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.

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

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

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

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

Biperiden for prevention of post-traumatic epilepsy: A protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial).

BACKGROUND: Traumatic brain injury (TBI) is one of the most important causes of acquired structural epilepsy, post-traumatic epilepsy (PTE), however, efficient preventative measures and treatment are still not available to patients. Preclinical studies indicated biperiden, an anticholinergic drug, as a potential drug to modify the epileptogenic process. The main objective of this clinical trial is to evaluate the efficacy of biperiden as an antiepileptogenic agent in patients that suffered TBI. METHODS: This prospective multicenter (n = 10) interventional study will include 312 adult patients admitted to emergency care units with a diagnosis of moderate or severe TBI. Following inclusion and exclusion criteria, patients will be randomized, using block randomization, to receive double-blind treatment with placebo or biperiden for 10 days. Follow-up will occur at specific time windows up to 2 years. Main outcomes are incidence of PTE after TBI and occurrence of severe adverse events. Other outcomes include exploratory investigation of factors that might have benefits for the treatment or might influence its results, such as genetic background, clinical progression, electroencephalographic abnormalities, health-related quality of life and neuropsychological status. Analyses will be conducted following the safety, intention-to-treat and efficacy concepts. DISCUSSION: We hypothesize that biperiden treatment will be effective to prevent or mitigate the development of post-traumatic epilepsy in TBI patients. Other health measures from this population also may benefit from treatment with biperiden. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04945213. Registered on June 30, 2021.

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

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

Occurrence of early epilepsy in children with traumatic brain injury: a retrospective study.

BACKGROUND: Early post-traumatic seizures (EPTS) refer to epileptic seizures occurring within one week after brain injury. This study aimed to define the risk factors of EPTS and the protective factors that could prevent its occurrence. METHODS: This is a single-center retrospective study in the PICU, Beijing Children's Hospital. Patients diagnosed with traumatic brain injury (TBI), admitted with and without EPTS between January 2016 and December 2020 were included in the study. RESULTS: We included 108 patients diagnosed with TBI. The overall EPTS incidence was 33.98% (35/108). The correlation between EPTS and depressed fractures is positive (P = 0.023). Positive correlations between EPTS and intracranial hemorrhage and subarachnoid hemorrhage had been established (P = 0.011and P = 0.004, respectively). The detection rates of EPTS in the electroencephalogram (EEG) monitoring was 80.00%. There was a significant difference in the EEG monitoring rate between the two groups (P = 0.041). Forty-one (37.86%, 41/108) post-neurosurgical patients were treated with prophylactic antiepileptic drugs (AEDs), and eight (19.51%, 8/41) still had seizures. No statistical significance was noted between the two groups in terms of prophylactic AEDs use (P = 0.519). Logistic regression analysis revealed that open craniocerebral injury and fever on admission were risk factors for EPTS, whereas, surgical intervention and use of hypertonic saline were associated with not developing EPTS. CONCLUSIONS: Breakthrough EPTS occurred after severe TBI in 33.98% of pediatric cases in our cohort. This is a higher seizure incidence than that reported previously. Patients with fever on admission and open craniocerebral injuries are more likely to develop EPTS.

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

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

Modeling of post-traumatic epilepsy and experimental research aimed at its prevention

Research on the prevention of post-traumatic epilepsy (PTE) has seen remarkable advances regarding its physiopathology in recent years. From the search for biomarkers that might be used to indicate individual susceptibility to the development of new animal models and the investigation of new drugs, a great deal of knowledge has been amassed. Various groups have concentrated efforts in generating new animal models of traumatic brain injury (TBI) in an attempt to provide the means to further produce knowledge on the subject. Here we forward the hypothesis that restricting the search of biomarkers and of new drugs to prevent PTE by using only a limited set of TBI models might hamper the understanding of this relevant and yet not preventable medical condition.

Modeling of post-traumatic epilepsy and experimental research aimed at its prevention.

Research on the prevention of post-traumatic epilepsy (PTE) has seen remarkable advances regarding its physiopathology in recent years. From the search for biomarkers that might be used to indicate individual susceptibility to the development of new animal models and the investigation of new drugs, a great deal of knowledge has been amassed. Various groups have concentrated efforts in generating new animal models of traumatic brain injury (TBI) in an attempt to provide the means to further produce knowledge on the subject. Here we forward the hypothesis that restricting the search of biomarkers and of new drugs to prevent PTE by using only a limited set of TBI models might hamper the understanding of this relevant and yet not preventable medical condition.

