Systemic immune dysregulation and neutrophil activation define prognostic inflammatory signatures in drug-resistant epilepsy.

Systemic inflammation is now recognized as a key contributor to epilepsy pathophysiology, yet the role of innate immune cells, particularly neutrophils, remains poorly defined in epilepsy. Preclinical studies in rodent models have implicated neutrophils in seizure activity, but their phenotype in human epilepsy has not been thoroughly investigated. In this study, we aimed to characterize systemic inflammatory profiles and neutrophil-associated immune signatures in the blood of patients with drug-resistant epilepsy compared with healthy controls. We identified a systemic low-grade inflammatory profile in patients characterized by elevated neutrophil-to-lymphocyte ratio, C-reactive protein, proinflammatory cytokines (IL-6, CXCL8/IL-8, TNF-α), and activated neutrophils (CXCR4+CD62Llo). Neutrophil phenotyping revealed two distinct immune profiles. Patients with longer disease duration exhibited a more immature systemic signature characterized by immature neutrophils (CD15+CD10-), resting neutrophils (CXCR4+CD62L+), and elevated IL-6 levels. In contrast, patients with higher seizure frequency displayed a more inflammatory profile, marked by increased IL-12 and activated (CXCR4+CD62Llo) and hyperactivated (CXCR4hiCD62Llo) neutrophil subsets. Moreover, elevated presurgical levels of inflammatory profile TNF-α, IL-6, and hyperactivated CXCR4hiCD62Llo neutrophils were associated with seizure recurrence 1 year after surgery. This pioneering study highlights the heterogeneity of peripheral immune responses in drug-resistant epilepsy and identifies neutrophil-related signatures as promising prognostic biomarkers in this context.