BACKGROUND:Identifying long-term outcome substrates in pediatric multiple sclerosis (Ped-MS) can inform treatment selection. We investigated clinical/magnetic resonance imaging (MRI) correlates over a median 12.3-year follow-up. METHODS:Fifty-two Ped-MS patients and 23 healthy controls underwent baseline 3.0 T MRI. Neurological evaluations were performed every 6 months. MRI metrics included regional lesion burden, brain and choroid plexus (CP) volumes, diffusion tensor-derived fractional anisotropy (FA), averaged in normal-appearing white matter (NAWM). Multivariable Cox, Andersen-Gill, linear regression models identified long-term outcome correlates. RESULTS:At follow-up, 69% relapsed, 21% had 6-month confirmed disability worsening (6m-CDW), and 35% showed EDSS worsening. Infratentorial lesion number (hazard ratio (HR) = 1.09, 95% confidence interval (CI) = 1.02 to 1.18), spinal cord lesion presence (HR = 2.45, 95% CI = 1.18 to 5.10), and thalamic volume (HR = 0.77, 95% CI = 0.60 to 0.99) were associated with shorter time to first relapse; high-efficacy treatment (HET) exposure with longer (HR = 0.20, 95% CI = 0.06 to 0.68), and CP volume (HR = 1.58, 95% CI = 0.93 to 2.68) was associated marginally. WM lesion volume (HR = 1.04, 95% CI = 1.01 to 1.06) and HET exposure (HR = 0.21, 95% CI = 0.11 to 0.40) were associated with higher/lower overall relapse risk, respectively; baseline EDSS (HR = 1.29, 95% CI = 0.96 to 1.73), spinal cord lesion presence (HR = 1.52, 95% CI = 0.95 to 2.44), and CP volume (HR = 1.35, 95% CI = 1.00 to 1.83) contributed marginally. Younger age (HR = 0.82, 95% CI = 0.68 to 0.98) and NAWM FA (HR = 0.67, 95% CI = 0.51 to 0.88) were associated with earlier 6m-CDW; NAWM FA with EDSS worsening (β = -0.26, 95% CI = -0.50 to -0.03). CONCLUSION:Advanced MRI markers and HET exposure associate with long-term outcomes in Ped-MS.

The therapeutic scenario for multiple sclerosis (MS) has expanded rapidly over the last few years. Among the available treatments, anti-CD20 monoclonal antibodies, including rituximab, ocrelizumab, ofatumumab, and ublituximab, have shown significant results in reducing disease activity and slowing progression, particularly in relapsing MS. The distinct mechanisms of action, including the pharmacokinetic and pharmacodynamic profiles as well as the immunogenicity of these drugs, require careful consideration to tailor treatment for individual patients. A comprehensive review of the literature was conducted by searching PubMed and evaluating key studies, trials, and congress abstracts related to the use of anti-CD20 monoclonal antibodies. The analysis focused on the pharmacokinetic and pharmacodynamic profiles, as well as the immunogenicity, of anti-CD20 therapies currently available, with particular emphasis on the recently approved ublituximab. Ocrelizumab is effective in both relapsing-remitting and primary-progressive MS, using antibodydependent cellular cytotoxicity (ADCC) as its primary mechanism of action, with intravenous and subcutaneous administration options ensuring flexible treatment delivery. Ofatumumab depletes B-cells through enhanced complement-dependent cytotoxicity, offering convenient monthly subcutaneous self-administration. Ublituximab's unique glycoengineered fragment crystallizable region enhances ADCC, resulting in rapid B-cell depletion and potentially improving its safety profile. Ublituximab allows for a shorter infusion time without requiring post-infusion monitoring after the second dose, provided there have been no prior reactions. Understanding the characteristics of different anti-CD20 monoclonal antibodies is critical for optimizing treatment, enhancing patient outcomes, and minimizing treatment burden. Ublituximab represents a promising option, offering a shorter infusion time and higher ADCC activity, which complements existing treatments such as ocrelizumab and ofatumumab.

