Charmi Mehta

Introduction. PTE is a type of structural epilepsy caused by an insult to the brain, most commonly due to TBI. 20% of all symptomatic epilepsies are a result of TBI. Some of the important risk factors leading to PTE are skull fracture, loss of consciousness for more than 30 min after initial TBI, and the patient’s age when the trauma occurred.^1-3 The current treatment strategy for PTE consists of administering Anti-Epileptic Drugs (AEDs) such as Levetiracetam or Phenytoin as prophylaxis for the first seven days post-TBI.⁴ Due to lack of curing capability of AEDs, this research focuses on proposing new methods to cure rather than treat PTE. Several studies on the use of mesenchymal cell (MSC) transplantation are currently being done where these MSCs can provide a neuroprotective layer by decreasing the release of inflammatory cytokines such as IL-6, TNF-α, and IL-1β and increasing anti-inflammatory cytokine IL-10.^5,6 These findings could suggest potential MSC transplantation as a therapeutic measure for PTE patients. Methods. This literature review explores current PTE molecular pathogenesis and possible treatments. First, I examined studies of mouse models where they look at the impact of depletion and repopulation of microglia on cytokine levels such as IL-6 and their learning and memory.⁷ Another study examined IL-1β levels post-TBI. They also injected rIL-1Ra to see measure reversal of seizure susceptibility post-TBI.⁸ Finally, I examined two studies using neural progenitor cell (NPC; w/ & w/o IGF-1) and MSC transplantation on mice and human models, respectively.^9,10 Results. Re-populating pro-neurogenic and neuroprotective microglia, especially during the acute phase, showed a surge of IL-6 cytokine, which correlated with behavioral improvements and augmented survival of neurons (including the birth of new neurons).⁷ rIL-1Ra reduces cognitive impairment, degree of cortical loss, and astrogliosis; however, it does not protect against white matter damage or injury-induced hyperactivity.⁸ NPC implantation is the key factor in reversing injury-induced cognitive deficits. The presence or absence of IGF-1 did not lead to a difference in injury reversal in mice model.⁹ Pilot study with MSC implantation in human model showed statistically significant transformation in generalized tonic-clonic and simple partial seizures and increased cognitive performance and decreased anxiety.¹⁰ Conclusion. Molecular pathogenesis of PTE showed that cytokine signaling could be playing a pivotal role in developing seizure susceptibility. Modulating these levels using MSC implantation to decrease seizure susceptibility could be a solution.¹⁰ Other non-invasive options to explore include AEDs that can modulate cytokine levels.

1. Pitkänen A, Kyyriäinen J, Andrade P, Pasanen L, Ndode-Ekane XE. Epilepsy After Traumatic Brain Injury. Models of Seizures and Epilepsy. 2017:661-681. doi:10.1016/b978-0-12-804066-9.00046-8
2. DeGrauw X, Thurman D, Xu L, Kancherla V, DeGrauw T. Epidemiology of traumatic brain injury-associated epilepsy and early use of anti-epilepsy drugs: An analysis of insurance claims data, 2004-2014. Epilepsy Res. 2018;146:41-49. doi:10.1016/j.eplepsyres.2018.07.012
3. Perucca P, Smith G, Santana-Gomez C, Bragin A, Staba R. Electrophysiological biomarkers of epileptogenicity after traumatic brain injury. Neurobiology of Disease. 2019;123:69-74. doi:10.1016/j.nbd.2018.06.002
4. Saletti PG, Ali I, Casillas-Espinosa PM, et al. In search of antiepileptogenic treatments for post-traumatic epilepsy. Neurobiol Dis. 2019;123:86-99. doi:10.1016/j.nbd.2018.06.017
5. Webster KM, Sun M, Crack P, O’Brien TJ, Shultz SR, Semple BD. Inflammation in epileptogenesis after traumatic brain injury. J Neuroinflammation. 2017;14(1):10. Published 2017 Jan 13. doi:10.1186/s12974-016-0786-1
6. Hlebokazov F, Dakukina T, Ihnatsenko S, et al. treatment of refractory epilepsy patients with autologous mesenchymal stem cells reduces seizure frequency: An open label study. Adv Med Sci. 2017;62(2):273-279. doi:10.1016/j.advms.2016.12.004
7. Willis EF, MacDonald KPA, Nguyen QH, et al. Re-populating Microglia Promote Brain Repair in an IL-6-Dependent Manner. Cell. 2020;180(5):833-846.e16. doi:10.1016/j.cell.2020.02.013
8. Semple BD, O’Brien TJ, Gimlin K, et al. Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain. J Neurosci. 2017;37(33):7864-7877. doi:10.1523/JNEUROSCI.0982-17.2017
9. Koutsoudaki PN, Papastefanaki F, Stamatakis A, et al. Neural stem/progenitor cells differentiate into oligodendrocytes, reduce inflammation, and ameliorate learning deficits after transplantation in a mouse model of traumatic brain injury. Glia. 2015;64(5):763-779. doi:10.1002/glia.22959
10. Hlebokazov F, Dakukina T, Ihnatsenko S, et al. treatment of refractory epilepsy patients with autologous mesenchymal stem cells reduces seizure frequency: An open label study. Adv Med Sci. 2017;62(2):273-279. doi:10.1016/j.advms.2016.12.004