Inflammasomes at the crossroads of traumatic brain injury and post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) is one of the most debilitating consequences of traumatic brain injury (TBI) and is one of the most drug-resistant forms of epilepsy. Novel therapeutic treatment options are an urgent unmet clinical need. The current focus in healthcare has been shifting to disease prevention, rather than treatment, though, not much progress has been made due to a limited understanding of the disease pathogenesis. Neuroinflammation has been implicated in the pathophysiology of traumatic brain injury and may impact neurological sequelae following TBI including functional behavior and post-traumatic epilepsy development. Inflammasome signaling is one of the major components of the neuroinflammatory response, which is increasingly being explored for its contribution to the epileptogenic mechanisms and a novel therapeutic target against epilepsy. This review discusses the role of inflammasomes as a possible connecting link between TBI and PTE with a particular focus on clinical and preclinical evidence of therapeutic inflammasome targeting and its downstream effector molecules for their contribution to epileptogenesis. Finally, we also discuss emerging evidence indicating the potential of evaluating inflammasome proteins in biofluids and the brain by non-invasive neuroimaging, as potential biomarkers for predicting PTE development.

A role of dentate gyrus mechanistic target of rapamycin activation in epileptogenesis in a mouse model of posttraumatic epilepsy.

OBJECTIVE: The mechanistic target of rapamycin (mTOR) pathway has been implicated in promoting epileptogenesis in animal models of acquired epilepsy, such as posttraumatic epilepsy (PTE) following traumatic brain injury (TBI). However, the specific anatomical regions and neuronal populations mediating mTOR's role in epileptogenesis are not well defined. In this study, we tested the hypothesis that mTOR activation in dentate gyrus granule cells promotes neuronal death, mossy fiber sprouting, and PTE in the controlled cortical impact (CCI) model of TBI. METHODS: An adeno-associated virus (AAV)-Cre viral vector was injected into the hippocampus of Rptorflox/flox (regulatory-associated protein of mTOR) mutant mice to inhibit mTOR activation in dentate gyrus granule cells. Four weeks after AAV-Cre or AAV-vehicle injection, mice underwent CCI injury and were subsequently assessed for mTOR pathway activation by Western blotting, neuronal death, and mossy fiber sprouting by immunopathological analysis, and posttraumatic seizures by video-electroencephalographic monitoring. RESULTS: AAV-Cre injection primarily affected the dentate gyrus and inhibited hippocampal mTOR activation following CCI injury. AAV-Cre-injected mice had reduced neuronal death in dentate gyrus detected by Fluoro-Jade B staining and decreased mossy fiber sprouting by ZnT3 immunostaining. Finally, AAV-Cre-injected mice exhibited a decrease in incidence of PTE. SIGNIFICANCE: mTOR pathway activation in dentate gyrus granule cells may at least partly mediate pathological abnormalities and epileptogenesis in models of TBI and PTE. Targeted modulation of mTOR activity in this hippocampal network may represent a focused therapeutic approach for antiepileptogenesis and prevention of PTE.

EEG biomarkers for the prediction of post-traumatic epilepsy - a systematic review of an emerging field.

Traumatic brain injury (TBI) is often followed by post-traumatic epilepsy (PTE), a condition often difficult to treat and leading to a substantial decline in quality of life as well as increased long-term mortality. The latent period between TBI and the emergence of spontaneous recurrent seizures provides an opportunity for pharmacological intervention to prevent epileptogenesis. Biomarkers capable of predicting PTE development are urgently needed to facilitate clinical trials of putative anti-epileptogenic drugs. EEG is a widely available and flexible diagnostic modality that plays a fundamental role in epileptology. We systematically review the advances in the field of the discovery of EEG biomarkers for the prediction of PTE in humans. Despite recent progress, the field faces several challenges including short observation periods, a focus on early post-injury monitoring, difficulties in translating findings from animal models to scalp EEG, and emerging evidence indicating the importance of assessing altered background scalp EEG activity alongside epileptiform activity using quantitative EEG methods while also considering sleep abnormalities in future studies.

