Insights into epileptogenesis from post-traumatic epilepsy

Popescu, C., Anghelescu, A., Daia, C. & Onose, G. Actual data on epidemiological evolution and prevention endeavours regarding traumatic brain injury. J. Med Life 8, 272–277 (2015).CAS 
PubMed 
PubMed Central 

Google Scholar 
Frieden, T. R., Houry, D. & Baldwin, G. Report to Congress on traumatic brain injury in the United States: epidemiology and rehabilitation. Centers for Disease Control and Prevention. https://www.cdc.gov/traumaticbraininjury/pdf/TBI_Report_to_Congress_Epi_and_Rehab-a.pdf (2015).GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 56–87 (2019).Article 

Google Scholar 
Farrell, J. S., Wolff, M. D. & Teskey, G. C. Neurodegeneration and pathology in epilepsy: clinical and basic perspectives. Adv. Neurobiol. 15, 317–334 (2017).Article 
PubMed 

Google Scholar 
Sharma, R. et al. Neuroinflammation in post-traumatic epilepsy: pathophysiology and tractable therapeutic targets. Brain Sci. 9, 318 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Pease, M. et al. Association of posttraumatic epilepsy with long-term functional outcomes in individuals with severe traumatic brain injury. Neurology 100, e1967–e1975 (2023).Article 
PubMed 

Google Scholar 
Burke, J. et al. Association of posttraumatic epilepsy with 1-year outcomes after traumatic brain injury. JAMA Netw. Open 4, e2140191 (2021).Article 
PubMed 
PubMed Central 

Google Scholar 
Fordington, S. & Manford, M. A review of seizures and epilepsy following traumatic brain injury. J. Neurol. 267, 3105–3111 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Lucke-Wold, B. P. et al. Traumatic brain injury and epilepsy: underlying mechanisms leading to seizure. Seizure 33, 13–23 (2015).Article 
PubMed 

Google Scholar 
Annegers, J. F., Hauser, W. A., Coan, S. P. & Rocca, W. A. A population-based study of seizures after traumatic brain injuries. N. Engl. J. Med. 338, 20–24 (1998).Article 
CAS 
PubMed 

Google Scholar 
Pease, M. et al. Risk factors and incidence of epilepsy after severe traumatic brain injury. Ann. Neurol. 92, 663–669 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Schmidt, D., Friedman, D. & Dichter, M. A. Anti-epileptogenic clinical trial designs in epilepsy: issues and options. Neurotherapeutics 11, 401–411 (2014).Article 
PubMed 
PubMed Central 

Google Scholar 
Pitkänen, A., Lukasiuk, K., Dudek, F. E. & Staley, K. J. Epileptogenesis. Cold Spring Harb. Perspect. Med. 5, a022822 (2015).Article 
PubMed 
PubMed Central 

Google Scholar 
Löscher, W., Potschka, H., Sisodiya, S. M. & Vezzani, A. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol. Rev. 72, 606–638 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Kehne, J. H., Klein, B. D., Raeissi, S. & Sharma, S. The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP). Neurochem. Res. 42, 1894–1903 (2017).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
French, J. A. et al. Antiepileptogenesis and disease modification: clinical and regulatory issues. Epilepsia Open 6, 483–492 (2021).Article 
PubMed 
PubMed Central 

Google Scholar 
Löscher, W. & Schmidt, D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52, 657–678 (2011).Article 
PubMed 

Google Scholar 
World Health Organization. Epilepsy: a public health imperative. WHO. https://iris.who.int/bitstream/handle/10665/325440/WHO-MSD-MER-19.2-eng.pdf (2019).Gugger, J. J. et al. Multimodal quality of life assessment in post-9/11 veterans with epilepsy: impact of drug resistance, traumatic brain injury, and comorbidity. Neurology 98, E1761–E1770 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Raymont, V. et al. Correlates of posttraumatic epilepsy 35 years following combat brain injury. Neurology 75, 224–229 (2010).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Vespa, P. M. et al. The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: study design and protocol. Neurobiol. Dis. 123, 110–114 (2019).Article 
PubMed 

Google Scholar 
Saletti, P. G. et al. Tau phosphorylation patterns in the rat cerebral cortex after traumatic brain injury and sodium selenate effects: an Epibios4rx Project 2 study. J. Neurotrauma 41, 222–243 (2024).Article 

Google Scholar 
Saletti, P. G. et al. Early preclinical plasma protein biomarkers of brain trauma are influenced by early seizures and levetiracetam. Epilepsia Open 8, 586–608 (2023).Article 
PubMed 
PubMed Central 

Google Scholar 
Engel, J. J. Epileptogenesis, traumatic brain injury, and biomarkers. Neurobiol. Dis. 123, 3–7 (2019).Article 
CAS 
PubMed 

Google Scholar 
Correa, D. J. et al. Applying participatory action research in traumatic brain injury studies to prevent post-traumatic epilepsy. Neurobiol. Dis. 123, 137–144 (2019).Article 
PubMed 

Google Scholar 
Duncan, D. et al. Big data sharing and analysis to advance research in post-traumatic epilepsy. Neurobiol. Dis. 123, 127–136 (2019).Article 
PubMed 

Google Scholar 
Christensen, J. The epidemiology of posttraumatic epilepsy. Semin. Neurol. 35, 218–222 (2015).Article 
PubMed 

Google Scholar 
Thapa, A. et al. Post-traumatic seizures — a prospective study from a tertiary level trauma center in a developing country. Seizure 19, 211–216 (2010).Article 
PubMed 

Google Scholar 
Ritter, A. C. et al. Incidence and risk factors of posttraumatic seizures following traumatic brain injury: a Traumatic Brain Injury Model Systems Study. Epilepsia 57, 1968–1977 (2016).Article 
PubMed 

Google Scholar 
Haltiner, A. M., Temkin, N. R. & Dikmen, S. S. Risk of seizure recurrence after the first late posttraumatic seizure. Arch. Phys. Med. Rehabil. 78, 835–840 (1997).Article 
CAS 
PubMed 

Google Scholar 
Ngugi, A. K., Bottomley, C., Kleinschmidt, I., Sander, J. W. & Newton, C. R. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia 51, 883–890 (2010).Article 
PubMed 
PubMed Central 

Google Scholar 
Thijs, R. D., Surges, R., O’Brien, T. J. & Sander, J. W. Epilepsy in adults. Lancet 393, 689–701 (2019).Article 
PubMed 

Google Scholar 
Angeleri, F. et al. Posttraumatic epilepsy risk factors: one-year prospective study after head injury. Epilepsia 40, 1222–1230 (1999).Article 
CAS 
PubMed 

Google Scholar 
Englander, J. et al. Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch. Phys. Med. Rehabil. 84, 365–373 (2003).Article 
PubMed 

Google Scholar 
Ferguson, P. L. et al. A population-based study of risk of epilepsy after hospitalization for traumatic brain injury. Epilepsia 51, 891–898 (2010).Article 
PubMed 

