Antiepileptic Drugs as Potential Dementia Prophylactics Following Traumatic Brain Injury.

Seizures and other forms of neurovolatility are emerging as druggable prodromal mechanisms that link traumatic brain injury (TBI) to the progression of later dementias. TBI neurotrauma has both acute and long-term impacts on health, and TBI is a leading risk factor for dementias, including chronic traumatic encephalopathy and Alzheimer's disease. Treatment of TBI already considers acute management of posttraumatic seizures and epilepsy, and impressive efforts have optimized regimens of antiepileptic drugs (AEDs) toward that goal. Here we consider that expanding these management strategies could determine which AED regimens best prevent dementia progression in TBI patients. Challenges with this prophylactic strategy include the potential consequences of prolonged AED treatment and that a large subset of patients are refractory to available AEDs. Addressing these challenges is warranted because the management of seizure activity following TBI offers a rare opportunity to prevent the onset or progression of devastating dementias.

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.

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.

Image data harmonization tools for the analysis of post-traumatic epilepsy development in preclinical multisite MRI studies.

Preclinical MRI studies have been utilized for the discovery of biomarkers that predict post-traumatic epilepsy (PTE). However, these single site studies often lack statistical power due to limited and homogeneous datasets. Therefore, multisite studies, such as the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx), are developed to create large, heterogeneous datasets that can lead to more statistically significant results. EpiBioS4Rx collects preclinical data internationally across sites, including the United States, Finland, and Australia. However, in doing so, there are robust normalization and harmonization processes that are required to obtain statistically significant and generalizable results. This work describes the tools and procedures used to harmonize multisite, multimodal preclinical imaging data acquired by EpiBioS4Rx. There were four main harmonization processes that were utilized, including file format harmonization, naming convention harmonization, image coordinate system harmonization, and diffusion tensor imaging (DTI) metrics harmonization. By using Python tools and bash scripts, the file formats, file names, and image coordinate systems are harmonized across all the sites. To harmonize DTI metrics, values are estimated for each voxel in an image to generate a histogram representing the whole image. Then, the Quantitative Imaging Toolkit (QIT) modules are utilized to scale the mode to a value of one and depict the subsequent harmonized histogram. The standardization of file formats, naming conventions, coordinate systems, and DTI metrics are qualitatively assessed. The histograms of the DTI metrics were generated for all the individual rodents per site. For inter-site analysis, an average of the individual scans was calculated to create a histogram that represents each site. In order to ensure the analysis can be run at the level of individual animals, the sham and TBI cohort were analyzed separately, which depicted the same harmonization factor. The results demonstrate that these processes qualitatively standardize the file formats, naming conventions, coordinate systems, and DTI metrics of the data. This assists in the ability to share data across the study, as well as disseminate tools that can help other researchers to strengthen the statistical power of their studies and analyze data more cohesively.

Levetiracetam Pharmacokinetics and Brain Uptake in a Lateral Fluid Percussion Injury Rat Model.

Post-traumatic epilepsy (PTE) occurs in some patients after moderate/severe traumatic brain injury (TBI). Although there are no approved therapies to prevent epileptogenesis, levetiracetam (LEV) is commonly given for seizure prophylaxis due to its good safety profile. This led us to study LEV as part of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Project. The objective of this work is to characterize the pharmacokinetics (PK) and brain uptake of LEV in naïve control rats and in the lateral fluid percussion injury (LFPI) rat model of TBI after either single intraperitoneal doses or a loading dose followed by a 7-day subcutaneous infusion. Sprague-Dawley rats were used as controls and for the LFPI model induced at the left parietal region using injury parameters optimized for moderate/severe TBI. Naïve and LFPI rats received either a bolus injection (intraperitoneal) or a bolus injection followed by subcutaneous infusion over 7 days. Blood and parietal cortical samples were collected at specified time points throughout the study. LEV concentrations in plasma and brain were measured using validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods. Noncompartmental analysis and a naive-pooled compartmental PK modeling approach were used. Brain-to-plasma ratios ranged from 0.54 to 1.4 to 1. LEV concentrations were well fit by one-compartment, first-order absorption PK models with a clearance of 112 ml/h per kg and volume of distribution of 293 ml/kg. The single-dose pharmacokinetic data were used to guide dose selection for the longer-term studies, and target drug exposures were confirmed. Obtaining LEV PK information early in the screening phase allowed us to guide optimal treatment protocols in EpiBioS4Rx. SIGNIFICANCE STATEMENT: The characterization of levetiracetam pharmacokinetics and brain uptake in an animal model of post-traumatic epilepsy is essential to identify target concentrations and guide optimal treatment for future studies.

