Applying Proteomics and Computational Approaches to Identify Novel Targets in Blast-Associated Post-Traumatic Epilepsy.

Traumatic brain injury (TBI) can lead to post-traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents with several complications, including cognitive and behavioral disturbances and PTE; however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased proteomics approach in a mouse model of repeated bTBI (rbTBI), this study addresses this gap in the knowledge. After rbTBI, mice were monitored using continuous, uninterrupted video-EEG for up to four months. Following this period, we collected cortex and hippocampus tissues from three groups of mice: those with post-traumatic epilepsy (PTE+), those without epilepsy (PTE-), and the control group (sham). Hundreds of differentially expressed proteins were identified in the cortex and hippocampus of PTE+ and PTE- relative to sham. Focusing on protein pathways unique to PTE+, pathways related to mitochondrial function, post-translational modifications, and transport were disrupted. Computational metabolic modeling using dysregulated protein expression predicted mitochondrial proton pump dysregulation, suggesting electron transport chain dysregulation in the epileptic tissue relative to PTE-. Finally, data mining enabled the identification of several novel and previously validated TBI and epilepsy biomarkers in our data set, many of which were found to already be targeted by drugs in various phases of clinical testing. These findings highlight novel proteins and protein pathways that may drive the chronic PTE sequelae following rbTBI.

Post-traumatic seizures and factors associated among adult patients with depressed skull fractures at Mulago National Referral hospital; cross-sectional study.

INTRODUCTION: Post-traumatic seizures (PTS) are common among patients with depressed skull fractures (DSF). Understanding the burden of post traumatic seizures and the factors associated among adult patients with DSF is important to improve clinical care. OBJECTIVE: To determine the prevalence and factors associated with post-traumatic seizures among adult patients with DSF at Mulago National Referral hospital (MNRH). METHODS: A cross-sectional study was conducted among 333 study participants between March 2021 and February 2022. Socio-demographic, clinical laboratory factors and anti-seizure medications were collected using a study questionnaire. Data was analysed to determine the prevalence of PTS and factors associated with occurrence of PTS among patients with DSF. RESULTS: The mean age (±SD) of study participants was 31.2, (±10.5) years, with a male to female ratio of 10.4:1. Nearly half of the study participants had attained secondary level of education, while 31.6 % (105) were peasants (subsistence farmers). The overall prevalence of PTS among DSF study participants was 16.2 % (54participants). Late presentation of PTS was the highest at 9.0 % (30) followed by early PTS at 3.9 % [13] and immediate PTS at 3.3 % [11]. Moderate Glasgow coma score (GCS: 9-13), p < 0.015, severe traumatic brain injury (GCS: 3-8), p < 0.026 at the time of admission and midline brain shift (≥5mm), p < 0.009 were associated with PTS. Phenytoin (94.3 %) was the most commonly used ASM followed by phenobarbitone (1.4 %) and Valproate (1.1 %) among study participants. CONCLUSION: Patients with moderate and severe traumatic brain injury and midline brain shift were associated with post traumatic seizures. Early identification and intervention may reduce the burden of posttraumatic seizures in this category of patients.

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.

Celecoxib treatment alleviates cerebral injury in a rat model of post-traumatic epilepsy.