Google Scholar 
Laing, J. et al. Risk factors and prognosis of early posttraumatic seizures in moderate to severe traumatic brain injury. JAMA Neurol. 79, 334–341 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Christensen, J. et al. Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study. Lancet 373, 1105–1110 (2009).Article 
PubMed 

Google Scholar 
Karlander, M., Ljungqvist, J. & Zelano, J. Post-traumatic epilepsy in adults: a nationwide register-based study. J. Neurol. Neurosurg. Psychiatry 92, 617–621 (2021).Article 
PubMed 

Google Scholar 
DeGrauw, X. et al. Epidemiology of traumatic brain injury-associated epilepsy and early use of anti-epilepsy drugs: an analysis of insurance claims data, 2004–2014. Epilepsy Res. 146, 41–49 (2019).Article 

Google Scholar 
Annegers, J. F. et al. Seizures after head trauma: a population study. Neurology 30, 683–689 (1980).Article 
CAS 
PubMed 

Google Scholar 
Mahler, B. et al. Unprovoked seizures after traumatic brain injury: a population-based case–control study. Epilepsia 56, 1438–1444 (2015).Article 
PubMed 

Google Scholar 
Santos, S., Murphy, G., Baxter, K. & Robinson, K. M. Organisational factors affecting the quality of hospital clinical coding. Heal. Inf. Manag. 37, 25–37 (2008).
Google Scholar 
O’Malley, K. J. et al. Measuring diagnoses: ICD code accuracy. Health Serv. Res. 40, 1620–1639 (2005).Article 
PubMed 
PubMed Central 

Google Scholar 
Langlois, J. A., Rutland-Brown, W. & Wald, M. M. The epidemiology and impact of traumatic brain injury: a brief overview. J. Head Trauma Rehabil. 21, 375–378 (2006).Article 
PubMed 

Google Scholar 
Pugh, M. J. V. et al. The prevalence of epilepsy and association with traumatic brain injury in veterans of the Afghanistan and Iraq wars. J. Head Trauma Rehabil. 30, 29–37 (2015).Article 
PubMed 

Google Scholar 
Lolk, K., Dreier, J. W. & Christensen, J. Repeated traumatic brain injury and risk of epilepsy: a Danish nationwide cohort study. Brain 144, 875–884 (2021).Article 
PubMed 

Google Scholar 
Tubi, M. A. et al. Early seizures and temporal lobe trauma predict post-traumatic epilepsy: a longitudinal study. Neurobiol. Dis. 123, 115–121 (2019).Article 
PubMed 

Google Scholar 
Salazar, A. M. et al. Epilepsy after penetrating head injury. I. Clinical correlates: a report of the Vietnam Head Injury Study. Neurology 35, 1406–1414 (1985).Article 
CAS 
PubMed 

Google Scholar 
The World Bank. World bank country and lending groups. Worldbank.org. https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups (2023).Ogunrin, O. A. & Adeyekun, A. A. Profile of post-traumatic epilepsy in Benin City, Nigeria. West Afr. J. Med. 29, 153–157 (2011).Article 

Google Scholar 
Rabiu, T. B. & Adetunmbi, B. Posttraumatic seizures in a rural Nigerian neurosurgical service. World Neurosurg. 104, 367–371 (2017).Article 
PubMed 

Google Scholar 
Wang, X. P. et al. Development and external validation of a predictive nomogram model of posttraumatic epilepsy: a retrospective analysis. Seizure 88, 36–44 (2021).Article 
PubMed 

Google Scholar 
Espinosa-Jovel, C., Toledano, R., Aledo-Serrano, Á., García-Morales, I. & Gil-Nagel, A. Epidemiological profile of epilepsy in low income populations. Seizure 56, 67–72 (2018).Article 
PubMed 

Google Scholar 
Gennarelli, T., Champion, H., Copes, W. & Sacco, W. Comparison of mortality, morbidity, and severity of 59,713 head injured patients with 114,447 patients with extracranial injuries. J. Trauma 37, 962–968 (1994).Article 
CAS 
PubMed 

Google Scholar 
Eagle, S. R., Pease, M., Nwachuku, E., Deng, H. & Okonkwo, D. O. Prognostic models for traumatic brain injury have good discrimination but poor overall model performance for predicting mortality and unfavorable outcomes. Neurosurgery 92, 137–143 (2023).Article 
PubMed 

Google Scholar 
Eagle, S. R. et al. Performance of CRASH and IMPACT prognostic models for traumatic brain injury at 12 and 24 months post-injury. Neurotrauma Rep. 4, 118–123 (2023).Article 
PubMed 
PubMed Central 

Google Scholar 
Hanna Siig Hausted, J. F. N. & Odgaard, L. Epilepsy after severe traumatic brain injury: frequency and injury severity. Brain Inj. 34, 889–894 (2020).Article 
PubMed 

Google Scholar 
Ritter, A. C. et al. Prognostic models for predicting posttraumatic seizures during acute hospitalization, and at 1 and 2 years following traumatic brain injury. Epilepsia 57, 1503–1514 (2016).Article 
PubMed 

Google Scholar 
Xu, T. et al. Risk factors for posttraumatic epilepsy: a systematic review and meta-analysis. Epilepsy Behav. 67, 1–6 (2017).Article 
PubMed 

Google Scholar 
Temkin, N. R. Risk factors for posttraumatic seizures in adults. Epilepsia 44, 18–20 (2003).Article 
PubMed 

Google Scholar 
Arefan, D., Pease, M., Eagle, S. R., Okonkwo, D. O. & Wu, S. Comparison of machine learning models to predict long-term outcomes after severe traumatic brain injury. Neurosurg. Focus 54, E14 (2023).Article 
PubMed 

Google Scholar 
Dijkland, S. A. et al. Prognosis in moderate and severe traumatic brain injury: a systematic review of contemporary models and validation studies. J. Neurotrauma 37, 1–13 (2020).Article 
PubMed 

Google Scholar 
Steyerberg, E. W. et al. Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med 5, 1251–1261 (2008).Article 

Google Scholar 
Immonen, R. et al. Imaging biomarkers of epileptogenecity after traumatic brain injury — preclinical frontiers. Neurobiol. Dis. 123, 75–85 (2019).Article 
PubMed 

Google Scholar 
Garner, R. et al. Imaging biomarkers of posttraumatic epileptogenesis. Epilepsia 60, 2151–2162 (2019).Article 
PubMed 
PubMed Central 

Google Scholar 
Prince, D. A. et al. Epilepsy following cortical injury: cellular and molecular mechanisms as targets for potential prophylaxis. Epilepsia 50, 30–40 (2009).Article 
PubMed 
PubMed Central 