INTRODUCTION:Pediatric-onset multiple sclerosis (POMS) is uncommon but clinically relevant, as inflammatory demyelination occurs during brain maturation. Compared with adult-onset MS, POMS is characterized by higher early relapse rate and MRI inflammatory activity, better recovery from individual relapses, yet disability milestones are reached at a younger age. Early identification is essential to avoid treatment delays, while preventing misdiagnosis of mimics. AREAS COVERED:This review summarizes the diagnostic work-up of children with a first acquired demyelinating syndrome, differential diagnosis, the role of MRI, cerebrospinal fluid (CSF) markers, antibody testing, serum neurofilament light chain, optical pathway assessment and the 2024 McDonald criteria. Early prognostic factors and therapeutic implications are discussed, including evidence supporting early high-efficacy therapies in selected children. References for this review were identified through searches of PubMed, authors' own files, abstracts presented at main congresses, from 1 January 1979 to 1 July 2026. EXPERT OPINION:Early identification of POMS requires integrated assessment of clinical presentation, MRI lesion topography, CSF findings, antibody testing, and emerging biomarkers. Although central vein sign, paramagnetic rim lesions, kappa free light chains and serum neurofilament light chain may refine stratification, pediatric validation remains incomplete. Earlier, more accurate diagnosis should support individualized treatment to preserve long-term outcomes.

Pediatric-acquired demyelinating syndromes, including multiple sclerosis (MS), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) constitute distinct entities arising during critical periods of neurodevelopment. Early and effective treatment is therefore crucial to prevent long-term disability. Converging evidence supports a central role of B-cells in central nervous system autoimmunity, extending beyond antibody production to include antigen presentation, cytokine production, and T-cell modulation. B-cell-depleting anti-CD20 therapies are increasingly used in this setting, but the strength and consistency of evidence differ substantially across diseases and individual drugs. Available data indicate that anti-CD20 treatment provides significant suppression of relapses and MRI activity in pediatric MS. Rituximab, although used off-label, has shown a significant reduction in annualized relapse rates and inflammatory MRI activity across observational cohorts. Ocrelizumab has the most advanced pediatric evidence among approved anti-CD20 agents, including dose-selection data from OPERETTA I and comparative Phase 3 data from OPERETTA II, where it reduced MRI activity compared with fingolimod and showed sustained B-cell depletion. In contrast, evidence for ofatumumab in pediatric MS remains limited to very small case series, although dedicated pediatric trials are ongoing. No pediatric data are currently available for ocrelizumab or ofatumumab in AQP4+NMOSD or MOGAD. In pediatric AQP4+NMOSD, rituximab remains the best-supported anti-CD20 option, with observational studies showing relapse reduction and a close relationship between CD19-positive B-cell repopulation and breakthrough disease activity. In relapsing MOGAD, responses to rituximab are heterogeneous: some cohorts report reduced relapse frequency during sustained B-cell depletion, whereas others describe continued relapses despite treatment, suggesting that pathogenic mechanisms beyond CD20-positive B-cells, including long-lived plasma cells or non-B-cell immune pathways, may contribute to disease activity. Across pediatric cohorts, anti-CD20 therapies are generally well tolerated. Infusion-related reactions are common but usually mild, infections are typically non-severe, and hypogammaglobulinemia, leukopenia, delayed neutropenia, vaccine-response attenuation, and early B-cell repopulation require individualized monitoring. Upcoming trials of ofatumumab, ublituximab, and rituximab-based strategies in MOGAD will be critical to refine pediatric dosing, define biomarkers of treatment durability, and establish age-specific safety surveillance for the developing immune system. This review summarizes knowledge on B-cell maturation in early life and anti-CD20 treatment outcomes in pediatric patients with these conditions. Safety and tolerability considerations, optimal timing of therapy, and remaining gaps in evidence are also explored, highlighting the need for age-specific biomarkers and prospective studies to better define individualized treatment strategies and to clarify long-term consequences of B-cell-depleting therapies in children.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy where disability is largely relapse-driven. Cerebrovascular risk factors (cVRFs) may exacerbate astrocytic and small-vessel injury. Therefore, we investigated their impact on MRI damage and disability in NMOSD. Twenty-eight aquaporin 4 immunoglobulin G-positive NMOSD patients and 56 age- and sex-matched healthy controls (HC) underwent 3T brain and cervical MRI, cVRF and neurological assessment, including the Expanded Disability Status Scale (EDSS). Brain T2-hyperintense white matter lesion volume (WMLV), normalized global and regional volumes, normal-appearing WM (NAWM) fractional anisotropy (FA) and mean diffusivity (MD), diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) index, spinal cord lesion volume (SCLV) and normalized cross-sectional area (nCSA) were quantified. cVRF were present in 57

