Search

Objective: Frequency properties of the EEG characteristics of different seizure types including absence seizures have been described for various rodent models of epilepsy. However, little attention has been paid to the frequency properties of individual spike-wave complexes (SWCs), the constituting elements characterizing the different generalized seizure types. Knowledge of their properties is not only important for understanding the mechanisms underlying seizure generation but also for the identification of epileptiform activity in various seizure types. Here, we compared the frequency properties of SWCs in different epilepsy models., Methods: A software package was designed and used for the extraction and frequency analysis of SWCs from long-term EEG of four spontaneously seizing, chronic epilepsy models: a post-status epilepticus model of temporal lobe epilepsy, a lateral fluid percussion injury model of post-traumatic epilepsy, and two genetic models of absence epilepsy-GAERS and rats of the WAG/Rij strain. The SWCs within the generalized seizures were separated into fast (three-phasic spike) and slow (mostly containing the wave) components. Eight animals from each model were used (32 recordings, 104 510 SWCs in total). A limitation of our study is that the recordings were hardware-filtered (high-pass), which could affect the frequency composition of the EEG., Results: We found that the three-phasic spike component was similar in all animal models both in time and frequency domains, their amplitude spectra showed a single expressed peak at 18-20 Hz. The slow component showed a much larger variability across the rat models., Significance: Despite differences in the morphology of the epileptiform activity in different models, the frequency composition of the spike component of single SWCs is identical and does not depend on the particular epilepsy model. This fact may be used for the development of universal algorithms for seizure detection applicable to different rat models of epilepsy., Plain Language Summary: There is a large variety between people with epilepsy regarding the clinical manifestations and the electroencephalographic (EEG) phenomena accompanying the epileptic seizures. Here, we show that one of the EEG signs of epilepsy, an epileptic spike, is universal, since it has the same shape and frequency characteristics in different animal models of generalized epilepsies, despite differences in recording sites and location., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Traumatic brain injury (TBI) is a leading cause of acquired epilepsy referred to as post-traumatic epilepsy (PTE), characterized by spontaneous recurrent seizures (SRS) that start in the months or years following TBI. There is a critical need to develop small animal models for advancing the neurotherapeutics of PTE, which accounts for 20% of all acquired epilepsy cases. Despite many previous attempts, there are few PTE models with demonstrated consistency or longitudinal incidence of SRS, a critical feature for creating models for investigation of novel therapeutics for preventing PTE. Over the past few years, we have made in-depth updates and several advances to our mouse model of TBI in which SRS consistently occurs upon 24/7 monitoring for 4 months. Here, we show that an advanced cortical contusion damage in mice elicits a chronic state of PTE with SRS and robust epileptiform activity, along with cognitive comorbidities. We observed SRS in 33% and 87% of moderate and severe injury cohorts, respectively. Though incidence was higher in the severe cohort, moderate injury elicited a robust epileptogenesis. Progressive neuronal damage, neurodegeneration, and inflammation signals were evident in many brain regions; comorbid behavior and cognitive deficits were observed for up to 4-months. SRS onset was correlated with the inception of interneuron loss after TBI. Contralateral hippocampal sclerosis was unique and well correlated with SRS, confirming a potential network basis for epileptogenesis. Collectively, this mouse model exhibits a number of hallmark TBI sequelae reminiscent of human PTE. This model provides a vital tool for probing molecular pathological mechanisms and therapeutic interventions for post-traumatic epileptogenesis. SIGNIFICANCE STATEMENT: TBI is a leading cause of post-traumatic epilepsy (PTE). Despite many attempts to create PTE in animals, success has been limited due to a lack of consistent spontaneous "epileptic" seizures after TBI. We present a comprehensive phenotype of PTE after contusion brain injury in mice, which exhibits robust spontaneous seizures along with neuronal loss, inflammation, and cognitive dysfunction. Our broad profiling of a TBI mouse reveals features of progressive, long-lasting epileptic activity, unique contralateral hippocampal sclerosis, and comorbid mood and memory deficits. The PTE mouse shows a striking consistency in recapitulating major pathological sequelae of human PTE. This mouse model will be helpful in assessing mechanisms and interventions for TBI-induced epilepsy and mood dysfunction., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: Traumatic brain injury (TBI) may lead to the disruption of the intestinal barrier (IB), and to the escape of products of commensal gut bacteria, including lipopolysaccharide (LPS), into the bloodstream. We examined whether lateral fluid percussion injury (LFPI) and post-traumatic epilepsy (PTE) are associated with the increased intestinal permeability and endotoxemia, and whether these events in turn are associated with PTE., Methods: LFPI was delivered to adult male Sprague-Dawley rats. Before, 1 week, and 7 months after LFPI, the IB permeability was examined by measuring plasma concentration of fluorescein isothiocyanate-labeled dextran (FD4) upon its enteral administration. Plasma LPS concentration was measured in the same animals, using enzyme-linked immunosorbent assay. PTE was examined 7 months after LFPI, with use of video-EEG (electroencephalography) monitoring., Results: One week after LFPI, the IB disruption was detected in 14 of 17 and endotoxemia - in 10 of 17 rats, with a strong positive correlation between FD4 and LPS levels, and between plasma levels of each of the analytes and the severity of neuromotor deficit. Seven months after LFPI, IB disruption was detected in 13 of 15 and endotoxemia in 8 of 15 rats, with a strong positive correlation between plasma levels of the two analytes. Five of 15 LFPI rats developed PTE. Plasma levels of both FD4 and LPS were significantly higher in animals with PTE than among the animals without PTE. The analysis of seven rats, which were examined repeatedly at 1 week and at 7 months, confirmed that late IB disruption and endotoxemia were not due to lingering of impairments occurring shortly after LFPI., Significance: LFPI leads to early and remote disruption of IB and a secondary endotoxemia. Early and late perturbations may occur in different subjects. Early changes reflect the severity of acute post-traumatic motor dysfunction, whereas late changes are associated with PTE., (© 2021 International League Against Epilepsy.)

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies and 10-20% of the acquired forms. The latency between traumatic brain injury (TBI) and epilepsy onset in high-risk patients offers a therapeutic window for intervention to prevent or improve the disease course. However, progress towards effective treatments has been hampered by the lack of sensitive prognostic biomarkers of PTE, and of therapeutic targets. There is therefore a pressing clinical need for preclinical PTE models suitable for biomarker discovery and drug testing. We characterized in-depth a model of severe TBI induced by controlled cortical impact evolving into PTE in CD1 adult male mice. To identify sensitive measures predictive of PTE development and severity, TBI mice were longitudinally monitored by video-electrocorticography (ECoG), examined by MRI, and tested for sensorimotor and cognitive deficits and locomotor activity. At the end of the video-ECoG recording mice were killed for brain histological analysis. PTE occurred in 58% of mice with frequent motor seizures (one seizure every other day), as determined up to 5 months post-TBI. The weight loss of PTE mice in 1 week after TBI correlated with the number of spontaneous seizures at 5 months. Moreover, the recovery rate of the sensorimotor deficit detected by the SNAP test before the predicted time of epilepsy onset was significantly lower in PTE mice than in those without epilepsy. Neuroscore, beam walk and cognitive deficit were similar in all TBI mice. The increase in the contusion volume, the volume of forebrain regions contralateral to the lesioned hemisphere and white matter changes over time assessed by MRI were similar in PTE and no-PTE mice. However, brain histology showed a more pronounced neuronal cell loss in the cortex and hippocampus contralateral to the injured hemisphere in PTE than in no-PTE mice. The extensive functional and neuropathological characterization of this TBI model, provides a tool to identify sensitive measures of epilepsy development and severity clinically useful for increasing PTE prediction in high-risk TBI patients. The high PTE incidence and spontaneous seizures frequency in mice provide an ideal model for biomarker discovery and for testing new drugs.