Google Scholar 
Jennett, W. B. & Lewin, W. Traumatic epilepsy after closed head injuries. J. Neurol. Neurosurg. Psychiatry 23, 295–301 (1960).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Al-Haddad, S. A. & Kirollos, R. A 5-year study of the outcome of surgically treated depressed skull fractures. Ann. R. Coll. Surg. Engl. 84, 196–200 (2002).PubMed 
PubMed Central 

Google Scholar 
De Reuck, J. Risk factors for late-onset seizures related to cerebral contusions in adults with a moderate traumatic brain injury. Clin. Neurol. Neurosurg. 113, 469–471 (2011).Article 
PubMed 

Google Scholar 
La Rocca, M. et al. Distribution and volume analysis of early hemorrhagic contusions by MRI after traumatic brain injury: a preliminary report of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx). Brain Imaging Behav. 15, 2804–2812 (2021).Article 
PubMed 

Google Scholar 
Messori, A., Polonara, G., Carle, F., Gesuita, R. & Salvolini, U. Predicting posttraumatic epilepsy with MRI: prospective longitudinal morphologic study in adults. Epilepsia 46, 1472–1481 (2005).Article 
PubMed 

Google Scholar 
Gupta, P. K. et al. Subtypes of post-traumatic epilepsy: clinical, electrophysiological, and imaging features. J. Neurotrauma 31, 1439–1443 (2014).Article 
PubMed 
PubMed Central 

Google Scholar 
Won, S. Y. et al. A systematic review of epileptic seizures in adults with subdural haematomas. Seizure 45, 28–35 (2017).Article 
PubMed 

Google Scholar 
La Rocca, M. et al. Multiplex networks to characterize seizure development in traumatic brain injury patients. Front. Neurosci. 14, 591662 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Lutkenhoff, E. S. et al. Early brain biomarkers of post-traumatic seizures: initial report of the multicentre epilepsy bioinformatics study for antiepileptogenic therapy (EpiBioS4Rx) prospective study. J. Neurol. Neurosurg. Psychiatry 91, 1154–1157 (2020).Article 
PubMed 

Google Scholar 
Manninen, E. et al. Acute thalamic damage as a prognostic biomarker for post-traumatic epileptogenesis. Epilepsia 62, 1852–1864 (2021).Article 
PubMed 

Google Scholar 
Graham, N. S. N., Cole, J. H., Bourke, N. J., Schott, J. M. & Sharp, D. J. Distinct patterns of neurodegeneration after TBI and in Alzheimer’s disease. Alzheimers Dement. 19, 3065–3077 (2023).Article 
CAS 
PubMed 

Google Scholar 
Dinkel, J. et al. Long-term white matter changes after severe traumatic brain injury: a 5-year prospective cohort. Am. J. Neuroradiol. 35, 23–29 (2014).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Zelano, J. & Westman, G. Epilepsy after brain infection in adults. Neurology 95, e3213–e3220 (2020).Article 
CAS 
PubMed 

Google Scholar 
Yu, T., Liu, X., Sun, L., Wu, J. & Wang, Q. Clinical characteristics of post-traumatic epilepsy and the factors affecting the latency of PTE. BMC Neurol. 21, 301 (2021).Article 
PubMed 
PubMed Central 

Google Scholar 
Candy, N., Tsimiklis, C., Poonnoose, S. & Trivedi, R. The use of antiepileptic medication in early post traumatic seizure prophylaxis at a single institution. J. Clin. Neurosci. 69, 198–205 (2019).Article 
PubMed 

Google Scholar 
DJohn, J., Ibrahim, R., Patel, P., DeHoff, K. & Kolbe, N. Administration of levetiracetam in traumatic brain injury: is it warranted? Cureus 12, e9117 (2020).PubMed 
PubMed Central 

Google Scholar 
Pease, M. et al. Multicenter and prospective trial of anti-epileptics for early seizure prevention in mild traumatic brain injury with a positive computed tomography scan. Surg. Neurol. Int. 13, 241 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Lee, S. T., Lui, T. N., Wong, C. W., Yeh, Y. S. & Tzaan, W. C. Early seizures after moderate closed head injury. Acta Neurochir. 137, 151–154 (1995).Article 
CAS 
PubMed 

Google Scholar 
Temkin, N. R. et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N. Engl. J. Med. 323, 497–502 (1990).Article 
CAS 
PubMed 

Google Scholar 
Gugger, J. J. & Diaz-Arrastia, R. Early posttraumatic seizures — putting things in perspective. JAMA Neurol. 79, 325–326 (2022).Article 
PubMed 

Google Scholar 
Jennett, B. Early traumatic epilepsy: incidence and significance after nonmissile injuries. Arch. Neurol. 30, 394–398 (1974).Article 
CAS 
PubMed 

Google Scholar 
Glaser, A. C. et al. The effect of antiseizure medication administration on mortality and early posttraumatic seizures in critically ill older adults with traumatic brain injury. Neurocrit. Care 37, 538–546 (2022).Article 
CAS 
PubMed 

Google Scholar 
Zhao, Y., Wu, H., Wang, X., Li, J. & Zhang, S. Clinical epidemiology of posttraumatic epilepsy in a group of Chinese patients. Seizure 21, 322–326 (2012).Article 
PubMed 

Google Scholar 
Bakr, A. & Belli, A. A systematic review of levetiracetam versus phenytoin in the prevention of late post-traumatic seizures and survey of UK neurosurgical prescribing practice of antiepileptic medication in acute traumatic brain injury. Br. J. Neurosurg. 32, 237–244 (2018).Article 
PubMed 

Google Scholar 
Carney, N. et al. Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery 80, 6–15 (2017).Article 
PubMed 

Google Scholar 
Wilson, C. D. et al. Early and late posttraumatic epilepsy in the setting of traumatic brain injury: a meta-analysis and review of antiepileptic management. World Neurosurg. 110, e901–e906 (2018).Article 
PubMed 

Google Scholar 
Sundararajan, K., Milne, D., Edwards, S., Chapman, M. J. & Shakib, S. Anti-seizure prophylaxis in critically ill patients with traumatic brain injury in an intensive care unit. Anaesth. Intensive Care 43, 646–651 (2015).Article 
CAS 
PubMed 

Google Scholar 
Sun, Y. et al. Early post-traumatic seizures are associated with valproic acid plasma concentrations and UGT1A6/CYP2C9 genetic polymorphisms in patients with severe traumatic brain injury. Scand. J. Trauma Resusc. Emerg. Med 25, 85 (2017).Article 
PubMed 
PubMed Central 

Google Scholar 
Temkin, N. R. et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J. Neurosurg. 91, 593–600 (1999).Article 
CAS 
PubMed 

Google Scholar 
Wang, B. C. et al. Comparative efficacy of prophylactic anticonvulsant drugs following traumatic brain injury: a systematic review and network meta-analysis of randomized controlled trials. PLoS ONE 17, e0265932 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Kwon, S. J. et al. Lacosamide versus phenytoin for the prevention of early post traumatic seizures. J. Crit. Care 50, 50–53 (2019).Article 
CAS 
PubMed 

