Posttraumatic epilepsy in chronic disorders of consciousness due to severe traumatic brain injury after traffic accidents.

PURPOSE: To evaluate the clinical state of posttraumatic epilepsy (PTE) in patients with chronic disorders of consciousness (CDC) due to severe traumatic brain injury (STBI) after traffic accidents and clarify the risk factors for seizure occurrence in such patients. METHODS: Two hundred ninety-three patients with CDC due to STBI (mean age at admission [±standard deviation]: 36.4 ± 17.9 years; men: 71.7 %; mean duration of injury to admission: 416 ± 732 days; mean hospitalization time: 899 ± 319 days) were enrolled in this study. We retrospectively investigated the relationship between seizure conditions (type and frequency) and clinical data, including age, sex, pathological types of brain injury, with/without surgical intervention, degree of CDC, and administration of antiseizure medications (ASMs). RESULTS: Overall, 52.9 % (n = 155/293) and 64.2 % of the patients (n = 183/of 285 patients surviving at discharge) were administered ASMs at admission and discharge, respectively. One hundred thirty-two patients (45.1 %) experienced epileptic seizures during hospitalization, and the mean seizure frequency was 4.0 ± 0.4 times per year. In multivariate analysis, significant and independent risk factors of seizure occurrence were revealed to be male sex, high National Agency for Automotive Safety and Victims' Aid score, hypoxic encephalopathy, and history of the neurosurgical operations. CONCLUSION: The high prevalence of PTE in patients with CDC due to STBI, and the significant and independent risk factors for seizure occurrence in the chronic clinical phase were revealed. We expect that this study will aid toward improving clinical assessment and management of epileptic seizures in the population.

Clinical characteristics and associated factors of posttraumatic epilepsy after traumatic brain injury in children: A retrospective case-control study.

BACKGROUND: Traumatic brain injury (TBI) affects approximately 69 million individuals annually, often resulting in well-documented complications such as epilepsy. Although numerous studies have been performed on posttraumatic epilepsy (PTE) in adults over the past decade, research on chronic consequences of TBI in children remains limited. Herein, we retrospectively assessed children who had experienced moderate to severe TBI to determine their clinical characteristics and identify associated factors associated with the development of PTE in the pediatric population. METHODS: The study population comprised children aged 0-18 years who had experienced moderate to severe TBI and underwent treatment at the Children's Hospital of Chongqing Medical University between 2011 and 2021. They were categorized into two groups: the PTE group, comprising individuals diagnosed with PTE within a one-year follow-up period, and the nPTE group, consisting of those who did not develop PTE during the same timeframe. The primary objective was to investigate the clinical characteristics and identify related associated factors. The relationship between various clinical factors and the incidence of PTE was assessed through univariate and multivariate logistic regression. RESULTS: A total of 132 patients were assessed. Most participants were male (65%) and the age distribution skewed towards younger children, with a median age of 41.0 months (interquartile range: 45.3). Upon their last clinical visit, 64 children (49%) were diagnosed with PTE. Notably, the first posttraumatic seizure predominantly occurred within the first week following the traumatic event. Further analyses revealed that increasing injury severity, as indicated by a lower Glasgow Coma Scale (GCS) score (odds ratio [OR]: 0.78, 95% confidence interval [CI]: 0.54-1.12, p= 0.018), a contusion load ≥3 (OR: 8.1, 95% CI: 2.3-28.9, p= 0.001), immediate posttraumatic seizures (IPTS) (OR: 8.9, 95% CI: 2.5-31.2, p < 0.001), and early posttraumatic seizures (EPTS) (OR: 54, 95% CI: 11-276, p < 0.001), were all significantly associated with a higher risk of developing PTE. CONCLUSION: This study highlights that the onset of PTE was associated with the markers of injury severity or PTS and identified GCS scores, contusion loads of ≥3, IPTS, and EPTS as independent associated factors significantly associated with the development of PTE.

Epilepsy phenotype and its reproducibility after lateral fluid percussion-induced traumatic brain injury in rats: Multicenter EpiBioS4Rx study project 1.

