Abstract
BACKGROUND/OBJECTIVES: Pediatric-onset multiple sclerosis (POMS), defined as onset before age 18, is increasingly recognized as a distinct entity, often associated with a more burdensome disease course and earlier disability milestones than adult-onset MS. Although comorbidities may significantly affect disease progression and outcomes, their prevalence, incidence, risk, and characteristics in POMS remain poorly understood. To date, no systematic review has comprehensively evaluated comorbidities in POMS. The primary aim is to systematically identify and synthesize available evidence on the prevalence, incidence, risk, and characteristics of these comorbidities in POMS populations, as well as any reported effects on disease course, treatment outcomes, and overall clinical management. METHODS: We will conduct a systematic review and meta-analysis following a hierarchical and pragmatic analytical strategy tailored to the expected heterogeneity and limited evidence base in POMS. MEDLINE (via PubMed) and Embase (produced by Elsevier) will be searched without date restrictions, combining controlled vocabulary terms (MeSH/Emtree) and relevant keywords for POMS and 15 predefined comorbidity categories. Study selection, abstract and full-text screening, and data extraction will be performed independently by two reviewers using predefined criteria and standardized forms. The primary quantitative outcome will be the pooled prevalence of comorbidities. Where study design and reporting permit, incidence rates will be assessed as secondary outcomes, and risk estimates (e.g., odds ratios) will be evaluated only in studies with appropriate comparator groups. Meta-analyses will be conducted using random-effects models when pooling is feasible. Heterogeneity will be assessed using the I(2) statistic and Cochran's Q test, with sensitivity and subgroup analyses performed only when sufficient data are available. When quantitative synthesis is not appropriate due to limited data or substantial heterogeneity, findings will be summarized descriptively. Publication bias will be evaluated using funnel plots and, where applicable, Egger's and Begg's tests. This protocol adheres to PRISMA and PRISMA-P guidelines. DISCUSSION: A systematic quantification of comorbidity prevalence, incidence (where available), and risk, together with POMS-specific characteristics and any reported impact on clinical outcomes, is anticipated to provide a crucial evidence base for guiding screening, refining management strategies, and informing future research directions. Ultimately, these findings may improve clinical outcomes and quality of life for children and adolescents with MS.