Google Scholar 
Herman, S. T. et al. Consensus statement on continuous EEG in critically ill adults and children, part I: indications. J. Clin. Neurophysiol. 32, 87–95 (2015).Article 
PubMed 
PubMed Central 

Google Scholar 
Vespa, P. et al. Metabolic crisis occurs with seizures and periodic discharges after brain trauma. Ann. Neurol. 79, 579–590 (2016).Article 
PubMed 

Google Scholar 
Khor, D. et al. Early seizure prophylaxis in traumatic brain injuries revisited: a prospective observational study. World J. Surg. 42, 1727–1732 (2018).Article 
PubMed 

Google Scholar 
Inglet, S. et al. Seizure prophylaxis in patients with traumatic brain injury: a single-center study. Cureus 8, 6–8 (2016).
Google Scholar 
Hazama, A. et al. The effect of Keppra prophylaxis on the incidence of early onset, post-traumatic brain injury seizures. Cureus 10, e2674 (2018).PubMed 
PubMed Central 

Google Scholar 
Pingue, V., Mele, C. & Nardone, A. Post-traumatic seizures and antiepileptic therapy as predictors of the functional outcome in patients with traumatic brain injury. Sci. Rep. 11, 4708 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Zaccara, G. et al. Do antiepileptic drugs increase the risk of infectious diseases? A meta-analysis of placebo-controlled studies. Br. J. Clin. Pharm. 83, 1873–1879 (2017).Article 
CAS 

Google Scholar 
Carpay, J. A., Aldenkamp, A. P. & van Donselaar, C. A. Complaints associated with the use of antiepileptic drugs: results from a community-based study. Seizure 14, 198–206 (2005).Article 
CAS 
PubMed 

Google Scholar 
Lu, X. & Wang, X. Hyponatremia induced by antiepileptic drugs in patients with epilepsy. Expert Opin. Drug Saf. 16, 77–87 (2017).Article 
CAS 
PubMed 

Google Scholar 
Aarabi, B., Taghipour, M., Haghnegahdar, A., Farokhi, M. & Mobley, L. Prognostic factors in the occurrence of posttraumatic epilepsy after penetrating head injury suffered during military service. Neurosurg. Focus 8, e1 (2000).Article 
CAS 
PubMed 

Google Scholar 
Galanopoulou, A. S. et al. Antiepileptogenesis and disease modification: progress, challenges, and the path forward — Report of the Preclinical Working Group of the 2018 NINDS-sponsored antiepileptogenesis and disease modification workshop. Epilepsia Open 6, 276–296 (2021).Article 
PubMed 
PubMed Central 

Google Scholar 
Pingue, V. et al. Impact of seizures and their prophylaxis with antiepileptic drugs on rehabilitation course of patients with traumatic or hemorrhagic brain injury. Front. Neurol. 13, 1060008 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Pugh, M. J. et al. The military injuries: understanding post-traumatic epilepsy study: understanding relationships among lifetime traumatic brain injury history, epilepsy, and quality of life. J. Neurotrauma 38, 2841–2850 (2021).Article 
PubMed 
PubMed Central 

Google Scholar 
Juengst, S. B. et al. Post-traumatic epilepsy associations with mental health outcomes in the first two years after moderate to severe TBI: a TBI Model Systems analysis. Epilepsy Behav. 73, 240–246 (2017).Article 
PubMed 

Google Scholar 
Mazzini, L. et al. Posttraumatic epilepsy: neuroradiologic and neuropsychological assessment of long-term outcome. Epilepsia 44, 569–574 (2003).Article 
PubMed 

Google Scholar 
Semple, B. D., Zamani, A., Rayner, G., Shultz, S. R. & Jones, N. C. Affective, neurocognitive and psychosocial disorders associated with traumatic brain injury and post-traumatic epilepsy. Neurobiol. Dis. 123, 27–41 (2020).Article 

Google Scholar 
Ngadimon, I. W. et al. An interplay between post-traumatic epilepsy and associated cognitive decline: a systematic review. Front. Neurol. 13, 827571 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Mukherjee, S. et al. Neuroinflammatory mechanisms of post-traumatic epilepsy. J. Neuroinflammation 17, 193 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
La Rocca, M. et al. Functional connectivity alterations in traumatic brain injury patients with late seizures. Neurobiol. Dis. 179, 106053 (2023).Article 
PubMed 

Google Scholar 
Pease, M. et al. Outcome prediction in patients with severe traumatic brain injury using deep learning from head CT scans. Radiology 304, 385–394 (2022).Article 
PubMed 

Google Scholar 
Lutkenhoff, E. S. et al. The subcortical basis of outcome and cognitive impairment in TBI: a longitudinal cohort study. Neurology 95, E2398–E2408 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Walker, W. C. et al. Global outcome and late seizures after penetrating versus closed traumatic brain injury: a NIDRR TBI Model Systems study. J. Head Trauma Rehabil. 30, 231–240 (2015).Article 
PubMed 

Google Scholar 
Bushnik, T., Englander, J., Wright, J. & Kolakowsky-Hayner, S. A. Traumatic brain injury with and without late posttraumatic seizures: what are the impacts in the post-acute phase: a NIDRR traumatic brain injury model systems study. J. Head Trauma Rehabil. 27, 36–44 (2012).Article 

Google Scholar 
Yu, T. et al. Predicting global functional outcomes among post-traumatic epilepsy patients after moderate-to-severe traumatic brain injury: development of a prognostic model. Front. Neurol. 13, 874491 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Uski, J., Lamusuo, S., Teperi, S., Löyttyniemi, E. & Tenovuo, O. Mortality after traumatic brain injury and the effect of posttraumatic epilepsy. Neurology 91, e878–e883 (2018).Article 
PubMed 

Google Scholar 
Karlander, M., Ljungqvist, J., Sörbo, A. & Zelano, J. Risk and cause of death in post-traumatic epilepsy: a register-based retrospective cohort study. J. Neurol. 269, 6014–6020 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Englander, J., Bushnik, T., Wright, J. M., Jamison, L. & Duong, T. T. Mortality in late post-traumatic seizures. J. Neurotrauma 26, 1471–1477 (2009).Article 
PubMed 
PubMed Central 

Google Scholar 
Rayner, G., Jackson, G. D. & Wilson, S. J. Two distinct symptom-based phenotypes of depression in epilepsy yield specific clinical and etiological insights. Epilepsy Behav. 64, 336–344 (2016).Article 
PubMed 

Google Scholar 
Ponsford, J. Anxiety and depression following TBI. in Neurobehavioural Disability and Social Handicap Following Traumatic Brain Injury 2nd edn (eds McMillan, T. M. & Wood, R. L. L.) 167–177 (Taylor & Francis, 2017).Foreman, B. et al. Seizures and cognitive outcome after traumatic brain injury: a post hoc analysis. Neurocrit. Care 36, 130–138 (2022).Article 
PubMed 