Objective: Posttraumatic epilepsy (PTE) is defined as recurrent and unprovoked seizures occurring >1 week after traumatic brain injury (TBI). Animal studies of PTE are lengthy and expensive. In this study, we developed a cost-effective PTE animal model using zebrafish to bridge the gap between in vitro studies and low-throughput animal studies., Methods: We used two different sets of parameters (G1 and G2) to induce closed-head TBI in adult zebrafish using pulsed high-intensity focused ultrasound. Injured fish and naive controls were evaluated for behavioral deficits and spontaneous behavioral seizure activity up to 21 days postinjury (DPI). We also assessed behavioral seizure susceptibility to a subconvulsive dose of pentylenetetrazole (PTZ; 2.5 mmol·L -1 ) and recorded electrophysiological signals to confirm seizure activity up to 40 DPI. In addition, we investigated injury-related changes in the blood-brain barrier and expression levels of various proteins altered in rodent and human TBI., Results: The G2 parameters resulted in a more severe TBI, with a mortality rate of 25%, as well as motor dysfunction and heightened anxiety persisting at 21 DPI. One hundred percent of the G2 group showed spontaneous myocloniclike behavior, and 80% demonstrated tonic-clonic-like behavioral seizures by 21 DPI. Such activities were not detected in the naive group. After the application of 2.5 mmol·L -1 PTZ, 100% of injured zebrafish had cloniclike seizures at 21 DPI, versus 30% of the naive group. We also demonstrated electrographic seizure activity at 40 DPI, which was not detected in the naive controls. Lastly, we observed acute blood-brain barrier dysfunction and increased levels of HMGB1 and ratios of phosphorylated/total Akt and tau through 21 DPI., Significance: Together, the results indicate that severe TBI in the adult zebrafish leads to similar behavioral and physiological changes to those of more traditional models, including the development of PTE, and suggest this may be a useful model that can accelerate research in TBI/PTE., (© 2020 International League Against Epilepsy.)

Objective: To determine the role of aquaporin-4 (AQP4) in posttraumatic epileptogenesis using long-term video-electroencephalographic (vEEG) recordings. Here, differences in EEG were analyzed between wild-type (WT) and AQP4 knockout (KO) mice and between mice with and without posttraumatic epilepsy (PTE)., Methods: WT and AQP4 KO mice were subjected to a single controlled cortical impact traumatic brain injury (TBI) in the frontal cortex, and vEEG was recorded in the ipsilateral hippocampus at 14, 30, 60, and 90 days postinjury (dpi). Intrahippocampal electrical stimulation was also used to assess electrographic seizure threshold and electrographic seizure duration (ESD)., Results: The mean seizure frequency per day for WT mice was 0.07 ± 0.07, 0.11 ± 0.07, 0.26 ± 0.13, and 0.12 ± 0.10 at 14, 30, 60, and 90 dpi, respectively. The mean seizure frequency per day for AQP4 KO mice was 0.45 ± 0.27, 0.29 ± 0.12, and 0.26 ± 0.19 at 14, 30, and 60 dpi, respectively. The mean seizure duration was 15 ± 2 seconds and 24 ± 3 seconds for WT and AQP4 KO mice, respectively. The percentage of mice that developed PTE were 28% and 37% for WT and AQP4 KO mice, respectively. Power spectral density (PSD) analysis revealed alterations in EEG frequency bands between sham and TBI in both genotypes. Additionally, PSD analysis of spontaneous recurrent seizures revealed alterations in delta power between genotypes. Morlet wavelet analysis detected heterogeneity in EEG seizure subtypes and dynamic EEG power patterns after TBI. Compared with AQP4 KO mice, a significant increase in ESD was observed in WT mice at 14 dpi., Significance: Posttraumatic seizures (PTSs) may be modulated by the astrocyte water channel AQP4. Absence of AQP4 increases the number of spontaneous seizures, increases seizure duration, and alters EEG power patterns of PTSs., (© 2020 International League Against Epilepsy.)

Traumatic brain injury (TBI) is a leading cause of acquired epilepsy. TBI can result in a focal or diffuse brain injury. Focal injury is a result of direct mechanical forces, sometimes penetrating through the cranium, creating a direct lesion in the brain tissue. These are visible during brain imaging as areas with contusion, laceration, and hemorrhage. Focal lesions induce neuronal death and glial scar formation and are present in 20%-25% of all people who incur a TBI. However, in the majority of TBI cases, injury is caused by acceleration-deceleration forces and subsequent tissue shearing, resulting in nonfocal, diffuse damage. A subpopulation of TBI patients continues to develop post-traumatic epilepsy (PTE) after a latency period of months or years. Currently, it is impossible to predict which patients will develop PTE, and seizures in PTE patients are challenging to control, necessitating further research. Until recently, the field was limited to only two animal/rodent models with validated spontaneous post-traumatic seizures, both presenting with large focal lesions with massive tissue loss in the cortex and sometimes subcortical structures. In contrast to these approaches, it was determined that diffuse TBI induced using a modified weight drop model is sufficient to initiate development of spontaneous convulsive and non-convulsive seizures, even in the absence of focal lesions or tissue loss. Similar to human patients with acquired post-traumatic epilepsy, this model presents with a latency period after injury before seizure onset. In this protocol, the community will be provided with a new model of post-traumatic epilepsy, detailing how to induce diffuse non-lesional TBI followed by continuous long-term video-electroencephalographic animal monitoring over the course of several months. This protocol will detail animal handling, the weight drop procedure, the electrode placement for two acquisition systems, and the frequent challenges encountered during each of the steps of surgery, postoperative monitoring, and data acquisition.

Posttraumatic epilepsy (PTE) is a long-term negative consequence of traumatic brain injury (TBI) in which recurrent spontaneous seizures occur after the initial head injury. PTE develops over an undefined period during which circuitry reorganization in the brain causes permanent hyperexcitability. The pathophysiology by which trauma leads to spontaneous seizures is unknown and clinically relevant models of PTE are key to understanding the molecular and cellular mechanisms underlying the development of PTE. In the present study, we used the controlled-cortical impact (CCI) injury model of TBI to induce PTE in mice and to characterize changes in aquaporin-4 (AQP4) expression. A moderate-severe TBI was induced in the right frontal cortex and video-electroencephalographic (vEEG) recordings were performed in the ipsilateral hippocampus to monitor for spontaneous seizures at 14, 30, 60, and 90 days post injury (dpi). The percentage of mice that developed PTE were 13%, 20%, 27%, and 14% at 14, 30, 60, and 90 dpi, respectively. We found a significant increase in AQP4 in the ipsilateral frontal cortex and hippocampus of mice that developed PTE compared to those that did not develop PTE. Interestingly, AQP4 was found to be mislocalized away from the perivascular endfeet and towards the neuropil in mice that developed PTE. Here, we report for the first time, AQP4 dysregulation in a model of PTE which may carry significant implications for epileptogenesis after TBI., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Studies of chronic epilepsy show pathological high frequency oscillations (HFOs) are associated with brain areas capable of generating epileptic seizures. Only a few of these studies have focused on HFOs during the development of epilepsy, but results suggest pathological HFOs could be a biomarker of epileptogenesis. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy" (EpiBioS4Rx) is a multi-center project designed to identify biomarkers of epileptogenesis after a traumatic brain injury (TBI) and evaluate treatments that could modify or prevent the development of post-traumatic epilepsy. One goal of the EpiBioS4Rx project is to assess whether HFOs could be a biomarker of post-traumatic epileptogenesis. The current study describes the work towards this goal, including the development of common surgical procedures and EEG protocols, an interim analysis of the EEG for HFOs, and identifying issues that need to be addressed for a robust biomarker analysis. At three participating sites - University of Eastern Finland (UEF), Monash University in Melbourne (Melbourne) and University of California, Los Angeles (UCLA) - TBI was induced in adult male Sprague-Dawley rats by lateral fluid-percussion injury. After injury and in sham-operated controls, rats were implanted with screw and microwire electrodes positioned in neocortex and hippocampus to record EEG. A separate group of rats had serial magnetic resonance imaging after injury and then implanted with electrodes at 6 months. Recordings 28 days post-injury were available from UEF and UCLA, but not Melbourne due to technical issues with their EEG files. Analysis of recordings from 4 rats - UEF and UCLA each had one TBI and one sham-operated control - showed EEG contained evidence of HFOs. Computer-automated algorithms detected a total of 1,819 putative HFOs and of these only 40 events (2%) were detected by all three sites. Manual review of all events verified 130 events as HFO and the remainder as false positives. Review of the 40 events detected by all three sites was associated with 88% agreement. This initial report from the EpiBioS4Rx Consortium demonstrates the standardization of EEG electrode placements, recording protocol and long-term EEG monitoring, and differences in detection algorithm HFO results between sites. Additional work on detection strategy, detection algorithm performance, and training in HFO review will be performed to establish a robust, preclinical evaluation of HFOs as a biomarker of post-traumatic epileptogenesis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) is a devastating condition that often triggers a sequel of neurological disorders that can last throughout lifespan. From a metabolic viewpoint, the compromising of the energy metabolism of the brain has produced evidence linking the severity of brain injury to the extent of disturbances in the cerebral metabolism. The cerebral metabolic crisis, however, displays that regional heterogeneity varies temporally post-injury. It is important to note that energy generation and mitochondrial function are closely related and interconnected with delayed secondary manifestations of brain injury, including early neuromotor dysfunction, cognitive impairment, and post-traumatic epilepsy (PTE). Given the extent of post-traumatic changes in neuronal function and the possibility of amplifying secondary cascades, different therapies designed to minimize damage and retain/restore cellular function after TBI are currently being studied. One of the possible strategies may be the inclusion of ergogenic compounds, which is a class of supplements that typically includes ingredients used by athletes to enhance their performance. The combination of these compounds offers specific physiological advantages, which include enhanced energy availability/metabolism and improved buffering capacity. However, the literature on their effects in certain biological systems and neurological diseases, such as TBI, has yet to be determined. Thus, the present review aims to discuss the role of ergogenic compounds popularly used in secondary damage induced by this neurological injury. In this narrative review, we also discuss how the results from animal studies can be applied to TBI clinical settings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Context: Loss of consciousness (LOC) and impact seizures associated with concussion represent different clinical presentations of concussion; however, they are often investigated and treated similarly. The biomechanical parameters differentiating these 2 distinct signs of injury are poorly described., Objective: To differentiate between cases of concussions with LOC and those with impact seizures by comparing the impact velocity, peak linear and peak rotational acceleration, as well as brain tissue deformation in the cerebral cortex, white matter, brainstem, cerebellum, thalamus, and corpus callosum., Design: Descriptive laboratory study., Patients or Other Participants: Elite American football players who sustained an LOC (n = 20) or impact seizures (n = 21)., Main Outcome Measure(s): Impact velocity, peak linear and peak rotational acceleration, maximum principal strain, cumulative strain damage measure at 10%, and strain rate (SR)., Results: The SR in the cerebral white matter was greater in the LOC group than in the impact-seizure group. Similar trends were observed for SRs in the cerebral cortex, brainstem, and corpus callosum. No differences were present between groups for the other variables in this study., Conclusions: A lower SR in certain brain regions helps to explain why motor function is preserved and can be observed in patients with impact seizures versus LOC from concussive injuries.