Background: An important factor contributing to the development and occurrence of post-traumatic epilepsy (PTE) is neuroinflammation and oxidative stress. The effects of celecoxib include inhibiting inflammatory reactions and antioxidant stress and reducing seizures, making it a potential epilepsy treatment solution. Objective: To observe the effect of celecoxib on early epilepsy in post-traumatic epilepsy rats. Methods: Twenty-four adult healthy male Sprague-Dawley rats were randomly assigned to three groups: sham-operated, PTE, and celecoxib. A rat model of PTE was established by injecting ferrous chloride into the right frontal cortex. Afterward, the behavior of rats was observed and recorded. 3.0T superconducting magnetic resonance imaging (MRI) was used to describe the changes in ADC values of the brain. HE and Nissl staining were also used to detect the damage to frontal lobe neurons. Furthermore, the expression of COX-2 protein in the right frontal lobe was detected by Western blot. Moreover, the contents of IL-1 and TNF-α in the right frontal lobe were detected by enzyme-linked immunosorbent assay. Results: Compared with the PTE group, the degree of seizures in rats treated with celecoxib declined dramatically (P < 0.05). Celecoxib-treated rats had significant decreases in tissue structural damage and cell death in the brain. The results of the MRI showed that celecoxib reduced the peripheral edema zone and ADC value of the cortex around the damaged area of the right frontal lobe in the celecoxib-treatment group, which was significantly decreased compared with the PTE group (P < 0.05). Furthermore, celecoxib decreased the expression of COX-2, IL-1ß, and TNF-α in brain tissue (P < 0.05). Conclusions: In PTE rats, celecoxib significantly reduced brain damage and effectively reduced seizures. As a result of celecoxib's ability to inhibit inflammation, it can reduce the edema caused by injury in rat brain tissue.

ECoG spiking activity and signal dimension are early predictive measures of epileptogenesis in a translational mouse model of traumatic brain injury.

The latency between traumatic brain injury (TBI) and the onset of epilepsy (PTE) represents an opportunity for counteracting epileptogenesis. Antiepileptogenesis trials are hampered by the lack of sensitive biomarkers that allow to enrich patient's population at-risk for PTE. We aimed to assess whether specific ECoG signals predict PTE in a clinically relevant mouse model with ∼60% epilepsy incidence. TBI was provoked in adult CD1 male mice by controlled cortical impact on the left parieto-temporal cortex, then mice were implanted with two perilesional cortical screw electrodes and two similar electrodes in the hemisphere contralateral to the lesion site. Acute seizures and spikes/sharp waves were ECoG-recorded during 1 week post-TBI. These early ECoG events were analyzed according to PTE incidence as assessed by measuring spontaneous recurrent seizures (SRS) at 5 months post-TBI. We found that incidence, number and duration of acute seizures during 3 days post-TBI were similar in PTE mice and mice not developing epilepsy (No SRS mice). Control mice with cortical electrodes (naïve, n = 5) or with electrodes and craniotomy (sham, n = 5) exhibited acute seizures but did not develop epilepsy. The daily number of spikes/sharp waves at the perilesional electrodes was increased similarly in PTE (n = 15) and No SRS (n = 8) mice vs controls (p < 0.05, n = 10) from day 2 post-injury. Differently, the daily number of spikes/sharp waves at both contralateral electrodes showed a progressive increase in PTE mice vs No SRS and control mice. In particular, spikes number was higher in PTE vs No SRS mice (p < 0.05) at 6 and 7 days post-TBI, and this measure predicted epilepsy development with high accuracy (AUC = 0.77, p = 0.03; CI 0.5830-0.9670). The cut-off value was validated in an independent cohort of TBI mice (n = 12). The daily spike number at the contralateral electrodes showed a circadian distribution in PTE mice which was not observed in No SRS mice. Analysis of non-linear dynamics at each electrode site showed changes in dimensionality during 4 days post-TBI. This measure yielded the best discrimination between PTE and No SRS mice (p < 0.01) at the cortical electrodes contralateral to injury. Data show that epileptiform activity contralateral to the lesion site has the the highest predictive value for PTE in this model reinforcing the hypothesis that the hemisphere contralateral to the lesion core may drive epileptogenic networks after TBI.

Impact of genetic polymorphisms on the risk of epilepsy amongst patients with acute brain injury: A systematic review.

