Post-traumatic Epilepsy Research Articles

Posttraumatic epilepsy: clinical, diagnostic and therapeutic features

According to 2019 statistics records, traumatic brain injuries (TBI) are the most common type of injuries and one of the main causes for disability in Russia. Every year 200 people per 10,000 subjects around the world suffer from serious brain injuries. Severe TBI can result in long-term disability. Posttraumatic epilepsy (PTE) is one of the most dramatic consequences of TBI with an estimated incidence rate ranging from 2% to 50% based on severity of injury. Conducting studies on PTE poses numerous challenges because epilepsy never develops in many patients with TBI or it may occur more than 10 years after TBI.In this review, which includes data from studies conducted by Russian researchers, including us, and foreign colleagues over the last few years (mainly 2017–2022), we analyzed and generalized currently known risk factors, clinical and diagnostic features of PTE in order to increase the awareness about modern methods of laboratory and instrumental diagnostics related to this disease (including electroencephalography and routine/special neuroimaging techniques that allow to identify PTE biomarkers). We also aimed to promote development of preventive strategies for patient management. It has been proved that no clear algorithms for PTE diagnostics and treatment are currently available, which often leads to insufficient patient care.

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

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

Military Injuries-Understanding Posttraumatic Epilepsy, Health, and Quality-of-Life Effects of Caregiving: Protocol for a Longitudinal Mixed Methods Observational Study.

BackgroundVeterans with posttraumatic epilepsy (PTE), particularly those with comorbidities associated with epilepsy or traumatic brain injury (TBI), have poorer health status and higher symptom burden than their peers without PTE. One area that has been particularly poorly studied is that of the role of caregivers in the health of veterans with PTE and the impact caring for someone with PTE has on the caregivers themselves.ObjectiveIn this study, we aim to address the following: describe and compare the health and quality of life of veterans and caregivers of veterans with and without PTE; evaluate the change in available supports and unmet needs for services among caregivers of post-9/11 veterans with PTE over a 2-year period and to compare support and unmet needs with those without PTE; and identify veteran and caregiver characteristics associated with the 2-year health trajectories of caregivers and veterans with PTE compared with veterans without PTE.MethodsWe conducted a prospective cohort study of the health and quality of life among 4 groups of veterans and their caregivers: veterans with PTE, nontraumatic epilepsy, TBI only, and neither epilepsy nor TBI. We will recruit participants from previous related studies and collect information about both the veterans and their primary informal caregivers on health, quality of life, unmet needs for care, PTE and TBI symptoms and treatment, relationship, and caregiver experience. Data sources will include existing data supplemented with primary data, such as survey data collected at baseline, intermittent brief reporting using ecological momentary assessment, and qualitative interviews. We will make both cross-sectional and longitudinal comparisons, using veteran-caregiver dyads, along with qualitative findings to better understand risk and promotive factors for quality of life and health among veterans and caregivers, as well as the bidirectional impact of caregivers and care recipients on one another.ResultsThis study was approved by the institutional review boards of the University of Utah and Salt Lake City Veterans Affairs and is under review by the Human Research Protection Office of the United States Army Medical Research and Development Command. The Service Member, Veteran, and Caregiver Community Stakeholders Group has been formed and the study questionnaire will be finalized once the panel reviews it. We anticipate the start of recruitment and primary data collection by January 2022.ConclusionsNew national initiatives aim to incorporate the caregiver into the veteran’s treatment plan; however, we know little about the impact of caregiving—both positive and negative—on the caregivers themselves and on the veterans for whom they provide care. We will identify specific needs in this understudied population, which will inform clinicians, patients, families, and policy makers about the specific impact and needs to equip caregivers in caring for veterans at home.International Registered Report Identifier (IRRID)PRR1-10.2196/30975

