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.

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.

Risk Factors and Outcomes of Late Posttraumatic Seizures in Combat-Related Traumatic Brain Injury.

INTRODUCTION: Post-traumatic seizures (PTSs) contribute to morbidity after traumatic brain injury (TBI). Early PTS are rare in combat casualties sustaining TBI, but the prevalence of late PTS is poorly described. We sought to define the prevalence and risk factors of late PTS in combat casualties with computed tomography evidence of TBI. METHODS: From 2010 to 2015, 687 combat casualties were transferred to a military treatment facility and included in the Department of Defense Trauma Registry. 71 patients with radiographic evidence of TBI were analyzed. Data collection included demographics, injury characteristics, interventions, medications, and outcomes. RESULTS: Of the 71 patients with evidence of TBI, 66 patients survived hospitalization and were followed. No patients had early PTS, and most received antiepileptic drugs (AEDs) for prophylaxis. At a median follow-up of 7.4 y, late PTS occurred in 25.8% of patients. Patients with late PTS were more severely injured (median Injury severity score 30 versus 24, P = 0.005) and required more blood products (18 units versus 2, P = 0.045). Patients with late PTS were more likely to have had a penetrating TBI (76.5% versus 38.8%, P = 0.01), multiple types of intracranial hemorrhage (94.1% versus 63.3%, P = 0.02), and cranial decompression (76.5% versus 28.6%, P = 0.001). Six-month Glasgow outcome scores were worse (3.5 versus 4.1 P = 0.001) in the late PTS population. No significant relationship was observed between administration of AEDs for early PTS prophylaxis and late PTS. CONCLUSIONS: Combat casualties with TBI suffering late PTS are more severely injured and require more blood products. Penetrating TBI, intracranial hemorrhage, and need for cranial decompression are correlated with late PTS, and associated with worse Glasgow Outcome Score. The administration of prophylactic AEDs for early PTS was not associated with a difference in rates of late PTS.

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.

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.

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.

Gabapentin Prevents Progressive Increases in Excitatory Connectivity and Epileptogenesis Following Neocortical Trauma.

Neocortical injury initiates a cascade of events, some of which result in maladaptive epileptogenic reorganization of surviving neural circuits. Research focused on molecular and organizational changes that occur following trauma may reveal processes that underlie human post-traumatic epilepsy (PTE), a common and unfortunate consequence of traumatic brain injury. The latency between injury and development of PTE provides an opportunity for prophylactic intervention, once the key underlying mechanisms are understood. In rodent neocortex, injury to pyramidal neurons promotes axonal sprouting, resulting in increased excitatory circuitry that is one important factor promoting epileptogenesis. We used laser-scanning photostimulation of caged glutamate and whole-cell recordings in in vitro slices from injured neocortex to assess formation of new excitatory synapses, a process known to rely on astrocyte-secreted thrombospondins (TSPs), and to map the distribution of maladaptive circuit reorganization. We show that this reorganization is centered principally in layer V and associated with development of epileptiform activity. Short-term blockade of the synaptogenic effects of astrocyte-secreted TSPs with gabapentin (GBP) after injury suppresses the new excitatory connectivity and epileptogenesis for at least 2 weeks. Results reveal that aberrant circuit rewiring is progressive in vivo and provide further rationale for prophylactic anti-epileptogenic use of gabapentinoids following cortical trauma.

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.

Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures.

BACKGROUND: The incidence of early post-traumatic seizures after civilian traumatic brain injury ranges 4-25%. The control of early post-traumatic seizure is mandatory because these acute insults may add secondary damage to the already damaged brain with poor outcome. Prophylactic use of anti-epileptic drugs have been found to be have variable efficacy against early post-traumatic seizures. The objective of this study was to compare the efficacy of Phenytion and Levetiracetam in prevention of early post-traumatic seizures in moderate to severe traumatic brain injury. METHODS: This randomized controlled trial was conducted in department of Neurosurgery, Ayub Medical College, Abbottabad from March, 2012 to March 2013. The patients with moderate to severe head injury were randomly allocated in two groups. Patients in group A were given phenytoin and patients in group B were given Levetiracetam. Patients were followed for one week to detect efficacy of drug in terms of early post traumatic seizures. RESULTS: The 154 patients included in the study were equally divided into two groups. Out of 154 patients 115 (74.7%) were male while 29 (25.3%) were females. Age of patients ranges from 7-48 (24.15±9.56) years. Ninety one (59.1%) patients had moderate head injury while 63 (40.9%) patients had severe head injury. Phenytoin was effective in preventing early post traumatic seizures in 73 (94.8%) patients whereas Levetiracetam effectively controlled seizures in 70 (90.95%) cases (p-value of .348). CONCLUSIONS: There is no statistically significant difference in the efficacy of Phenytoin and Levetiracetam in prophylaxis of early posttraumatic seizures in cases of moderate to severe traumatic brain injury.