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.

Chemical Kindling as an Experimental Model to Assess the Conventional Drugs in the Treatment of Post-traumatic Epilepsy.

BACKGROUND: Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality today, which will surpass many infectious diseases in the coming years/decades. Posttraumatic epilepsy (PTE) is one of the most common debilitating consequences of TBI. PTE is a secondary, acquired epilepsy that causes recurrent, spontaneous seizures more than a week after TBI. The extent of head injury in individuals who develop PTE is unknown; however, trauma is thought to account for 20% of symptomatic epilepsy worldwide. Understanding the mechanisms of epilepsy following TBI is crucial for the discovery of new anticonvulsant drugs for the treatment of PTE, as well as for improving the quality of life of patients with PTE. OBJECTIVE: This review article explains the rationale for the usage of a chemical model to access new treatments for post-traumatic epilepsy. RESULTS: There are multiple methods to control and manage PTE. The essential and available remedy for the management of epilepsy is the use of antiepileptic drugs. Antiepileptic drugs (AEDs) decrease the frequency of seizures without affecting the disease's causality. Antiepileptic drugs are administrated for the prevention and treatment of PTE; however, 30% of epilepsy patients are drug-resistant, and AED side effects are significant in PTE patients. There are different types of animal models, such as the liquid percussion model, intracortical ferric chloride injection, and cortical subincision model, to study PTE and neurophysiological mechanisms underlying the development of epilepsy after head injury. However, these animal models do not easily mimic the pathological events occurring in epilepsy. Therefore, animal models of PTE are an inappropriate tool for screening new and putatively effective AEDs. Chemical kindling is the most common animal model used to study epilepsy. There is a strong similarity between the kindling model and different types of human epilepsy. CONCLUSION: Today, researchers use experimental animal models to evaluate new anticonvulsant drugs. The chemical kindling models, such as pentylenetetrazol, bicuculline, and picrotoxin-induced seizures, are important experimental models to analyze the impact of putative antiepileptic drugs.

Evaluation of levetiracetam for early post-traumatic seizure prophylaxis: A level II trauma center experience.

INTRODUCTION: Traumatic brain injury (TBI) can induce early or late post-traumatic seizures (PTS). While PTS incidence is low, prophylaxis is used despite a lack of consensus on agent or duration. Levetiracetam (LEV) for early PTS prophylaxis is preferred due to its safety and efficacy. The purpose of this study was to evaluate LEV for early PTS prophylaxis. METHODS AND MATERIALS: A single-center, retrospective chart review of TBI patients ≥18 years who received LEV for early PTS prophylaxis between August 2018-July 2019. The primary outcome was LEV duration. Secondary outcomes were incidence of seizure, intensive care unit (ICU) and hospital length of stay (LOS). RESULTS: Of the 137 included, mean age was 59 ± 20 years and 69.3% were male. The mean admission GCS was 13 ± 4 and 77.4% had mild TBI. Median LEV duration was 7 (IQR 4-10) days and 13.9% met recommended 7-day duration. Those prescribed LEV >7 days had more than twice the median LEV duration than those prescribed ≤7 days [10.25 (8.5-15.5) vs 4 (1.5-4.5) days, p < 0.0001]. Electroencephalography-confirmed PTS occurred in 2.2%, with an early PTS incidence of 0.73%. Median ICU and hospital LOS were 2 (IQR 1-7) and 7 (IQR 3-16) days, respectively. CONCLUSIONS: The incidence of PTS was low as most patients in our study had mild or moderate TBI. Early PTS prophylaxis with LEV for 7 days is appropriate, although the majority of patients did not meet the recommended duration. Efforts to standardize and implement PTS prophylaxis protocols are needed.