Examining the role of astrogliosis and JNK signaling in post-traumatic epilepsy

ObjectivePost-traumatic epilepsy is a devastating complication of traumatic brain injury that has no targeted pharmacological therapy. Previous literature has explored the role of the c-Jun N-terminal kinase (JNK) pathway in epilepsy and the creation of epileptogenic foci by reactive astrogliosis; however, the relationship between reactive astrogliosis and the c-Jun N-terminal kinase signaling pathway in the development of post-traumatic epilepsy has not been thoroughly examined.MethodsFour experimental groups, consisting of c57/b16 male mice, were examined: (1) control, (2) traumatic brain injury of graded severity (mild, moderate, severe), (3) sub-convulsive kainic acid alone without traumatic brain injury (15 mg/kg i.p.), and (4) sub-convulsive kainic acid administered 72 h after moderate traumatic brain injury. Modified Racine scale from 1 to 72 h and total beam breaks at 72 h were used to assess seizure activity. Immunohistochemistry and western blot were utilized to examine astrogliosis (GFAP), microglia activation (IBA-1), and phosphorylated JNK in prefrontal cortex samples collected from the contracoup side at 72 h post-injury.ResultsAstrogliosis, measured by GFAP, was increased after traumatic brain injury and increased commensurately based on the degree of injury. Mice with traumatic brain injury demonstrated a four-fold increase in phosphorylated JNK: p < 0.001. Sub-convulsive kainic acid administration did not increase seizure activity nor phosphorylation of JNK in mice without traumatic brain injury; however, sub-convulsive kainic acid administration in mice with moderate traumatic brain injury did increase phosphorylated JNK. Seizure activity was worse in mice, with traumatic brain injury, administered kainic acid than mice administered kainic acid.ConclusionsReactive astrocytes may have dysfunctional glutamate regulation causing an increase in phosphorylated JNK after kainic acid administration. Future studies exploring the effects of JNK inhibition on post-traumatic epilepsy are recommended.

Vagus nerve stimulation outcome prediction: from simple parameters to advanced models.

Since its approval as an adjunct treatment for refractory partial epilepsy, the positive effects of vagus nerve stimulation (VNS) on seizure frequency and severity have been supported by many studies. Seizure reduction of more than 50 % can be expected in at least 50 % of patients. However, a complete post-VNS seizure freedom is rarely achieved and 25 % of patients do not benefit from VNS. Our study provides an overview of the potential predictors of VNS response, from the most simple and basic data to sophisticated EEG processing studies and functional imaging studying brain connectivity. The data support better outcomes in younger patients with early VNS implantation, in patients with posttraumatic epilepsy or tuberous sclerosis, and in patients without bilateral interictal epileptiform discharges. The variability of heart activity has also been studied with some promising results. Because the generally accepted hypothesis of the VNS mechanism is the modulation of synaptic activity in multiple cortical and subcortical regions of the brain, the studies of brain response to external stimulation and/or of brain connectivity were used for models predicting the effect of VNS in individual patients. Although the predictive value of these models is high, the required special equipment and sophisticated mathematical tools limit their routine use (Ref. 58). Keywords: epilepsy, vagus nerve stimulation, response predictor, EEG.

Diagnostic and prognostic significance of the level of IgM antibodies to myelin basic protein in children with traumatic brain injury

To study the content of antibodies to the basic protein of myelin IgM in the blood of children with traumatic brain injury for a comprehensive assessment of the severity and prediction of outcomes of TBI. 81 children with traumatic brain injury (TBI) of varying severity and 29 children of the comparison group aged 2 months to 18 years were examined, in whom the content of IgM antibodies in blood plasma was determined. In groups of children with different severity of TBI, the average content of IgM antibodies in the blood is higher than in children of the comparison group, and the values of IgM antibodies correlate with the severity of TBI. In children with moderate TBI, the average level of IgM antibodies in the blood is significantly higher than in children with mild TBI, and in children with severe TBI, the average level of IgM antibodies in the blood is significantly higher than in children with moderate TBI. A repeated study found a significant decrease in the average content of IgM antibodies in severe TBI in children without post-traumatic epilepsy compared to their average content in children with post-traumatic epilepsy. Normalization (elimination) of IgM antibodies in children in the late period of TBI is associated with a prognostically favorable course of the autoimmune process in the brain; its absence indicates a prolonged autoimmune process. After TBI, it is recommended to include in the examination of children an immunological study of the content of antibodies to the basic protein of myelin IgM in the blood, the indicators of which, in combination with other data, make it possible to predict the outcomes of TBI.

