormalities in normal‐appearing cortex in cortical MOGAD and is a promising marker of residual cortical damage linked to cognitive dysfunction.

To investigate the intrathecal effect of cladribine tablets on cerebrospinal fluid (CSF) inflammatory proteomic profile, cortical lesions (CLs), paramagnet

Objective: To evaluate the real-world effectiveness and safety of eculizumab in patients with AQP4-IgG–positive neuromyelitis optica spectrum disorder (NMOSD) and to identify predictors of disability outcomes. Methods: This multinational, retrospective cohort study analyzed data from 46 patients across 26 centers. The outcomes included the annualized relapse rate (ARR), relapse-free status, change in expanded disability status scale (EDSS) scores, and adverse events. To identify predictors of EDSS improvement or worsening, patients were stratified into subgroups (improved vs. stable/worsened) at each follow-up time point and compared based on demographic, clinical, and radiological variables. Results: This retrospective cohort study included 46 patients with AQP4-IgG-positive NMOSD from 26 centers, followed for a mean of 27.3 months. The mean ARR significantly decreased from 1.1 in the 2 years pre-treatment to 0.1 during eculizumab therapy. The relapse-free rate increased from 6.5% pre-treatment to 80.4%. Mean EDSS scores improved from 4.2 at baseline to 3.6 at 24 months. The presence of area postrema syndrome was associated with a favorable prognosis, while the presence of spinal attacks was associated with a poor prognosis at 12 months. Adverse events occurred in 7 patients (18.9%), leading to permanent discontinuation in only two. Conclusion: Eculizumab demonstrated robust real-world effectiveness in reducing relapse rates and stabilizing disability, with an acceptable safety profile. Clinical outcomes may be influenced by attack phenotype, underscoring the importance of early intervention.

The objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS). This five-year prospective study included 80 treatment-naïve patients with RRMS enrolled at time of diagnosis. All patients underwent a lumbar puncture, regular neurologic evaluations including an Expanded Disability Status Scale (EDSS) assessment every 6 months, and an annual 3T brain MRI. PIRA was defined as having a confirmed disability progression independent of relapse activity. CSF levels of 68 inflammatory molecules were evaluated in combination with white matter and cortical lesion number (CLn) and volume, and regional gray matter thickness and volume. During the follow-up, 23 patients with RRMS (28.8%) experienced PIRA. At diagnosis, participants with PIRA were older (44.0 ± 10.7 vs 37.4 ± 12.4, p = 0.017) and with more disability (median EDSS score [interquartile range] of 3 [range 2-4] for PIRA vs 1.5 [range 1-2] for no PIRA group, p < 0.001). Random forest selected LIGHT, CXCL13, sTNFR1, sTNFR2, CCL7, MIF, sIL6Rbeta, IL35, CCL2, and IFNβ as the CSF markers best associated with PIRA. sTNFR1 (hazard ratio [HR] 10.11 [2.61-39.10], p = 0.001), sTNFR2 (HR 5.05 [1.63-15.64], p = 0.005), and LIGHT (HR 1.79 [1.11-2.88], p = 0.018) were predictors of PIRA at regression analysis. Baseline thalamus volume (HR 0.98 [0.97-0.99], p = 0.005), middle frontal gyrus thickness (HR 0.05 [0.01-0.72], p = 0.028), and CLn (HR 1.15 [1.05-1.25], p = 0.003) were MRI predictors of PIRA. A specific intrathecal inflammatory profile associated with TNF superfamily markers, CLn, and atrophy of several cortical and deep gray matter regions, assessed at time of diagnosis, is predictive of PIRA in early MS.