Post-Traumatic Epilepsy and Comorbidities: Advanced Models, Molecular Mechanisms, Biomarkers, and Novel Therapeutic Interventions

Abstract

Post-traumatic epilepsy (PTE) is one of the most devastating long-term, network consequences of traumatic brain injury (TBI). There is currently no approved treatment that can prevent onset of spontaneous seizures associated with brain injury, and many cases of PTE are refractory to antiseizure medications. Post-traumatic epileptogenesis is an enduring process by which a normal brain exhibits hypersynchronous excitability after a head injury incident. Understanding the neural networks and molecular pathologies involved in epileptogenesis are key to preventing its development or modifying disease progression. In this article, we describe a critical appraisal of the current state of PTE research with an emphasis on experimental models, molecular mechanisms of post-traumatic epileptogenesis, potential biomarkers, and the burden of PTE-associated comorbidities. The goal of epilepsy research is to identify new therapeutic strategies that can prevent PTE development or interrupt the epileptogenic process and relieve associated neuropsychiatric comorbidities. Therefore, we also describe current preclinical and clinical data on the treatment of PTE sequelae. Differences in injury patterns, latency period, and biomarkers are outlined in the context of animal model validation, pathophysiology, seizure frequency, and behavior. Improving TBI recovery and preventing seizure onset are complex and challenging tasks; however, much progress has been made within this decade demonstrating disease modifying, anti-inflammatory, and neuroprotective strategies, suggesting this goal is pragmatic. Our understanding of PTE is continuously evolving, and improved preclinical models allow for accelerated testing of critically needed novel therapeutic interventions in military and civilian persons at high risk for PTE and its devastating comorbidities. Significance Statement Post-traumatic epilepsy is a chronic seizure condition after brain injury. With few models and limited understanding of the underlying progression of epileptogenesis, progress is extremely slow to find a preventative treatment for PTE. This study reviews the current state of modeling, pathology, biomarkers, and potential interventions for PTE and comorbidities. There’s new optimism in finding a drug therapy for preventing PTE in people at risk, such as after traumatic brain injury, concussion, and serious brain injuries, especially in military persons.

A Comprehensive and Advanced Mouse Model of Post‐Traumatic Epilepsy with Robust Spontaneous Recurrent Seizures

“…2. Use MATLAB software and a two-step automated statistical algorithm custom developed using MATLAB packages and scripts previously described by our group (Golub & Reddy, 2022b;Kuruba, Dushi, & Reddy, 2016) to detect seizure episodes and discharges from EEG recordings (Fig. 8A).…”

“…As previously described (Golub & Reddy, 2022b), spontaneous recurrent seizures (SRSs) are defined as events that last between 12 and 90 s, where the amplitude and frequency of the spikes are at least tripled from each animal's respective baseline. Epileptiform discharge events are defined as a minimum of a 300% increase in spike amplitude and frequency over baseline for 3 to 9 s, with no convulsive and motor epileptiform activity.…”

“…Cell tracing and quantitative analysis of neuronal morphology as well as anatomical mapping can be performed using advanced scientific software like Neurolucida, NeuroExplorer, or NIH ImageJ software (see Current Protocols article: Milatovic et al., 2010). Experiments can be designed to track progressive pathology by generating large initial cohorts and performing IHC staining at incremental timepoints (Golub & Reddy, 2022b). As an example, we have provided a set of higher‐magnification images taken from the CA1 of the contralateral hippocampus, which display the contrasting differences in histopathology at days 7 and 120 post‐injury (Fig.…”

“…A hallmark feature of TBI is diffuse neuronal dysfunction and degeneration. Neurodegeneration is highly correlated to the injury severity, and recent reports show that cell loss can be robust both proximal and distal to the injury site (Golub & Reddy, 2022b). Cell loss can lead to disrupted neural network functioning and further downstream behavioral deficits, such as cognitive impairment or psychiatric comorbidities.…”

“…Perhaps some of the low incidence rates can be attributed to limited recording and/or analysis of EEG data. Therefore, it is becoming the gold standard for PTE models to include continuous long-term recordings to accurately portray epileptic and non-epileptic activity (Golub & Reddy, 2022b). A recent review of PTE literature has been published that describes the body of animal research in detail (Golub & Reddy, 2022a).…”