OBJECTIVE: This study was undertaken to assess reproducibility of the epilepsy outcome and phenotype in a lateral fluid percussion model of posttraumatic epilepsy (PTE) across three study sites. METHODS: A total of 525 adult male Sprague Dawley rats were randomized to lateral fluid percussion-induced brain injury (FPI) or sham operation. Of these, 264 were assigned to magnetic resonance imaging (MRI cohort, 43 sham, 221 traumatic brain injury [TBI]) and 261 to electrophysiological follow-up (EEG cohort, 41 sham, 220 TBI). A major effort was made to harmonize the rats, materials, equipment, procedures, and monitoring systems. On the 7th post-TBI month, rats were video-EEG monitored for epilepsy diagnosis. RESULTS: A total of 245 rats were video-EEG phenotyped for epilepsy on the 7th postinjury month (121 in MRI cohort, 124 in EEG cohort). In the whole cohort (n = 245), the prevalence of PTE in rats with TBI was 22%, being 27% in the MRI and 18% in the EEG cohort (p > .05). Prevalence of PTE did not differ between the three study sites (p > .05). The average seizure frequency was .317 ± .725 seizures/day at University of Eastern Finland (UEF; Finland), .085 ± .067 at Monash University (Monash; Australia), and .299 ± .266 at University of California, Los Angeles (UCLA; USA; p < .01 as compared to Monash). The average seizure duration did not differ between UEF (104 ± 48 s), Monash (90 ± 33 s), and UCLA (105 ± 473 s; p > .05). Of the 219 seizures, 53% occurred as part of a seizure cluster (≥3 seizures/24 h; p >.05 between the study sites). Of the 209 seizures, 56% occurred during lights-on period and 44% during lights-off period (p > .05 between the study sites). SIGNIFICANCE: The PTE phenotype induced by lateral FPI is reproducible in a multicenter design. Our study supports the feasibility of performing preclinical multicenter trials in PTE to increase statistical power and experimental rigor to produce clinically translatable data to combat epileptogenesis after TBI.

Association between pediatric traumatic brain injury and epilepsy at later ages in Finland: A nationwide register-based cohort study.

OBJECTIVE: This study was undertaken to examine how pediatric traumatic brain injury (pTBI) correlates with incidence of epilepsy at later ages in Finland. METHODS: This nationwide retrospective register-based cohort study extended from 1998 to 2018. The study group consisted of 71 969 pediatric (<18 years old) patients hospitalized with TBI and a control group consisting of 64 856 pediatric patients with distal extremity fracture. Epilepsy diagnoses were gathered from the Finnish Social Insurance Institution. Kaplan-Meier and multivariable Cox regression models were conducted to analyze the probability of epilepsy with 95% confidence intervals (CIs). RESULTS: Cumulative incidence rates (CIRs) for the first 2 years were .5% in the pTBI group and .1% in the control group. The corresponding rates after 15 years of follow-up were 1.5% in the pTBI group and .7% in the control group. Due to proportional hazard violations, the study population was split to the first 2 years and in subgroup analysis 4 years. During the first 2 years of surveillance, the hazard ratio (HR) for the pTBI group was 4.38 (95% CI = 3.39-5.66). However, between years 2 and 20, the HR for the pTBI group was 2.02 (95% CI = 1.71-2.38). A total of 337 patients (.47%) underwent neurosurgery, and 36 (10.7%) patients subsequently developed epilepsy. The CIR for the first year after TBI was 4.5% (95% CI = 2.3-6.7) in operatively managed patients and .3% (95% CI = .3-.4) in nonoperatively managed patients. Corresponding figures after 15 years were 12.0% (95% CI = 8.2-15.8) and 1.5% (95% CI = 1.4-1.6). During the first 4 years of surveillance, the HR for the operative pTBI group was 14.37 (95% CI = 9.29-20.80) and 3.67 (95% CI = 1.63-8.22) between years 4 and 20. SIGNIFICANCE: pTBI exposes patients to a higher risk for posttraumatic epilepsy for many years after initial trauma. Children who undergo operative management for TBI have a high risk for epilepsy, and this risk was highest during the first 4 years after injury.

Research Progress on the Immune-Inflammatory Mechanisms of Posttraumatic Epilepsy.

