Anthony Eshareturi

Background:  The growing incidence of epilepsy has spurred research on therapies for epileptogenesis. While there are several promising small compounds being targeted as epileptogenic therapies, a prominent roadblock prevents the translation of research into clinical trials. The heterogenous nature of epilepsy in terms of its mode of initiation and frequency, the need for a large patient population, and the duration of necessary follow-up, are some of the barriers in designing clinical trials for novel anti-epileptogenic therapies.

Recent data indicate that approximately 2.5 million people experience Traumatic Brain Injuries (TBI) annually in Europe and the USA¹. With 20-25% of these TBI patients experiencing recurrent seizures at least 1 week after the incidence–described as Post Traumatic Epilepsy (PTE), making PTE the most commonly encountered form of epilepsy.^1,3

Importantly, PTE presents an excellent clinical opportunity for the investigation of epileptogenic mechanisms as typically the time of initiation of epileptogenesis is known, the population of at-risk patients is large, and preclinical studies of mechanisms and treatment targets are available.

Research Objectives:  Validating the potential of identifying bioanatomical and biochemical changes in the body during the latent period between patients’ TBI and the onset of PTE as biomarkers of epileptogenesis. Reliable biomarkers will help researchers stratify patient population while developing clinical trials for novel antiepileptogenic therapies.

Methods:  Pubmed queries including the terms “epileptogenesis”, “biomarkers of post traumatic epilepsy”, “Traumatic Brain Injury and Post Traumatic Epilepsy”.

Results:  Analyzing bioanatomical variations in control and study populations using machine learning algorithms, researchers were able to identify differences in edema, hematoa, and hemorrhage between TBI patients that developed PTE and those that did not.²  Another study differentiated TBI patients with an 80% accuracy based on the rotation of the hippocampi in the horizontal and vertical axis into PTE and non PTE groups.⁴

Furthermore, several biochemical studies identified key cytokines and proteins present in the patients’ serum following TBI. With an 80% accuracy, the cytokine IL-6 was discovered to have a significantly higher serum concentration in TBI patients who progressed to developing PTE.⁵

Conclusion:  Post Traumatic Epilepsy provides the best opportunity to identify biomarkers and indications of epileptogenic pathways. A combination of the various identified mechanisms and markers of epileptogenesis increases the ability to stratify patient populations for clinical studies in developing novel antiepileptogenic therapies.

Works Cited:

1. Dulla CG, Pitkänen A. Novel Approaches to Prevent Epileptogenesis After Traumatic Brain Injury. Neurotherapeutics. 2021;18(3):1582-1601. doi:10.1007/s13311-021-01119-1
2. Akrami H, Leahy RM, Irimia A, Kim PE, Heck CN, Joshi AA. Neuroanatomic Markers of Posttraumatic Epilepsy Based on MR Imaging and Machine Learning. AJNR Am J Neuroradiol. 2022;43(3):347-353. doi:10.3174/ajnr.A7436
3. van Vliet EA, Ndode-Ekane XE, Lehto LJ, et al. Long-lasting blood-brain barrier dysfunction and neuroinflammation after traumatic brain injury. Neurobiol Dis. 2020;145:105080. doi:10.1016/j.nbd.2020.105080
4. De Feo R, Manninen E, Chary K, et al. Hippocampal position and orientation as prognostic biomarkers for posttraumatic epileptogenesis: An experimental study in a rat lateral fluid percussion model. Epilepsia. 2022;63(7):1849-1861. doi:10.1111/epi.17264
5. Choudhary A, Varshney R, Kumar A, Kaushik K. A Prospective Study of Novel Therapeutic Targets Interleukin 6, Tumor Necrosis Factor α, and Interferon γ as Predictive Biomarkers for the Development of Posttraumatic Epilepsy. World Neurosurg X. 2021;12:100107. Published 2021 May 28. doi:10.1016/j.wnsx.2021.100107