The lateral fluid percussion injury (FPI) model is well established and has been used to study TBI and post-traumatic epilepsy (PTE). However, considerable variability has been reported for the specific parameters used in different studies that have employed this model, making it difficult to harmonize and interpret the results between laboratories. For example, variability has been reported regarding the size and location of the craniectomy, how the Luer lock hub is placed relative to the craniectomy, the atmospheric pressure applied to the dura and the duration of the pressure pulse. Each of these parameters can impact injury severity, which directly correlates with the incidence of PTE. This has been manifested as a wide range of mortality rates, righting reflex times and incidence of convulsive seizures reported. Here we provide a detailed protocol for the method we have used to help facilitate harmonization between studies. We used FPI in combination with a wireless EEG telemetry system to continuously monitor for electrographic changes and detect seizure activity.  FPI is induced by creating a 5 mm craniectomy over the left hemisphere, between the Bregma and Lambda and adjacent to the lateral ridge. A Luer lock hub is secured onto the skull over the craniectomy. This hub is connected to the FPI device, and a 20-millisecond pressure pulse is delivered directly to the intact dura through pressure tubing connected to the hub via a twist lock connector. Following recovery, rats are re-anesthetized to remove the hub. Five 0.5 mm, stainless steel EEG electrode screws are placed in contact with the dura through the skull and serve as four recording electrodes and one reference electrode. The electrode wires are collected into a pedestal connector which is secured into place with bone cement. Continuous video/EEG recordings are collected for up to 4 weeks post TBI.

Purpose: To compare the efficacy and safety of lacosamide versus phenytoin for seizure prophylaxis following TBI., Materials and Methods: All TBI patients who received prophylaxis with either phenytoin or lacosamide were retrospectively identified. The incidence of seizures within the first 7 days of injury were compared along with adverse effects requiring drug discontinuation. A planned sub-group analysis was performed for patients with severe TBI (GCS < 9)., Results: There were 481 patients (phenytoin, n = 116; lacosamide, n = 365). Demographics were similar but age (50 ± 21 vs 58 ± 22 years, P < .001) and initial GCS (11.3 ± 4.3 vs 12.5 ± 3.8, P = .010) were lower in the phenytoin group. The need for mechanical ventilation was higher (53% vs 38%, P = .004). Seizures occurred in 0.9% of the phenytoin group and 1.4% of the lacosamide group (P = 1.00). ADEs were significantly higher with phenytoin (5.2% vs 0.5%, P = .003). This difference remained significant upon multivariate analysis [OR(95% CI) = 9.4(1.8-48.9)]. Subgroup analysis for patients with severe TBI revealed no difference in seizures (phenytoin, 0% vs lacosamide, 1.5%; P = 1.00) but more ADEs with phenytoin (12.5% vs 0%, P = .010)., Conclusion: There was no difference between lacosamide and phenytoin in the prevention of early post traumatic seizures in patients following TBI. Lacosamide may have a more tolerable side effect profile., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial fibrillary acidic protein was limited. Surprisingly, an unrelated population of atypical reactive astrocytes was characterized by the lack of glial fibrillary acidic protein expression, rapid and sustained downregulation of homeostatic proteins and impaired astrocyte coupling. After a latency period, a subset of mice developed spontaneous recurrent seizures reminiscent of PTE in human TBI patients. Seizing mice had larger areas of atypical astrocytes compared with nonseizing mice, suggesting that these atypical astrocytes might contribute to epileptogenesis after diffuse TBI. SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is a leading cause of acquired epilepsies. Reactive astrocytes have long been associated with seizures and epilepsy in patients, particularly after focal/lesional brain injury. However, most TBIs also include nonfocal, diffuse injuries. Here, we showed that repetitive diffuse TBI is sufficient for the development of spontaneous recurrent seizures in a subset of mice. We identified an atypical response of astrocytes induced by diffuse TBI characterized by the rapid loss of homeostatic proteins and lack of astrocyte coupling while reactive astrocyte markers or glial scar formation was absent. Areas with atypical astrocytes were larger in animals that later developed seizures suggesting that this response may be one root cause of epileptogenesis after diffuse TBI., (Copyright © 2019 the authors 0270-6474/19/391945-20$15.00/0.)

