Abnormal Interleukin 1-B Inflammasome Activation and Epilpesy Surgery Outcomes

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Project Summary: Seizures recur in 50% of patients after temporal lobe epilepsy surgery and in 60%-70% after extra-temporal lobe epilepsy surgery. An exclusive focus on refining “epilepsy localization” has not yet drastically improved seizure outcomes. We recently proposed that de-novo epileptogenesis in genetically predisposed patients may influence “late” recurrences first manifesting after months to years of postoperative seizure-freedom. Evidence is accruing on neuro-inflammation's role in epilepsy, and genetic variation in Interleukin-1β (IL-1β) expression was linked to the risk of posttraumatic human epilepsy. We will explore the central hypothesis that genetic variability in IL- 1β and its related inflammasome translates into an altered pattern of microglial activation after epilepsy surgery, facilitating subsequent epileptogenesis in brain tissue at the edge of the resection and later seizure recurrence. Time to first seizure recurrence is our primary outcome. Spikes on 6-month postoperative EEG in patients who were seizure-free up to that point is our secondary outcome. In Specific Aim 1, we retrospectively explore the relationship between seizure outcomes and genetic variability in IL-1β and related inflammasome activation in resected epileptic brain tissue. We focus on SA1a)- the SNP) rs1143634 IL-1β gene variant ; and SA1b)- activation of the multi-protein complex controlling the synthesis of IL- 1β [the nucleotide binding and oligomerization domain like receptor family pyrin domain-containing 3(NLRP3)inflammasome], as measured by RNA/protein extraction of inflammasome components and their immunohistochemical localization to microglia. In Specific Aim 2, we explore the relationship between MRI signatures of peri-operative neuroinflammation and postoperative epileptogenesis using brain MRI done in the University of Campinas 24-72 hours after surgery. In Specific Aim 3, we expand the questions of SA1 and 2 using a prospective cohort of 25 patients enrolled from Mayo Clinic and Cleveland Clinic as we (SA3a) determine if peri-operative serum measurements of IL-1β, MMP-9, or IL-18 correlate with the primary and secondary outcome, and identify the ideal collection time to study in a future definitive project; (SA3b) study the timeframe for development of our proposed postoperative epileptogenesis biomarkers; and (SA3c) explore our proposed mechanism by studying the relative (margin vs.core of resected epileptic tissue) degree of microglial activation, IL-1β tissue expression in those with favorable vs unfavorable outcomes. Our strong preliminary data support our hypothesis. The collaboration of multiple sites (Cleveland Clinic, Mayo Clinic, and University of Campinas) will indirectly test the feasibility and build infrastructure needed for a future definitive study. We take advantage of existing resources and a track record of productive collaborations among our investigators to optimize the efficiency of study conduct and ensure study completion. If successful, this work will open the door for an innovative line of research on surgical outcomes after epilepsy surgery with a significant potential for altering clinical care given the multitude of selective IL-1β modifiers on the market.