Association of Posttraumatic Epilepsy With 1-Year Outcomes After Traumatic Brain Injury

Posttraumatic epilepsy (PTE) is a recognized sequela of traumatic brain injury (TBI), but the long-term outcomes associated with PTE independent of injury severity are not precisely known. To determine the incidence, risk factors, and association with functional outcomes and self-reported somatic, cognitive, and psychological concerns of self-reported PTE in a large, prospectively collected TBI cohort. This multicenter, prospective cohort study was conducted as part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study and identified patients presenting with TBI to 1 of 18 participating level 1 US trauma centers from February 2014 to July 2018. Patients with TBI, extracranial orthopedic injuries (orthopedic controls), and individuals without reported injuries (eg, friends and family of participants; hereafter friend controls) were prospectively followed for 12 months. Data were analyzed from January 2020 to April 2021. Demographic, imaging, and clinical information was collected according to TBI Common Data Elements. Incidence of self-reported PTE was assessed using the National Institute of Neurological Disorders and Stroke Epilepsy Screening Questionnaire (NINDS-ESQ). Primary outcomes included Glasgow Outcome Scale Extended, Rivermead Cognitive Metric (RCM; derived from the Rivermead Post Concussion Symptoms Questionnaire), and the Brief Symptom Inventory-18 (BSI). Of 3296 participants identified as part of the study, 3044 met inclusion criteria, and 1885 participants (mean [SD] age, 41.3 [17.1] years; 1241 [65.8%] men and 644 [34.2%] women) had follow-up information at 12 months, including 1493 patients with TBI; 182 orthopedic controls, 210 uninjured friend controls; 41 patients with TBI (2.8%) and no controls had positive screening results for PTE. Compared with a negative screening result for PTE, having a positive screening result for PTE was associated with presenting Glasgow Coma Scale score (8.1 [4.8] vs.13.5 [3.3]; P < .001) as well as with anomalous acute head imaging findings (risk ratio, 6.42 [95% CI, 2.71-15.22]). After controlling for age, initial Glasgow Coma Scale score, and imaging findings, compared with patients with TBI and without PTE, patients with TBI and with positive PTE screening results had significantly lower Glasgow Outcome Scale Extended scores (mean [SD], 6.1 [1.7] vs 4.7 [1.5]; P < .001), higher BSI scores (mean [SD], 50.2 [10.7] vs 58.6 [10.8]; P = .02), and higher RCM scores (mean [SD], 3.1 [2.6] vs 5.3 [1.9]; P = .002) at 12 months. In this cohort study, the incidence of self-reported PTE after TBI was found to be 2.8% and was independently associated with unfavorable outcomes. These findings highlight the need for effective antiepileptogenic therapies after TBI.

Ferrostatin-1 obviates seizures and associated cognitive deficits in ferric chloride-induced posttraumatic epilepsy via suppressing ferroptosis