Preventing epilepsy after traumatic brain injury: A propensity score analysis.

BACKGROUND: Due to the potential consequences of post-traumatic epilepsy (PTE) exacerbating secondary injury following traumatic brain injury (TBI), the use of antiepileptic drugs (AEDs) is an accepted option for seizure prophylaxis. However, there is only a paucity of data that can be found regarding outcomes surrounding the use of AEDs. The purpose of this retrospective study is to evaluate whether the prophylactic administration of AEDs significantly decreased the incidence of PTE, when considering the severity of TBI. METHODS: All trauma patients who had been newly diagnosed with TBI from January 1, 2010 to December 31, 2017 were retrospectively analyzed. Statistical comparisons were made using the chi-square test, Mann-Whitney U test, and Cox regression modeling. After excluding any exposed subjects with no appropriate match, patients who had received AED prophylaxis were matched by propensity score with those who did not receive AEDs. All of the TBI populations were followed up until June 30, 2018. RESULTS: We identified 1316 patients who met the inclusion and exclusion criteria in our matched cohort through their propensity scores, where 138 patients had been receiving prophylactic AEDs and 138 patients had not. Baseline characteristics were similar in gender, age, Glasgow Coma Scale (GCS) scores, and risk factors of PTE including skull fracture, chronic alcoholism, subdural hematoma, epidural hematoma, and intracerebral hematoma. After adjusting for those risk factors, the relative incidence of seizure was not statistically significant in either of the groups (p = 0.566). CONCLUSION: In our cohort analysis, AED prophylaxis was ineffective in preventing seizures, as the rate of seizures was similar whether patients had been receiving the drugs or not. We therefore concluded that the benefits of routine prophylactic anticonvulsant therapy in patients with TBI need to be re-evaluated.

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

Modulating neuroinflammation and oxidative stress to prevent epilepsy and improve outcomes after traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and disability in young adults worldwide. TBI survival is associated with persistent neuropsychiatric and neurological impairments, including posttraumatic epilepsy (PTE). To date, no pharmaceutical treatment has been found to prevent PTE or ameliorate neurological/neuropsychiatric deficits after TBI. Brain trauma results in immediate mechanical damage to brain cells and blood vessels that may never be fully restored given the limited regenerative capacity of brain tissue. This primary insult unleashes cascades of events, prominently including neuroinflammation and massive oxidative stress that evolve over time, expanding the brain injury, but also clearing cellular debris and establishing homeostasis in the region of damage. Accumulating evidence suggests that oxidative stress and neuroinflammatory sequelae of TBI contribute to posttraumatic epileptogenesis. This review will focus on possible roles of reactive oxygen species (ROS), their interactions with neuroinflammation in posttraumatic epileptogenesis, and emerging therapeutic strategies after TBI. We propose that inhibitors of the professional ROS-generating enzymes, the NADPH oxygenases and myeloperoxidase alone, or combined with selective inhibition of cyclooxygenase mediated signaling may have promise for the treatment or prevention of PTE and other sequelae of TBI. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.

The use of antiepileptic medication in early post traumatic seizure prophylaxis at a single institution.

BACKGROUND: Current international guidelines for traumatic brain injury (TBI) recommend the use of phenytoin for the prevention of early post traumatic seizures (PTS) when the benefits are thought to outweigh the risks. In practice however, alternative antiepileptic drugs (AEDs) such as levetiracetam and valproate are being used as they are believed to have a more favourable risk profile. This is despite there being insufficient evidence to support their efficacy. The purpose of this study was to identify which AED was prescribed to patients presenting with a TBI at a single institution, and to determine the rate of early PTSs. METHODS: This was a retrospective case-note review study done at the Flinders Medical Centre including patients admitted from May 2013 to June 2017. All patients with traumatic intracranial haematomas were included. Patients were excluded if they had seizures prior to presentation to hospital or died within 24 h of injury. The primary outcomes were rate of early PTSs and the type of prophylactic AED prescribed. RESULTS: During this study period, 610 patients presented with a mild, moderate or severe traumatic brain injury. Overall, 16% of patients were prescribed an AED, with more than 90% of these patients being prescribed levetiracetam. Overall, the rate of early PTSs for patients prescribed AEDs was 2.9% compared with 3.5% for patients not prescribed AEDs (OR 0.83 CI 0.24-2.85 p = 1). CONCLUSIONS: This study showed that levetiracetam was the most commonly prescribed AED. It also demonstrated no statistically significant difference in the rate of early PTSs in patients with TBI, with or without prophylactic AEDs. This is in keeping with other contemporary studies, and therefore the routine administration of prophylactic AEDs may need to be re-examined.