Google Scholar 
Lee, H. et al. Continuous electroencephalography after moderate to severe traumatic brain injury. Crit. Care Med 47, 574–582 (2019).Article 
PubMed 
PubMed Central 

Google Scholar 
He, X. et al. Resective surgery for drug-resistant posttraumatic epilepsy: predictors of seizure outcome. J. Neurosurg. 133, 1568–1575 (2019).Article 

Google Scholar 
Chartrain, A. G. et al. Antiepileptics for post-traumatic seizure prophylaxis after traumatic brain injury. Curr. Pharm. Des. 23, 6428–6441 (2017).Article 
CAS 
PubMed 

Google Scholar 
Zimmermann, L. L., Martin, R. M. & Girgis, F. Treatment options for posttraumatic epilepsy. Curr. Opin. Neurol. 30, 580–586 (2017).Article 
PubMed 

Google Scholar 
Hamed, R., Hussein, R., Ibraheem, S. & Jumaily, M. Comparative study between leviteracetam, phenytoin & carbamazepine in treating post traumatic epilepsy. NeuroQuantology 18, 1–5 (2020).Article 

Google Scholar 
Scheffer, I. E. et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58, 512–521 (2017).Article 
PubMed 
PubMed Central 

Google Scholar 
Hitti, F. L. et al. Surgical outcomes in post-traumatic epilepsy: a single institutional experience. Oper. Neurosurg. 18, 12–18 (2020).Article 

Google Scholar 
Marks, D. A., Kim, J., Spencer, D. D. & Spencer, S. S. Seizure localization and pathology following head injury in patients with uncontrolled epilepsy. Neurology 45, 2051–2057 (1995).Article 
CAS 
PubMed 

Google Scholar 
Hakimian, S. et al. Long-term outcome of extratemporal resection in posttraumatic epilepsy. Neurosurg. Focus 32, E10 (2012).Article 
PubMed 

Google Scholar 
Schuele, S. U. & Lüders, H. O. Intractable epilepsy: management and therapeutic alternatives. Lancet Neurol. 7, 514–524 (2008).Article 
PubMed 

Google Scholar 
Ferreira, L. D., Tabaeizadeh, M. & Haneef, Z. Surgical outcomes in post-traumatic temporal lobe epilepsy: a systematic review and meta-analysis. J. Neurotrauma 41, 319–330 (2024).Article 
PubMed 

Google Scholar 
Wiebe, S., Blume, W. T., Girvin, J. P. & Eliasziw, M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345, 311–318 (2001).Article 
CAS 
PubMed 

Google Scholar 
Lee, H.-O. et al. Effect of vagus nerve stimulation in post-traumatic epilepsy and failed epilepsy surgery: preliminary report. J. Korean Neurosurg. Soc. 44, 196–198 (2008).Article 
PubMed 
PubMed Central 

Google Scholar 
Shen, C.-C. & Jiang, J.-F. Auricular electroacupuncture for late posttraumatic epilepsy after severe brain injury: a retrospective study. Evid. Based Complement Altern. Med. 2019, 5798912 (2019).Article 

Google Scholar 
Chen, Y. et al. Quantitative epileptiform burden and electroencephalography background features predict post-traumatic epilepsy. J. Neurol. Neurosurg. Psychiatry 94, 245–249 (2023).Article 
CAS 
PubMed 

Google Scholar 
Kim, J. A. et al. Epileptiform activity in traumatic brain injury predicts post-traumatic epilepsy. Ann. Neurol. 83, 858–862 (2018).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Faghihpirayesh, R. et al. Automatic detection of EEG epileptiform abnormalities in traumatic brain injury using deep learning. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. 2021, 302–305 (2021).PubMed 
PubMed Central 

Google Scholar 
Di Sapia, R. et al. ECoG spiking activity and signal dimension are early predictive measures of epileptogenesis in a translational mouse model of traumatic brain injury. Neurobiol. Dis. 185, 106251 (2023).Article 
PubMed 

Google Scholar 
Kumar, U., Li, L., Bragin, A. & Engel, J. J. Spike and wave discharges and fast ripples during posttraumatic epileptogenesis. Epilepsia 62, 1842–1851 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Li, L. et al. Spatial and temporal profile of high-frequency oscillations in posttraumatic epileptogenesis. Neurobiol. Dis. 161, 105544 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Pease, M. et al. Predicting post-traumatic epilepsy using admission electroencephalography after severe traumatic brain injury. Epilepsia 64, 1842–1852 (2023).Article 
PubMed 

Google Scholar 
Ghaith, H. S. et al. A literature review of traumatic brain injury biomarkers. Mol. Neurobiol. 59, 4141–4158 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Misra, S. et al. Common pathways of epileptogenesis in patients with epilepsy post-brain injury: findings from a systematic review and meta-analysis. Neurology 101, e2243–e2256 (2023).Article 
PubMed 

Google Scholar 
Cotter, D., Kelso, A. & Neligan, A. Genetic biomarkers of posttraumatic epilepsy: a systematic review. Seizure 46, 53–58 (2017).Article 
PubMed 

Google Scholar 
Nam, J.-W. et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol. Cell 53, 1031–1043 (2014).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Yu, Y. et al. The role of exosomal microRNAs in central nervous system diseases. Mol. Cell. Biochem. 476, 2111–2124 (2021).Article 
CAS 
PubMed 

Google Scholar 
Gitaí, D. L. G. et al. Extracellular vesicles in the forebrain display reduced miR-346 and miR-331-3p in a rat model of chronic temporal lobe epilepsy. Mol. Neurobiol. 57, 1674–1687 (2020).Article 
PubMed 

Google Scholar 
Chen, S.-D. et al. Circulating microRNAs from serum exosomes may serve as a putative biomarker in the diagnosis and treatment of patients with focal cortical dysplasia. Cells 9, 1867 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Brennan, G. P. & Henshall, D. C. microRNAs in the pathophysiology of epilepsy. Neurosci. Lett. 667, 47–52 (2018).Article 
CAS 
PubMed 

Google Scholar 
Wang, Y. et al. Circulating microRNAs from plasma small extracellular vesicles as potential diagnostic biomarkers in pediatric epilepsy and drug-resistant epilepsy. Front. Mol. Neurosci. 15, 823802 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Heiskanen, M. et al. Discovery and validation of circulating microRNAs as biomarkers for epileptogenesis after experimental traumatic brain injury — the EPITARGET Cohort. Int. J. Mol. Sci. 24, 2823 (2023).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Kumar, P. miRNA dysregulation in traumatic brain injury and epilepsy: a systematic review to identify putative biomarkers for post-traumatic epilepsy. Metab. Brain Dis. 38, 749–765 (2023).Article 
CAS 
PubMed 

Google Scholar 
Karnati, H. K. et al. Neuronal enriched extracellular vesicle proteins as biomarkers for traumatic brain injury. J. Neurotrauma 36, 975–987 (2019).Article 
PubMed 
PubMed Central 