BACKGROUND AND PURPOSE: The genetics of late seizure or epilepsy secondary to traumatic brain injury (TBI) or stroke are poorly understood. We undertook a systematic review to test the association of single-nucleotide polymorphisms (SNPs) with the risk of post-traumatic epilepsy (PTE) and post-stroke epilepsy (PSE). METHODS: We followed methods from our prespecified protocol on PROSPERO to identify indexed articles for this systematic review. We collated the association statistics from the included articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed study quality using the Q-Genie tool. We report odds ratios (OR) and hazard ratios with 95% confidence intervals (CIs). RESULTS: The literature search yielded 420 articles. We included 16 studies in our systematic review, of which seven were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Eleven SNPs were associated with a significantly increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, and CD40 -1C/T, were significantly associated with an increased risk of PSE, while two, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. The meta-analysis for the association of the APOE ɛ4 with PTE was nonsignificant (OR 1.8, CI 0.6-5.6). CONCLUSIONS: The current evidence on the association of genetic polymorphisms in epilepsy secondary to TBI or stroke is of low quality and lacks validation. A collaborative effort to pool genetic data linked to epileptogenesis in stroke and TBI patients is warranted.

Incidence and risk factors of posttraumatic epilepsy following pediatric traumatic brain injury: A systematic review and meta-analysis.

Posttraumatic epilepsy (PTE) is a well-known chronic complication following traumatic brain injury (TBI). Despite some evidence that age at the time of injury may influence the likelihood of PTE, the incidence of PTE in pediatric populations remains unclear. We therefore conducted a systematic review to determine the overall reported incidence of PTE, and explore potential risk factors associated with PTE after pediatric TBI. A comprehensive literature search of the PubMed, Embase, and Web of Science databases was conducted, including randomized controlled trials and cohort studies assessing the incidence of PTE in TBI pediatric patients. We excluded studies with a sample size of <10 patients and those in which a pediatric cohort was not clearly discernable. The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We found that the overall incidence of PTE following pediatric TBI was 10% (95% confidence interval [CI] = 5.9%-15%). Subgroup analysis of a small number of studies demonstrated that the occurrence of early seizures (cumulative incidence ratio [CIR] = 7.28, 95% CI = 1.09-48.4, p = .040), severe TBI (CIR = 1.81, 95% CI = 1.23-2.67, p < .001), and intracranial hemorrhage (CIR = 1.60, 95% CI = 1.06-2.40, p = .024) increased the risk of PTE in this population. Other factors, including male sex and neurosurgical intervention, were nonsignificantly associated with a higher incidence of PTE. In conclusion, PTE is a significant chronic complication following childhood TBI, similar to in the adult population. Further standardized investigation into clinical risk factors and management guidelines is warranted. PROSPERO ID# CRD42021245802.

Risk factors for Drug-resistant Epilepsy (DRE) and a nomogram model to predict DRE development in post-traumatic epilepsy patients.

OBJECTIVES: To identify factors affecting the development of drug-resistant epilepsy (DRE), and establish a reliable nomogram to predict DRE development in post-traumatic epilepsy (PTE) patients. METHODS: This study conducted a retrospective clinical analysis in patients with PTE who visited the Epilepsy Center, Beijing Tiantan Hospital from January 2013 to December 2018. All participants were followed up for at least 3 years, and the development of DRE was assessed. Data from January 2013 to December 2017 were used as development dataset for model building. Those independent predictors of DRE were included in the final multivariable logistic regression, and a derived nomogram was built. Data from January 2018 to December 2018 were used as validation dataset for internal validation. RESULTS: Complete clinical information was available for 2830 PTE patients (development dataset: 2023; validation dataset: 807), of which 21.06% (n = 596) developed DRE. Among all parameters of interest including gender, age at PTE, family history, severity of traumatic brain injury (TBI), single or multiple injuries, lesion location, post-TBI treatments, acute seizures, PTE latency, seizure type, status epilepticus (SE), and electroencephalogram (EEG) findings, four predictors showed independent effect on DRE, they were age at PTE, seizure type, SE, and EEG findings. A model incorporating these four variables was created, and a nomogram to calculate the probability of DRE using the coefficients of the model was developed. The C-index of the predictive model and the validation was 0.662 and 0.690, respectively. The goodness-of-fit test indicated good calibration for model development and validation (p = 0.272, 0.572). CONCLUSIONS: The proposed nomogram achieved significant potential for clinical utility in the prediction of DRE among PTE patients. The risk of DRE for individual PTE patients can be estimated by using this nomogram, and identified high-risk patients might benefit from non-pharmacological therapies at an early stage.