Posttraumatic epilepsy (PTE) is a prevalent complication of brain trauma. Current anti-epileptic drugs available do not have satisfactory response to PTE. It is of desperate need to explore novel therapeutic approaches for curing PTE. Our prior work revealed that ferroptosis, a recently discovered mode of cell death, occurs in rodent model of PTE. In the present study, we aimed to further investigate the effect of ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, on seizure behavior and cognitive deficit in a mouse model of PTE. The preparation of PTE was performed by stereotaxical injection in the somatosensory cortex region of 50 mM FeCl3. Seizure activity was assessed via Racine scoring and electroencephalogram analysis. PTE-related cognitive function was evaluated by novel object recognition and Morris water maze tests. Ferroptosis-related indices including glutathione peroxidase (GPx) activity and protein expressions of 4-hydroxynonenal (4-HNE) were detected using a commercial kit and immunofluorescence, respectively. It was found that treatment with Fer-1 significantly exerted protective effects against acute seizure and memory decline, although no evident effect on epileptic progression. Fer-1 also exhibited good tolerability and safety as we observed that it hardly influenced the body weight. Furthermore, it was noted that administration of Fer-1 suppressed ferroptosis-related indices including GPx activity and protein expressions of 4-HNE in hippocampus. These data altogether indicate that Fer-1 has potent therapeutic effects against seizures and cognitive impairment following PTE-induced brain insult. Fer-1 may act as a promising drug for curing PTE patients.

Norwegian population-based study of long-term effects, safety, and predictors of response of vagus nerve stimulation treatment in drug-resistant epilepsy: The NORPulse study.

This study was undertaken to evaluate the efficacy of vagus nerve stimulation (VNS) over time, and to determine which patient groups derive the most benefit. Long-term outcomes are reported in 436 epilepsy patients from a VNS quality registry (52.8% adults, 47.2% children), with a median follow-up of 75months. Patients were stratified according to evolution of response into constant responders, fluctuating responders, and nonresponders. The effect was evaluated at 6, 12, 24, 36, and 60months. Multivariate regression analysis was used to identify predictors of response. The cumulative probability of ≥50% seizure reduction was 60%; however, 15% of patients showed a fluctuating course. Of those becoming responders, 89.5% (230/257) did so within 2years. A steady increase in effect was observed among constant responders, with 48.7% (19/39) of those becoming seizure-free and 29.3% (39/133) with ≥75% seizure reduction achieving these effects within 2-5years. Some effect (25%-<50%) at 6months was a positive predictor of becoming a responder (odds ratio [OR] = 10.18, p<.0001) and having ≥75% reduction at 2years (OR = 3.34, p=.03). Patients without intellectual disability had ORs of 3.34 and 3.11 of having ≥75% reduction at 2 and 5years, respectively, and an OR of 6.22 of being seizure-free at last observation. Patients with unchanged antiseizure medication over the observation period showed better responder rates at 2 (63.0% vs. 43.1%, p=.002) and 5years (63.4% vs. 46.3%, p=.031) than patients whose antiseizure medication was modified. Responder rates were higher for posttraumatic (70.6%, p=.048) and poststroke epilepsies (75.0%, p=.05) than other etiologies (46.5%). Our data indicate that the effect of VNS increases over time and that there are important clinical decision points at 6 and 24months for evaluating and adjusting the treatment. There should be better selection of candidates, as certain patient groups and epilepsy etiologies respond more favorably.

Role of the &lt;i&gt;GRIN1&lt;/i&gt; gene polymorphism in the formation of post-traumatic epilepsy

