In pediatric multiple sclerosis (MS), assessment of disease burden predominantly relies on outcome measures developed and validated in adult populations. The application of these tools to children and adolescents may compromise sensitivity and specificity, potentially resulting in an underestimation of disease impact. Symptoms such as fatigue, mood disorders, and cognitive impairment may present subtly in younger patients and are therefore prone to underrecognition in routine clinical practice. Comprehensive evaluation of pediatric MS requires integration of the perspectives of both patients and their caregivers to fully capture the multidimensional effects of the disease, including psychosocial and functional consequences. Incorporation of patient-reported outcome measures (PROMs) into routine clinical care enables a more patient-centered assessment and supports informed clinical decision-making and personalized disease management. Furthermore, PROMs may provide insight into long-term health trajectories and help identify early predictors of adult outcomes. In recognition of the need for a coordinated global approach, the PROMS Initiative was established in 2019 to promote the development, validation, and implementation of PROMs in both research and clinical settings. Its objectives include facilitating the integration of PROMs into clinical trials, routine care, and regulatory frameworks across adult and pediatric populations. To optimize clinical utility, PROMs should demonstrate validity, reliability, and responsiveness, and their use should be standardized while remaining developmentally appropriate and tailored to age and disease stage. This article summarizes the current landscape of PROM use in pediatric MS and highlights key gaps to guide future research and clinical implementation.

Sun exposure may influence MS susceptibility, but evidence in pediatric-onset MS (PedMS) is limited. We examined whether reduced early-childhood outdoor time (a proxy for lower sun exposure) is associated with PedMS risk. In the Italian multicenter PEDIGREE Study, environmental data were collected using the PEQ-IT questionnaire. We enrolled individuals < 18 years with PedMS and disease duration ≤ 5 years and controls without CNS inflammatory disorders. Outdoor time was reported by season and age (0–1, 1–2, 3–5 years); reduced activity was defined as < 60 min/week. We included 114 PedMS cases and 121 controls. Cases were 77.2

Radiologically isolated syndrome (RIS) is defined by incidental MRI findings suggestive of central nervous system (CNS) demyelination in asymptomatic individuals. While uncommon in adults, RIS is exceptionally rare in the pediatric population. Its management, particularly regarding the timing and potential benefits of high-efficacy disease-modifying therapies (DMT), remains debated. We describe a 12-year-old girl who underwent an incidental brain MRI during a school visit, revealing multiple white matter lesions. Despite being asymptomatic, the presence of cerebrospinal fluid oligoclonal bands and a high radiological lesion burden, with evidence of dissemination in space and time during follow-up, indicated a high risk of conversion to multiple sclerosis (MS). Rapid radiological worsening and marked inflammatory activity (multiple gadolinium-enhancing lesions in repeated MRI scans) despite corticosteroid treatment prompted initiation of natalizumab in 2009. Over 18 years of continuous therapy, the patient remained clinically asymptomatic, with no new MRI lesions. The patient maintained an excellent quality of life, successfully completing medical school and residency. In this case of pediatric RIS, early intervention of a high-efficacy DMT prevented clinical conversion to MS, despite aggressive radiological activity in the pre-treatment phase. The patient remained free of clinical and radiological activity over an 18-year follow-up supporting the long-term safety and sustained efficacy of natalizumab, and suggesting that proactive treatment may be beneficial in patients with high-risk RIS.

Air pollution is linked to an increased risk of multiple sclerosis (MS) in adults. To investigate the link between air pollutant exposure and pediatric MS (pedMS) in an Italian cohort. PEDIGREE (Pediatric Italian Genetic and Environment Exposure) is a multicenter case–control study investigating genetic and environmental factors in MS before the age of 18. Information on environmental and perinatal exposures was collected through the PEQ-IT questionnaire. Air pollution data during the first, second, and third years prior to MS onset (PM2.5, PM10, O3, NO2, SO2, and CO levels) were obtained from the European Monitoring and Evaluation Program database. Data were available for 113 pedMS cases and 117 controls. We found statistically significant associations between pedMS and higher exposure to ozone (O3) in the first (OR = 1.11; 95