Risk Factors and Outcomes of Late Posttraumatic Seizures in Combat-Related Traumatic Brain Injury.

INTRODUCTION: Post-traumatic seizures (PTSs) contribute to morbidity after traumatic brain injury (TBI). Early PTS are rare in combat casualties sustaining TBI, but the prevalence of late PTS is poorly described. We sought to define the prevalence and risk factors of late PTS in combat casualties with computed tomography evidence of TBI. METHODS: From 2010 to 2015, 687 combat casualties were transferred to a military treatment facility and included in the Department of Defense Trauma Registry. 71 patients with radiographic evidence of TBI were analyzed. Data collection included demographics, injury characteristics, interventions, medications, and outcomes. RESULTS: Of the 71 patients with evidence of TBI, 66 patients survived hospitalization and were followed. No patients had early PTS, and most received antiepileptic drugs (AEDs) for prophylaxis. At a median follow-up of 7.4 y, late PTS occurred in 25.8% of patients. Patients with late PTS were more severely injured (median Injury severity score 30 versus 24, P = 0.005) and required more blood products (18 units versus 2, P = 0.045). Patients with late PTS were more likely to have had a penetrating TBI (76.5% versus 38.8%, P = 0.01), multiple types of intracranial hemorrhage (94.1% versus 63.3%, P = 0.02), and cranial decompression (76.5% versus 28.6%, P = 0.001). Six-month Glasgow outcome scores were worse (3.5 versus 4.1 P = 0.001) in the late PTS population. No significant relationship was observed between administration of AEDs for early PTS prophylaxis and late PTS. CONCLUSIONS: Combat casualties with TBI suffering late PTS are more severely injured and require more blood products. Penetrating TBI, intracranial hemorrhage, and need for cranial decompression are correlated with late PTS, and associated with worse Glasgow Outcome Score. The administration of prophylactic AEDs for early PTS was not associated with a difference in rates of late PTS.

Incidence and predictors of posttraumatic epilepsy and cognitive impairment in patients with traumatic brain injury: A retrospective cohort study in Malaysia.

OBJECTIVE: Posttraumatic epilepsy (PTE) significantly impacts morbidity and mortality, yet local PTE data remain scarce. In addition, there is a lack of evidence on cognitive comorbidity in individuals with PTE in the literature. We sought to identify potential PTE predictors and evaluate cognitive comorbidity in patients with PTE. METHODS: A 2-year retrospective cohort study was employed, in which adults with a history of admission for traumatic brain injury (TBI) in 2019 and 2020 were contacted. Three hundred one individuals agreed to participate, with a median follow-up time of 30.75 months. The development of epilepsy was ascertained using a validated tool and confirmed by our neurologists during visits. Clinical psychologists assessed the patients' cognitive performance. RESULTS: The 2-year cumulative incidence of PTE was 9.3% (95% confidence interval [CI] 5.9-12.7). The significant predictors of PTE were identified as a previous history of brain injury [hazard ratio [HR] 4.025, p = .021], and intraparenchymal hemorrhage (HR: 2.291, p = .036), after adjusting for other confounders. TBI patients with PTE performed significantly worse on the total ACE-III cognitive test (73.5 vs 87.0, p = .018), CTMT (27.5 vs 33.0, p = .044), and PSI (74.0 vs 86.0, p = .006) than TBI patients without PTE. A significantly higher percentage of individuals in the PTE group had cognitive impairment, compared to the non-PTE group based on ACE-III (53.6% vs 46.4%, p = .001) and PSI (70% vs 31.7%, p = .005) scores at 2 years post-TBI follow-up. SIGNIFICANCE: This study emphasizes the link between TBI and PTE and the chance of developing cognitive impairment in the future. Clinicians can target interventions to prevent PTE by identifying specific predictors, which helps them make care decisions and develop therapies to improve patients' quality of life.