Introduction: NMDA receptors are involved in the pathogenesis of seizures, as it subunit is coded for by the GRIN1 gene. Different GRIN1 mutations are known in patients with different forms of epilepsy and encephalopathy. However, no data are available on the participation of the GRIN1 gene and its polymorphisms in the development of post-traumatic epilepsy (PTE). Aim: To determine the influence of single-nucleotide rs1126442 polymorphism of GRIN1 on the risk of PTE formation. Materials and methods: A total of 140 patients were examined, which included 69 patients with PTE and 71 patients with genetic epilepsy. All patients underwent a comprehensive examination, with evaluation of history, neurological status, electroencephalography (EEG) and neuroimaging results, and genotyping of blood samples by real-time polymerase chain reaction. The control sample for genetic examination was venous blood from 60 healthy individuals. Results: Focal seizures with transition to bilateral and tonicclonic seizures were predominant in the PTE group. Neuroimaging revealed dystrophic, cystic, and cystogliotic alterations and signs of external hydrocephaly. EEG recorded interictal and ictal epileptiform activity and slowing of theta waves. Genotyping by rs1126442 polymorphism of GRIN1 revealed predominance of heterozygous G/A and homozygous A/A genotypes in patients with PTE in the codominant (odds ratio (OD)=3.43; 95% confidence index (CI) 1.567.55; p=0.0047), dominant (OR=3.24; 95% CI 1.576.68; p=0.0011), and superdominant (OR=2.90; 95% CI 1.366.22; p=0.0048) inheritance models. The carriage of heterozygous G/A rs1126442 genotype of GRIN1 was associated with an epileptiform activity in the EEG of all patients with epilepsy (OR=2.40; 95% CI 1.115.20; p=0.024). Conclusion: The carriage of heterozygous G/A genotype and homozygous A/A rs 1126442 genotype of GRIN1 in the dominant and codominant inheritance models is associated with a high risk of development of epilepsy after craniocerebral trauma. The carriage of heterozygous G/A rs 1126442 genotype of GRIN1 is associated with an epileptiform activity in EEG.

Gibbs Free Energy, a Thermodynamic Measure of Protein–Protein Interactions, Correlates with Neurologic Disability

Modern network science has been used to reveal new and often fundamental aspects of brain network organization in physiological as well as pathological conditions. As a consequence, these discoveries, which relate to network hierarchy, hubs and network interactions, have begun to change the paradigms of neurodegenerative disorders. In this paper, we explore the use of thermodynamics for protein–protein network interactions in Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), traumatic brain injury and epilepsy. To assess the validity of using network interactions in neurological diseases, we investigated the relationship between network thermodynamics and molecular systems biology for these neurological disorders. In order to uncover whether there was a correlation between network organization and biological outcomes, we used publicly available RNA transcription data from individual patients with these neurological conditions, and correlated these molecular profiles with their respective individual disability scores. We found a linear correlation (Pearson correlation of −0.828) between disease disability (a clinically validated measurement of a person’s functional status) and Gibbs free energy (a thermodynamic measure of protein–protein interactions). In other words, we found an inverse relationship between disease disability and thermodynamic energy. Because a larger degree of disability correlated with a larger negative drop in Gibbs free energy in a linear disability-dependent fashion, it could be presumed that the progression of neuropathology such as is seen in Alzheimer’s disease could potentially be prevented by therapeutically correcting the changes in Gibbs free energy.

Contusion brain damage in mice for modelling of post-traumatic epilepsy with contralateral hippocampus sclerosis: Comprehensive and longitudinal characterization of spontaneous seizures, neuropathology, and neuropsychiatric comorbidities

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 statementTBI 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.

Epilepsy Due to Mild TBI in Children: An Experience at a Tertiary Referral Center.