Posttraumatic epilepsy (PTE) is a severe complication arising from a traumatic brain injury caused by various violent actions on the brain. The underlying mechanisms for the pathogenesis of PTE are complex and have not been fully defined. Approximately, one-third of patients with PTE are resistant to antiepileptic therapy. Recent research evidence has shown that neuroinflammation is critical in the development of PTE. This article reviews the immune-inflammatory mechanisms regarding microglial activation, astrocyte proliferation, inflammatory signaling pathways, chronic neuroinflammation, and intestinal flora. These mechanisms offer novel insights into the pathophysiological mechanisms of PTE and have groundbreaking implications in the prevention and treatment of PTE. Immunoinflammatory cross-talk between glial cells and gut microbiota in posttraumatic epilepsy. This graphical abstract depicts the roles of microglia and astrocytes in posttraumatic epilepsy, highlighting the influence of the gut microbiota on their function. TBI traumatic brain injury, AQP4 aquaporin-4, Kir4.1 inward rectifying K channels.

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.

Right-to-Left Displacement of an Airgun Lead Bullet after Transorbital Entry into the Skull Complicated by Posttraumatic Epilepsy : A Case Report.

Penetrating head injury is a serious open cranial injury. In civilians, it is often caused by non-missile, low velocity flying objects that penetrate the skull through a weak cranial structure, forming intracranial foreign bodies. The intracranial foreign body can be displaced due to its special quality, shape, and location. In this paper, we report a rare case of right-to-left displacement of an airgun lead bullet after transorbital entry into the skull complicated by posttraumatic epilepsy, as a reminder to colleagues that intracranial metal foreign bodies maybe displaced intraoperatively. In addition, we have found that the presence of intracranial metallic foreign bodies may be a factor for the posttraumatic epilepsy, and their timely removal appears to be beneficial for epilepsy control.

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.

Predicting posttraumatic epilepsy using admission electroencephalography after severe traumatic brain injury.

OBJECTIVE: Posttraumatic epilepsy (PTE) develops in as many as one third of severe traumatic brain injury (TBI) patients, often years after injury. Analysis of early electroencephalographic (EEG) features, by both standardized visual interpretation (viEEG) and quantitative EEG (qEEG) analysis, may aid early identification of patients at high risk for PTE. METHODS: We performed a case-control study using a prospective database of severe TBI patients treated at a single center from 2011 to 2018. We identified patients who survived 2 years postinjury and matched patients with PTE to those without using age and admission Glasgow Coma Scale score. A neuropsychologist recorded outcomes at 1 year using the Expanded Glasgow Outcomes Scale (GOSE). All patients underwent continuous EEG for 3-5 days. A board-certified epileptologist, blinded to outcomes, described viEEG features using standardized descriptions. We extracted 14 qEEG features from an early 5-min epoch, described them using qualitative statistics, then developed two multivariable models to predict long-term risk of PTE (random forest and logistic regression). RESULTS: We identified 27 patients with and 35 without PTE. GOSE scores were similar at 1 year (p = .93). The median time to onset of PTE was 7.2 months posttrauma (interquartile range = 2.2-22.2 months). None of the viEEG features was different between the groups. On qEEG, the PTE cohort had higher spectral power in the delta frequencies, more power variance in the delta and theta frequencies, and higher peak envelope (all p < .01). Using random forest, combining qEEG and clinical features produced an area under the curve of .76. Using logistic regression, increases in the delta:theta power ratio (odds ratio [OR] = 1.3, p < .01) and peak envelope (OR = 1.1, p < .01) predicted risk for PTE. SIGNIFICANCE: In a cohort of severe TBI patients, acute phase EEG features may predict PTE. Predictive models, as applied to this study, may help identify patients at high risk for PTE, assist early clinical management, and guide patient selection for clinical trials.

Efficiency of surgery on posttraumatic epilepsy: a systematic review and meta-analysis.