We describe the infrastructure and functionality for a centralized preclinical and clinical data repository and analytic platform to support importing heterogeneous multi-modal data, automatically and manually linking data across modalities and sites, and searching content. We have developed and applied innovative image and electrophysiology processing methods to identify candidate biomarkers from MRI, EEG, and multi-modal data. Based on heterogeneous biomarkers, we present novel analytic tools designed to study epileptogenesis in animal model and human with the goal of tracking the probability of developing epilepsy over time., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Posttraumatic epilepsy (PTE) is one of the most debilitating and understudied consequences of traumatic brain injury (TBI). It is challenging to study the effects, underlying pathophysiology, biomarkers, and treatment of TBI and PTE purely in human patients for a number of reasons. Rodent models can complement human PTE studies as they allow for the rigorous investigation into the causal relationship between TBI and PTE, the pathophysiological mechanisms of PTE, the validation and implementation of PTE biomarkers, and the assessment of PTE treatments, in a tightly controlled, time- and cost-efficient manner in experimental subjects known to be experiencing epileptogenic processes. This article will review several common rodent models of TBI and/or PTE, including their use in previous studies and discuss their relative strengths, limitations, and avenues for future research to advance our understanding and treatment of PTE., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the quest for developing new therapeutic targets for post-traumatic epilepsies (PTE), identifying mechanisms relevant to development and progression of disease is critical. A growing body of literature suggests involvement of neurodegenerative mechanisms in the pathophysiology of acquired epilepsies, including following traumatic brain injury (TBI). In this review, we discuss the potential of some of these mechanisms to be targets for the development of a therapy against PTE., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy (EpiBioS4Rx) is a longitudinal prospective observational study funded by the National Institute of Health (NIH) to discover and validate observational biomarkers of epileptogenesis after traumatic brain injury (TBI). A multidisciplinary approach has been incorporated to investigate acute electrical, neuroanatomical, and blood biomarkers after TBI that may predict the development of post-traumatic epilepsy (PTE). We plan to enroll 300 moderate-severe TBI patients with a frontal and/or temporal lobe hemorrhagic contusion. Acute evaluation with blood, imaging and electroencephalographic monitoring will be performed and then patients will be tracked for 2 years to determine the incidence of PTE. Validation of selected biomarkers that are discovered in planned animal models will be a principal feature of this work. Specific hypotheses regarding the discovery of biomarkers have been set forth in this study. An international cohort of 13 centers spanning 2 continents will be developed to facilitate this study, and for future interventional studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Post-traumatic epilepsy is the architype of acquired epilepsies, wherein a brain insult initiates an epileptogenic process culminating in an unprovoked seizure after weeks, months or years. Identifying biomarkers of such process is a prerequisite for developing and implementing targeted therapies aimed at preventing the development of epilepsy. Currently, there are no validated electrophysiological biomarkers of post-traumatic epileptogenesis. Experimental EEG studies using the lateral fluid percussion injury model have identified three candidate biomarkers of post-traumatic epileptogenesis: pathological high-frequency oscillations (HFOs, 80-300 Hz); repetitive HFOs and spikes (rHFOSs); and reduction in sleep spindle duration and dominant frequency at the transition from stage III to rapid eye movement sleep. EEG studies in humans have yielded conflicting data; recent evidence suggests that epileptiform abnormalities detected acutely after traumatic brain injury carry a significantly increased risk of subsequent epilepsy. Well-designed studies are required to validate these promising findings, and ultimately establish whether there are post-traumatic electrophysiological features which can guide the development of 'antiepileptogenic' therapies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Posttraumatic epilepsy (PTE) is a recurrent seizure disorder that often develops secondary to traumatic brain injury (TBI) that is caused by an external mechanical force. Recent evidence shows that the brain extracellular matrix plays a major role in the remodeling of neuronal connections after injury. One of the proteases that is presumably responsible for this process is matrix metalloproteinase-9 (MMP-9). The levels of MMP-9 are elevated in rodent brain tissue and human blood samples after TBI. However, no studies have described the influence of MMP-9 on the development of PTE. The present study used controlled cortical impact (CCI) as a mouse model of TBI. We examined the detailed kinetics of MMP-9 levels for 1 month after TBI and observed two peaks after injury (30 min and 6 h after injury). We tested the hypothesis that high levels of MMP-9 predispose individuals to the development of PTE, and MMP-9 inhibition would protect against PTE. We used transgenic animals with either MMP-9 knockout or MMP-9 overexpression. MMP-9 overexpression increased the number of mice that exhibited TBI-induced spontaneous seizures, and MMP-9 knockout decreased the appearance of seizures. We also evaluated changes in responsiveness to a single dose of the chemoconvulsant pentylenetetrazol. MMP-9-overexpressing mice exhibited a significantly shorter latency between pentylenetetrazol administration and the first epileptiform spike. MMP-9 knockout mice exhibited the opposite response profile. Finally, we found that the occurrence of PTE was correlated with the size of the lesion after injury. Overall, our data emphasize the contribution of MMP-9 to TBI-induced structural and physiological alterations in brain circuitry that may lead to the development of PTE.