Rationale: Posttraumatic epilepsy (PTE) is a common cause of morbidity in children after a traumatic brain injury (TBI), occurring in 10–20% of children following severe TBI. PTE is diagnosed after two or more unprovoked seizures occurring 1-week post TBI. More often, studies have focused on children with epilepsy due to severe TBI. We aim to understand the utility of head computed tomography (HCT), EEG, and the risk of developing drug-resistant epilepsy in children after mild TBI. Method: We retrospectively studied 321 children with TBI at a tertiary pediatric referral center during a 10-year period. Mild TBI was defined as loss of consciousness (LOC) or amnesia < 30 min, moderate TBI as LOC or amnesia between 30 min and 1 day, and severe TBI as LOC or amnesia > 1 day, subdural hemorrhage, or contusion. Multiple clinical variables were reviewed, including past and present antiepileptic drug(s), seizure control, and mode of injury. First and subsequent post-TBI EEGs/prolonged video-EEGs were obtained acutely, subacutely, and/or chronically (range, day 1–3 years, median 1 month). Descriptive analyses were conducted using medians and ranges for continuous data. Categorical data were reported using frequencies and percentages, while comparisons between groups were made using Fisher’s exact test for small sample sizes. Results: Forty-seven children were diagnosed with posttraumatic epilepsy: eight children (17%) due to mild TBI, 39 children (83%) due to severe TBI. For the eight children with mild TBI whom all had an accidental trauma (non-inflicted), the median follow-up time was 25 months (range 1.5 months–84 months). The median age was 10 years (range 4–18 years), and the median age at the time of injury was seven years (range: 23 months–13 years). No relevant previous medical history was present for six patients (80%), and two patients’ (20%) relevant previous medical histories were unknown. Seven patients (88%) had no history of seizures, and patient #6 (12%) had unknown seizure history. Six patients (75%) had normal routine EEG(s). Patient #6 (13%) had an abnormal VEEG 3 months after the initial normal routine EEG, while patient #1 (13%) had an initial prolonged EEG 8 months after TBI. Compared to the 39 patients with severe TBI, 31 (79%) of whom had abnormal EEGs (routine and/or prolonged with video), mild TBI patients were more likely to have normal EEGs, p = 0.005. Head CT scans were obtained acutely for seven patients (90%), all of which were normal. One patient only had brain magnetic resonance imaging (MRI) 8 months after the injury. Compared to the 39 patients with severe TBI, all of whom had abnormal HCTs, mild TBI patients were less likely to have abnormal HCTs, p < 0.0001. In patients with mild TBI, no patient had both abnormal EEG/VEEG and HCT, and no one was on more than one Antiepileptic drug (AED), p < 0.005. Six patients (75%) had MRIs, of which five (63%) were normal. Two patients (#1, 7) did not have MRIs, while one patient’s (#4) MRI was unavailable. Five patients (63%) had a seizure <24 h post TBI, while the rest had seizures after the first week of injury. Conclusion: Children with epilepsy due to mild TBI, loss of consciousness, or amnesia < 30 min are more likely to have normal HCT and EEG and to be on 0–1 AED. Limitations of our study include the small sample size and retrospective design. The current findings add to the paucity of data in children who suffer from epilepsy due to mild TBI.

Alpha/Beta-Hydrolase Domain-Containing 6: Signaling and Function in the Central Nervous System.

Endocannabinoid (eCB) signaling plays an important role in the central nervous system (CNS). α/β-Hydrolase domain-containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes monoacylglycerol (MAG) lipids such as endocannabinoid 2-arachidonoyl glycerol (2-AG). ABHD6 participates in neurotransmission, inflammation, brain energy metabolism, tumorigenesis and other biological processes and is a potential therapeutic target for various neurological diseases, such as traumatic brain injury (TBI), multiple sclerosis (MS), epilepsy, mental illness, and pain. This review summarizes the molecular mechanisms of action and biological functions of ABHD6, particularly its mechanism of action in the pathogenesis of neurological diseases, and provides a theoretical basis for new pharmacological interventions via targeting of ABHD6.

Pediatric traumatic brain injury and a subsequent transient immune challenge independently influenced chronic outcomes in male mice

