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

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

miRNA dysregulation in traumatic brain injury and epilepsy: a systematic review to identify putative biomarkers for post-traumatic epilepsy.

Traumatic brain injury (TBI) leads to post-traumatic epilepsy (PTE); hence, both TBI and PTE share various similar molecular mechanisms. MicroRNA (miRNA) is a small noncoding RNA that acts as a gene-silencing molecule. Notably, the dysregulation of miRNAs in various neurological diseases, including TBI and epilepsy, has been reported in several studies. However, studies on commonly dysregulated miRNAs and the regulation of shared pathways in both TBI and epilepsy that can identify potential biomarkers of PTE are still lacking. This systematic review covers the peer-review publications of TBI and database studies of epilepsy-dysregulated miRNAs of clinical studies. For TBI, 290 research articles were identified after screening, and 12 provided data for dysregulated miRNAs in humans. The compiled data suggest that 85 and 222 miRNAs are consecutively dysregulated in TBI and epilepsy. In both, 10 miRNAs were found to be commonly dysregulated, implying that they are potentially dysregulated miRNAs for PTE. Furthermore, the targets and involvement of each putative miRNA in different pathways were identified and evaluated. Additionally, clusters of predicted miRNAs were analyzed. Each miRNA's regulatory role was linked with apoptosis, inflammation, and cell cycle regulation pathways. Hence, these findings provide insight for future diagnostic biomarkers.

[Predictive capability of Cys112Arg single nucleotide polymorphisms of the apolipoprotein E gene in assessing the risk of immediate and early post-traumatic seizures].

This study is aimed at investigating epileptic seizures, one of the consequences of traumatic brain injury (TBI). Immediate and early post-traumatic seizures, as well as late post-traumatic epileptic seizures or post-traumatic epilepsy, can have different pathogenetic bases. The following key risk factors associated with post-traumatic epilepsy are known: duration of unconsciousness, gunshot wounds, intracranial hemorrhage, diffuse axonal injury, prolonged (more than 3 days) post-traumatic amnesia, acute subdural hematoma with surgical evacuation, immediate and early post-traumatic epileptic seizures, fracture of the skull bones. The role of genetic factors in post-traumatic seizures is poorly understood due to the complexity and multiple causal mechanisms. This paper addresses the role of genetic factors in the occurrence and severity of epileptic events in patients with TBI. In particular, we investigated the role of the Cys112Arg single nucleotide polymorphism of the apolipoprotein E gene. Apolipoprotein E is known for its role in the transport and metabolism of lipids and, therefore, the development of cardiovascular diseases; it is also associated with Alzheimer's disease and has recently been studied in the context of association with epilepsy. The study shows an association between this polymorphism and the risk of immediate and early epileptic seizures in patients with severe TBI.

Novel Approaches to Prevent Epileptogenesis After Traumatic Brain Injury.

Traumatic brain injury (TBI) is defined as an alteration in brain function or other evidence of brain pathology caused by an external force. When epilepsy develops following TBI, it is known as post-traumatic epilepsy (PTE). PTE occurs in a subset of patients suffering from different types and severities of TBI, occurs more commonly following severe injury, and greatly impacts the quality of life for patients recovering from TBI. Similar to other types of epilepsy, PTE is often refractory to drug treatment with standard anti-seizure drugs. No therapeutic approaches have proven successful in the clinic to prevent the development of PTE. Therefore, novel treatment strategies are needed to stop the development of PTE and improve the quality of life for patients after TBI. Interestingly, TBI represents an excellent clinical opportunity for intervention to prevent epileptogenesis as typically the time of initiation of epileptogenesis (i.e., TBI) is known, the population of at-risk patients is large, and animal models for preclinical studies of mechanisms and treatment targets are available. If properly identified and treated, there is a true opportunity to prevent epileptogenesis after TBI and stop seizures from ever happening. With that goal in mind, here we review previous attempts to prevent PTE both in animal studies and in humans, we examine how biomarkers could enable better-targeted therapeutics, and we discuss how genetic variation may predispose individuals to PTE. Finally, we highlight exciting new advances in the field that suggest that there may be novel approaches to prevent PTE that should be considered for further clinical development.