This study assessed neuropeptide Y (NPY) expression in the hippocampus after long-term survival following traumatic brain injury (TBI) induced by controlled cortical impact (CCI) with or without the development of posttraumatic epilepsy (PTE). We hypothesized that following long-term survival after CCI, the severity of tissue injury and the development of PTE would correlate with the degree of hippocampal neurodegeneration as reflected by NPY+ and neuronal nuclear antigen (NeuN)+ cell loss. Adult Sprague-Dawley rats of 2-3 months of age were lesioned in the right parietal cortex and monitored for seizure activity by video and/or video-EEG. Neuropeptide Y and NeuN immunoreactivities (IRs) were quantified by light microscopy and semiautomatic image analysis approaches for unbiased quantification. Severely injured animals, marked by extensive tissue loss in the ipsilateral neocortex and adjacent hippocampus, resulted in significantly lower NeuN+ hilar cell density and NPY+ cell loss in the contralateral Cornu Ammonis (CA)-3 and dentate hilus (DH). The degree of NPY+ cell loss was more severe in CCI-injured animals with PTE than those animals that did not develop PTE. Mildly injured animals demonstrated no significant change of NPY expression compared with control animals. Our findings of long-term alterations of NPY expression in the hippocampus of severely brain-injured animals can provide important insights into the cellular and molecular consequences of severe TBI and posttraumatic epileptogenesis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Labor intensive electroencephalogram (EEG) analysis is a major bottleneck to identifying anti-epileptogenic treatments in experimental models of post-traumatic epilepsy. We aimed to develop an algorithm for automated seizure detection in experimental post-traumatic epilepsy., New Method: Continuous (24/7) 1-month-long video-EEG monitoring with three epidural screw electrodes was started 154 d after lateral fluid-percussion induced traumatic brain injury (TBI; n = 97) or sham-injury (n = 29) in adult male Sprague-Dawley rats. First, an experienced researcher screened a total of 90,720 h of digitized recordings on a computer screen to annotate the occurrence of spontaneous seizures. The same files were then analyzed using an algorithm in Spike2 (ver.9), which searching for temporally linked power peaks (14-42 Hz) in all three EEG channels, and then positive events were marked as a probable seizures. Finally, an experienced researcher confirmed all seizure candidates visually on the computer screen., Results: Visual analysis identified 197 seizures in 29 rats. Automatic detection identified 4346 seizure candidates in 109 rats, of which 202 in the same 29 rats were true positives, resulting in a false positive rate of 0.046/h or 1.10/d. The algorithm demonstrated 5% specificity and 100% sensitivity. The algorithm analyzed 1-month 3-channel EEG in 7 cohorts in 2 h, whereas analysis by an experienced technician took ∼500 h., Comparison With Existing Methods: The algorithm had 100% sensitivity. It performed slightly better and was substantially faster than investigator-performed visual analysis., Conclusions: We present a novel seizure detection algorithm for automated detection of seizures in a rat model of post-traumatic epilepsy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Children with traumatic brain injury (TBI) are at increased risk of posttraumatic epilepsy (PTE); the risk increases according to TBI severity. We examined the long-term incidence and risk factors for developing PTE in a cohort of children hospitalised at one medical centre with moderate or severe TBI., Methods: Moderate brain injury was classified as Glasgow Coma Score on Arrival (GCSOA) of 9-13, and severe brain injury as GCSOA ≤8. We collected demographics and clinical data from medical records and interviewed patients and parents at 5-11 years following the TBI event., Results: During a median follow-up period of 7.3 years, 9 (9%) of 95 children with moderate-to-severe TBI developed PTE; 4 developed intractable epilepsy. The odds for developing PTE was 2.9 in patients with severe compared to moderate TBI. CT findings showed fractures in 7/9 (78%) of patients with PTE, compared to 40/86 (47%) of those without PTE (p = 0.09). Of the patients with fractures, all those with PTE had additional features on CT (such as haemorrhage, contusion and mass effect), compared to 29/40 (73%) of those without PTE. One of nine (11%) PTE patients and 10 of 86 (12%) patients without PTE had immediate seizures. Two (22%) children with PTE had their first seizure more than 2 years after the TBI., Conclusion: Among children with moderate or severe TBI, the presence of additional CT findings, other than skull fractures, seem to increase the risk of PTE. In our cohort, the occurrence of an early seizure did not confer an increased risk of PTE., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Electrophysiological experiments in the partial cortical isolation ("undercut" or "UC") model of injury-induced neocortical epileptogenesis have shown alterations in GABAergic synaptic transmission attributable to abnormalities in presynaptic terminals. To determine whether the decreased inhibition was associated with structural abnormalities in GABAergic interneurons, we used immunocytochemical techniques, confocal microscopy and EM in UC and control sensorimotor rat cortex to analyze structural alterations in fast-spiking parvalbumin-containing interneurons and pyramidal (Pyr) cells of layer V. Principle findings were: 1) there were no decreases in counts of parvalbumin (PV)- or GABA-immunoreactive interneurons in UC cortex, however there were significant reductions in expression of VGAT and GAD-65 and -67 in halos of GABAergic terminals around Pyr somata in layer V. 2) Consistent with previous results, somatic size and density of Pyr cells was decreased in infragranular layers of UC cortex. 3) Dendrites of biocytin-filled FS interneurons were significantly decreased in volume. 4) There were decreases in the size and VGAT content of GABAergic boutons in axons of biocytin-filled FS cells in the UC, together with a decrease in colocalization with postsynaptic gephyrin, suggesting a reduction in GABAergic synapses. Quantitative EM of layer V Pyr somata confirmed the reduction in inhibitory synapses. 5) There were marked and lasting reductions in brain derived neurotrophic factor (BDNF)-IR and -mRNA in Pyr cells and decreased TrkB-IR on PV cells in UC cortex. 6) Results lead to the hypothesis that reduction in trophic support by BDNF derived from Pyr cells may contribute to the regressive changes in axonal terminals and dendrites of FS cells in the UC cortex and decreased GABAergic inhibition., Significance: Injury to cortical structures is a major cause of epilepsy, accounting for about 20% of cases in the general population, with an incidence as high as ~50% among brain-injured personnel in wartime. Loss of GABAergic inhibitory interneurons is a significant pathophysiological factor associated with epileptogenesis following brain trauma and other etiologies. Results of these experiments show that the largest population of cortical interneurons, the parvalbumin-containing fast-spiking (FS) interneurons, are preserved in the partial neocortical isolation model of partial epilepsy. However, axonal terminals of these cells are structurally abnormal, have decreased content of GABA synthetic enzymes and vesicular GABA transporter and make fewer synapses onto pyramidal neurons. These structural abnormalities underlie defects in GABAergic neurotransmission that are a key pathophysiological factor in epileptogenesis found in electrophysiological experiments. BDNF, and its TrkB receptor, key factors for maintenance of interneurons and pyramidal neurons, are decreased in the injured cortex. Results suggest that supplying BDNF to the injured epileptogenic brain may reverse the structural and functional abnormalities in the parvalbumin FS interneurons and provide an antiepileptogenic therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Treatment of TBI remains a major unmet medical need, with 2.5 million new cases of traumatic brain injury (TBI) each year in Europe and 1.5 million in the USA. This single-center proof-of-concept preclinical study tested the hypothesis that pharmacologic neurostimulation with proconvulsants, either atipamezole, a selective α 2 -adrenoceptor antagonist, or the cannabinoid receptor 1 antagonist SR141716A, as monotherapy would improve functional recovery after TBI. A total of 404 adult Sprague-Dawley male rats were randomized into two groups: sham-injured or lateral fluid-percussion-induced TBI. The rats were treated with atipamezole (started at 30min or 7 d after TBI) or SR141716A (2min or 30min post-TBI) for up to 9 wk. Total follow-up time was 14 wk after treatment initiation. Outcome measures included motor (composite neuroscore, beam-walking) and cognitive performance (Morris water-maze), seizure susceptibility, spontaneous seizures, and cortical and hippocampal pathology. All injured rats exhibited similar impairment in the neuroscore and beam-walking tests at 2 d post-TBI. Atipamezole treatment initiated at either 30min or 7 d post-TBI and continued for 9 wk via subcutaneous osmotic minipumps improved performance in both the neuroscore and beam-walking tests, but not in the Morris water-maze spatial learning and memory test. Atipamezole treatment initiated at 7 d post-TBI also reduced seizure susceptibility in the pentylenetetrazol test 14 wk after treatment initiation, although it did not prevent the development of epilepsy. SR141716A administered as a single dose at 2min post-TBI or initiated at 30min post-TBI and continued for 9 wk had no recovery-enhancing or antiepileptogenic effects. Mechanistic studies to assess the α 2 -adrenoceptor subtype specificity of the disease-modifying effects of atipametzole revealed that genetic ablation of α 2A -noradrenergic receptor function in Adra2A mice carrying an N79P point mutation had antiepileptogenic effects after TBI. On the other hand, blockade of α 2C -adrenoceptors using the receptor subtype-specific antagonist ORM-12741 had no favorable effects on the post-TBI outcome. Finally, to assess whether regulation of the post-injury inflammatory response by atipametzole in glial cells contributed to a favorable outcome, we investigated the effect of atipamezole on spontaneous and/or lipopolysaccharide-stimulated astroglial or microglial cytokine release in vitro. We observed no effect. Our data demonstrate that a 9-wk administration of α2A-noradrenergic antagonist, atipamezole, is recovery-enhancing after TBI., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Sleep disturbances commonly occur after traumatic brain injury (TBI) and may predispose patients to epileptic seizures. We hypothesized that unprovoked seizure occurrence post-TBI depends on the sleep-wake cycle, and that the electrographic characteristics of a given sleep stage provide biomarkers for post-traumatic epilepsy (PTE). We show, in a rat lateral fluid percussion model, that 92% of spontaneous generalized seizures occur during the transition from stage III to rapid eye movement sleep. Moreover, a reduction in spindle duration and dominant frequency during the transition stage present as specific and sensitive noninvasive biomarkers for experimentally induced PTE with generalized electrographic seizures.

Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures. Many of the available anti-seizure drugs target gamma-aminobutyric acid (GABA A ) receptors. The inhibitory activity of GABA A receptor activation depends on low intracellular Cl - , which is achieved by the opposing regulation of Na + -K + -Cl - cotransporter 1 (NKCC1) and K + -Cl - -cotransporter 2 (KCC2). Up-regulation of NKCC1 in neurons has been shown to be involved in neonatal seizures and in ammonia toxicity-induced seizures. Here, we report that TBI-induced up-regulation of NKCC1 and increased intracellular Cl - concentration. Genetic deletion of NKCC1 or pharmacological inhibition of NKCC1 with bumetanide suppresses TBI-induced seizures. TGFβ expression was also increased after TBI and competitive antagonism of TGFβ reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGFβ might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGFβ, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway.

To recognize epileptic spasms (ES) as a seizure type after traumatic brain injury (TBI), accidental or non-accidental, in infants and children. In the process, we aim to gain some insight into the mechanisms of epileptogenesis in ES. A retrospective electronic chart review was performed at the Children's Hospital of Michigan from 2002 to 2012. Electronic charts of 321 patients were reviewed for evidence of post-traumatic epilepsy. Various clinical variables were collected including age at TBI, mechanism of trauma, severity of brain injury, electroencephalography/neuroimaging data, and seizure semiology. Six (12.8%) of the 47 patients diagnosed with post-traumatic epilepsy (PTE) had ES. Epileptic spasms occurred between two months to two years after TBI. All patients with ES had multiple irritative zones, manifesting as multifocal epileptiform discharges, unilateral or bilateral. Cognitive delay and epileptic encephalopathy were seen in all six patients, five of whom were free of spasms after treatment with vigabatrin or adrenocorticotropic hormone. The risk of PTE is 47/321(14.6%) and the specific risk of ES after TBI is 6/321 (1.8%). The risk of ES appears to be high if the age at which severe TBI occurred was during infancy. Non-accidental head trauma is a risk factor of epileptic spasms. While posttraumatic epilepsy (not ES) may start 10 years after the head injury, ES starts within two years, according to our small cohort. The pathophysiology of ES is unknown, however, our data support a combination of previously proposed models in which the primary dysfunction is a focal or diffuse cortical abnormality, coupled with its abnormal interaction with the subcortical structures and brainstem at a critical maturation stage.

