Mild traumatic brain injury and post traumatic epilepsy: biological relevance and strategies for treatment

Abstract

INTRO: There is mounting evidence to suggest a causal link between mild traumatic brain injury (mTBI) and post traumatic epilepsy (PTE). Significant ranges in the methods and definitions of “mild” TBI, each with their own limitations, make drawing cohesive conclusions from the state of the literature difficult. However, this body of work attempts to compile the literature in order to better elucidate the relationship between these populations. Ultimately, I hope this source to be a useful reference for understanding the state of the research such that one can make critical considerations in the future design of methods to definitively improve the quality of work in this field. Meaningful improvements could radically improve the outcomes for the millions of people who suffer as a result of these injuries and their lasting implications. METHODS: PubMed searches used keywords: Traumatic Brain injury (mild), Epilepsy, Concussion, Loss of cortical inhibition, Post Traumatic Epilepsy. Combinations of terms including mTBI or PTE AND MRI, fMRI, DTI, MRS, Biomarkers, TMS, EEG, and pathology. RESULTS: Strong trends persist despite the limitation in consistency of terminology and methods. Relative risk scores between 1.5 and 2.2 percent have been established across multiple long-term studies across decades of research and millions of person years, a 2-3-fold change over the baseline incidence of epilepsy in the general population (0.7%; less than one in every 100). Preclinical studies in mice have recently shown progressive increased seizure susceptibility after repeated mTBI. Within the first three weeks after injury, Glutamate homeostasis is altered meaningfully. Increased neural excitability results as the balance between excitation and inhibition shifts in the brain. An increased Glu/GABA ratio has also been linked to dysfunction in GABAergic cell populations, including parvalbumin positive inhibitory interneurons (PVI). Oxidative stress, as measured by a decreased GSH/GSSG ratio, suggests a dysregulation in homeostatic processes than can outlive clinical symptoms. Animals also display a decreased latency to induced seizure by Pentelynetetrazole (PTZ) a potent GABA receptor antagonist. Six weeks after injury, these mice have been shown to display; decreased GABA driving an increased Glu/GABA ratio, decreased EEG gamma power, and prominent signs of gliosis involving both astrocytes and microglia. Clinical investigations into the biology of this injury, utilizing a wide range of techniques, point to a loss of cortical inhibitory tone, an early hallmark of PTE. TMS findings of both reduced resting motor threshold and a shorter cortical silent period suggest a loss of cortical inhibitory tone likely shifting the excitation/inhibition balance. Signs of microstructural damage and altered cell permeability point to a disruption in chemical gradients which leads to greater functional deficits, as the parameters for normal cell function are no longer maintained. Changes in function and metabolism have been shown to outlast many of the behavioral and acute clinical symptoms suggesting a slow development but long duration of this insidious process. CONCLUSION: Mechanisms that link mTBI to PTE include a loss of cortical inhibition, increased oxidative stress and gliosis which over time increases Glu/GABA ratio, in turn increasing the likelihood of developing epilepsy. Although the relationship between mTBI and PTE has been suggested before through epidemiological studies, there is now emerging biochemical evidence to better describe this connection. Due to the high incidence of mTBI, any small increase in risk to develop PTE pursuant to concussion will affect millions of lives. With this new evidence, treatments can be designed to halt the progression and alleviate symptoms for those afflicted. The investigation of the biological mechanisms that link concussion and epilepsy is a critical step in developing treatment strategies and prophylaxis that could prove to be crucial for so many.