Google Scholar 
Lin, Z. et al. Serum exosomal proteins F9 and TSP-1 as potential diagnostic biomarkers for newly diagnosed epilepsy. Front. Neurosci. 14, 737 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Karttunen, J., Heiskanen, M., Lipponen, A., Poulsen, D. & Pitkänen, A. Extracellular vesicles as diagnostics and therapeutics for structural epilepsies. Int. J. Mol. Sci. 20, 1259 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Upadhya, D. & Shetty, A. K. Promise of extracellular vesicles for diagnosis and treatment of epilepsy. Epilepsy Behav. 121, 106499 (2021).Article 
PubMed 

Google Scholar 
Redell, J. B., Moore, A. N., Ward, N. H. III, Hergenroeder, G. W. & Dash, P. K. Human traumatic brain injury alters plasma microRNA levels. J. Neurotrauma 27, 2147–2156 (2010).Article 
PubMed 
PubMed Central 

Google Scholar 
Qin, X. et al. Expression profile of plasma microRNAs and their roles in diagnosis of mild to severe traumatic brain injury. PLoS ONE 13, e0204051 (2018).Article 
PubMed 
PubMed Central 

Google Scholar 
Ko, J. et al. Diagnosis of traumatic brain injury using miRNA signatures in nanomagnetically isolated brain-derived extracellular vesicles. Lab Chip 18, 3617–3630 (2018).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Hicks, S. D. et al. Overlapping microRNA expression in saliva and cerebrospinal fluid accurately identifies pediatric traumatic brain injury. J. Neurotrauma 35, 64–72 (2018).Article 
PubMed 
PubMed Central 

Google Scholar 
Di Pietro, V. et al. MicroRNAs as novel biomarkers for the diagnosis and prognosis of mild and severe traumatic brain injury. J. Neurotrauma 34, 1948–1956 (2017).Article 
PubMed 

Google Scholar 
Bhomia, M., Balakathiresan, N. S., Wang, K. K., Papa, L. & Maheshwari, R. K. A panel of serum miRNA biomarkers for the diagnosis of severe to mild traumatic brain injury in humans. Sci. Rep. 6, 28148 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Yan, S. et al. Altered microRNA profiles in plasma exosomes from mesial temporal lobe epilepsy with hippocampal sclerosis. Oncotarget 8, 4136–4146 (2017).Article 
PubMed 

Google Scholar 
Raoof, R. et al. Dual-center, dual-platform microRNA profiling identifies potential plasma biomarkers of adult temporal lobe epilepsy. eBioMedicine 38, 127–141 (2018).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Medel-Matus, J.-S. et al. Susceptibility to epilepsy after traumatic brain injury is associated with preexistent gut microbiome profile. Epilepsia 63, 1835–1848 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Medel-Matus, J.-S. et al. Modification of post-traumatic epilepsy by fecal microbiota transfer. Epilepsy Behav. 134, 108860 (2022).Article 
PubMed 

Google Scholar 
French, J. A. et al. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann. Neurol. 34, 774–780 (1993).Article 
CAS 
PubMed 

Google Scholar 
Löscher, W. The search for new screening models of pharmacoresistant epilepsy: is induction of acute seizures in epileptic rodents a suitable approach? Neurochem. Res. 42, 1926–1938 (2017).Article 
PubMed 

Google Scholar 
Dudek, F. E. & Staley, K. J. The time course and circuit mechanisms of acquired epileptogenesis. in Jasper’s Basic Mechanisms of the Epilepsies 4th edn (eds Noebels, J. L. et al.) (Oxford Univ. Press, 2012).Santhakumar, V., Ratzliff, A. D., Jeng, J., Toth, Z. & Soltesz, I. Long-term hyperexcitability in the hippocampus after experimental head trauma. Ann. Neurol. 50, 708–717 (2001).Article 
CAS 
PubMed 

Google Scholar 
Dudek, F. E. & Spitz, M. Hypothetical mechanisms for the cellular and neurophysiologic basis of secondary epileptogenesis: proposed role of synaptic reorganization. J. Clin. Neurophysiol. 14, 90–101 (1997).Article 
CAS 
PubMed 

Google Scholar 
Cantu, D. et al. Traumatic brain injury increases cortical glutamate network activity by compromising GABAergic control. Cereb. Cortex 25, 2306–2320 (2015).Article 
PubMed 

Google Scholar 
Lowenstein, D. H., Thomas, M. J., Smith, D. H. & McIntosh, T. K. Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J. Neurosci. 12, 4846–4853 (1992).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Raible, D. J., Frey, L. C., Cruz Del Angel, Y., Russek, S. J. & Brooks-Kayal, A. R. GABA(A) receptor regulation after experimental traumatic brain injury. J. Neurotrauma 29, 2548–2554 (2012).Article 
PubMed 
PubMed Central 

Google Scholar 
Gupta, A., Elgammal, F. S., Proddutur, A., Shah, S. & Santhakumar, V. Decrease in tonic inhibition contributes to increase in dentate semilunar granule cell excitability after brain injury. J. Neurosci. 32, 2523–2537 (2012).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Webster, K. M. et al. Inflammation in epileptogenesis after traumatic brain injury. J. Neuroinflammation 14, 10 (2017).Article 
PubMed 
PubMed Central 

Google Scholar 
Hunt, R. F., Scheff, S. W. & Smith, B. N. Synaptic reorganization of inhibitory hilar interneuron circuitry after traumatic brain injury in mice. J. Neurosci. 31, 6880–6890 (2011).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Bolkvadze, T., Puhakka, N. & Pitkänen, A. Epileptogenesis after traumatic brain injury in Plaur-deficient mice. Epilepsy Behav. 60, 187–196 (2016).Article 
PubMed 

Google Scholar 
Kumar, P. et al. Single-cell transcriptomics and surface epitope detection in human brain epileptic lesions identifies pro-inflammatory signaling. Nat. Neurosci. 25, 956–966 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Srinivasan, D., Yen, J.-H., Joseph, D. J. & Friedman, W. Cell type-specific interleukin-1beta signaling in the CNS. J. Neurosci. 24, 6482–6488 (2004).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Shiozaki, T. et al. Cerebrospinal fluid concentrations of anti-inflammatory mediators in early-phase severe traumatic brain injury. Shock 23, 406–410 (2005).Article 
CAS 
PubMed 

Google Scholar 
Fan, L. et al. Experimental brain injury induces expression of interleukin-1 beta mRNA in the rat brain. Brain Res. Mol. Brain Res. 30, 125–130 (1995).Article 
CAS 
PubMed 

Google Scholar 
Clausen, F. et al. Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice. Eur. J. Neurosci. 30, 385–396 (2009).Article 
PubMed 

Google Scholar 
Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).Article 
CAS 
PubMed 