In multiple sclerosis (MS), functional network abnormalities arise as structural damage accumulates. However their biological basis and spatial distribution remain unclear. This study investigated the associations between MS-related functional network abnormalities and physiological gene expression using the Allen Human Brain Atlas (AHBA). Five-hundred fifty-eight MS patients and 214 healthy controls (HC) underwent neurological assessment and 3 T MRI; 491 patients also completed a neuropsychological evaluation. Resting-state functional MRI was used to generate degree centrality maps to identify network topography alterations. Spatial correlations between centrality abnormalities (p < 0.01 uncorrected) and the expression of 3634 MS-related genes was evaluated using AHBA and the Multimodal Environment for Neuroimaging and Genomic Analysis. Genes showing significant associations (p < 0.001, R2 ≥ 0.15) underwent pathway enrichment analysis (p < 0.05, Bonferroni-corrected). Compared to HC, MS patients showed higher centrality mainly in the default-mode network (DMN), linked to genes regulating inflammation resolution and immune functions, and lower centrality in regions mostly located in the salience network and cerebellum, associated with genes implicated in cytokine response. Compared to HC and relapsing-remitting MS, progressive MS patients showed higher centrality in DMN and cerebellar regions, correlating with genes related to epigenetic and mitochondrial functions. Of the MS cohort, 144 (29.3%) patients were cognitively impaired. Compared to cognitively preserved MS and HC, they showed higher centrality in DMN and mesial temporal lobe regions, negatively correlated with expression of DNASE1, regulating DNA degradation, and CP, encoding ceruloplasmin, involved in iron homeostasis and potentially iron-driven neurodegeneration. Physiological regional gene expression spatially correlates with MS-related functional network alterations. Biological factors may shape regional vulnerability or resilience to MS pathology, influencing functional reorganization.

Sleep modulates brain-fluid transport and glymphatic clearance. In multiple sclerosis (MS), lower diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index has been reported, but whether sleep quality contributes to DTI-ALPS variability is unknown. We assessed whether sleep disturbances are associated with a lower DTI-ALPS index in MS. 77 MS patients and 84 age- and sex-matched healthy controls (HC) underwent 3 T brain MRI. In MS patients, disability was assessed with the expanded disability status scale (EDSS), sleep quality with the Pittsburgh sleep quality index (PSQI; >5 defining sleep disturbances), and fatigue with the modified fatigue impact scale (MFIS). DTI-ALPS index was derived from fractional anisotropy (FA) maps after lesion exclusion. Sleep disturbances were reported in 32 (41.6