Post-traumatic epilepsy (PTE) is defined as the development of unprovoked seizures in a delayed fashion after traumatic brain injury (TBI). PTE lies at the intersection of two distinct fields of study, epilepsy and neurotrauma. TBI is associated with a myriad of both focal and diffuse anatomic injuries, and an ideal animal model of epilepsy after TBI must mimic the characteristics of human PTE. The three most commonly used models of TBI are lateral fluid percussion, controlled cortical injury, and weight drop. Much of what is known about PTE has resulted from use of these models. In this review, we describe the most commonly used animal models of TBI with special attention to their advantages and disadvantages with respect to their use as a model of PTE., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To analyze seizure-like motor phenomena immediately occurring after concussion (concussive convulsions)., Methods: Twenty-five videos of concussive convulsions were obtained from YouTube as a result of numerous sports-related search terms. The videos were analyzed by four independent observers, documenting observations of the casualty, the head injury, motor symptoms of the concussive convulsions, the postictal period, and the outcome., Results: Immediate responses included the fencing response, bear hug position, and bilateral leg extension. Fencing response was the most common. The side of the hit (p = 0.039) and the head turning (p = 0.0002) was ipsilateral to the extended arm. There was a tendency that if the blow had only a vertical component, the bear hug position appeared more frequently (p = 0.12). The motor symptom that appeared with latency of 6 ± 3 s was clonus, sometimes superimposed with tonic motor phenomena. Clonus was focal, focally evolving bilateral or bilateral, with a duration of 27 ± 19 s (5-72 s). Where lateralization of clonus could be determined, the side of clonus and the side of hit were contralateral (p = 0.039)., Significance: Concussive convulsions consist of two phases. The short-latency first phase encompasses motor phenomena resembling neonatal reflexes and may be of brainstem origin. The long-latency second phase consists of clonus. We hypothesize that the motor symptoms of the long-latency phase are attributed to cortical structures; however, they are probably not epileptic in origin but rather a result of a transient cortical neuronal disturbance induced by mechanical forces., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

To determine whether post-traumatic seizure severity would be affected by the interval between seizures and head injury, we measured seizures after various times with or without fluid percussion brain injury (2atm fluid percussion injury; FPI). To determine efficacy of anti-seizure medication, we also determined if levetiracetam (LEV) would alter the relationship between injury and subsequent seizures. Early post-traumatic seizures were induced by Kainic acid (KA) at one week after 2atm fluid percussion injury (FPI) in one group (FPI-ES). Seizures were induced at two weeks after FPI by KA in another group (FPI-LS). In addition, one group had induced seizures by KA without FPI, (sham-ES). Finally one group of animals received the antiepileptic agent (levetiracetam) infusion for one week after FPI and then had seizures induced by KA (FPI-LEV-ES). We measured seizure onset time, ictal duration and severity of seizures using a modified Racine's scale. Histopathological changes in the hippocampus CA1 region were also analyzed. Severity of seizures were increased in the FPI-ES group compared with sham-ES animals. Severity was also enhanced in early post-injury seizures induced by KA (FPI-ES vs. FPI-LS); this exacerbation of seizure severity could be ameliorated by levetiracetam infusion (FPI-ES vs. FPI-LEV-ES). Neuronal degeneration in CA1 was more severe in the FPI-ES group and this degeneration was also diminished by LEV. We conclude that early post injury seizures exacerbate susceptibility and severity of post traumatic seizures and increase neuronal degeneration in the CA1 layer of hippocampus. These changes are partially reversed by LEV infusion after FPI., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Posttraumatic epilepsy (PTE) usually develops in a small percentage of patients of traumatic brain injury after a varying latent period. Modeling this chronic neurological condition in rodents is time consuming and inefficient, which constitutes a significant obstacle in studying its mechanism and discovering novel therapeutics for its prevention and treatment. Partially isolated neocortex, or undercut, is known to induce cortical hyperexcitability and epileptiform activity in vitro, and has been used extensively for studying the neurophysiological mechanism of posttraumatic epileptogenesis. However, whether the undercut lesion in rodents causes chronic epileptic seizures has not been systematically characterized. Here we used a miniature telemetry system to continuously monitor electroencephalography (EEG) in adult C57BL mice for up to 3 months after undercut surgery. We found that 50% of animals developed spontaneous seizures between 16-50 days after injury. The mean seizure duration was 8.9±3.6 seconds, and the average seizure frequency was 0.17±0.17 times per day. There was no progression in seizure frequency and duration over the recording period. Video monitoring revealed behavioral arrests and clonic limb movement during seizure attacks. A pentylenetetrazol (PTZ) test further showed increased seizure susceptibility in the undercut mice. We conclude that undercut lesion in mice is a model of chronic PTE that involves spontaneous epileptic seizures.

Posttraumatic epilepsy (PTE) is one of the most common and devastating complications of traumatic brain injury (TBI). Currently, the etiopathology and mechanisms of PTE are poorly understood and as a result, there is no effective treatment or means to prevent it. Antiepileptic drugs remain common preventive strategies in the management of TBI to control acute posttraumatic seizures and to prevent the development of PTE, although their efficacy in the latter case is disputed. Different strategies of PTE prophylaxis have been showing promise in preclinical models, but their translation to the clinic still remains elusive due in part to the variability of these models and the fact they do not recapitulate all complex pathologies associated with human TBI. TBI is a multifaceted disorder reflected in several potentially epileptogenic alterations in the brain, including mechanical neuronal and vascular damage, parenchymal and subarachnoid hemorrhage, subsequent toxicity caused by iron-rich hemoglobin breakdown products, and energy disruption resulting in secondary injuries, including excitotoxicity, gliosis, and neuroinflammation, often coexisting to a different degree. Several in vivo models have been developed to reproduce the acute TBI cascade of events, to reflect its anatomical pathologies, and to replicate neurological deficits. Although acute and chronic recurrent posttraumatic seizures are well-recognized phenomena in these models, there is only a limited number of studies focused on PTE. The most used mechanical TBI models with documented electroencephalographic and behavioral seizures with remote epileptogenesis include fluid percussion, controlled cortical impact, and weight-drop. This chapter describes the most popular models of PTE-induced TBI models, focusing on the controlled cortical impact and the fluid percussion injury models, the methods of behavioral and electroencephalogram seizure assessments, and other approaches to detect epileptogenic properties, and discusses their potential application for translational research.

Objectives: Post-traumatic epilepsy (PTE) is a common consequence of traumatic brain injury (TBI) and significant predictor of poor prognosis in TBI patients. To develop clinical interventions for PTE risk reduction, there is a need to elucidate the epileptogenic mechanisms induced by brain injury., Methods: The iron-induced rat model of epilepsy used here mimics many aspects of human PTE. Intracortical injection of iron results in local neuronal damage and the establishment of an epileptic focus, leading to chronic spontaneous electroencephalographic (EEG) signals and motor seizures, with progressively increasing frequency over many months. Identifying unique aspects of PTE seizure semiology for prognosis and treatment may be aided by novel methods of EEG analysis. Here, autoregressive (AR) methods were compared to the conventional fast Fourier transform (FFT) for processing EEG signals in iron-induced epilepsy., Results: Power spectra obtained using AR showed higher frequency resolution over a given epoch than the spectra obtained using FFT. Moreover, changes in total AR spectral power and frequency distribution over brief successive periods provided convenient indexes for long-term monitoring of seizures., Discussion: Autoregression analysis may prove complementary to FFT for EEG analysis in PTE patients.