Advancing post-traumatic seizure classification and biomarker identification: Information decomposition based multimodal fusion and explainable machine learning with missing neuroimaging data.

A late post-traumatic seizure (LPTS), a consequence of traumatic brain injury (TBI), can potentially evolve into a lifelong condition known as post-traumatic epilepsy (PTE). Presently, the mechanism that triggers epileptogenesis in TBI patients remains elusive, inspiring the epilepsy community to devise ways to predict which TBI patients will develop PTE and to identify potential biomarkers. In response to this need, our study collected comprehensive, longitudinal multimodal data from 48 TBI patients across multiple participating institutions. A supervised binary classification task was created, contrasting data from LPTS patients with those without LPTS. To accommodate missing modalities in some subjects, we took a two-pronged approach. Firstly, we extended a graphical model-based Bayesian estimator to directly classify subjects with incomplete modality. Secondly, we explored conventional imputation techniques. The imputed multimodal information was then combined, following several fusion and dimensionality reduction techniques found in the literature, and subsequently fitted to a kernel- or a tree-based classifier. For this fusion, we proposed two new algorithms: recursive elimination of correlated components (RECC) that filters information based on the correlation between the already selected features, and information decomposition and selective fusion (IDSF), which effectively recombines information from decomposed multimodal features. Our cross-validation findings showed that the proposed IDSF algorithm delivers superior performance based on the area under the curve (AUC) score. Ultimately, after rigorous statistical comparisons and interpretable machine learning examination using Shapley values of the most frequently selected features, we recommend the two following magnetic resonance imaging (MRI) abnormalities as potential biomarkers: the left anterior limb of internal capsule in diffusion MRI (dMRI), and the right middle temporal gyrus in functional MRI (fMRI).

Prognostic Implications of Early Prediction in Posttraumatic Epilepsy.

Posttraumatic epilepsy (PTE) is a complication of traumatic brain injury that can increase morbidity, but predicting which patients may develop PTE remains a challenge. Much work has been done to identify a variety of risk factors and biomarkers, or a combination thereof, for patients at highest risk of PTE. However, several issues have hampered progress toward fully adapted PTE models. Such issues include the need for models that are well-validated, cost-effective, and account for competing outcomes like death. Additionally, while an accurate PTE prediction model can provide quantitative prognostic information, how such information is communicated to inform shared decision-making and treatment strategies requires consideration of an individual patient's clinical trajectory and unique values, especially given the current absence of direct anti-epileptogenic treatments. Future work exploring approaches integrating individualized communication of prediction model results are needed.

The Role of the Orexin System in Craniocerebral Trauma-Induced Epilepsy in Mice.

BACKGROUND: Following traumatic brain injury (TBI), an imbalance arises in the central nervous system within the hippocampus region, resulting in the proliferation of mossy cell fibers, causing abnormal membrane discharge. Moreover, disruptions in cellular neurotransmitter secretion induce post-traumatic epilepsy. Extensive experimental and clinical data indicate that the orexin system plays a regulatory role in the hippocampal central nervous system, but the specific regulatory effects are unclear. Therefore, further experimental evaluation of its relevance is needed. OBJECTIVE: This study aims to investigate the effects of orexin receptor agonists (OXA) on the seizure threshold and intensity in controlled cortical impact (CCI) mice, and to understand the role of the orexin system in post-traumatic epilepsy (PTE). METHODS: Male C57BL/6 mice weighing 18-22 g were randomly divided into three groups: Sham, CCI, and CCI+OXA. The three groups of mice were sequentially constructed with models, implanted with electrodes, and established drug-delivery cannulas. After a 30-day recovery, the Sham and CCI groups were injected with physiological saline through the administration cannulas, while the CCI+OXA group was injected with OXA. Subsequently, all mice underwent electrical stimulation every 30 minutes for a total of 15 times. Epileptic susceptibility, duration, intensity, and cognitive changes were observed. Concurrently, the expression levels and changes of GABAergic neurons in the hippocampus of each group were examined by immunofluorescence. RESULTS: Injecting OXA into hippocampal CA1 reduces the threshold of post-traumatic seizures, prolongs the post-discharge duration, prolongs seizure duration, reduces cognitive ability, and exacerbates the loss of GABAergic neurons in the hippocampal region. CONCLUSIONS: Based on the results, we can find that injecting OXA antagonists into the CA1 region of the hippocampus can treat or prevent the occurrence and progression of post-traumatic epilepsy.