Hippocampal position and orientation as prognostic biomarkers for posttraumatic epileptogenesis: An experimental study in a rat lateral fluid percussion model.

OBJECTIVE: This study was undertaken to identify prognostic biomarkers for posttraumatic epileptogenesis derived from parameters related to the hippocampal position and orientation. METHODS: Data were derived from two preclinical magnetic resonance imaging (MRI) follow-up studies: EPITARGET (156 rats) and Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx; University of Eastern Finland cohort, 43 rats). Epileptogenesis was induced with lateral fluid percussion-induced traumatic brain injury (TBI) in adult male Sprague Dawley rats. In the EPITARGET cohort, T 2 ∗ -weighted MRI was performed at 2, 7, and 21 days and in the EpiBioS4Rx cohort at 2, 9, and 30 days and 5 months post-TBI. Both hippocampi were segmented using convolutional neural networks. The extracted segmentation mask was used for a geometric construction, extracting 39 parameters that described the position and orientation of the left and right hippocampus. In each cohort, we assessed the parameters as prognostic biomarkers for posttraumatic epilepsy (PTE) both individually, using repeated measures analysis of variance, and in combination, using random forest classifiers. RESULTS: The extracted parameters were highly effective in discriminating between sham-operated and TBI rats in both the EPITARGET and EpiBioS4Rx cohorts at all timepoints (t; balanced accuracy > .9). The most discriminating parameter was the inclination of the hippocampus ipsilateral to the lesion at t = 2 days and the volumes at t ≥ 7 days after TBI. Furthermore, in the EpiBioS4Rx cohort, we could effectively discriminate epileptogenic from nonepileptogenic animals with a longer MRI follow-up, at t = 150 days (area under the curve = .78, balanced accuracy = .80, p = .0050), based on the orientation of both hippocampi. We found that the ipsilateral hippocampus rotated outward on the horizontal plane, whereas the contralateral hippocampus rotated away from the vertical direction. SIGNIFICANCE: We demonstrate that assessment of TBI-induced hippocampal deformation by clinically translatable MRI methodologies detects subjects with prior TBI as well as those at high risk of PTE, paving the way toward subject stratification for antiepileptogenesis studies.

Post-Traumatic Epilepsy and Comorbidities: Advanced Models, Molecular Mechanisms, Biomarkers, and Novel Therapeutic Interventions.

Post-traumatic epilepsy (PTE) is one of the most devastating long-term, network consequences of traumatic brain injury (TBI). There is currently no approved treatment that can prevent onset of spontaneous seizures associated with brain injury, and many cases of PTE are refractory to antiseizure medications. Post-traumatic epileptogenesis is an enduring process by which a normal brain exhibits hypersynchronous excitability after a head injury incident. Understanding the neural networks and molecular pathologies involved in epileptogenesis are key to preventing its development or modifying disease progression. In this article, we describe a critical appraisal of the current state of PTE research with an emphasis on experimental models, molecular mechanisms of post-traumatic epileptogenesis, potential biomarkers, and the burden of PTE-associated comorbidities. The goal of epilepsy research is to identify new therapeutic strategies that can prevent PTE development or interrupt the epileptogenic process and relieve associated neuropsychiatric comorbidities. Therefore, we also describe current preclinical and clinical data on the treatment of PTE sequelae. Differences in injury patterns, latency period, and biomarkers are outlined in the context of animal model validation, pathophysiology, seizure frequency, and behavior. Improving TBI recovery and preventing seizure onset are complex and challenging tasks; however, much progress has been made within this decade demonstrating disease modifying, anti-inflammatory, and neuroprotective strategies, suggesting this goal is pragmatic. Our understanding of PTE is continuously evolving, and improved preclinical models allow for accelerated testing of critically needed novel therapeutic interventions in military and civilian persons at high risk for PTE and its devastating comorbidities. SIGNIFICANCE STATEMENT: Post-traumatic epilepsy is a chronic seizure condition after brain injury. With few models and limited understanding of the underlying progression of epileptogenesis, progress is extremely slow to find a preventative treatment for PTE. This study reviews the current state of modeling, pathology, biomarkers, and potential interventions for PTE and comorbidities. There's new optimism in finding a drug therapy for preventing PTE in people at risk, such as after traumatic brain injury, concussion, and serious brain injuries, especially in military persons.

