Traumatic Brain Injuries Linked to Epilepsy Development

Oleksii Shandra MD, PhD

Investigators from Fralin Biomedical Research Institute at Virginia Tech have found a link between concussions and epilepsy development via mice models. More specifically, the team found atypical responses from brain cells known as astrocytes, which follow traumatic brain injuries (TBIs), may be the cause of epilepsy development.

In an exclusive interview, lead investigator Oleksii Shandra MD, PhD, explained the new data to MD Magazine® and outlined what its potential clinical implications may be.

[Editor’s note: Transcript is lightly modified for readability.]

MD Mag®: What was your inspiration for conducting this study?

Shandra: “TBI is a leading cause of acquired epilepsy. While the timeframe of when the injury took place is typically known, it remains a mystery which patients will develop post-traumatic epilepsy and at what time. Some TBI patients don’t develop epilepsy for years, which makes it difficult to causally link the TBI and epilepsy. Despite this long time window between TBI and epilepsy, there is no treatment that interrupts the transformation of the brain leading to epilepsy.

The field is currently limited to 2 animal models with spontaneous post-traumatic seizures. These models replicate injuries that are only present in a fraction of TBI patients. As a result, it was still impossible to investigate the mechanisms leading to spontaneous seizures and test new therapeutic candidates after milder and non-penetrating TBIs.

The main inspiration for this research was to potentially help patients with post-traumatic epilepsy by developing a new animal model that could shed light on novel mechanisms and therapeutic targets. In addition, our research was driven by the existing debate in the medical and research community about whether mild/concussive TBI is sufficient to induce post-traumatic epilepsy.”

MD Mag®: What were the hallmarks you observed in the results?

Shandra: “In our research, we focused on astrocytes, which are glial cells in the brain that are a crucial part of the brain’s response to TBI since their altered functions are linked with epilepsy. Loss of function of even small number astrocytes can significantly affect multiple neurons as their connections cover hundreds of dendrites and hundreds of thousands of synapses.

However, astrocytes can act as ‘double-agents’ after brain injury. On one hand, they form glial scars that help to seal off injured areas of the brain. On the other hand, these scars may become a seizure focus. In our model, we found a new and atypical response of astrocytes after mild, non-penetrating traumatic brain injury, which we linked with further development of spontaneous seizures in those animals with post-traumatic epilepsy. These astrocytes, did not form scars and did not cause an increased production of glial acidic fibrillary protein (GFAP), which is a commonly used marker of reactive astrocytes.

In contrast, these atypical astrocytes lost their ability to produce proteins involved in glutamate and potassium clearance, which is essential for neuronal health and proper function. To summarize the hallmarks in our study, we demonstrated—for the first time—that repeated mild TBI/concussions are sufficient for the development of post-traumatic epilepsy. We also showed that a link to this process is atypical astrocytes, which loose their ability to ‘talk’ to their neighbors and support nerve cells.”

MD Mag®: Are there any clinical implications with this data?

Shandra: “In mice, mild TBI is sufficient to develop epilepsy, which highlights the importance of clinical research that assess whether this finding might translate to patients.

Currently, it is difficult to link mild TBI and epilepsy using epidemiological data due to different definitions in use for mild TBI, the long latency period between TBI and onset of epilepsy, and the fact that people incurring a mild TBI/concussion do not always seek medical help, which calls into question the accuracy of medical records in regards to previous injuries.

Importantly, this study suggests that diffuse injury affects not only neuronal connections but also glial cells and that this type of injury which is present in most TBIs is sufficient to induce the development of spontaneous, unprovoked, recurrent seizures.”

MD Mag®: What are the next steps with this data?

Shandra: “As we identified a cellular mechanism that identifies the loss of function in a subset of astrocytes, we will now identify the molecular mechanisms by initiating this process.

Another big goal is to develop reliable biomarkers that can be used to stratify during the latency period to identify which patient or animal will develop spontaneous seizures after TBI. This will enable research for treatment targets and initiate interventions sooner.

Ultimately, this data will help to not only determine ‘who’ is going to develop epilepsy, but also which molecular targets may be effective in preventing or reversing the brain transformation that leads to epilepsy.”

The study, titled, “Repetitive Diffuse Mild Traumatic Brain Injury Causes an Atypical Astrocyte Response and Spontaneous Recurrent Seizures,” was published online in The Journal of Neuroscience.