Assessing the environmental impact on multiple sclerosis (MS) is complex because of long disease latency and potential recall bias, especially for perinatal exposures. This study aimed to investigate the association between parental smoking and the development of pediatric MS (PedMS). As part of the Italian multicenter PEDIGREE study, the PEQ-IT questionnaire was used for prospective data collection. We enrolled subjects under 18 years with PedMS (2013 Krupp criteria) and disease duration ≤ 5 years from onset, along with matched controls. The study included 114 PedMS cases and 121 controls. Female participants represented 77.2

MS is the result of an immune-mediated disorder triggered by environmental factors in subjects genetically predisposed. Pediatric MS (pedMS) offers a unique window to study environmental triggers, as patients are close to the actual onset of the disease and have been exposed to fewer confounding factors. PedMS is strongly associated to HLA-DRB1*15:01 and to non–MHC (Major Histocompatibility Complex) variants, with a higher burden compared to adults. HLA-A*02 allele seems to reduce MS risk. The role of rare variants is still under investigation. Several environmental causative factors have been identified: obesity, passive smoke, sun exposure, vitamin D, and others but the strongest candidate is the Epstein-Barr virus, considered a prerequisite for MS development. In this paper we provide a summary of the results obtained so far in pediatric age. Some years ago, the Italian PEDIGREE study (PEDiatric Italian Genetic and enviRonmental ExposurE) has been created to help clarify the role of genetic and environmental factors in pedMS, through a study of the genetic, epigenetic, metagenomic, transcriptomic, along with assessment of environmental factors (viral exposure, second-hand smoke and sun exposure, breastfeeding history, and other factors. A network of 29 Italian MS centers has been established, 154 pedMS patients (mean age 13.5 years) and matched controls have been recruited. For the genetic study, a cohort of 364 adult MS patients with onset < 18 years was included. The study is ongoing, the results of exposure to environmental risk factors and of genetic background will be available in the next future.

OBJECTIVES:We aim to investigate cognitive phenotype distribution and MRI correlates across pediatric-, elderly-, and adult-onset MS patients as a function of disease duration. METHODS:In this cross-sectional study, we enrolled 1262 MS patients and 238 healthy controls, with neurological and cognitive assessments. A subset of 222 MS patients and 92 controls underwent 3T-MRI scan for brain atrophy and lesion analysis. Multinomial probabilistic models identified likelihood of belonging to cognitive phenotypes ("preserved-cognition," "mild verbal memory/semantic fluency," "mild multi-domain," "severe attention/executive," and "severe multi-domain") and experiencing MRI abnormalities based on disease duration and age at onset. RESULTS:In all groups, the likelihood of "preserved-cognition" phenotype decreased, whereas "mild multi-domain" increased with longer disease duration. In pediatric- and adult-onset patients, the likelihood of "mild verbal memory/semantic fluency" phenotypes decreased with longer disease duration, and that of "severe multi-domain" increased with longer disease duration. Only in adult-onset patients, the likelihood of "severe executive/attention" phenotype increased with longer disease duration. All groups displayed escalating probabilities of cortical, thalamic, hippocampal, and deep gray matter atrophy over disease course. Compared to adult, pediatric-onset patients showed lower probability of experiencing thalamic atrophy with longer disease duration, while elderly-onset showed higher probability of experiencing cortical and hippocampal atrophy. INTERPRETATION:Age at MS onset significantly influences the distribution of cognitive phenotypes and the patterns of regional gray matter atrophy throughout the disease course.

Up to 10 years ago the most common approach to the treatment of pediatric MS (ped-MS) was to start with IFNB or GA (so-called first-line therapies or moderate-efficacy disease-modifying therapies [ME-DMTs]) and to switch to more aggressive treatments (or high-efficacy disease-modifying therapies [HE-DMTs]) in non-responder patients. The use of HE-DMTs as first choice was recommended in selected cases with an active, aggressive form of MS. Indications for the treatment of ped-MS were essentially derived from data of observational studies. Recently, results of three randomized clinical trials have been published as well as data from many observational studies evaluating the effect of new and more active DMTs, with clear evidence that HE-DMTs are more effective than ME-DMTs. Therefore, the paradigm of treatment for patients with MS onset before 18 years of age should be changed, offering treatment with HE-DMTs as first option, because of their superior effectiveness to prevent relapses and disease progression. HE-DMTs present an overall reassuring safety profile and obtain better adherence to treatment.