Google Scholar 
Shi, Y., Zhang, L., Teng, J. & Miao, W. HMGB1 mediates microglia activation via the TLR4/NF-κB pathway in coriaria lactone induced epilepsy. Mol. Med. Rep. 17, 5125–5131 (2018).CAS 
PubMed 
PubMed Central 

Google Scholar 
Chiavegato, A., Zurolo, E., Losi, G., Aronica, E. & Carmignoto, G. The inflammatory molecules IL-1β and HMGB1 can rapidly enhance focal seizure generation in a brain slice model of temporal lobe epilepsy. Front. Cell. Neurosci. 8, 155 (2014).Article 
PubMed 
PubMed Central 

Google Scholar 
Semple, B. D., Kossmann, T. & Morganti-Kossmann, M. C. Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J. Cereb. Blood Flow Metab. 30, 459–473 (2010).Article 
CAS 
PubMed 

Google Scholar 
Gosselin, R. D. et al. Constitutive expression of CCR2 chemokine receptor and inhibition by MCP-1/CCL2 of GABA-induced currents in spinal cord neurones. J. Neurochem. 95, 1023–1034 (2005).Article 
CAS 
PubMed 

Google Scholar 
Patabendige, A. & Janigro, D. The role of the blood–brain barrier during neurological disease and infection. Biochem. Soc. Trans. 51, 613–626 (2023).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Marchi, N., Granata, T., Alexopoulos, A. & Janigro, D. The blood–brain barrier hypothesis in drug resistant epilepsy. Brain 135, e211 (2012).Article 
PubMed 
PubMed Central 

Google Scholar 
Bargerstock, E. et al. Is peripheral immunity regulated by blood–brain barrier permeability changes? PLoS ONE 9, e101477 (2014).Article 
PubMed 
PubMed Central 

Google Scholar 
Dadas, A. & Janigro, D. Breakdown of blood–brain barrier as a mechanism of post-traumatic epilepsy. Neurobiol. Dis. 123, 20–26 (2019).Article 
CAS 
PubMed 

Google Scholar 
Weissberg, I. et al. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood–brain barrier dysfunction. Neurobiol. Dis. 78, 115–125 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Ivens, S. et al. TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130, 535–547 (2007).Article 
PubMed 

Google Scholar 
Saletti, P. G. et al. In search of antiepileptogenic treatments for post-traumatic epilepsy. Neurobiol. Dis. 123, 86–99 (2019).Article 
PubMed 

Google Scholar 
Kendirli, M. T., Rose, D. T. & Bertram, E. H. A model of posttraumatic epilepsy after penetrating brain injuries: effect of lesion size and metal fragments. Epilepsia 55, 1969–1977 (2014).Article 
PubMed 
PubMed Central 

Google Scholar 
Takei, N. & Nawa, H. mTOR signaling and its roles in normal and abnormal brain development. Front. Mol. Neurosci. 7, 28 (2014).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Lee, D. Y. Roles of mTOR signaling in brain development. Exp. Neurobiol. 24, 177–185 (2015).Article 
PubMed 
PubMed Central 

Google Scholar 
Butler, C. R., Boychuk, J. A. & Smith, B. N. Effects of rapamycin treatment on neurogenesis and synaptic reorganization in the dentate gyrus after controlled cortical impact injury in mice. Front. Syst. Neurosci. 9, 163 (2015).Article 
PubMed 
PubMed Central 

Google Scholar 
Niu, L.-J., Xu, R.-X., Zhang, P., Du, M.-X. & Jiang, X.-D. Suppression of Frizzled-2-mediated Wnt/Ca2+ signaling significantly attenuates intracellular calcium accumulation in vitro and in a rat model of traumatic brain injury. Neuroscience 213, 19–28 (2012).Article 
CAS 
PubMed 

Google Scholar 
Mardones, M. D. & Gupta, K. Transcriptome profiling of the hippocampal seizure network implicates a role for Wnt signaling during epileptogenesis in a mouse model of temporal lobe epilepsy. Int. J. Mol. Sci. 23, 12030 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Gupta, K. & Schnell, E. Neuronal network remodeling and Wnt pathway dysregulation in the intra-hippocampal kainate mouse model of temporal lobe epilepsy. PLoS ONE 14, e0215789 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Raza, M. et al. Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy. Proc. Natl Acad. Sci. USA 101, 17522–17527 (2004).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Powell, K. L., Cain, S. M., Snutch, T. P. & O’Brien, T. J. Low threshold T-type calcium channels as targets for novel epilepsy treatments. Br. J. Clin. Pharm. 77, 729–739 (2014).Article 
CAS 

Google Scholar 
Conboy, K., Henshall, D. C. & Brennan, G. P. Epigenetic principles underlying epileptogenesis and epilepsy syndromes. Neurobiol. Dis. 148, 105179 (2021).Article 
CAS 
PubMed 

Google Scholar 
Dębski, K. J. et al. Etiology matters — genomic DNA methylation patterns in three rat models of acquired epilepsy. Sci. Rep. 6, 25668 (2016).Article 
PubMed 
PubMed Central 

Google Scholar 
Nelson, E. D., Kavalali, E. T. & Monteggia, L. M. Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J. Neurosci. 28, 395–406 (2008).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Machnes, Z. M. et al. DNA methylation mediates persistent epileptiform activity in vitro and in vivo. PLoS ONE 8, e76299 (2013).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Deutsch, S. I., Mastropaolo, J., Burket, J. A. & Rosse, R. B. An epigenetic intervention interacts with genetic strain differences to modulate the stress-induced reduction of flurazepam’s antiseizure efficacy in the mouse. Eur. Neuropsychopharmacol. 19, 398–401 (2009).Article 
CAS 
PubMed 

Google Scholar 
Perez-Pinera, P. et al. RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat. Methods 10, 973–976 (2013).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Dominguez, A. A., Lim, W. A. & Qi, L. S. Beyond editing: repurposing CRISPR-Cas9 for precision genome regulation and interrogation. Nat. Rev. Mol. Cell Biol. 17, 5–15 (2016).Article 
CAS 
PubMed 

Google Scholar 
Sasa, M. A new frontier in epilepsy: novel antiepileptogenic drugs. J. Pharmacol. Sci. 100, 487–494 (2006).Article 
CAS 
PubMed 

Google Scholar 
Brady, R. D. et al. Modelling traumatic brain injury and posttraumatic epilepsy in rodents. Neurobiol. Dis. 123, 8–19 (2020).Article 

Google Scholar 
Ford, I. & Norrie, J. Pragmatic trials. N. Engl. J. Med. 375, 454–463 (2016).Article 
PubMed 

Google Scholar 
Casey, J. D., Beskow, L. M. & Brown, J. Use of pragmatic and explanatory trial designs in acute care research: lessons from COVID-19. Lancet Respir. Med. 10, 700–714 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Braun, R. It’s been a TRACK-TBI LONG time coming but well worth the wait. Neurology 101, 287–289 (2023).Article 
PubMed 