BACKGROUND AND OBJECTIVES:The choroid plexus (ChP) regulates CSF production and CNS homeostasis. In multiple sclerosis (MS), ChP enlargement occurs early in the disease course, yet its normative lifespan trajectory and relationship with MS-specific features remain poorly defined. We aimed to define the normative ChP volume model, to characterize its trajectory across the healthy lifespan, and to assess ChP enlargement in MS using z-scores, evaluating associations with demographic, clinical, MRI, and genetic variables, including human leukocyte antigen (HLA) and non-HLA polygenic risk scores (PRSs). METHODS:This monocentric retrospective cross-sectional study included 461 healthy controls (HCs) and 727 patients with MS (age 18-70 years) who underwent 3T brain MRI and neurologic assessment. ChP volumes were quantified using ASCHOPLEX, normalized for head size, and modeled in HCs. We derived age-related normalized ChP volume (NChPV) trajectory across adulthood. Z-scores for patients with MS were computed. PRSs were calculated from established MS susceptibility loci, encompassing both HLA and non-HLA regions. RESULTS:In HCs, normalized brain volume, lateral ventricle volume, and its squared term were independently associated with NChPV (R2 = 0.54). Model-derived NChPV trajectory remained stable until age 35 and then increased nonlinearly (p-FDR<0.002), with annualized growth rates rising from 0.24% at age 35 to over 0.7% in later decades. Patients with MS had significantly higher NChPV z-scores than controls (estimated mean [EM] z-score = 0.452, p-FDR<0.001), consistently across phenotypes (p = 0.744) and ages, with no evidence of age-dependent variation (β = 0.02 × 10-2, p = 0.957). In cross-sectional analyses, NChPV z-scores, already elevated 1 year after disease onset (EM z-scores = 0.252, p-FDR<0.001), increased further up to 5 years after disease onset (EM z-scores = 0.463, p-FDR<0.001), before plateauing. Higher z-scores were associated with greater T2-hyperintense white matter lesion volume (β = 0.012 × 10-2, p < 0.001) and HLA genetic burden (standardized β = 0.097, p = 0.038), but not non-HLA PRSs (p ≥ 0.177). DISCUSSION:We provided a normative ChP volume model, characterized its trajectory across the healthy lifespan, and showed early, consistently higher ChP volume in patients with MS across ages and disease durations in cross-sectional analyses, linked to inflammatory lesion burden and HLA-mediated genetic risk. The ChP may represent a noninvasive biomarker of neuroinflammation and HLA-related immunogenetic background in MS.

BACKGROUND:Only a few longitudinal studies, with follow-up duration up to 3.6 years, have assessed the substrates of relapses and disability in aquaporin-4 (AQP4) IgG-positive neuromyelitis optica spectrum disorders (NMOSD), primarily focusing on clinical and conventional MRI variables. OBJECTIVE:We evaluated the association of clinical and MRI measures, including a comprehensive multimodal advanced MRI protocol, with key long-term clinical outcomes in AQP4 IgG-positive NMOSD patients over a median follow-up of 8.5 years (interquartile range [IQR] = 3.5; 13.3). METHODS:Forty-six NMOSD patients and 77 healthy controls underwent 3T brain MRI. In patients, neurological evaluations were collected at baseline and every six months. Time to first relapse and 6-month confirmed disability worsening (6m-CDW) were recorded. Lesion volume and topography, global and regional brain volumes, normal-appearing white matter and gray matter fractional anisotropy and mean diffusivity, choroid plexus volume, enlarged perivascular spaces number and glymphatic system function were assessed. RESULTS:During the follow-up, 30% patients experienced at least one clinical relapse, while 22% had 6m-CDW. Higher number of previous attacks (hazard ratio [HR] = 1.17, 95%-confidence interval [CI] = 1.04; 1.32) and presence of anterior optic pathway lesions (HR = 4.92, 95%-CI = 1.12; 21.852) were risk factors independently associated with a shorter time to a first clinical relapse; lower thalamic volume was marginally associated (HR = 0.93, 95%-CI = 0.87; 1.00). Presence of cervical cord lesions (HR = 3.93, 95%-CI = 1.16; 13.31) and lower normalized cortical volume (HR = 0.94, 95%-CI = 0.89;0.99) were risk factors independently associated with a shorter time to 6m-CDW; higher number of previous attacks contributed marginally (HR = 1.19, 95% = 0.99; 1.43). High efficacy treatments (HETs) delayed time to first relapse and 6m-CDW. CONCLUSIONS:Previous attacks, optic nerve/spinal cord involvement, cortical/thalamic atrophy and the use of HETs associate with long-term outcomes in NMOSD.

