Sex-Specific Complement and Cytokine Imbalances in Drug-Resistant Epilepsy: Biomarkers of Immune Vulnerability

Objective: Drug-resistant epilepsy (DRE) poses significant challenges in treatment and management. While seizure-related alterations in peripheral immune players are increasingly recognized, the involvement of the complement system, central to immune function, remains insufficiently explored in DRE. This study aimed to investigate the levels of complement system components and their association with cytokine profiles in patients with DRE. Methods: We analyzed serum samples from DRE patients (n = 46) and age- and sex-matched healthy controls (n = 45). Complement components and cytokines were quantified using Multi- and Single-plex ELISA. Statistical analyses examined relationships between complement molecules, cytokines, and clinical outcomes including epilepsy duration, Full-Scale Intelligence Quotient (FSIQ) scores, and age. Results: We found common alterations in all DRE cases, including significant complement deficiencies (C1q, Factor H, C4, C4b, C3, and C3b/iC3b) and detectable bFGF levels. DRE females showed significantly lower levels of TNF-α and IL-8 compared to healthy females. In DRE males, we observed a trend towards elevated CCL2 and CCL5 levels compared to healthy males. These findings suggest potential sex-dimorphism in immune profiles. Our analysis also indicated associations between specific complement and inflammatory markers (C2, IL-8, and IL-9) and Full-Scale Intelligence Quotient (FSIQ) scores in DRE patients. Interpretation: Our study reveals sex-specific peripheral complement deficiencies and cytokine dysregulation in DRE patients, indicating an underlying immune system vulnerability. These findings provide new insights into DRE mechanisms, potentially guiding future research on complement and cytokine signaling towards personalized treatments for DRE patients.