Insights into epileptogenesis from post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies. The incidence of PTE after traumatic brain injury (TBI) depends on the severity of injury, approaching one in three in groups with the most severe injuries. The repeated seizures that characterize PTE impair neurological recovery and increase the risk of poor outcomes after TBI. Given this high risk of recurrent seizures and the relatively short latency period for their development after injury, PTE serves as a model disease to understand human epileptogenesis and trial novel anti-epileptogenic therapies. Epileptogenesis is the process whereby previously normal brain tissue becomes prone to recurrent abnormal electrical activity, ultimately resulting in seizures. In this Review, we describe the clinical course of PTE and highlight promising research into epileptogenesis and treatment using animal models of PTE. Clinical, imaging, EEG and fluid biomarkers are being developed to aid the identification of patients at high risk of PTE who might benefit from anti-epileptogenic therapies. Studies in preclinical models of PTE have identified tractable pathways and novel therapeutic strategies that can potentially prevent epilepsy, which remain to be validated in humans. In addition to improving outcomes after TBI, advances in PTE research are likely to provide therapeutic insights that are relevant to all epilepsies.

Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) stands as one of the numerous debilitating consequences that follow traumatic brain injury (TBI). Despite its impact on many individuals, the current landscape offers only a limited array of reliable treatment options, and our understanding of the underlying mechanisms and susceptibility factors remains incomplete. Among the potential contributors to epileptogenesis, astrocytes, a type of glial cell, have garnered substantial attention as they are believed to promote hyperexcitability and the development of seizures in the brain following TBI. The current study evaluated the transcriptomic changes in cortical astrocytes derived from animals that developed seizures as a result of severe focal TBI. Using RNA-Seq and ingenuity pathway analysis (IPA), we unveil a distinct gene expression profile in astrocytes, including alterations in genes supporting inflammation, early response modifiers, and neuropeptide-amidating enzymes. The findings underscore the complex molecular dynamics in astrocytes during PTE development, offering insights into therapeutic targets and avenues for further exploration.

Posttraumatic epilepsy in chronic disorders of consciousness due to severe traumatic brain injury after traffic accidents.

PURPOSE: To evaluate the clinical state of posttraumatic epilepsy (PTE) in patients with chronic disorders of consciousness (CDC) due to severe traumatic brain injury (STBI) after traffic accidents and clarify the risk factors for seizure occurrence in such patients. METHODS: Two hundred ninety-three patients with CDC due to STBI (mean age at admission [±standard deviation]: 36.4 ± 17.9 years; men: 71.7 %; mean duration of injury to admission: 416 ± 732 days; mean hospitalization time: 899 ± 319 days) were enrolled in this study. We retrospectively investigated the relationship between seizure conditions (type and frequency) and clinical data, including age, sex, pathological types of brain injury, with/without surgical intervention, degree of CDC, and administration of antiseizure medications (ASMs). RESULTS: Overall, 52.9 % (n = 155/293) and 64.2 % of the patients (n = 183/of 285 patients surviving at discharge) were administered ASMs at admission and discharge, respectively. One hundred thirty-two patients (45.1 %) experienced epileptic seizures during hospitalization, and the mean seizure frequency was 4.0 ± 0.4 times per year. In multivariate analysis, significant and independent risk factors of seizure occurrence were revealed to be male sex, high National Agency for Automotive Safety and Victims' Aid score, hypoxic encephalopathy, and history of the neurosurgical operations. CONCLUSION: The high prevalence of PTE in patients with CDC due to STBI, and the significant and independent risk factors for seizure occurrence in the chronic clinical phase were revealed. We expect that this study will aid toward improving clinical assessment and management of epileptic seizures in the population.

