Mediators of epilepsy risk after traumatic brain injury: A 20-year U.S. veteran cohort study.

Objective: Traumatic brain injury (TBI) is a significant risk factor for epilepsy, but little work has explored whether risk of epilepsy after TBI may operate through intermediary mechanisms. The objective of this study was to statistically screen for potentially mediating effects among 64 comorbidities for epilepsy risk following TBI among Post-9/11 U.S. veterans.

Methods: This longitudinal matched cohort study used an established algorithm to identify veterans in Department of Defense (DoD) and Veterans Health Administration (VHA) records with a history of the primary exposure, TBI, between 2003 and 2023, who were demographically matched 1:1 with veterans without history of TBI exposure from the same cohort. In the observation time window after index date, mediation models estimated the proportion eliminated of the total TBI-epilepsy relationship by other factors. Cox proportional hazard models were implemented for 64 comorbidities determined using International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) codes, each individually tested for the potential mediation of epilepsy onset after date of first TBI (index date), adjusting for demographic and military covariates. Age-stratified mediation analyses were conducted. Biologically plausible mechanisms were investigated.

Results: Among N = 292 200 veterans in the TBI and matched groups, 8458 (2.9%) had an epilepsy diagnosis that met study criteria between 2003 and 2023. The adjusted hazard ratio (HR, 95% CI) for epilepsy given TBI was 6.76 [6.33-7.21]. The median duration between TBI documentation and epilepsy diagnosis was 3.3 years. In the observation time after index date (median duration: 12.2 years), Cox proportional hazard models identified the primary meditators of epilepsy risk after TBI as post-concussive symptoms (10.3%), cognitive dysfunction (7.0%), suicidal ideation/attempt (5.1%), overdose and drug abuse (3.8%-4.8%), and stroke (3.8%).

Significance: This study identified neurological conditions and symptoms that may play an intermediary role in the TBI-epilepsy relationship. Specific changes in health status after TBI may present useful targets for future trials and experimental approaches of PTE prevention.