The Role of Blood-Brain Barrier Pathology in Post-Traumatic Epilepsy and its Co-Morbidities

Abstract

Traumatic brain injury (TBI) is becoming a global epidemic with an up-to-date figure putting its toll at 69 million people affected worldwide. In Canada, TBI accounts for 150,000 annual emergency room visits and about half-a-million people are living with a TBI-related disability. The more debilitating forms of TBI have also been associated with a higher risk of about 10-40% for developing post-traumatic epilepsy (PTE) as well as long-term cognitive impairments, neurodegenerative and neuropsychiatric diseases. There are currently no effective therapeutics for the prevention of PTE and associated co-morbidities. Accumulating evidence indicates that blood-brain barrier dysfunction (BBBD) is common following TBI and has a role in epileptogenesis. The goal of the present study was to test whether imaging BBB dysfunction following TBI can be used to predict the development of PTE and its associate co-morbidities. Methods: We used a weight drop model of moderate traumatic brain injury in young adult rats. Rats were assessed for primary injury using a neurological score at baseline, 24, 48 hours and 1-week after injury. The magnitude of BBBD was assessed using a contrast-enhanced magnetic resonance imaging (CE-MRI) at 48 hours and 1-month time points. PTE was assessed using telemetric continuous electrographic recordings between 2-6 months after injury. Cognitive impairment was assessed using the Morris water maze test at 1 month after the trauma. Results: CE-MRI confirmed BBBD 48hrs after injury in contrast to healthy controls. To this end, 6 rats (26%) developed PTE at 6-months post injury. Epileptic rats showed abnormal pattern of brain activity with increased occurrence of slow frequency events, termed “paroxysmal slow wave events” (PSWEs). Morris water maze confirmed a reduction in learning skills in animals after injury. The extent of BBBD at 48 hours was inversely related to performance at the Morris water maze, but not with the development of epilepsy at 6-months. Conclusion: Post-traumatic epilepsy is fairly common following moderate traumatic brain injury. PSWEs may reflect an underlying neuronal hypersynchronous activity and may offer a novel non-invasive biomarker for neural injury and epileptogenesis. BBBD imaging may serve as a predicting biomarker for the development of cognitive impairment.