Posttraumatic epilepsy (PTE) accounts for approximately 20% of structural epilepsy, and surgical intervention may be a potential treatment option for these patients. Therefore, the purpose of this meta-analysis is to evaluate the effectiveness of surgical interventions for the management of PTE. Four electronic databases (Pubmed, Embase, Scopus and Cochrane library) were searched to identify studies on surgical management of PTE. Seizures reduction rate were analyzed quantitatively in a meta-analysis. Fourteen studies involving 430 PTE patients were selected for analysis, out of which 12 reported on resective surgery (RS), 2 on vagus nerve stimulation (VNS), and 2 of the 12 RS studies reported that 14 patients underwent VNS. The seizure reduction rate for surgical interventions (both RS and VNS) was 77.1% (95% confidence interval [CI]: 69.8%-83.7%) with moderate heterogeneity (I2 = 58.59%, Phetero = 0.003). Subgroup analysis based on different follow-up times revealed that the seizure reduction rate was 79.4% (95% CI: 69.1%-88.2%) within 5 years and 71.9% (95% CI: 64.5%-78.8%) beyond 5 years. The seizure reduction rate for RS alone was 79.9% (95% CI: 70.3%-88.2%) with high heterogeneity (I2 = 69.85%, Phetero = 0.001). Subgroup analysis showed that the seizure reduction rate was 77.9% (95% CI: 66%-88.1%) within 5 years and 85.6% (95% CI: 62.4%-99.2%) beyond 5 years, with 89.9% (95% CI: 79.2%-97.5%) for temporal lobectomy and 84% (95% CI: 68.2%-95.9%) for extratemporal lobectomy. The seizure reduction rate for VNS alone was 54.5% (95% CI: 31.6%-77.4%). Surgical interventions appeared to be effective for PTE patients without severe complications, RS seemed more beneficial than VNS, while temporal lobectomy is more favorable than extratemporal resection. However, further studies with long-term follow-up data are needed to better understand the relationship between VNS and PTE.

Putative roles for homeostatic plasticity in epileptogenesis.

Homeostatic plasticity allows neural circuits to maintain an average activity level while preserving the ability to learn new associations and efficiently transmit information. This dynamic process usually protects the brain from excessive activity, like seizures. However, in certain contexts, homeostatic plasticity might produce seizures, either in response to an acute provocation or more chronically as a driver of epileptogenesis. Here, we review three seizure conditions in which homeostatic plasticity likely plays an important role: acute drug withdrawal seizures, posttraumatic or disconnection epilepsy, and cyclic seizures. Identifying the homeostatic mechanisms active at different stages of development and in different circuits could allow better targeting of therapies, including determining when neuromodulation might be most effective, proposing ways to prevent epileptogenesis, and determining how to disrupt the cycle of recurring seizure clusters.

The Role of Decreased Levels of Neuronal Autophagy in Increased Susceptibility to Post-traumatic Epilepsy.

Post-traumatic epilepsy (PTE) caused by mild TBI (mild traumatic brain injury, mTBI) has a high incidence and poor prognosis, but its mechanisms are unclear. Herein, we investigated the role of reduced levels of neuronal autophagy during the latency period in the increased susceptibility to PTE. In the study, a gentle whole-body mechanical trauma rat model was prepared using Noble-Collip drums, and the extent of injury was observed by cranial CT and HE staining of hippocampal tissue. The incidence of epilepsy and its seizure form were observed 7-90 days after mTBI, and electroencephalography (EEG) was recorded during seizures in rats. Subcortical injection of non-epileptogenic dose of ferrous chloride (FeCl2) was used to observe the changes of PTE incidence after mTBI. Western blot and Real-time PCR were used to detect the level of autophagy in hippocampal cells at different time points during the latency period of PTE, and its incidence was observed after up-regulation of autophagy after administration of autophagy agonist-rapamycin. The results showed that mTBI was prepared by Noble-Collip drum, which could better simulate the clinical mTBI process. There was no intracerebral hemorrhage and necrosis in rats, no early-onset seizures, and the incidence of PTE after mTBI was 26.7%. The incidence of PTE was 56.7% in rats injected cortically with FeCl2 at a dose lower than the epileptogenic dose 48 h after mTBI, and the difference was significant compared with no FeCl2 injection, suggesting an increased susceptibility to PTE after mTBI. Further study of neuronal autophagy during PTE latency revealed that autophagy levels were reduced, and the incidence of PTE was significantly reduced after administration of rapamycin to upregulate autophagy. Taken together, the decreased level of neuronal autophagy during the latency period may be a possible mechanism for the increased susceptibility to PTE after mTBI.

Traumatic brain injury, stroke, and epilepsy: A mediation study in a Danish nationwide cohort.