Traumatic brain injury (TBI) is a major contributor to death and disability worldwide. Children are at particularly high risk of both sustaining a TBI and experiencing serious long-term consequences, such as cognitive deficits, mental health problems and post-traumatic epilepsy. Severe TBI patients are highly susceptible to nosocomial infections, which are mostly acquired within the first week of hospitalization post-TBI. Yet the potential chronic impact of such acute infections following pediatric TBI remains unclear. In this study, we hypothesized that a peripheral immune challenge, such as lipopolysaccharide (LPS)—mimicking a hospital-acquired infection—would worsen inflammatory, neurobehavioral, and seizure outcomes after experimental pediatric TBI. To test this, three-week old male C57Bl/6J mice received a moderate controlled cortical impact or sham surgery, followed by 1 mg/kg i.p. LPS (or 0.9% saline vehicle) at 4 days TBI. Mice were randomized to four groups; sham-saline, sham-LPS, TBI-saline or TBI-LPS (n = 15/group). Reduced general activity and increased anxiety-like behavior were observed within 24 h in LPS-treated mice, indicating a transient sickness response. LPS-treated mice also exhibited a reduction in body weights, which persisted chronically. From 2 months post-injury, mice underwent a battery of tests for sensorimotor, cognitive, and psychosocial behaviors. TBI resulted in hyperactivity and spatial memory deficits, independent of LPS; whereas LPS resulted in subtle deficits in spatial memory retention. At 5 months post-injury, video-electroencephalographic recordings were obtained to evaluate both spontaneous seizure activity as well as the evoked seizure response to pentylenetetrazol (PTZ). TBI increased susceptibility to PTZ-evoked seizures; whereas LPS appeared to increase the incidence of spontaneous seizures. Post-mortem analyses found that TBI, but not LPS, resulted in robust glial reactivity and loss of cortical volume. A TBI × LPS interaction in hippocampal volume suggested that TBI-LPS mice had a subtle increase in ipsilateral hippocampus tissue loss; however, this was not reflected in neuronal cell counts. Both TBI and LPS independently had modest effects on chronic hippocampal gene expression. Together, contrary to our hypothesis, we observed minimal synergy between TBI and LPS. Instead, pediatric TBI and a subsequent transient immune challenge independently influenced chronic outcomes. These findings have implications for future preclinical modeling as well as acute post-injury patient management.

In Reply: Recommendation to Create New Neuropathological Guidelines for the Postmortem Diagnosis of Chronic Traumatic Encephalopathy

In Reply: Recommendation to Create New Neuropathological Guidelines for the Postmortem Diagnosis of Chronic Traumatic Encephalopathy

Surgical treatment of traumatic epilepsy

Our report is based on a clinical analysis of 28 patients operated on in the neurosurgical department in 1946-1958.

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

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

Automatic Detection of EEG Epileptiform Abnormalities in Traumatic Brain Injury using Deep Learning.

Traumatic brain injury (TBI) is a sudden injury that causes damage to the brain. TBI can have wide-ranging physical, psychological, and cognitive effects. TBI outcomes include acute injuries, such as contusion or hematoma, as well as chronic sequelae that emerge days to years later, including cognitive decline and seizures. Some TBI patients develop posttraumatic epilepsy (PTE), or recurrent and unprovoked seizures following TBI. In recent years, significant efforts have been made to identify biomarkers of epileptogenesis, the process by which a normal brain becomes capable of generating seizures. These biomarkers would allow for a higher standard of care by identifying patients at risk of developing PTE as candidates for antiepileptogenic interventions. In this paper, we use deep neural network architectures to automatically detect potential biomarkers of PTE from electroencephalogram (EEG) data collected between post-injury day 1-7 from patients with moderate-to-severe TBI. Continuous EEG is often part of multimodal monitoring for TBI patients in intensive care units. Clinicians review EEG to identify the presence of epileptiform abnormalities (EAs), such as seizures, periodic discharges, and abnormal rhythmic delta activity, which are potential biomarkers of epileptogenesis. We show that a recurrent neural network trained with continuous EEG data can be used to identify EAs with the highest accuracy of 80.78%, paving the way for robust, automated detection of epileptiform activity in TBI patients.

Incidence of post-traumatic epilepsy following paediatric traumatic brain injury: protocol for systematic review and meta-analysis

IntroductionPost-traumatic epilepsy (PTE) is a recognised complication of traumatic brain injury (TBI), and is associated with higher rates of mortality and morbidity when compared with patients with TBI who do...