Infections Promote Post-Traumatic Epilepsy and Poor Outcomes After Traumatic Brain Injury
Abstract
Uncontrolled, unprovoked, and recurrent seizures, known as epilepsy, is a common consequence after a traumatic brain injury (TBI), in both the general population as well as in military personnel. For those that develop epilepsy, this condition adds a considerable additional burden to their lives. We currently have a poor understanding of why epilepsy develops after TBI in some individuals but not others, so it remains unclear who is most at risk. Identification of this subset of “at-risk” patients would be a significant leap forward by allowing for improved prediction of long-term outcomes for patients, as well as the identification of new treatment targets to prevent or reduce epilepsy after TBI. In this proposal, we hypothesize that exposure to infections during acute hospital care may promote the development of epilepsy, which contributes to poor outcomes. Infections are known risk factors for seizures and epilepsy, thought to be mediated at least in part by the inflammatory immune response. Infections are also very common in TBI patients during acute hospital care, who are vulnerable due to post-injury suppression of their immune response as well as a high level of exposure due to the necessity of invasive surgical procedures and monitoring devices. Limited but intriguing studies have suggested that the rate of post-traumatic epilepsy (i.e., epilepsy that develops after a TBI) is particularly high in the subset of patients who also sustained infections or had wounds that were delayed in healing. Based on this rationale, we propose that hospital-acquired infections contribute to the development of post-traumatic epilepsy and associated poor long-term outcomes after a TBI. We will address this hypothesis by probing a large patient dataset, and examine a new preclinical model incorporating brain injury and bacterial infection. Aim 1 will investigate the association between hospital-acquired infections and post-traumatic epilepsy in a large database of TBI patients (~15,000 patients) in the Victorian State Trauma Registry (VSTR), in Melbourne, Australia. Aim 2 will establish clinically relevant models of hospital-acquired infection after TBI in mice. Aim 3 will evaluate the influence of infections on chronic outcomes and post-traumatic epilepsy in the mouse models. This proposal is particularly unique and innovative by its cross-disciplinary application of a live bacterial infection in an experimental TBI model, made possible by integration of an interdisciplinary research team with expertise in neuroscience, immunology and microbiology. Together, these studies will represent a transformational advancement in understanding the mechanisms that underlie the development of acquired epilepsy, as well as the chronic consequences of an infectious immune challenge. Findings are expected to identify infections as a modifiable risk factor for post-traumatic epilepsy, with critical implications for acute care management in both military and civilian populations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010848
Entities
People
- Bridgette D Semple
Organizations
- Monash University
- United States Army