Efficacy Of Phenytoin In Prevention Of Early Posttraumatic Seizures.

BACKGROUND: The use of anti-epileptic drugs for prophylaxis of early post-traumatic seizures after traumatic brain injury has been very promising. The objective of this study was to determine the outcome of phenytoin in prevention of early post-traumatic seizures in moderate to severe traumatic brain injuries and to compare the frequency of seizures in moderate to severe traumatic brain injury, with phenytoin started within 12 hours and after 12 hours of injury. METHODS: This cross-sectional study was conducted at Department of Neurosurgery, Ayub Medical Institute, Abbottabad from April to October, 2015. All the patients with moderate to severe head injury presenting within 48 hours of injury were included in this study in consecutive manner. Patients were started on phenytoin and observed for early post-traumatic seizures. RESULTS: A total of 163 patients were included in this study with a mean age of 24.69±10.186 years. One hundred and twenty-two (74.8%) were males and rest of 41 (25.2%) were females. A total of 26 (16%) patients had early post-traumatic seizures. 9.89% patients in whom phenytoin was started within 12 hours had seizures, while 23.11% patients in whom phenytoin was started after 12 hours of injury had seizures, the difference being statistically significant (p-value .018).. CONCLUSIONS: Frequency of early post-traumatic seizures is high in patients with moderate to severe head injured patients. Anti-epileptics like phenytoin should be started within 12 hours for seizure prophylaxis.

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.

Applying participatory action research in traumatic brain injury studies to prevent post-traumatic epilepsy.

The increased focus on stakeholder engagement in determining the aims, design, conduct of research and dissemination of results is substantially changing the biomedical research paradigm. In this era of patient-centered care, incorporating participatory action research methodology into large-scale multi-center studies is essential. The adoption of community engagement facilitates meaningful contribution to the design and implementation of clinical studies. Consequently, encouraging citizen participation and involving key organizations may guide the effective development of future clinical research protocols. Here, we discuss our experience in engaging individuals, their caregivers, as well as scientific and consumer organizations in public outreach and knowledge transfer to assist in the development of effective strategies for recruitment and retention in a future post-traumatic epilepsy prevention randomized controlled trial within the National Institute of Neurologic Disorders and Stroke Center Without Walls, Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx). The study includes a Public Engagement Core with a diverse consortium of stakeholder partners. Based on the Core's ongoing experience, it is recommended that multicenter studies integrate a participatory action research based approach to harness the benefits of a collective inquiry. The blueprint created by the EpiBioS4Rx Public Engagement Core is a resource that could be applied in other areas of biomedical research.

The Effectiveness of Antiepileptic Medications as Prophylaxis of Early Seizure in Patients with Traumatic Brain Injury Compared with Placebo or No Treatment: A Systematic Review and Meta-Analysis.

BACKGROUND: The use of antiepileptic drugs (AEDs) to prevent early posttraumatic seizure (PTS) for patients with severe traumatic brain injury (TBI) is currently recommended, although published studies present contradictory results concerning the protective effect of AEDs. OBJECTIVE: The purpose of this study was to quantify the association between the use of prophylactic AEDs, particularly of the 4 main drugs of interest (phenytoin, levetiracetam, valproate, or carbamazepine) versus placebo or no treatment, and risk of early seizures after TBI. METHODS: A comprehensive search was performed on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. The selection criteria were English written randomized controlled trials (RCTs) and observational studies, comparing AEDs with placebo or no treatment, for prevention of early PTS. Random-effects models were used to calculate pooled relative risk (RR). Subgroup analysis and meta-regression were used to assess heterogeneity sources. RESULTS: This research included 3 RCTs (750 patients) and 6 observational studies (3362 patients), analyzing the efficacy of phenytoin, levetiracetam, and valproate. The pooled RR estimate across RCTs trended toward a protective effect (RR, 0.58; 95% confidence interval, 0.20-1.72; I2 = 59.5%); a significant protective association was shown when pooling the results across all 6 observational studies (RR, 0.42; 95% confidence interval, 0.29-0.62; I2 = 0%). When stratifying the observational studies by drug, no significant difference was observed (P interaction = 0.73). Begg and Egger tests indicated no publication bias among observational studies. CONCLUSIONS: Only modest evidence suggested effectiveness of AEDs as prophylaxis of early PTS. Phenytoin was the most studied drug; more prospective studies are needed to assess the efficacy of other AEDs.