Brivaracetam prevents the development of epileptiform activity when administered early after cortical neurotrauma in rats.

OBJECTIVES: There is no effective therapy to prevent the development of posttraumatic epilepsy (PTE). Recently, we reported that administration of the antiseizure medication (ASM) levetiracetam (LEV) shortly after trauma prevented the development of epileptiform activity in two experimental models of neurotrauma. However, the time window for effective intervention with LEV may be too narrow for most clinical settings. Using the controlled cortical impact (CCI) injury model, the current study tested whether early administration of brivaracetam (BRV), an ASM with 20 times the affinity of LEV for the SV2A synaptic vesicle protein, could improve upon the antiepileptogenic action observed with LEV. METHODS: Rats (postnatal day [P] 24-32) subjected to CCI injury were given a single dose of BRV (21 or 100 mg/kg, i.p.) at one of three post-injury time points: immediately (0-2 minutes), 30 minutes, or 60 minutes. Control animals received only vehicle (0.9% saline). Posttraumatic electrographic epileptiform activity was assayed ex vivo from coronal neocortical slices collected proximal to the injury (four per rat) 3-4 weeks after injury. In this model, ictal-like burst discharges occur spontaneously or can be evoked in an "all or none" manner with applied electrical stimulation within the first 2 weeks after injury. RESULTS: A single dose of BRV administered to rats up to 60 minutes after traumatic brain injury (TBI) significantly reduced the development of posttraumatic epileptiform activity by (1) inhibiting the development of both evoked and spontaneous epileptiform activity, (2) raising the threshold for stimulus-evoked epileptiform discharges, and (3) reducing the intensity of epileptiform bursts that arise after cortical neurotrauma. SIGNIFICANCE: Clinically there has been little success preventing the development of posttraumatic epilepsy. The results of this study support the hypothesis that early intervention with BRV has the potential to prevent or reduce posttraumatic epileptogenesis, and that there may be a limited time window for successful prophylactic intervention.

Therapeutic Effects of Time-Limited Treatment with Brivaracetam on Posttraumatic Epilepsy after Fluid Percussion Injury in the Rat.