Early post-traumatic seizures in hospitalized patients with traumatic brain injury.

OBJECTIVES: Early post-traumatic seizures (EPTS) are a well-known complication of traumatic brain injury (TBI). EPTS increase the risk of secondary brain injury and may cause significant challenges during the period of critical care. Routine use of prophylactic anti-seizure medication is controversial due to conflicting reports on efficacy and risk of adverse effects. The purpose of this study was to expand the understanding of EPTS by examining incidence and risk factors in hospitalized patients with TBI. MATERIAL & METHODS: Adult patients with TBI and evidence of intracranial injury admitted to Oslo University Hospital between 2015 and 2019 were identified from the Oslo TBI Registry - Neurosurgery. Demographic and clinical data including occurrence of seizures were retrieved from the registry. The patients did not receive routine seizure prophylaxis. Univariate and multivariable logistic regression analyses were used to investigate risk factors associated with EPTS. RESULTS: 103 of 1827 patients (5.6%) had new-onset seizures within the first week after TBI. The following factors were in multivariable analyses associated with EPTS; alcohol abuse (odds ratio [OR] 3.6, 95% CI 2.3-5.7, p < .001), moderate and severe brain injury (OR 2.2, 95% CI 1.3-3.8, p = .004 and OR 2.1, 95% CI 1.2-3.6, p = .012), brain contusion (OR 1.6, 95% CI 1.0-2.4, p = .046) and subdural hematoma (OR 1.6, 95% CI 1.0-2.6, p = .052). CONCLUSION: In our material, EPTS occurred in 5.6% of hospital-admitted TBI-patients. Alcohol abuse was the most significant risk factor, followed by moderate and severe brain injury. The results of this study contribute to the discussion about preventive treatment of EPTS in certain risk groups.

Multimodal Quality of Life Assessment in Post-9/11 Veterans With Epilepsy: Impact of Drug Resistance, Traumatic Brain Injury, and Comorbidity.

BACKGROUND AND OBJECTIVES: Epilepsy is defined by the occurrence of multiple unprovoked seizures, but quality of life (QOL) in people with epilepsy is determined by multiple factors, in which psychiatric comorbid conditions play a pivotal role. Therefore, understanding the interplay between comorbid conditions and QOL across epilepsy phenotypes is an important step toward improved outcomes. Here, we report the impact of QOL across distinct epilepsy phenotypes in a cohort of post-9/11 veterans with high rates of traumatic brain injury (TBI). METHODS: This observational cohort study from the Veterans Health Administration included post-9/11 veterans with epilepsy. A process integrating an epilepsy identification algorithm, chart abstraction, and self-reported measures was used to classify patients into 1 of 4 groups: (1) epilepsy controlled with medications, (2) drug-resistant epilepsy (DRE), (3) posttraumatic epilepsy (PTE), or (4) drug-resistant PTE (PT-DRE). Summary scores for 6 QOL measures were compared across the groups after adjustment for age, sex, and number of comorbid conditions. RESULTS: A total of 529 survey respondents with epilepsy were included in the analysis: 249 controls (i.e., epilepsy without DRE or PTE), 124 with DRE, 86 with PTE, and 70 with PT-DRE. DRE was more common in those with PTE compared with those with nontraumatic epilepsy (45% vs 33%, odds ratio 1.6 [95% CI 1.1-2.4], p = 0.01). Patients with PTE and PT-DRE had significantly more comorbid conditions in health records than those with nontraumatic epilepsy. Those with both PTE and DRE reported the lowest QOL across all 6 measures, and this persisted after adjustment for comorbid conditions and in further linear analyses. DISCUSSION: Among those with PTE, DRE prevalence was significantly higher than prevalence of nontraumatic epilepsies. PTE was also associated with higher burden of comorbidity and worse overall QOL compared to nontraumatic epilepsies. People with PTE are distinctly vulnerable to the comorbid conditions associated with TBI and epilepsy. This at-risk group should be the focus of future studies aimed at elucidating the factors associated with adverse health outcomes and developing antiepileptogenic therapies.