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.

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.

Gabapentin decreases epileptiform discharges in a chronic model of neocortical trauma.

Gabapentin (GBP) is an anticonvulsant that acts at the α2δ-1 submit of the L-type calcium channel. It is recently reported that GBP is a potent inhibitor of thrombospondin (TSP)-induced excitatory synapse formation in vitro and in vivo. Here we studied effects of chronic GBP administration on epileptogenesis in the partial cortical isolation ("undercut") model of posttraumatic epilepsy, in which abnormal axonal sprouting and aberrant synaptogenesis contribute to occurrence of epileptiform discharges. Results showed that 1) the incidence of evoked epileptiform discharges in undercut cortical slices studied 1 day or ~2 weeks after the last GBP dose, was significantly reduced by GBP treatments, beginning on the day of injury; 2) the expression of GFAP and TSP1 protein, as well as the number of FJC stained cells was decreased in GBP treated undercut animals; 3) in vivo GBP treatment of rats with undercuts for 3 or 7 days decreased the density of vGlut1-PSD95 close appositions (presumed synapses) in comparison to saline treated controls with similar lesions;4) the electrophysiological data are compatible with the above anatomical changes, showing decreases in mEPSC and sEPSC frequency in the GBP treated animals. These results indicate that chronic administration of GBP after cortical injury is antiepileptogenic in the undercut model of post-traumatic epilepsy, perhaps by both neuroprotective actions and decreases in excitatory synapse formation. The findings may suggest the potential use of GBP as an antiepileptogenic agent following traumatic brain injury.

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.

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.

Adverse cognitive effects of phenytoin in severe brain injury: a case report.

BACKGROUND: The use of prophylactic anticonvulsants following brain injury is controversial. When used for this reason or for treatment of early seizures, anticonvulsants, particularly phenytoin, can cause severe cognitive side-effects. CASE REPORT: This study presents a case of a woman with a severe brain injury with severe cognitive impairment who improved dramatically following withdrawal of phenytoin. The literature regarding such cognitive side-effects is contradictory with no consistent indication of choice of anticonvulsants to use in this situation. CONCLUSION: As a result of the dramatic improvement in this case, one should now routinely withdraw or change phenytoin treatment in all brain injury patients with significant cognitive impairment.

Incidence and risk factors of early post-traumatic seizures in Nigerians.

OBJECTIVES: To determine the incidence and risk factors of early post-traumatic seizures (PTS) in Nigerian subjects. METHODS: Subjects were recruited consecutively, classified as mild, moderate or severe traumatic brain injury (TBI), and followed for 168 hrs for development of seizures. RESULTS: There were 266 subjects, 213 (80%) males and 53 (20%) females, with mean age 31 years (sd 18, range 1-80, median 30). Causes of TBI were motor traffic accident (MTA) related in 217 (82%), falls in 25 (9%), struck by objects in 15 (5%), firearms in 4 (2%), sports and recreation in 3 (1%), and failed suicide in 2 (1%). Cumulative incidence of early PTS was 119‰ (95% CI 80-156). Risk factors were age ≤12 years, severity of TBI, history of seizures, and TBI at weekend, but gender and GCS were not. Skeletomotor palsy was independently associated with early PTS. CONCLUSIONS: Incidence of early PTS is high in this population, probably due to the relatively high proportion of severe TBI. Risk factors are TBI severity, young age, history of seizures, and TBI at weekends. The best preventive strategy is reduction of MTA, which causes over 80% of TBI. Prophylactic anti-seizure therapy may benefit subjects with severe TBI and skeletomotor deficits.