Mounting evidence suggests the synaptic vesicle glycoprotein 2A (SV2A) targeted by levetiracetam may contribute to epileptogenesis. Levetiracetam has shown anti-inflammatory, antioxidant, neuroprotective, and possible antiepileptogenic effects in brain injury and seizure/epilepsy models, and a phase 2 study has signaled a possible clinical antiepileptogenic effect. Brivaracetam shows greater affinity and specificity for SV2A than levetiracetam and broader preclinical antiseizure effects. Thus, we assessed the antiepileptogenic/disease-modifying potential of brivaracetam in an etiologically realistic rat posttraumatic epilepsy model optimized for efficient drug testing. Brivaracetam delivery protocols were designed to maintain clinical moderate-to-high plasma levels in young (5-week-old) male Sprague-Dawley rats for 4 weeks. Treatment protocols were rapidly screened in 4-week experiments using small groups of animals to ensure against rigorous testing of futile treatment protocols. The antiepileptogenic effects of brivaracetam treatment initiated 30 minutes, 4 hours, and 8 hours after rostral parasagittal fluid percussion injury (rpFPI) were then compared with vehicle-treated controls in a fully powered blind and randomized 16-week validation. Seizures were evaluated by video-electrocorticography using a 5-electrode epidural montage. Endpoint measures included incidence, frequency, duration, and spread of seizures. Group sizes and recording durations were supported by published power analyses. Three months after treatment ended, rats treated with brivaracetam starting at 4 hours post-FPI (the best-performing protocol) experienced a 38% decrease in overall incidence of seizures, 59% decrease in seizure frequency, 67% decrease in time spent seizing, and a 45% decrease in the proportion of spreading seizures that was independent of duration-based seizure definition. Thus, brivaracetam shows both antiepileptogenic and disease-modifying properties after rpFPI. SIGNIFICANCE STATEMENT: The rpFPI model, which likely incorporates epileptogenic mechanisms operating after human head injury, can be used to efficiently screen investigational treatment protocols and assess antiepileptogenic/disease-modifying effects. Our studies 1) support a role for SV2A in epileptogenesis, 2) suggest that brivaracetam and other drugs targeting SV2A should be considered for human clinical trials of prevention of post-traumatic epilepsy after head injury, and 3) provide data to inform the design of treatment protocols for clinical trials.

Post-Traumatic Epilepsy in Zebrafish Is Drug-Resistant and Impairs Cognitive Function.

Post-traumatic epilepsy (PTE) is acquired epilepsy after traumatic brain injury (TBI). Despite the availability of more than 20 antiseizure medications (ASMs), there is no way at present to prevent epileptogenesis in TBI survivors, and many cases of PTE become drug-resistant. Importantly, the adverse effects of ASMs can significantly affect patients' quality of life. Mammalian models are commonly used for studying refractory PTE, but are expensive and laborious. Zebrafish models have become popular for studying epilepsy, but most focus on larvae, and there have been no reports to date of pharmacological screening in an adult zebrafish model of acquired epilepsy. Valid animal models are critical for understanding PTE and for developing novel therapeutics. The aim of the present study was to characterize the cognitive impairments of a zebrafish model of TBI that leads to the development of PTE. Using combined behavioral and electrophysiological approaches, we also characterized the pharmacological effects of the most commonly used ASMs to manage PTE (valproate, carbamazepine, and phenytoin). Zebrafish with PTE exhibited impairments in learning and memory, difficulty in decision making, and reduced social preference. Valproate and carbamazepine had a limited protective effect against behavioral seizures, and all three drugs failed to significantly reduce electrographical seizures. The negative impacts of TBI and ASMs in zebrafish parallel those observed in other animals, making the zebrafish model of PTE a promising high-throughput model of refractory and drug-resistant epilepsy.

Post-traumatic seizures and antiepileptic therapy as predictors of the functional outcome in patients with traumatic brain injury.

Post-traumatic seizures (PTS) are a common and debilitating complication of traumatic brain injury (TBI) and could have a harmful impact on the progress of patient rehabilitation. To assess the effect of PTS and relative therapy on outcome in the initial phase after TBI, during the rehabilitation process when neuroplasticity is at its highest, we retrospectively examined the clinical data of 341 adult patients undergoing rehabilitation for at least 6 months post-TBI in our neurorehabilitation unit between 2008 and 2019. We correlated through logistic regression the occurrence of seizures and use of anti-seizure medication (ASM) with neurological and functional outcomes, respectively assessed with the Glasgow Coma Scale (GCS) and the Functional Independence Measure (FIM). PTS were documented in 19.4% of patients: early PTS (EPTS) in 7.0%; late PTS (LPTS) in 9.4%; both types in 3.0%. Patients who developed EPTS had an increased risk of developing LPTS (OR = 3.90, CI 95% 1.58-9.63, p = 0.003). Patients with LPTS had a significantly higher risk of worse neurological (p < 0.0001) and rehabilitation (p < 0.05) outcome. Overall, 38.7% of patients underwent therapy with ASM; prophylactic therapy was prescribed in 24.0% of patients, of whom 14.6% subsequently developed seizures. Mortality was associated with a lower FIM and GCS score on admission but not significantly with PTS. The use of ASM was associated with a worse rehabilitation outcome, independently of the onset of epilepsy during treatment. LPTS appear to exert a negative impact on rehabilitation outcome and their occurrence is not reduced by prophylactic therapy, whereas EPTS do not influence outcome. Our findings caution against the generic use of prophylactic therapy to prevent post-traumatic epilepsy in patients with TBI.