Posttraumatic epilepsy (PTE) has been modeled with different techniques of experimental traumatic brain injury (TBI) using mice and rats at various ages. We hypothesized that the technique of controlled cortical impact (CCI) could be used to establish a model of PTE in young adult rats. A total of 156 male Sprague-Dawley rats of 2-3 months of age (128 CCI-injured and 28 controls) was used for monitoring and/or anatomical studies. Provoked class 3-5 seizures were recorded by video monitoring in 7/57 (12.3%) animals in the week immediately following CCI of the right parietal cortex; none of the 7 animals demonstrated subsequent spontaneous convulsive seizures. Monitoring with video and/or video-EEG was performed on 128 animals at various time points 8-619 days beyond one week following CCI during which 26 (20.3%) demonstrated nonconvulsive or convulsive epileptic seizures. Nonconvulsive epileptic seizures of >10s were demonstrated in 7/40 (17.5%) animals implanted with 2 or 3 depth electrodes and usually characterized by an initial change in behavior (head raising or animal alerting) followed by motor arrest during an ictal discharge that consisted of high-amplitude spikes or spike-waves with frequencies ranging between 1 and 2Hz class 3-5 epileptic seizures were recorded by video monitoring in 17/88 (19%) and by video-EEG in 2/40 (5%) CCI-injured animals. Ninety of 156 (58%) animals (79 CCI-injured, 13 controls) underwent transcardial perfusion for gross and microscopic studies. CCI caused severe brain tissue loss and cavitation of the ipsilateral cerebral hemisphere associated with cell loss in the hippocampal CA1 and CA3 regions, hilus, and dentate granule cells, and thalamus. All Timm-stained CCI-injured brains demonstrated ipsilateral hippocampal mossy fiber sprouting in the inner molecular layer. These results indicate that the CCI model of TBI in adult rats can be used to study the structure-function relationships that underlie epileptogenesis and PTE., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Variable-duration oscillations and repetitive, high-voltage spikes have been recorded in the electrocorticogram (ECoG) of rats weeks and months after fluid percussion injury (FPI), a model of traumatic brain injury. These ECoG events, which have many similarities to spike-wave-discharges (SWDs) and absence seizures, have been proposed to represent nonconvulsive seizures characteristic of post-traumatic epilepsy (PTE). The present study quantified features of SWD episodes in rats at different time points after moderate to severe FPI, and compared them with age-matched control rats. Control and FPI-injured rats at 1 year of age displayed large-amplitude and frequent SWD events at frontal and parietal recording sites. At 3-6 months, SWDs were shorter in duration and less frequent; extremely brief SWDs (i.e., "larval") were detected as early as 1 month. The onset of the SWDs was nearly always synchronous across electrodes and of larger amplitude in frontal regions. A sensory stimulus, such as a click, immediately and consistently stopped the occurrence of the SWDs. SWDs were consistently accompanied by behavioral arrest. All features of SWDs in control and experimental (FPI) rats were indistinguishable. None of the FPI-treated rats developed nonconvulsive or convulsive seizures that could be distinguished electrographically or behaviorally from SWDs. Because SWDs have features similar to genetic absence seizures, these results challenge the hypothesis that SWDs after FPI reflect PTE., (Copyright © 2015 the authors 0270-6474/15/359194-11$15.00/0.)

Traumatic brain injury (TBI) can cause a myriad of sequelae depending on its type, severity, and location of injured structures. These can include mood disorders, posttraumatic stress disorder and other anxiety disorders, personality disorders, aggressive disorders, cognitive changes, chronic pain, sleep problems, motor or sensory impairments, endocrine dysfunction, gastrointestinal disturbances, increased risk of infections, pulmonary disturbances, parkinsonism, posttraumatic epilepsy, or their combinations. The progression of individual pathologies leading to a given phenotype is variable, and some progress for months. Consequently, the different post-TBI phenotypes appear within different time windows. In parallel with morbidogenesis, spontaneous recovery occurs both in experimental models and in human TBI. A great challenge remains; how can we dissect the specific mechanisms that lead to the different endophenotypes, such as posttraumatic epileptogenesis, in order to identify treatment approaches that would not compromise recovery?, (Copyright © 2014 Elsevier Inc. All rights reserved.)

Post-traumatic epilepsy (PTE) is a consequence of traumatic brain injury (TBI), occurring in 10-25% of patients with moderate to severe injuries. The development of animal models for testing antiepileptogenic therapies and validation of biomarkers to follow epileptogenesis in humans necessitates sophisticated understanding of the subtypes of PTE, which is the objective of this study. In this study, retrospective review was performed of patients with moderate to severe TBI with subsequent development of medically refractory epilepsy referred for video-electroencephalography (EEG) monitoring at a single center over a 10-year period. Information regarding details of injury, neuroimaging studies, seizures, video-EEG, and surgery outcomes were collected and analyzed. There were 123 patients with PTE identified, representing 4.3% of all patients evaluated in the epilepsy monitoring unit. Most of them had localization-related epilepsy, of which 57% had temporal lobe epilepsy (TLE), 35% had frontal lobe epilepsy (FLE), and 3% each had parietal and occipital lobe epilepsy. Of patients with TLE, 44% had mesial temporal sclerosis (MTS), 26% had temporal neocortical lesions, and 30% were nonlesional. There was no difference in age at injury between the different PTE subtypes. Twenty-two patients, 13 of whom had MTS, proceeded to surgical resection. At a mean follow-up of 2.5 years, Engel Class I outcomes were seen in 69% of those with TLE and 33% of those with FLE. Our findings suggest PTE is a heterogeneous condition, and careful evaluation with video-EEG monitoring and high resolution MRI can identify distinct syndromes. These results have implications for the design of clinical trials of antiepileptogenic therapies for PTE.

Objective: We conducted a systematic review of the literature to explore the longitudinal course of PTSD in DSM-5-defined trauma exposed populations to identify the course of illness and recovery for individuals and populations experiencing PTSD., Methods: We reviewed the published literature from January 1, 1998 to December 31, 2010 for longitudinal studies of directly exposed trauma populations in order to: (1) review rates of PTSD in the first year after a traumatic event; (2) examine potential types of proposed DSM-5 direct trauma exposure (intentional and non-intentional); and (3) identify the clinical course of PTSD (early onset, later onset, chronicity, remission, and resilience). Of the 2537 identified articles, 58 articles representing 35 unique subject populations met the proposed DSM-5 criteria for experiencing a traumatic event, and assessed PTSD at two or more time points within 12 months of the traumatic event., Results: The mean prevalence of PTSD across all studies decreases from 28.8% (range =3.1-87.5%) at 1 month to 17.0% (range =0.6-43.8%) at 12 months. However, when traumatic events are classified into intentional and non-intentional, the median prevalences trend down for the non-intentional trauma exposed populations, while the median prevalences in the intentional trauma category steadily increase from 11.8% to 23.3%. Across five studies with sufficient data, 37.1% of those exposed to intentional trauma develop PTSD. Among those with PTSD, about one third (34.8%) remit after 3 months. Nearly 40% of those with PTSD (39.1%) have a chronic course, and only a very small fraction (3.5%) of new PTSD cases appears after three months., Conclusions: Understanding the trajectories of PTSD over time, and how it may vary by type of traumatic event (intentional vs. non-intentional) will assist public health planning and treatment.

Purpose: In humans, traumatic brain injury (TBI) is one of the most common causes of acquired (symptomatic) epilepsy, but as yet there is no treatment to prevent the development of epilepsy after TBI. Animal models of posttraumatic epilepsy (PTE) are important to characterize epileptogenic mechanisms of TBI and to identify clinically effective antiepileptogenic treatments. The prevalence and phenomenology of naturally occurring canine epilepsy are similar to those in human epilepsy. However, the risk of epilepsy after TBI has not been systemically studied in dogs. We therefore performed a large retrospective study in 1,000 dogs referred to our clinical department over a period of 11.5 years with the aim to determine the incidence of early and late seizures after head trauma in this species., Methods: Two strategies were used: in group I (n = 392), we evaluated whether dogs referred for the treatment of a head trauma (group Ia) or other trauma (group Ib) developed seizures after the trauma, whereas in group II (n = 608) we evaluated whether dogs referred for the treatment of recurrent epileptic seizures had a history of head trauma. Data for this study were obtained from our clinical database, questionnaires sent to the dogs' owners, and owner interviews., Key Findings: In group Ia, 6.6% of the dogs developed PTE, which was significantly different from group Ib (1.9%), indicating that head trauma increased the risk of developing epilepsy by a factor of 3.4. The risk of PTE increased with severity of TBI; 14.3% of the dogs with skull fracture developed PTE. In group II, 15.5% of the dogs with epilepsy had a history of head injury, which was significantly higher than the incidence of PTE determined for group Ia., Significance: Our study indicates that head trauma in dogs is associated with a significant risk of developing epilepsy. Therefore, dogs with severe TBI are an interesting natural model of PTE that provides a novel translational platform for studies on human PTE., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

To study the possibility of application of nootropics and antioxidants in the complex antiepileptic therapy, we examined 75 patients with symptomatic focal posttraumatic epilepsy. A statistically significant reduction in the number of epileptic seizures, improvement of cognitive function and quality of life of the patients as well as a decrease in the severity of depression and epileptic changes in the EEG were identified. The potentiation of antiepileptic activity of basic drugs, normalization of brain's electrical activity and reduction in EEG epileptiform activity, in particular coherent indicators of slow-wave activity, were noted after treatment with the antioxidant mexidol. A trend towards the improvement of neuropsychological performance and quality of life was observed. There was a lack of seizure aggravation typical of many nootropic drugs. Thus, phenotropil and mexidol can be recommended for complex treatment of symptomatic posttraumatic epilepsy.