Perforating brain injury from a speargun. A case report.

A case of a perforating brain injury caused by a speargun in a suicide attempt is described. Although this kind of injuries has been previously reported, the present case is specially interesting because the patient showed no neurological deficit after surgery. Some advices about the medical and surgical management are proposed based on this case and our literature review. The use of antibiotics and antiepileptic drugs and the anterograde extraction of the harpoon aided by the performance of a craniotomy surrounding the exit point are recommended.

Are the neurotrophic factors a suitable therapeutic target for the prevention of epileptogenesis?

Neurotrophic factors are involved in the survival of neurons as well as in the proliferation and differentiation of neuronal precursors. Therefore, modulating their levels in lesion areas may exert favorable effects on seizure-induced damage. However, it is unclear if damage limitation or repair may prevent epileptogenesis; it is also uncertain which neurotrophic factor should be administered for limiting or repairing damage while avoiding possible proepileptic effects. We used viral vectors to locally supplement fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF), when an epileptogenic damage was already in place. These vectors were tested in the pilocarpine model of status epilepticus-induced neurodegeneration and epileptogenesis. FGF-2/BDNF expressing vectors increased neuronogenesis, limited neuronal damage, and reduced the occurrence of spontaneous seizures. These findings are discussed with consideration of the hurdles that will have to be overcome before clinical application.

A population-based study of risk of epilepsy after hospitalization for traumatic brain injury.

PURPOSE: This study was undertaken to determine the risk of developing posttraumatic epilepsy (PTE) within 3 years after discharge among a population-based sample of older adolescents and adults hospitalized with traumatic brain injury (TBI) in South Carolina. It also identifies characteristics related to development of PTE within this population. METHODS: A stratified random sample of persons aged 15 and older with TBI was selected from the South Carolina nonfederal hospital discharge dataset for four consecutive years. Medical records of recruits were reviewed, and they participated in up to three yearly follow-up telephone interviews. RESULTS: The cumulative incidence of PTE in the first 3 years after discharge, after adjusting for loss to follow-up, was 4.4 per 100 persons over 3 years for hospitalized mild TBI, 7.6 for moderate, and 13.6 for severe. Those with severe TBI, posttraumatic seizures prior to discharge, and a history of depression were most at risk for PTE. This higher risk group also included persons with three or more chronic medical conditions at discharge. DISCUSSION: These results raise the possibility that although some of the characteristics related to development of PTE are nonmodifiable, other factors, such as depression, might be altered with intervention. Further research into factors associated with developing PTE could lead to risk-reducing treatments.

Sodium valproate for prevention of early posttraumatic seizures.

OBJECTIVE: To assess the preventive effect of sodium valproate on early posttraumatic seizures in traumatic brain injury (TBI) patients. METHODS: The retrospective study was based on 159 patients with TBI treated at Department of Neurosurgery, Nanjing General Hospital of Nanjing Command enrolled between January 1, 2008 and December 31, 2009. The in-hospital section of the retrospectively collected database includes information on age, sex, initial Glasgow Coma Score (GCS), results of CT scanning, operation, usage of sodium valproate, seizures in the first week after injury and outcome. RESULTS: Seven patients (4.4%) showed early posttraumatic seizures. Although the incidence was zero in patients who received sodium valproate treatment, the difference between the treatment and control groups was not statistically significant. Of the 87 severe TBI patients (GCS 3-8), 6 patients in the control group (6.9%) suffered from early seizures during the first week after TBI and no patient who received preventive therapy suffered from seizures. The difference between the treatment and the control groups was still not statistically significant. Of the 72 mild and moderate TBI patients (GCS 9-15), only 1 patient in the control group suffered from seizures and no patient in the treatment group suffered. CONCLUSIONS: Although the results suggest that the study is not sufficiently powerful to detect a clinically important difference in the seizure rates between the treatment and control groups, sodium valproate is effective in decreasing the risk of early posttraumatic seizures in severe TBI patients. Further prospective studies are recommended.