Pyrazolo[4,3-c]pyridine-4-one (PP-4-one) Exhibits Anti-Epileptogenic Effect in Rat Model of Traumatic Epilepsy by Mammalian Target of Rapamycin (mTOR) Signaling Pathway Downregulation.

BACKGROUND Post-traumatic epilepsy (PTE) is a common type of acquired epilepsies secondary to traumatic brain injury (TBI), accounting for approximately 10-25% of patients. The present study evaluated activity of PP-4-one against mTOR signaling activation in a rat model of FeCl2-induced post-traumatic epilepsy. MATERIAL AND METHODS Epilepsy in rats was induced by injecting 10 µl FeCl2 (concentration 100 mM) at a uniform rate of 1 µl/minute. The iNOS expression was detected using a Leica microscope connected to a digital camera system. Reverse transcription polymerase chain reaction (RT­PCR) was used for determination of NR1 mRNA expression. RESULTS The post-traumatic epilepsy induced neuronal degeneration in the hippocampus and frontal cortex of the rats. Treatment with PP-4-one prevented neuronal degeneration in the hippocampus and frontal cortex in rats with post-traumatic epilepsy. The data revealed markedly higher levels of p-mTOR and p-P70S6K in rat hippocampal tissues after induction of traumatic epilepsy. Treatment of post-traumatic epilepsy rats with PP-4-one significantly suppressed p-mTOR and p-P70S6K expression, and PP-4-one treatment reduced epileptic brain injury in the rats with post-traumatic epilepsy. CONCLUSIONS PP-4-one exhibits an anti-epileptogenic effect in the rat model of PTE by inhibiting behavioral seizures through suppression of iNOS and astrocytic proliferation. Moreover, PP-4-one treatment suppressed NR1 expression and targeted the mTOR pathway in PTE-induced rats. Thus, PP-4-one shows promise as a novel and effective therapeutic agent for treatment of epilepsy induced by PTE.

Tumor Necrosis Factor-α, the Pathological Key to Post-Traumatic Epilepsy: A Comprehensive Systematic Review.

Post-traumatic epilepsy (PTE) is one of the detrimental outcomes of traumatic brain injury (TBI), resulting in recurrent seizures that impact daily life. However, the pathological relationship between PTE and TBI remains unclear, and commonly prescribed antiepileptic drugs (AED) are ineffective against PTE. Fortunately, emerging research implicates neuroinflammation, particularly, tumor necrosis factor-α (TNF-α), as the key mediator for PTE development. Thus, this review aims to examine the available literature regarding the role of TNF-α in PTE pathology and, subsequently, evaluate TNF-α as a possible target for its treatment. A comprehensive literature search was conducted on four databases including PubMed, CINAHL, Embase, and Scopus. Articles with relevance in investigating TNF-α expression in PTE were considered in this review. Critical evaluation of four articles that met the inclusion criteria suggests a proportional relationship between TNF-α expression and seizure susceptibilit and that neutralization or suppression of TNF-α release results in reduced susceptibility to seizures. In conclusion, this review elucidates the importance of TNF-α expression in epileptogenesis postinjury and urges future research to focus more on clinical studies involving TNF-α, which may provide clearer insight into PTE prevention, therefore improving the lives of PTE patients.