Primary Objective: To better characterize, describe and highlight issues that individuals with TBI and active LPTS may face in their daily lives., Design: Prospective multi-centre mixed method qualitative and quantitative interview., Participants: Twenty-five individuals, 5-13 years post-injury, who had reported having LPTS and TBI., Measures: Disability Rating Scale (DRS); Supervision Rating Scale (SRS); Glasgow Outcome Scale-Extended (GOS-E); Perceived Stress Scale (PSS); Craig Handicap Assessment Reporting Technique-Short Form (CHART-SF) sub-scales: Physical Independence, Cognitive Independence, Mobility, Occupation, Social Integration; and Craig Hospital Inventory of Environmental Factors (CHIEF); and qualitative interview questions pertaining to management of the seizure disorder and its effect on the individual's health, function, community integration and participation., Results: Data are presented regarding seizure activity and management; return to driving post-seizure; coping and participation; and standardized outcome measures., Conclusions: Individuals with TBI and LPTS are at a double-barrelled disadvantage regarding ongoing physical, cognitive, psychosocial and reintegration issues following brain injury and epilepsy. Clearer clinical guidelines and treatment strategies need to be developed to help ameliorate these ongoing issues. Additional research is needed to identify what the rehabilitation community can do to continue to facilitate people living safely and independently.

Post-traumatic epileptic seizure is a common complication of brain trauma including military injuries. We present clinical characteristics and correlates of post-traumatic epilepsy in 163 head-injured veterans suffering from intractable epilepsy due to blunt or penetrating head injuries sustained during the Iraq-Iran war. The medical records of 163 war veterans who were admitted by the Epilepsy Department of the Shefa Neuroscience Center between 2005 and 2009 were retrospectively reviewed. The mean follow-up period after developing epilepsy was 17.2 years. The time interval between the trauma and the first seizure was shorter and the seizure frequency was higher in epileptic patients suffering from penetrating head trauma. There was no difference in seizure type between epileptic patients traumatised by blunt or penetrating injury. Patients with seizure frequency of more than 30 per month mostly had simple partial seizure. Frontal and parietal semiologies were observed more frequently in patients with penetrating trauma, whereas patients with blunt trauma showed a higher temporal semiology. The most common brain lesion observed by CT scan was encephalomalacia followed by porencephaly and focal atrophy. There was no association between intracerebral retained fragments and different characteristic features of epilepsy. Patients with military brain injury carry a high risk of intractable post-traumatic epilepsy decades after their injury, and thus require a long-term medical follow-up., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Progress toward developing effective prophylaxis and treatment of posttraumatic epilepsy depends on a detailed understanding of the basic underlying mechanisms. One important factor contributing to epileptogenesis is decreased efficacy of GABAergic inhibition. Here we tested the hypothesis that the output of neocortical fast-spiking (FS) interneurons onto postsynaptic targets would be decreased in the undercut (UC) model of chronic posttraumatic epileptogenesis. Using dual whole-cell recordings in layer IV barrel cortex, we found a marked increase in the failure rate and a very large reduction in the amplitude of unitary inhibitory postsynaptic currents (uIPSCs) from FS cells to excitatory regular spiking (RS) neurons and neighboring FS cells. Assessment of the paired pulse ratio and presumed quantal release showed that there was a significant, but relatively modest, decrease in synaptic release probability and a non-significant reduction in quantal size. A reduced density of boutons on axons of biocytin-filled UC FS cells, together with a higher coefficient of variation of uIPSC amplitude in RS cells, suggested that the number of functional synapses presynaptically formed by FS cells may be reduced. Given the marked reduction in synaptic strength, other defects in the presynaptic vesicle release machinery likely occur, as well., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Epileptogenesis following traumatic brain injury (TBI) is likely due to a combination of increased excitability, disinhibition, and increased excitatory connectivity via aberrant axon sprouting. Targeting these pathways could be beneficial in the prevention and treatment of posttraumatic epilepsy. Here, we tested this possibility using the novel anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide [LCM]), which acts on both voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2), an axonal growth/guidance protein. LCM inhibited CRMP2-mediated neurite outgrowth, an effect phenocopied by CRMP2 knockdown. Mutation of LCM-binding sites in CRMP2 reduced the neurite inhibitory effect of LCM by ∼8-fold. LCM also reduced CRMP2-mediated tubulin polymerization. Thus, LCM selectively impairs CRMP2-mediated microtubule polymerization, which underlies its neurite outgrowth and branching. To determine whether LCM inhibits axon sprouting in vivo, LCM was injected into rats subjected to partial cortical isolation, an animal model of posttraumatic epileptogenesis that exhibits axon sprouting in cortical pyramidal neurons. Two weeks following injury, excitatory synaptic connectivity of cortical layer V pyramidal neurons was mapped using patch clamp recordings and laser scanning photostimulation of caged glutamate. In comparison with injured control animals, there was a significant decrease in the map size of excitatory synaptic connectivity in LCM-treated rats, suggesting that LCM treatment prevented enhanced excitatory synaptic connectivity due to posttraumatic axon sprouting. These findings suggest, for the first time, that LCM's mode of action involves interactions with CRMP2 to inhibit posttraumatic axon sprouting., (Copyright © 2012 IBRO. All rights reserved.)

Brain damage and neuronal loss caused by traumatic brain injury, ischemic stroke, and symptomatic status epilepticus can lead to severe long-term consequences, such as impairment in learning and memory and cognitive functions, and development of chronic epilepsy. This can be the result of morphologic and functional changes underlying temporal lobe epilepsy. Epilepsy patients have increased risk of status epilepticus. It is a life-threatening condition when seizures last for more than 30 min and trigger processes leading to neuronal apoptosis and necrosis in various parts of brain. Administration of neuroprotective drugs preventing these pathologic processes could improve the prognosis for such patients. However despite of active research of neuroprotective drugs, the effective ways to prevent brain damage resulting from prolonged seizures are yet to be found. Studies of neuroprotective properties of classic and novel anticonvulsant drugs showed that most of them do not have the sufficient neuroprotective effect and are not able to prevent epileptogenesis. Thus the studies of other potential neuroprotective drugs seem to be promising.

The present study investigated the development of hyperexcitability and epilepsy in mice with traumatic brain injury (TBI) induced by controlled cortical impact (CCI) or lateral fluid-percussion injury (FPI), which are the two most commonly used experimental models of human TBI in rodents. TBI was induced with CCI to 50 (14 controls) and with lateral FPI to 45 (15 controls) C57BL/6S adult male mice. The animals were followed-up for 9 months, including three 2-week periods of continuous video-electroencephalographic (EEG) monitoring, and a seizure susceptibility test with pentylenetetrazol (PTZ). In the end, the animals were perfusion-fixed for histology. The experiment included two independent cohorts of animals. Late post-traumatic spontaneous electrographic seizures were detected in 9% of mice after CCI and 3% after lateral FPI. Eighty-two percent of mice after CCI and 71% after lateral FPI had spontaneous epileptiform spiking on EEG. In addition, 58% of mice with lateral FPI showed spontaneous epileptiform discharges. A PTZ test demonstrated increased seizure susceptibility in the majority of mice in both models, compared to control mice. There was no further progression in the occurrence of epilepsy or epileptiform spiking when follow-up was extended from 6 to 9 months. The severity of cortical or hippocampal damage did not differentiate mice with or without epileptiform activity in either model. Finally, two independent series of experiments in both injury models provided comparable data demonstrating reproducibility of the modeling. These data show that different types of impact can trigger epileptogenesis in mice. Even though the frequency of spontaneous seizures in C57BL/6S mice is low, a large majority of animals develop hyperexcitability.