OBJECTIVE: Traumatic brain injury (TBI) and stroke are well-known causes of acquired epilepsy. TBI is also a risk factor for stroke, and injury-induced stroke may indirectly convey a proportion of the epilepsy risk following TBI. We studied the extent to which the effect of TBI on epilepsy operated through intermediary stroke. METHODS: We analyzed a nationwide, matched, register-based cohort of adults ≥ 40 years of age whose first TBI at Danish hospitals was recorded between 2004 and 2016. A matched reference population was sampled for comparison. During follow-up, we recorded all acute strokes. Cox proportional hazard models and the difference method were used to estimate the total and controlled direct effect hazard ratios (HRs) of TBI on epilepsy and the indirect effect HRs of TBI on epilepsy operating through stroke, and to calculate the proportion eliminated. Analyses were stratified by severity of, age at, and time since TBI. RESULTS: We followed 57 900 persons with TBI (48.6% males) from median age 61 years (interquartile range = 51-75), and 561 977 age- and sex-matched references. The total effect of TBI on epilepsy was higher for persons aged 40-59 years (HR = 5.15, 95% confidence interval [CI] = 4.65-5.72) than for persons aged ≥ 60 years (HR = 4.55, 95% CI = 4.19-4.95). In contrast, the indirect effect of TBI mediated by stroke was lower for persons aged 40-59 years (HR = 1.02, 95% CI = 1.02-1.03) than for persons aged ≥ 60 years (HR = 1.05, 95% CI = 1.04-1.06). We estimated 2.3% and 5.6% of the risk of epilepsy after TBI to operate through stroke for these age groups, respectively. SIGNIFICANCE: Less than 6% of the risk of epilepsy following TBI operated through intermediary stroke. However, this mechanism seems to play an increasing role with age and for late onset epilepsies. This warrants further investigation.

International Survey of Antiseizure Medication Use in Patients with Complicated Mild Traumatic Brain Injury: A New York Neurotrauma Consortium Study.

BACKGROUND: Seizures and epilepsy after traumatic brain injury (TBI) negatively affect quality of life and longevity. Antiseizure medication (ASM) prophylaxis after severe TBI is associated with improved outcomes; these medications are rarely used in mild TBI. However, a paucity of research is available to inform ASM use in complicated mild TBI (cmTBI) and no empirically based clinical care guidelines for ASM use in cmTBI exist. We aim to identify seizure prevention and management strategies used by clinicians experienced in treating patients with cmTBI to characterize standard care and inform a systematic approach to clinical decision making regarding ASM prophylaxis. METHODS: We recruited a multidisciplinary international cohort through professional organizational listservs and social media platforms. Our questionnaire assessed factors influencing ASM prophylaxis after cmTBI at the individual, institutional, and health system-wide levels. RESULTS: Ninety-two providers with experience managing cmTBI completed the survey. We found a striking diversity of ASM use in cmTBI, with 30% of respondents reporting no/infrequent use and 42% reporting frequent use; these tendencies did not differ by provider or institutional characteristics. Certain conditions universally increased or decreased the likelihood of ASM use and represent consensus. Based on survey results, ASMs are commonly used in patients with cmTBI who experience acute secondary seizure or select positive neuroimaging findings; we advise caution in elderly patients and those with concomitant neuropsychiatric illness. CONCLUSIONS: This study is the first to characterize factors influencing clinical decision making in ASM prophylaxis after cmTBI based on multidisciplinary multicenter provider practices. Prospective controlled studies are necessary to inform standardized guideline development.

Dual orexin antagonist normalized sleep homeostatic drive, enhanced GABAergic inhibition, and suppressed seizures after traumatic brain injury.