Neuroanatomic Markers of Posttraumatic Epilepsy Based on MR Imaging and Machine Learning.

BACKGROUND AND PURPOSE: Although posttraumatic epilepsy is a common complication of traumatic brain injury, the relationship between these conditions is unclear and early posttraumatic epilepsy detection and prevention remain major unmet clinical challenges. This study aimed to identify imaging biomarkers that predict posttraumatic epilepsy among survivors of traumatic brain injury on the basis of an MR imaging data set. MATERIALS AND METHODS: We performed tensor-based morphometry to analyze brain-shape changes associated with traumatic brain injury and to derive imaging features for statistical group comparison. Additionally, machine learning was used to identify structural anomalies associated with brain lesions. Automatically generated brain lesion maps were used to identify brain regions where lesion load may indicate an increased incidence of posttraumatic epilepsy. We used 138 non-posttraumatic epilepsy subjects for training the machine learning method. Validation of lesion delineation was performed on 15 subjects. Group analysis of the relationship between traumatic brain injury and posttraumatic epilepsy was performed on an independent set of 74 subjects (37 subjects with and 37 randomly selected subjects without epilepsy). RESULTS: We observed significant F-statistics related to tensor-based morphometry analysis at voxels close to the pial surface, which may indicate group differences in the locations of edema, hematoma, or hemorrhage. The results of the F-test on lesion data showed significant differences between groups in both the left and right temporal lobes. We also saw significant differences in the right occipital lobe and cerebellum. CONCLUSIONS: Statistical analysis suggests that lesions in the temporal lobes, cerebellum, and the right occipital lobe are associated with an increased posttraumatic epilepsy incidence.

Risk Factors and Prognosis of Early Posttraumatic Seizures in Moderate to Severe Traumatic Brain Injury.

IMPORTANCE: Early posttraumatic seizures (EPS) that may occur following a traumatic brain injury (TBI) are associated with poorer outcomes and development of posttraumatic epilepsy (PTE). OBJECTIVE: To evaluate risk factors for EPS, associated morbidity and mortality, and contribution to PTE. DESIGN, SETTING, AND PARTICIPANTS: Data were collected from an Australian registry-based cohort study of adults (age ≥18 years) with moderate to severe TBI from January 2005 to December 2019, with 2-year follow-up. The statewide trauma registry, conducted on an opt-out basis in Victoria (population 6.5 million), had 15 152 patients with moderate to severe TBI identified via Abbreviated Injury Scale (AIS) head severity score, with an opt-out rate less than 0.5% (opt-out n = 136). MAIN OUTCOMES AND MEASURES: EPS were identified via International Statistical Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes recorded after the acute admission. Outcome measures also included in-hospital metrics, 2-year outcomes including PTE, and post-discharge mortality. Adaptive least absolute shrinkage and selection operator (LASSO) regression was used to build a prediction model for risk factors of EPS. RESULTS: Among the 15 152 participants (10 457 [69%] male; median [IQR] age, 60 [35-79] y), 416 (2.7%) were identified with EPS, including 27 (0.2%) with status epilepticus. Significant risk factors on multivariable analysis for developing EPS were younger age, higher Charlson Comorbidity Index, TBI sustained from a low fall, subdural hemorrhage, subarachnoid hemorrhage, higher Injury Severity Score, and greater head injury severity, measured using the AIS and Glasgow Coma Score. After adjustment for confounders, EPS were associated with increased ICU admission and ICU length of stay, ventilation and duration, hospital length of stay, and discharge to inpatient rehabilitation rather than home, but not in-hospital mortality. Outcomes in TBI admission survivors at 24 months, including mortality (relative risk [RR] = 2.14; 95% CI, 1.32-3.46; P = .002), development of PTE (RR = 2.91; 95% CI, 2.22-3.81; P < .001), and use of antiseizure medications (RR = 2.44; 95% CI, 1.98-3.02; P < .001), were poorer for cases with EPS after adjustment for confounders. The prediction model for EPS had an area under the receiver operating characteristic curve of 0.72 (95% CI, 0.66-0.79), sensitivity of 66%, and specificity of 73% in the validation set. DISCUSSION: We identified important risk factors for EPS following moderate to severe TBI. Early posttraumatic seizures were associated with longer ICU and hospital admissions, ICU ventilation, and poorer 24-month outcomes including mortality and development of PTE.

