Elevated neuroinflammation and region-specific clinical correlates in drug-resistant focal epilepsy

Purpose: Approximately one-third of patients with epilepsy become refractory to traditional anti-seizure medications. Evidence from animals and in humans suggests a bidirectional relationship between epilepsy and neuroinflammation, offering potential as a novel therapeutic pathway. This study investigates region-specific relationships between neuroinflammation and medication-refractory focal epilepsy using [¹⁸F]FEPPA, a next-generation translocator protein radioligand and biomarker for microglial density with favorable binding kinetics and signal-to-noise ratio compared to [¹¹C]PK11195. Methods: Patients aged 18–55 years and age-matched typical control participants were recruited for this cross-sectional study from the from the UW Health Epilepsy Monitoring Unit or the Dane County, Wisconsin area. Patients demonstrated no gross abnormalities on MRI other than hippocampal sclerosis and patients received a diagnosis of focal epilepsy. Clinical variables were obtained from chart review, interviews, and a patient seizure log. Imaging data were acquired on a GE Signa 3T PET/MR system, processed using PETSurfer, and FEPPA binding was quantified from motion-corrected PET images using standard uptake values (SUVs). Results: Analysis excluded participants with low binding affinity based on TSPO genetic polymorphism (n = 2 controls) or missing imaging data (n = 4), resulting in 12 patients (age=38.3 ± 13.1 years, 4 female) and 9 typical controls (age=35.2 ± 10.2 years, 4 female). Patients with epilepsy showed widespread increases in FEPPA uptake compared to controls. Significant region-specific correlations were revealed between FEPPA uptake and seizure frequency, recency, duration, and lifetime focal-to-bilateral tonic-clonic seizures. In one patient with frontal lobe epilepsy and pre- and post-ictal scans, greater mesiotemporal uptake was observed following seizure relative the interictal period, suggestive of secondary epileptogenesis. FEPPA did not correlate with systemic inflammatory markers. Conclusion: Findings detail a region-specific interplay between neuroinflammation, seizure activity, and recovery in focal epilepsy. Reductions in entorhinal cortex [¹⁸F]FEPPA SUVs with increasing time from seizure suggest its potential as a dynamic index of post-ictal recovery, while altered uptake in the hippocampus and amygdala may serve as more static markers of disease burden. These results lay the groundwork for further investigation of neuroinflammation as a therapeutic target in epilepsy and support the potential integration of [¹⁸F]FEPPA PET into clinical practice as a biomarker of disease burden and treatment response.