STUDY OBJECTIVES: Traumatic brain injury (TBI) can result in posttraumatic epilepsy (PTE) and sleep disturbances. We hypothesized that treatment with sleep aids after TBI can ameliorate PTE. METHODS: CD-1 mice underwent controlled cortical impact (CCI), sham injury, or no craniotomy. Sham and CCI groups underwent a monthlong daily treatment with sleep aids including a dual orexin antagonist (DORA-22) or THIP (gaboxadol) or a respective vehicle starting on the day of CCI. We performed continuous EEG (electroencephalography) recordings at week 1 and months 1, 2, and 3 for ~1 week each time. Seizure analysis occurred at all-time points and sleep analysis occurred in week 1 and month-1/2 in all groups. Subsets of CCI and sham groups were subjected to voltageclamp experiments in hippocampal slices to evaluate GABAergic synaptic inhibition. RESULTS: DORA-22 treatment suppressed seizures in month 1-3 recordings. TBI reduced the amplitude and frequency of miniature inhibitory synaptic currents (mIPSCs) in dentate granule cells and these changes were rescued by DORA-22 treatment. Sleep analysis showed that DORA-22 increased nonrapid eye movement (NREM) sleep during lights-off whereas THIP increased REM sleep during lights-on in week 1. Both treatments displayed subtle changes in time spent in NREM or REM at month-1/2 as well. TBI not only increased normalized EEG delta power (NΔ) at week-1 and month-1 but also resulted in the loss of the homeostatic diurnal oscillation of NΔ, which was restored by DORA-22 but not THIP treatment. CONCLUSIONS: Dual orexin antagonists may have a therapeutic potential in suppressing PTE potentially by enhancing GABAergic inhibition and impacting sleep homeostatic drive.

MRI-Guided Electrode Implantation for Chronic Intracerebral Recordings in a Rat Model of Post-Traumatic Epilepsy-Challenges and Gains.

Brain atrophy induced by traumatic brain injury (TBI) progresses in parallel with epileptogenesis over time, and thus accurate placement of intracerebral electrodes to monitor seizure initiation and spread at the chronic postinjury phase is challenging. We evaluated in adult male Sprague Dawley rats whether adjusting atlas-based electrode coordinates on the basis of magnetic resonance imaging (MRI) increases electrode placement accuracy and the effect of chronic electrode implantations on TBI-induced brain atrophy. One group of rats (EEG cohort) was implanted with two intracortical (anterior and posterior) and a hippocampal electrode right after TBI to target coordinates calculated using a rat brain atlas. Another group (MRI cohort) was implanted with the same electrodes, but using T2-weighted MRI to adjust the planned atlas-based 3D coordinates of each electrode. Histological analysis revealed that the anterior cortical electrode was in the cortex in 83% (25% in targeted layer V) of the EEG cohort and 76% (31%) of the MRI cohort. The posterior cortical electrode was in the cortex in 40% of the EEG cohort and 60% of the MRI cohort. Without MRI-guided adjustment of electrode tip coordinates, 58% of the posterior cortical electrodes in the MRI cohort will be in the lesion cavity, as revealed by simulated electrode placement on histological images. The hippocampal electrode was accurately placed in 82% of the EEG cohort and 86% of the MRI cohort. Misplacement of intracortical electrodes related to their rostral shift due to TBI-induced cortical and hippocampal atrophy and caudal retraction of the brain, and was more severe ipsilaterally than contralaterally (p < 0.001). Total lesion area in cortical subfields targeted by the electrodes (primary somatosensory cortex, visual cortex) was similar between cohorts (p > 0.05). MRI-guided adjustment of coordinates for electrodes improved the success rate of intracortical electrode tip placement nearly to that at the acute postinjury phase (68% vs. 62%), particularly in the posterior brain, which exhibited the most severe postinjury atrophy. Overall, MRI-guided electrode implantation improved the quality and interpretation of the origin of EEG-recorded signals.

Vagus nerve stimulation for refractory posttraumatic epilepsy: Efficacy and predictors of seizure outcome.

Background: Traumatic brain injury (TBI) has been recognized as an important and common cause of epilepsy since antiquity. Posttraumatic epilepsy (PTE) is usually associated with drug resistance and poor surgical outcomes, thereby increasing the burden of the illness on patients and their families. Vagus nerve stimulation (VNS) is an adjunctive treatment for medically refractory epilepsy. This study aimed to determine the efficacy of VNS for refractory PTE and to initially evaluate the potential predictors of efficacy. Methods: We retrospectively collected the outcomes of VNS with at least a 1-year follow-up in all patients with refractory PTE. Subgroups were classified as responders and non-responders according to the efficacy of VNS (≥50% or <50% reduction in seizure frequency). Preoperative data were analyzed to screen for potential predictors of VNS efficacy. Results: In total, forty-five patients with refractory PTE who underwent VNS therapy were enrolled. Responders were found in 64.4% of patients, and 15.6% of patients achieved seizure freedom at the last follow-up. In addition, the responder rate increased over time, with 37.8, 44.4, 60, and 67.6% at the 3-, 6-, 12-, and 24-month follow-ups, respectively. After multivariate analysis, generalized interictal epileptic discharges (IEDs) were found to be a negative predictor (OR: 4.861, 95% CI: 1.145-20.632) of VNS efficacy. Conclusion: The results indicated that VNS therapy was effective in refractory PTE patients and was well tolerated over a 1-year follow-up period. Patients with focal or multifocal IEDs were recognized to have better efficacy after VNS therapy.