Disruption of intestinal barrier and endotoxemia after traumatic brain injury: Implications for post-traumatic epilepsy.

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.

Delayed creatine supplementation counteracts reduction of GABAergic function and protects against seizures susceptibility after traumatic brain injury in rats.

Traumatic brain injury (TBI) is a devastating disease frequently followed by behavioral disabilities including post-traumatic epilepsy (PTE). Although reasonable progress in understanding its pathophysiology has been made, treatment of PTE is still limited. Several studies have shown the neuroprotective effect of creatine in different models of brain pathology, but its effects on PTE is not elucidated. Thus, we decided to investigate the impact of delayed and chronic creatine supplementation on susceptibility to epileptic seizures evoked by pentylenetetrazol (PTZ) after TBI. Our experimental data revealed that 4 weeks of creatine supplementation (300 mg/kg, p.o.) initiated 1 week after fluid percussion injury (FPI) notably increased the latency to first myoclonic and tonic-clonic seizures, decreased the time spent in tonic-clonic seizure, seizure intensity, epileptiform discharges and spindle oscillations induced by a sub-convulsant dose of PTZ (35 mg/kg, i.p.). Interestingly, this protective effect persists for 1 week even when creatine supplementation is discontinued. The anticonvulsant effect of creatine was associated with its ability to reduce cell loss including the number of parvalbumin positive (PARV+) cells in CA3 region of the hippocampus. Furthermore, creatine supplementation also protected against the reduction of GAD67 levels, GAD activity and specific [3H]flunitrazepam binding in the hippocampus. These findings showed that chronic creatine supplementation may play a neuroprotective role on brain excitability by controlling the GABAergic function after TBI, providing a possible new strategy for the treatment of PTE.

Affective, neurocognitive and psychosocial disorders associated with traumatic brain injury and post-traumatic epilepsy.

Survivors of traumatic brain injury (TBI) often develop chronic neurological, neurocognitive, psychological, and psychosocial deficits that can have a profound impact on an individual's wellbeing and quality of life. TBI is also a common cause of acquired epilepsy, which is itself associated with significant behavioral morbidity. This review considers the clinical and preclinical evidence that post-traumatic epilepsy (PTE) acts as a 'second-hit' insult to worsen chronic behavioral outcomes for brain-injured patients, across the domains of emotional, cognitive, and psychosocial functioning. Surprisingly, few well-designed studies have specifically examined the relationship between seizures and behavioral outcomes after TBI. The complex mechanisms underlying these comorbidities remain incompletely understood, although many of the biological processes that precipitate seizure occurrence and epileptogenesis may also contribute to the development of chronic behavioral deficits. Further, the relationship between PTE and behavioral dysfunction is increasingly recognized to be a bidirectional one, whereby premorbid conditions are a risk factor for PTE. Clinical studies in this arena are often challenged by the confounding effects of anti-seizure medications, while preclinical studies have rarely examined an adequately extended time course to fully capture the time course of epilepsy development after a TBI. To drive the field forward towards improved treatment strategies, it is imperative that both seizures and neurobehavioral outcomes are assessed in parallel after TBI, both in patient populations and preclinical models.

Targeting neurodegeneration to prevent post-traumatic epilepsy.