Clinical characteristics and associated factors of posttraumatic epilepsy after traumatic brain injury in children: A retrospective case-control study.

BACKGROUND: Traumatic brain injury (TBI) affects approximately 69 million individuals annually, often resulting in well-documented complications such as epilepsy. Although numerous studies have been performed on posttraumatic epilepsy (PTE) in adults over the past decade, research on chronic consequences of TBI in children remains limited. Herein, we retrospectively assessed children who had experienced moderate to severe TBI to determine their clinical characteristics and identify associated factors associated with the development of PTE in the pediatric population. METHODS: The study population comprised children aged 0-18 years who had experienced moderate to severe TBI and underwent treatment at the Children's Hospital of Chongqing Medical University between 2011 and 2021. They were categorized into two groups: the PTE group, comprising individuals diagnosed with PTE within a one-year follow-up period, and the nPTE group, consisting of those who did not develop PTE during the same timeframe. The primary objective was to investigate the clinical characteristics and identify related associated factors. The relationship between various clinical factors and the incidence of PTE was assessed through univariate and multivariate logistic regression. RESULTS: A total of 132 patients were assessed. Most participants were male (65%) and the age distribution skewed towards younger children, with a median age of 41.0 months (interquartile range: 45.3). Upon their last clinical visit, 64 children (49%) were diagnosed with PTE. Notably, the first posttraumatic seizure predominantly occurred within the first week following the traumatic event. Further analyses revealed that increasing injury severity, as indicated by a lower Glasgow Coma Scale (GCS) score (odds ratio [OR]: 0.78, 95% confidence interval [CI]: 0.54-1.12, p= 0.018), a contusion load ≥3 (OR: 8.1, 95% CI: 2.3-28.9, p= 0.001), immediate posttraumatic seizures (IPTS) (OR: 8.9, 95% CI: 2.5-31.2, p < 0.001), and early posttraumatic seizures (EPTS) (OR: 54, 95% CI: 11-276, p < 0.001), were all significantly associated with a higher risk of developing PTE. CONCLUSION: This study highlights that the onset of PTE was associated with the markers of injury severity or PTS and identified GCS scores, contusion loads of ≥3, IPTS, and EPTS as independent associated factors significantly associated with the development of PTE.

Genetic diversity drives extreme responses to traumatic brain injury and post-traumatic epilepsy.

Traumatic brain injury (TBI) is a complex and heterogeneous condition that can cause wide-spectral neurological sequelae such as behavioral deficits, sleep abnormalities, and post-traumatic epilepsy (PTE). However, understanding the interaction of TBI phenome is challenging because few animal models can recapitulate the heterogeneity of TBI outcomes. We leveraged the genetically diverse recombinant inbred Collaborative Cross (CC) mice panel and systematically characterized TBI-related outcomes in males from 12 strains of CC and the reference C57BL/6J mice. We identified unprecedented extreme responses in multiple clinically relevant traits across CC strains, including weight change, mortality, locomotor activity, cognition, and sleep. Notably, we identified CC031 mouse strain as the first rodent model of PTE that exhibit frequent and progressive post-traumatic seizures after moderate TBI induced by lateral fluid percussion. Multivariate analysis pinpointed novel biological interactions and three principal components across TBI-related modalities. Estimate of the proportion of TBI phenotypic variability attributable to strain revealed large range of heritability, including >70% heritability of open arm entry time of elevated plus maze. Our work provides novel resources and models that can facilitate genetic mapping and the understanding of the pathobiology of TBI and PTE.