Posttraumatic epilepsy: A single institution case series in Indonesia.

Background: Posttraumatic epilepsy (PTE) is a debilitating sequelae following traumatic brain injury (TBI). Risk of developing PTE is higher in the first 6 months following head trauma and remains increased for 10 years. Many cases of PTE developed into drug-resistant epilepsy in which need surgical treatment. Case Description: Fourteen patients were identified from 1998 until 2021. Mean age at onset was 21.00 ± 6.13 years, mean age of surgery was 29.50 ± 6.83 years. All patients had partial complex seizure with more than half of cases (n = 10, 71.4%) reported with focal impaired awareness seizure and focal to bilateral tonic-clonic type of seizure which were observed in the remained cases (n = 4, 28.6%). Abnormal magnetic resonance imaging findings were observed in 12 patients: mesial temporal sclerosis (n = 7), encephalomalacia (n = 4), brain atrophy (n = 4), and focal cortical dysplasia (n = 2). More than half of cases presented with mesial temporal lobe epilepsy despite site and type of brain injury. Most patients who undergone epileptogenic focus resection were free of seizure, but two patients remained to have seizure with worthwhile improvement. Conclusion: This study emphasizes the clinical characteristic of PTE cases in our center in Indonesia. While encephalomalacia is a typical finding following TBI and often responsible for epilepsy, electroencephalogram recording remains critical in determining epileptic focus. Most of PTE patients presented with temporal lobe epilepsy had excellent outcomes after surgical resection of epileptogenic focus.

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

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

Zolpidem Profoundly Augments Spared Tonic GABAAR Signaling in Dentate Granule Cells Ipsilateral to Controlled Cortical Impact Brain Injury in Mice.

Type A GABA receptors (GABAARs) are pentameric combinations of protein subunits that give rise to tonic (ITonicGABA) and phasic (i.e., synaptic; ISynapticGABA) forms of inhibitory GABAAR signaling in the central nervous system. Remodeling and regulation of GABAAR protein subunits are implicated in a wide variety of healthy and injury-dependent states, including epilepsy. The present study undertook a detailed analysis of GABAAR signaling using whole-cell patch clamp recordings from mouse dentate granule cells (DGCs) in coronal slices containing dorsal hippocampus at 1-2 or 8-13 weeks after a focal, controlled cortical impact (CCI) or sham brain injury. Zolpidem, a benzodiazepine-like positive modulator of GABAARs, was used to test for changes in GABAAR signaling of DGCs due to its selectivity for α1 subunit-containing GABAARs. Electric charge transfer and statistical percent change were analyzed in order to directly compare tonic and phasic GABAAR signaling and to account for zolpidem's ability to modify multiple parameters of GABAAR kinetics. We observed that baseline ITonicGABA is preserved at both time-points tested in DGCs ipsilateral to injury (Ipsi-DGCs) compared to DGCs contralateral to injury (Contra-DGCs) or after sham injury (Sham-DGCs). Interestingly, application of zolpidem resulted in modulation of ITonicGABA across groups, with Ipsi-DGCs exhibiting the greatest responsiveness to zolpidem. We also report that the combination of CCI and acute application of zolpidem profoundly augments the proportion of GABAAR charge transfer mediated by tonic vs. synaptic currents at both time-points tested, whereas gene expression of GABAAR α1, α2, α3, and γ2 subunits is unchanged at 8-13 weeks post-injury. Overall, this work highlights the shift toward elevated influence of tonic inhibition in Ipsi-DGCs, the impact of zolpidem on all components of inhibitory control of DGCs, and the sustained nature of these changes in inhibitory tone after CCI injury.