Combination Therapy of Gabapentin and N-Acetylcysteine Against Posttraumatic Epilepsy in Rats.

Traumatic brain injury (TBI) is a major public health problem worldwide that is associated with increased mortality and morbidity. Posttraumatic epilepsy (PTE) is one of the sequelae of TBI. The aim of this study was to investigate the role of N-acetylcysteine (NAC) as an adjuvant on the efficacy of levetiracetam (LEV) and gabapentin (GBP) in PTE model encouraged by pentylenetetrazol (PTZ) after mild-TBI in male Sprague-Dawley rats. Mild-TBI was performed by the weight-drop method in male Sprague-Dawley rats. PTE model was developed by injecting PTZ (30+15+15 mg/kg, 30 min intervals, i.p.) 7 days after head trauma. After the development of posttraumatic seizures, the rats were treated with NAC (100 mg/kg), LEV (50 mg/kg), GBP (100 mg/kg), NAC+LEV and NAC+GBP intraperitoneally for 14 days. Seizures related to PTE were scored by video-EEG recording. Motor performance of the animals was also evaluated in the rotarod test. 50 mg/kg LEV and 100 mg/kg GBP reduced seizures related to PTE. LEV alone (p = 0.009), but the administration of GBP+NAC (p = 0.015) was more effective on PTE-related seizure control. However, GBP+NAC application adversely affected the fall latency in the rotarod test. In terms of trauma-related seizure control, there was no statistically significant difference between the use of prophylactic LEV and symptomatic LEV. LEV alone or the combination of GBP with NAC provides more effective seizure control in the PTE facilitated by PTZ. On the other hand, the use of prophylactic LEV did not have any extra effect on posttraumatic seizure development and control.

Complement in the Development of Post-Traumatic Epilepsy: Prospects for Drug Repurposing.

Targeting neuroinflammation is a novel frontier in the prevention and treatment of epilepsy. A substantial body of evidence supports a key role for neuroinflammation in epileptogenesis, the pathological process that leads to the development and progression of spontaneous recurrent epileptic seizures. It is also well recognized that traumatic brain injury (TBI) induces a vigorous neuroinflammatory response and that a significant proportion of patients with TBI suffer from debilitating post-traumatic epilepsy. The complement system is a potent effector of innate immunity and a significant contributor to secondary tissue damage and to epileptogenesis following central nervous system injury. Several therapeutic agents targeting the complement system are already on the market to treat other central nervous system disorders or are well advanced in their development. The purpose of this review is to summarize findings on complement activation in experimental TBI and epilepsy models, highlighting the potential of drug repurposing in the development of therapeutics to ameliorate post-traumatic epileptogenesis.

Imaging biomarkers of posttraumatic epileptogenesis.

Traumatic brain injury (TBI) affects 2.5 million people annually within the United States alone, with over 300 000 severe injuries resulting in emergency room visits and hospital admissions. Severe TBI can result in long-term disability. Posttraumatic epilepsy (PTE) is one of the most debilitating consequences of TBI, with an estimated incidence that ranges from 2% to 50% based on severity of injury. Conducting studies of PTE poses many challenges, because many subjects with TBI never develop epilepsy, and it can be more than 10 years after TBI before seizures begin. One of the unmet needs in the study of PTE is an accurate biomarker of epileptogenesis, or a panel of biomarkers, which could provide early insights into which TBI patients are most susceptible to PTE, providing an opportunity for prophylactic anticonvulsant therapy and enabling more efficient large-scale PTE studies. Several recent reviews have provided a comprehensive overview of this subject (Neurobiol Dis, 123, 2019, 3; Neurotherapeutics, 11, 2014, 231). In this review, we describe acute and chronic imaging methods that detect biomarkers for PTE and potential mechanisms of epileptogenesis. We also describe shortcomings in current acquisition methods, analysis, and interpretation that limit ongoing investigations that may be mitigated with advancements in imaging techniques and analysis.