Epilepsy phenotype and its reproducibility after lateral fluid percussion-induced traumatic brain injury in rats: Multicenter EpiBioS4Rx study project 1.

OBJECTIVE: This study was undertaken to assess reproducibility of the epilepsy outcome and phenotype in a lateral fluid percussion model of posttraumatic epilepsy (PTE) across three study sites. METHODS: A total of 525 adult male Sprague Dawley rats were randomized to lateral fluid percussion-induced brain injury (FPI) or sham operation. Of these, 264 were assigned to magnetic resonance imaging (MRI cohort, 43 sham, 221 traumatic brain injury [TBI]) and 261 to electrophysiological follow-up (EEG cohort, 41 sham, 220 TBI). A major effort was made to harmonize the rats, materials, equipment, procedures, and monitoring systems. On the 7th post-TBI month, rats were video-EEG monitored for epilepsy diagnosis. RESULTS: A total of 245 rats were video-EEG phenotyped for epilepsy on the 7th postinjury month (121 in MRI cohort, 124 in EEG cohort). In the whole cohort (n = 245), the prevalence of PTE in rats with TBI was 22%, being 27% in the MRI and 18% in the EEG cohort (p > .05). Prevalence of PTE did not differ between the three study sites (p > .05). The average seizure frequency was .317 ± .725 seizures/day at University of Eastern Finland (UEF; Finland), .085 ± .067 at Monash University (Monash; Australia), and .299 ± .266 at University of California, Los Angeles (UCLA; USA; p < .01 as compared to Monash). The average seizure duration did not differ between UEF (104 ± 48 s), Monash (90 ± 33 s), and UCLA (105 ± 473 s; p > .05). Of the 219 seizures, 53% occurred as part of a seizure cluster (≥3 seizures/24 h; p >.05 between the study sites). Of the 209 seizures, 56% occurred during lights-on period and 44% during lights-off period (p > .05 between the study sites). SIGNIFICANCE: The PTE phenotype induced by lateral FPI is reproducible in a multicenter design. Our study supports the feasibility of performing preclinical multicenter trials in PTE to increase statistical power and experimental rigor to produce clinically translatable data to combat epileptogenesis after TBI.

Successful harmonization in EpiBioS4Rx biomarker study on post-traumatic epilepsy paves the way towards powered preclinical multicenter studies.

OBJECTIVE: Project 1 of the Preclinical Multicenter Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) consortium aims to identify preclinical biomarkers for antiepileptogenic therapies following traumatic brain injury (TBI). The international participating centers in Finland, Australia, and the United States have made a concerted effort to ensure protocol harmonization. Here, we evaluate the success of harmonization process by assessing the timing, coverage, and performance between the study sites. METHOD: We collected data on animal housing conditions, lateral fluid-percussion injury model production, postoperative care, mortality, post-TBI physiological monitoring, timing of blood sampling and quality, MR imaging timing and protocols, and duration of video-electroencephalography (EEG) follow-up using common data elements. Learning effect in harmonization was assessed by comparing procedural accuracy between the early and late stages of the project. RESULTS: The animal housing conditions were comparable between the study sites but the postoperative care procedures varied. Impact pressure, duration of apnea, righting reflex, and acute mortality differed between the study sites (p < 0.001). The severity of TBI on D2 post TBI assessed using the composite neuroscore test was similar between the sites, but recovery of acute somato-motor deficits varied (p < 0.001). A total of 99% of rats included in the final cohort in UEF, 100% in Monash, and 79% in UCLA had blood samples taken at all time points. The timing of sampling differed on day (D)2 (p < 0.05) but not D9 (p > 0.05). Plasma quality was poor in 4% of the samples in UEF, 1% in Monash and 14% in UCLA. More than 97% of the final cohort were MR imaged at all timepoints in all study sites. The timing of imaging did not differ on D2 and D9 (p > 0.05), but varied at D30, 5 months, and ex vivo timepoints (p < 0.001). The percentage of rats that completed the monthly high-density video-EEG follow-up and the duration of video-EEG recording on the 7th post-injury month used for seizure detection for diagnosis of post-traumatic epilepsy differed between the sites (p < 0.001), yet the prevalence of PTE (UEF 21%, Monash 22%, UCLA 23%) was comparable between the sites (p > 0.05). A decrease in acute mortality and increase in plasma quality across time reflected a learning effect in the TBI production and blood sampling protocols. SIGNIFICANCE: Our study is the first demonstration of the feasibility of protocol harmonization for performing powered preclinical multi-center trials for biomarker and therapy discovery of post-traumatic epilepsy.