In multiple sclerosis (MS), susceptibility-weighted imaging (SWI) may reveal white matter lesions (WML) with a paramagnetic rim (“paramagnetic rim lesions” [PRLs]) or diffuse hypointensity (“core-sign lesions”), reflecting different stages of WML evolution. Using the soma and neurite density imaging (SANDI) model on diffusion-weighted magnetic resonance imaging (MRI), we characterized microstructural abnormalities of MS PRLs and core-sign lesions and their clinical relevance. Forty MS patients and 20 healthy controls (HC) underwent a 3 T brain MRI. Using SANDI, the fractions of neurite (fneurite) and soma (fsoma) and size of soma (rsoma) were quantified in PRLs (including their core and rim separately), and core-sign lesions identified on SWI-phase. Among 1811 WMLs, 122 (6.7

Smouldering disease in multiple sclerosis (MS) refers to chronic central nervous system processes that occur beyond acute inflammation, driving long-term disability. Although current therapies effectively reduce relapse rates and MRI lesions, many individuals experience progression independent of relapse activity. While clinical progression is uncommon during childhood or adolescence, growing evidence suggests that subclinical progressive disease biology is already active even in this young age group, warranting early intervention to preserve function. Conventional MRI, while critical for diagnosis, lacks sensitivity for subtle damage. Advanced MRI techniques, including detection of chronic active lesions, global and focal brain damage, hold promise for early identification. Fluid biomarkers, such as neurofilament light chain and glial fibrillary acidic protein, provide non-invasive measures of neuroaxonal injury and ongoing chronic inflammation. This review summarises the role of MRI and fluid biomarkers in detecting smouldering disease in paediatric-onset MS and their application in supporting therapeutic decision-making.

OBJECTIVE:Cognitive impairment, fatigue, and depression are common in multiple sclerosis (MS), potentially due to disruption of regional functional connectivity caused by white matter (WM) lesions. We explored whether WM lesions functionally connected to specific brain regions contribute to these MS-related manifestations. METHODS:A total of 596 MS patients underwent 3T brain MRI acquisition, neurologic assessment, and neuropsychological evaluation (Brief Repeatable Battery, Modified Fatigue Impact Scale [MFIS], and Montgomery-Åsberg Depression Rating Scale [MADRS]). Voxel-wise lesion probability maps were compared between subgroups based on cognition, fatigue, or depression. Lesion distributions were linked to a brain functional connectivity atlas to map lesion network associations. Lesion network maps (LNMs) were then compared among subgroups (p < 0.05, FWE-corrected). RESULTS:One hundred twenty-six (27.2%) MS patients were cognitively impaired and showed significantly more widespread WM lesions, more strongly functionally connected to bilateral hippocampi, thalami, cerebellum, and occipital cortices (corrected-p < 0.05) than cognitively preserved patients. Lesion networks were similar for impaired processing speed/attention. Verbal memory deficits were associated with WM lesions connected to parahippocampi, temporal pole, and cerebellum (corrected-p ≤ 0.05), while verbal fluency deficits involved connections to thalami, putamen, caudate nuclei, anterior cingulate cortex, and cerebellum (corrected-p ≤ 0.05). No significant lesion distribution or network connectivity differences were found in patients with visual memory deficits, fatigue (MFIS ≥ 38, 184/493 [37.3%]) or depression (MADRS > 9, 192/495 [38.8%]). INTERPRETATION:Regional WM lesions disrupting connections to the hippocampus, thalamus, cerebellum, and temporo-occipital cortices contribute to cognitive impairment, but not fatigue or depression. LNM may clarify mechanisms underlying cognitive deficits in MS.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare central nervous system (CNS) demyelinating disease presenting heterogeneously across lifespan. Although frequent, epilepsy remains a poorly characterized MOGAD-associated manifestation. To describe age-related clinical, fluid, imaging, and neurophysiological features in MOGAD patients with epilepsy, we systematically reviewed online repositories up to April 2025, identifying 178 eligible studies. A total of 2487 MOGAD patients were included from clinical studies, and of 337 from case reports/series, 140 with adult-onset and 197 with pediatric-onset disease. Seizures prevalence was 30.6