Peripheral biochemical profiles and hippocampal asymmetry in children with febrile seizures: an exploratory canonical correlation analysis

Febrile seizures (FS) are the most common neurological emergency in young children, yet why only a minority of febrile children develop seizures remains unclear; differences may lie in brain structure, peripheral physiology, or their multivariate association. In this retrospective case–control study, 274 children aged 2–6 years underwent brain MRI and laboratory testing (febrile controls [FC] n = 68; simple FS n = 165; complex FS n = 41). Hippocampal head, body, and tail asymmetry indices were derived, and 36 laboratory markers were reduced to five components (inflammation, coagulation, immunity, metabolic/hepatorenal, blood cells). Univariate comparisons used general linear models with age and sex, with false-discovery-rate (FDR) control within domain. Canonical correlation analysis (CCA) linked component scores with asymmetry indices; the between-group difference in the first canonical correlation (Δr1) was permutation-tested. Peak temperature did not differ between groups. 9 of 36 markers differed after FDR correction, including C-reactive protein, erythrocyte sedimentation rate, IgA, IgG, IgM, uric acid, red-cell count, lymphocytes, and eosinophils. No hippocampal asymmetry index differed. The first canonical correlation was significant in both FS (r1 = 0.325, P = 0.044) and FC (r1 = 0.527, P = 0.032) without between-group difference. Loadings differed: in FS, immunity and blood-cell components coupled with tail–body asymmetry; in FC, blood-cell and metabolic components coupled with tail asymmetry. Out-of-sample validation substantially attenuated this association in FS, indicating the FS association was less stable. Children with FS showed a distinct peripheral laboratory profile relative to febrile controls. A laboratory–hippocampal multivariate association emerged in both febrile groups with group-specific coupling patterns; its lower replicability in FS warrants cautious interpretation. These findings delineate the peripheral context of typical FS and inform future studies of seizure susceptibility.