Epidemiology of traumatic brain injury-associated epilepsy and early use of anti-epilepsy drugs: An analysis of insurance claims data, 2004-2014.

BACKGROUND: About 2.8 million TBI-related emergency department visits, hospitalizations and deaths occurred in 2013 in the United States. Post-traumatic epilepsy (PTE) can be a disabling, life-long outcome of TBI. OBJECTIVES: The purpose of this study is to address the probability of developing PTE within 9 years after TBI, the risk factors associated with PTE, the prevalence of anti-epileptic drug (AEDs) use, and the effectiveness of using AEDs prophylactically after TBI to prevent the development of PTE. METHODS: Using MarketScan® databases covering commercial, Medicare Supplemental, and multi-state Medicaid enrollees from 2004 to 2014, we examined the incidence of early seizures (within seven days after TBI) and cumulative incidence of PTE, the hazard ratios (HR) of PTE by age, gender, TBI severity, early seizure and AED use (carbamazepine, clonazepam, divalproex sodium, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, acetazolamide). We used backward selection to build the final Cox proportional hazard model and conducted multivariable survival analysis to obtain estimates of crude and adjusted HR (cHRs, aHRs) of PTE and 95% confidence intervals (CI). RESULTS: The incidence of early seizure among TBI patients in our study was 0.5%. The cumulative incidence of PTE increased from 1.0% in one year to 4.0% in nine years. Most patients with TBI (93%) were not prescribed any AED. Gender was not associated with PTE. The risk of PTE was higher for individuals with older age, early seizures, and more severe TBI. Only individuals using prophylactic acetazolamide had significantly lower risk of PTE (aHR = 0.6, CI 0.4-0.9) compared to those not using any AED. CONCLUSION: The probability of developing PTE increased within the study period. The risk of developing PTE significantly increased with age, early seizure and TBI severity. Most of the individuals did not receive AED after TBI. There was no evidence suggesting AEDs helped to prevent PTE with the possible exception of acetazolamide. However, further studies may be needed to test the efficacy of acetazolamide in preventing PTE.

A systematic review of levetiracetam versus phenytoin in the prevention of late post-traumatic seizures and survey of UK neurosurgical prescribing practice of antiepileptic medication in acute traumatic brain injury.

BACKGROUND: Guidelines recommend 1 week of prophylactic phenytoin for post-traumatic seizures (PTS). Levetiracetam is gaining popularity as an alternative with a superior side-effect profile and may be suitable for extended use. We performed a systematic review comparing the efficacy of levetiracetam and phenytoin in reducing the incidence of late PTS. The secondary objectives were to compare their effects on the Extended Glasgow Outcome Scale (GOS-E) and length of stay. We also aimed to survey current prophylaxis prescribing practices. METHODS: A systematic review was performed using Medline, Pubmed, Embase and Cochrane. Trials and observational studies comparing the efficacy of phenytoin and levetiracetam in the prevention of late PTS were included. A survey assessing prescribing practices was e-mailed to all consultant members of the Society of British Neurological Surgeons (n = 249) in March 2013. RESULTS: One randomised controlled trial (RCT) (52 patients) and a cohort study (19 patients) met our criteria. Neither found a significant difference in the incidence of late PTS or length of hospital stay, although the RCT showed an improvement in the GOS-E with levetiracetam. Of the 249 consultants included in the survey, 55 responded (22.1%). Prophylaxis was prescribed by 32 consultants (58%), of whom 21 (65.6%) chose phenytoin, 7 (21.9%) chose levetiracetam, 3 (9.4%) chose valproate and 1 (3%) chose 'other'. Half indicated they would prescribe prophylaxis for 1 week, the remainder opting for extended use. CONCLUSION: While our review found no evidence of a difference in late seizure incidence, there is evidence of improved long-term outcomes with levetiracetam. Neither study used an extended course of levetiracetam or continuous electroencephalography. Further research which accounts for these factors is required for the development of guidelines which take levetiracetam into account. Our survey showed a lack of awareness of the potential harms of extended phenytoin use and a move towards levetiracetam.