Post-traumatic Epilepsy

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in persons under the age of 45 and is a primary public health concern in both civilian and military populations.  TBI is a complex disease process and is characterized by primary and secondary injury.  Primary injury results from the direct mechanical force at the time of brain impact while secondary injury results in a cascade of cellular and molecular events that occurs within hours to years after the TBI.  Consequences of secondary injury include edema, inflammation, neuronal death, and gliosis which can all contribute to the development of epilepsy.

Posttraumatic epilepsy (PTE) is a long-term negative consequence of TBI in which one or more unprovoked seizures occur at least one week after the initial trauma.  PTE accounts for up to 20% of all symptomatic epilepsy and 6% of all epilepsies.  Risk factors of PTE that have been identified include early posttraumatic seizures and severity of injury.  While certain risk factors have been recognized, predictors of PTE still remain highly variable.  Thus, there remains an unmet need to produce reliable biomarkers of PTE that may define the risk and the onset of epilepsy after TBI.

Astrocytes are essential components of the central nervous system (CNS) and possess multiple critical functions such as water regulation, potassium homeostasis, and blood-brain barrier (BBB) maintenance.  Reactive astrocytes have been observed in epilepsy and TBI; however, whether they play a protective or detrimental role is unclear.  Marked changes in expression of the astrocyte membrane channels aquaporin-4 (AQP4) and Kir4.1 have been implicated in human and animal studies of epilepsy and TBI; however, the relationship between astrocytes, AQP4, and Kir4.1 has not been explored in a chronic model of PTE.

Lack of progress in current studies of PTE has limited the development of PTE biomarkers. For instance, current models of PTE have focused on using pentylenetetrazole (PTZ) for testing seizure threshold and imaging studies, while limited, have not identified a correlation between trauma and seizure susceptibility. In our laboratory, we combine techniques such as optical coherence tomography (OCT) and video-electroencephalography (vEEG) to define the optical and electrographic biomarkers of PTE. OCT will define both structural and functional changes after trauma and chronic vEEG will be employed to identify spontaneous seizures. We also use intrahippocampal electrical stimulation to quantitatively define electrographic seizure threshold. Additionally, we assess histological endpoints such as albumin extravasation, reactive astrocytosis, and AQP4 and Kir4.1 expression using immunohistochemical (IHC) and Western blot (WB) analysis. Overall, we aim to elucidate differences in electrographic and optical signals, and identify the roles of astrocytes, AQP4, and Kir4.1 expression following injury-induced epileptogenesis, and provide insight into how astrocytes modulate chronic neuronal hyperexcitability after TBI.

Spontaneous electrographic seizures observed after TBI (highlighted box).