Google Scholar 
McCrea, M. A. et al. Functional outcomes over the first year after moderate to severe traumatic brain injury in the prospective, longitudinal TRACK-TBI study. JAMA Neurol. 78, 982–992 (2021).Article 
PubMed 
PubMed Central 

Google Scholar 
Andrews, P. J. et al. Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the Eurotherm3235 RCT. Health Technol. Assess. 22, 1–134 (2018).Article 
PubMed 
PubMed Central 

Google Scholar 
Bastian, L. A. et al. Stakeholder engagement in pragmatic clinical trials: emphasizing relationships to improve pain management delivery and outcomes. Pain Med. 21, S13–S20 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Morain, S. & Largent, E. Think pragmatically: investigators’ obligations to patient-subjects when research is embedded in care. Am. J. Bioeth. 23, 10–21 (2023).Article 
PubMed 

Google Scholar 
Diaz, V. Encouraging participation of minorities in research studies. Ann. Fam. Med. 10, 372–373 (2012).Article 
PubMed 
PubMed Central 

Google Scholar 
Boden-Albala, B. et al. Use of community-engaged research approaches in clinical interventions for neurologic disorders in the United States. Neurology 101, S27–S46 (2023).Article 
PubMed 

Google Scholar 
Griffith, D. M., Towfighi, A., Manson, S. M., Littlejohn, E. L. & Skolarus, L. E. Determinants of inequities in neurologic disease, health, and well-being: the NINDS Social Determinants of Health Framework. Neurology 101, S75–S81 (2023).Article 
PubMed 

Google Scholar 
Danziger, J. et al. Temporal trends in critical care outcomes in U.S. minority-serving hospitals. Am. J. Respir. Crit. Care Med 201, 681–687 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Kanter, G. P., Segal, A. G. & Groeneveld, P. W. Income disparities in access to critical care services. Health Aff. 39, 1362–1367 (2020).Article 

Google Scholar 
Nayfeh, A. & Fowler, R. A. Understanding patient- and hospital-level factors leading to differences, and disparities, in critical care. Am. J. Respir. Crit. Care Med 201, 642–644 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Brown, K. E., Fohner, A. E. & Woodahl, E. L. Beyond the individual: community-centric approaches to increase diversity in biomedical research. Clin. Pharmacol. Ther. 113, 509–517 (2023).Article 
PubMed 

Google Scholar 
Benizri, N., Hallot, S., Burns, K. & Goldfarb, M. Patient and family representation in randomized clinical trials published in 3 medical and surgical journals: a systematic review. JAMA Netw. Open 5, e2230858 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Gill, M. et al. Patient and family member-led research in the intensive care unit: a novel approach to patient-centered research. PLoS ONE 11, e0160947 (2016).Article 
PubMed 
PubMed Central 

Google Scholar 
Fairley, R. et al. Increasing clinical trial participation of Black women diagnosed with breast cancer. J. Racial Ethn. Health Disparities https://doi.org/10.1007/s40615-023-01644-z (2023).Article 
PubMed 

Google Scholar 
Barrett, N. J. et al. Factors associated with biomedical research participation within community-based samples across 3 National Cancer Institute-designated cancer centers. Cancer 126, 1077–1089 (2020).Article 
PubMed 

Google Scholar 
Miles, S. R. et al. Evolution of irritability, anger, and aggression after traumatic brain injury: identifying and predicting subgroups. J. Neurotrauma 38, 1827–1833 (2021).Article 
PubMed 
PubMed Central 

Google Scholar 
Driver, S., Reynolds, M. & Kramer, K. Modifying an evidence-based lifestyle programme for individuals with traumatic brain injury. Brain Inj. 31, 1612–1616 (2017).Article 
PubMed 

Google Scholar 
Sutton, K. M. et al. Engaging individuals with neurological conditions and caregivers in rural communities in a health research team. Prog. Community Health Partnersh. 13, 129–139 (2019).Article 
PubMed 

Google Scholar 
Shimia, M. et al. A placebo-controlled randomized clinical trial of amantadine hydrochloride for evaluating the functional improvement of patients following severe acute traumatic brain injury. J. Neurosurg. Sci. 67, 598–604 (2023).Article 
PubMed 

Google Scholar 
Morey, C. E., Cilo, M., Berry, J. & Cusick, C. The effect of Aricept in persons with persistent memory disorder following traumatic brain injury: a pilot study. Brain Inj. 17, 809–815 (2003).Article 
PubMed 

Google Scholar 
Jha, A. et al. A randomized trial of modafinil for the treatment of fatigue and excessive daytime sleepiness in individuals with chronic traumatic brain injury. J. Head Trauma Rehabil. 23, 52–63 (2008).Article 
PubMed 

Google Scholar 
Shultz, S. R. et al. Sodium selenate reduces hyperphosphorylated tau and improves outcomes after traumatic brain injury. Brain 138, 1297–1313 (2015).Article 
PubMed 
PubMed Central 

Google Scholar 
Liu, S.-J. et al. Sodium selenate retards epileptogenesis in acquired epilepsy models reversing changes in protein phosphatase 2A and hyperphosphorylated tau. Brain 139, 1919–1938 (2016).Article 
PubMed 

Google Scholar 
Li, Z. et al. Iron neurotoxicity and protection by deferoxamine in intracerebral hemorrhage. Front. Mol. Neurosci. 15, 927334 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Terrone, G., Balosso, S., Pauletti, A., Ravizza, T. & Vezzani, A. Inflammation and reactive oxygen species as disease modifiers in epilepsy. Neuropharmacology 167, 107742 (2020).Article 
CAS 
PubMed 

Google Scholar 
Serrano, G. E. et al. Ablation of cyclooxygenase-2 in forebrain neurons is neuroprotective and dampens brain inflammation after status epilepticus. J. Neurosci. 31, 14850–14860 (2011).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Desjardins, P. et al. Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis. Neurochem. Int. 42, 299–303 (2003).Article 
CAS 
PubMed 

Google Scholar 
Löscher, W. & Friedman, A. Structural, molecular, and functional alterations of the blood–brain barrier during epileptogenesis and epilepsy: a cause, consequence, or both? Int. J. Mol. Sci. 21, 591 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Henshall, D. C. & Kobow, K. Epigenetics and epilepsy. Cold Spring Harb. Perspect. Med. 5, a022731 (2015).Article 
PubMed 
PubMed Central 

Google Scholar 
Guo, D., Zeng, L., Brody, D. L. & Wong, M. Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury. PLoS ONE 8, e64078 (2013).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Galanopoulou, A. S., Gorter, J. A. & Cepeda, C. Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. Epilepsia 53, 1119–1130 (2012).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Coulter, D. A. & Steinhäuser, C. Role of astrocytes in epilepsy. Cold Spring Harb. Perspect. Med. 5, a022434 (2015).Article 
PubMed 
PubMed Central 

Google Scholar