Research Progress on the Immune-Inflammatory Mechanisms of Posttraumatic Epilepsy.

Posttraumatic epilepsy (PTE) is a severe complication arising from a traumatic brain injury caused by various violent actions on the brain. The underlying mechanisms for the pathogenesis of PTE are complex and have not been fully defined. Approximately, one-third of patients with PTE are resistant to antiepileptic therapy. Recent research evidence has shown that neuroinflammation is critical in the development of PTE. This article reviews the immune-inflammatory mechanisms regarding microglial activation, astrocyte proliferation, inflammatory signaling pathways, chronic neuroinflammation, and intestinal flora. These mechanisms offer novel insights into the pathophysiological mechanisms of PTE and have groundbreaking implications in the prevention and treatment of PTE. Immunoinflammatory cross-talk between glial cells and gut microbiota in posttraumatic epilepsy. This graphical abstract depicts the roles of microglia and astrocytes in posttraumatic epilepsy, highlighting the influence of the gut microbiota on their function. TBI traumatic brain injury, AQP4 aquaporin-4, Kir4.1 inward rectifying K channels.

4-AP challenge reveals that early intervention with brivaracetam prevents posttraumatic epileptogenesis in rats.

PURPOSE: There are currently no clinical treatments to prevent posttraumatic epilepsy (PTE). Recently, our group has shown that administration of levetiracetam (LEV) or brivaracetam (BRV) shortly after cortical neurotrauma prevents the development of epileptiform activity in rats, as measured ex vivo in neocortical slices. Due to the low incidence of spontaneous seizures in rodent-based models of traumatic brain injury (TBI), chemoconvulsants have been used to test injured animals for seizure susceptibility. We used a low dose of the voltage-gated potassium channel blocker 4-aminopyridine (4-AP) to evaluate posttraumatic epileptogenesis after controlled cortical impact (CCI) injury. We then used this assessment to further investigate the efficacy of BRV as an antiepileptogenic treatment. METHODS: Sprague-Dawley rats aged P24-35 were subjected to severe CCI injury. Following trauma, one group received BRV-21 mg/kg (IP) at 0-2 min after injury and the other BRV-100 mg/kg (IP) at 30 min after injury. Four to eight weeks after injury, animals were given a single, low dose of 4-AP (3.0-3.5 mg/kg, IP) and then monitored up to 90 min for stage 4/5 seizures. RESULTS: The chemoconvulsant challenge revealed that within four to eight weeks, CCI injury led to a two-fold increase in percentage of rats with 4-AP induced stage 4-5 seizures relative to sham-injured controls. Administration of a single dose of BRV within 30 min after trauma significantly reduced injury-induced seizure susceptibility, bringing the proportion of CCI-rats that exhibited evoked seizures down to control levels. CONCLUSIONS: This study is the first to use a low dose of 4-AP as a chemoconvulsant challenge to test epileptogenicity within the first two months after CCI injury in rats. Our findings show that a single dose of BRV administered within 30 min after TBI prevents injury-induced increases in seizure susceptibility. This supports our hypothesis that early intervention with BRV may prevent PTE.

Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis.

BACKGROUND: Posttraumatic epilepsy (PTE) is one of the most critical complications of traumatic brain injury (TBI), significantly increasing TBI patients' neuropsychiatric symptoms and mortality. The abnormal accumulation of glutamate caused by TBI and its secondary excitotoxicity are essential reasons for neural network reorganization and functional neural plasticity changes, contributing to the occurrence and development of PTE. Restoring glutamate balance in the early stage of TBI is expected to play a neuroprotective role and reduce the risk of PTE. AIMS: To provide a neuropharmacological insight for drug development to prevent PTE based on regulating glutamate homeostasis. METHODS: We discussed how TBI affects glutamate homeostasis and its relationship with PTE. Furthermore, we also summarized the research progress of molecular pathways for regulating glutamate homeostasis after TBI and pharmacological studies aim to prevent PTE by restoring glutamate balance. RESULTS: TBI can lead to the accumulation of glutamate in the brain, which increases the risk of PTE. Targeting the molecular pathways affecting glutamate homeostasis helps restore normal glutamate levels and is neuroprotective. DISCUSSION: Taking glutamate homeostasis regulation as a means for new drug development can avoid the side effects caused by direct inhibition of glutamate receptors, expecting to alleviate the diseases related to abnormal glutamate levels in the brain, such as PTE, Parkinson's disease, depression, and cognitive impairment. CONCLUSION: It is a promising strategy to regulate glutamate homeostasis through pharmacological methods after TBI, thereby decreasing nerve injury and preventing PTE.

Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy.

BACKGROUND: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus-a structure that is highly susceptible to injury-has been implicated in the evolution of seizure development. METHODS: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2-4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE+) vs. those animals that did not (PTE-), which may be associated with epileptogenesis. RESULTS: CCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE+ compared to PTE- mice. We uniquely identified Cst3 as a PTE+-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE+ hilus. CONCLUSIONS: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.

Predicting posttraumatic epilepsy using admission electroencephalography after severe traumatic brain injury.

OBJECTIVE: Posttraumatic epilepsy (PTE) develops in as many as one third of severe traumatic brain injury (TBI) patients, often years after injury. Analysis of early electroencephalographic (EEG) features, by both standardized visual interpretation (viEEG) and quantitative EEG (qEEG) analysis, may aid early identification of patients at high risk for PTE. METHODS: We performed a case-control study using a prospective database of severe TBI patients treated at a single center from 2011 to 2018. We identified patients who survived 2 years postinjury and matched patients with PTE to those without using age and admission Glasgow Coma Scale score. A neuropsychologist recorded outcomes at 1 year using the Expanded Glasgow Outcomes Scale (GOSE). All patients underwent continuous EEG for 3-5 days. A board-certified epileptologist, blinded to outcomes, described viEEG features using standardized descriptions. We extracted 14 qEEG features from an early 5-min epoch, described them using qualitative statistics, then developed two multivariable models to predict long-term risk of PTE (random forest and logistic regression). RESULTS: We identified 27 patients with and 35 without PTE. GOSE scores were similar at 1 year (p = .93). The median time to onset of PTE was 7.2 months posttrauma (interquartile range = 2.2-22.2 months). None of the viEEG features was different between the groups. On qEEG, the PTE cohort had higher spectral power in the delta frequencies, more power variance in the delta and theta frequencies, and higher peak envelope (all p < .01). Using random forest, combining qEEG and clinical features produced an area under the curve of .76. Using logistic regression, increases in the delta:theta power ratio (odds ratio [OR] = 1.3, p < .01) and peak envelope (OR = 1.1, p < .01) predicted risk for PTE. SIGNIFICANCE: In a cohort of severe TBI patients, acute phase EEG features may predict PTE. Predictive models, as applied to this study, may help identify patients at high risk for PTE, assist early clinical management, and guide patient selection for clinical trials.