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.

Antiepileptics for Post-Traumatic Seizure Prophylaxis after Traumatic Brain Injury.

Traumatic brain injury (TBI) is an important public health concern plagued by high rates of mortality and significant long-term disability in many survivors. Post-traumatic seizures (PTS) are not uncommon following TBI, both in the early (within 7 days post-injury) and late (after 7 days post-injury) period. Due to the potential of PTS to exacerbate secondary injury following TBI and the possibility of developing post-traumatic epilepsy (PTE), the medical community has explored preventative treatment strategies. Prophylactic antiepileptic drug (AED) administration has been proposed as a measure to reduce the incidence of PTS and the ultimate development of PTE in TBI patients. In this topical review, we discuss the pathophysiologic mechanisms of early and late PTS and the development of PTE following TBI, the pharmacodynamic and pharmacokinetic properties of AEDs commonly used to prevent post-traumatic seizures, and summarize the available clinical evidence for employing AEDs for seizure prophylaxis after TBI.

Post-traumatic epilepsy associations with mental health outcomes in the first two years after moderate to severe TBI: A TBI Model Systems analysis.

PURPOSE: Research suggests that there are reciprocal relationships between mental health (MH) disorders and epilepsy risk. However, MH relationships to post-traumatic epilepsy (PTE) have not been explored. Thus, the objective of this study was to assess associations between PTE and frequency of depression and/or anxiety in a cohort of individuals with moderate-to-severe TBI who received acute inpatient rehabilitation. METHODS: Multivariate regression models were developed using a recent (2010-2012) cohort (n=867 unique participants) from the TBI Model Systems (TBIMS) National Database, a time frame during which self-reported seizures, depression [Patient Health Questionnaire (PHQ)-9], and anxiety [Generalized Anxiety Disorder (GAD-7)] follow-up measures were concurrently collected at year-1 and year-2 after injury. RESULTS: PTE did not significantly contribute to depression status in either the year-1 or year-2 cohort, nor did it contribute significantly to anxiety status in the year-1 cohort, after controlling for other known depression and anxiety predictors. However, those with PTE in year-2 had 3.34 times the odds (p=.002) of having clinically significant anxiety, even after accounting for other relevant predictors. In this model, participants who self-identified as Black were also more likely to report clinical symptoms of anxiety than those who identified as White. PTE was the only significant predictor of comorbid depression and anxiety at year-2 (Odds Ratio 2.71; p=0.049). CONCLUSIONS: Our data suggest that PTE is associated with MH outcomes 2years after TBI, findings whose significance may reflect reciprocal, biological, psychological, and/or experiential factors contributing to and resulting from both PTE and MH status post-TBI. Future work should consider temporal and reciprocal relationships between PTE and MH as well as if/how treatment of each condition influences biosusceptibility to the other condition.

The Epidemiology of Posttraumatic Epilepsy.

Traumatic brain injury is an important contributor to morbidity and mortality, and results in reduced quality of life and lifespan: An estimated 1.7 million traumatic brain injuries occur annually in the United States alone. Traumatic brain injury carries an increased risk of epilepsy that correlates with the severity of the brain injury. Posttraumatic epilepsy accounts for less than 10% of epilepsy, but traumatic brain injury is one of only a few potentially preventable causes of epilepsy. Despite several well-controlled human studies, there is no current preventive treatment available for humans. Therefore, primary prevention is the only proven way to prevent posttraumatic epilepsy.

All that shakes is not epilepsy.

Experience from the clinic suggests that many people equate the term 'epilepsy' with the occurrence of convulsions, with the corollary that attacks involving shaking are likely to be due to epilepsy. However, just as many seizure types do not involve shaking, the differential diagnosis of intermittent shaking is wide and includes vasovagal syncope, cardiac disorders, concussive convulsions, psychogenic non-epileptic seizures, 'shaking transient ischaemic attacks', parasomnias, breath-holding attacks in children, hypoglycaemia and movement disorders.