Early post-traumatic seizures are associated with valproic acid plasma concentrations and UGT1A6/CYP2C9 genetic polymorphisms in patients with severe traumatic brain injury.

BACKGROUND: Seizure is a common complication for severe traumatic brain injury (TBI). Valproic acid (VPA) is a first-line antiepileptic drug, though its metabolism is affected by genetic polymorphisms and varies between individuals. The aim of this study was to investigate such association and to explore its influence on the occurrence of early post-traumatic seizure. METHODS: A prospective case control study was conducted from 2012 to 2016 recruiting adult patients with severe TBI. Electroencephalograph (EEG) monitoring was performed approximately 4 h for each patient from day 1 to day 7 after injury. If seizures were detected, EEG monitoring was extended until 12 h after seizures being controlled. Genetic polymorphisms in UGT1A6, UGT2B7, CYP2C9, and CYP2C19 were analyzed in association with daily VPA plasma concentrations, adjusted dosages, and occurrence of seizures. RESULTS: Among the 395 recruited patients, eighty-three (21%) had early post-traumatic seizure, of which 30 (36.14%) were non-convulsive. Most seizures were first detected on day 1 (34.94%) and day 2 (46.99%) after injury. Patients with seizure had longer ICU length of stay and relatively lower VPA plasma concentrations. Patients with UGT1A6_19T > G/541A > G/552A > C double heterozygosities or CYP2C9 extensive metabolizers (EMs) initially had lower adjusted VPA plasma concentrations (power >0.99) and accordingly require higher VPA dosages during later time of treatment (power >0.99). The odds ratio indicated a higher risk of early post-traumatic seizure occurrence in male patients (OR 1.96, 95% CI 1.01-3.81, p = 0.043), age over 65 (OR 2.13, 95% CI 1.01-4.48), and with UGT1A6_19T > G/541A > G/552A > C double heterozygosities (OR 2.38, 95% CI 1.11-5.10, p = 0.02), though the power of the difference was between 0.54 to 0.61. DISCUSSION: Due to limited facility, the actual frequency of non-convulsive seizures is suspected to be higher than identified. There has been discrepancy regarding to genetic polymorphisms and VPA metab olism between this study and some previous reports. This could be related to confounders such as sample size, race, and patient age. Another limitation is that the case numbers of certain genotypes are limited in this study. CONCLUSIONS: Continuous EEG monitoring is necessary to detect both convulsive and non-convulsive early post-traumatic seizures in severe TBI patients. UGT1A6/CYP2C9 polymorphisms have influence on VPA metabolism. UGT1A6_19T > G/541A > G/552A > C double heterozygositie is associated with occurrence of early post-traumatic seizures in addition to patients' age and gender. Further investigations with larger sample size are required to confirm the difference. TRIAL REGISTRATION: Retrospectively registered with Chinese Clinical Trail Registry on 1st Jan 2016 ( ChiCTR-OPC-16007687 ).

Genetic biomarkers of posttraumatic epilepsy: A systematic review.

INTRODUCTION: Posttraumatic epilepsy (PTE) is caused by traumatic brain injury (TBI) and is an important contributor to the overall social and economic burden of epilepsy. Epidemiological studies suggest that there is a genetic contribution to the development of PTE. Identification of clinically useful genetic biomarkers is important for advancements in diagnosis and treatment of PTE. METHODS: A systematic review was performed on the existing literature of genetic biomarkers of posttraumatic epilepsy (PTE). A multi-database search yielded 4 articles deemed suitable for review. Potential genetic biomarkers were identified and critically evaluated. RESULTS & DISCUSSION: Biomarkers identified included single nucleotide polymorphism (SNP) rs1143634 of the interkeukin-1ß (IL-1ß) gene, SNPs rs3828275, rs3791878, and rs769391 of the glutamic acid decarboxylase 1 (GAD1) gene, SNPs rs3766553 and rs10920573 of the adenosine A1 receptor (A1AR) gene, and the functional variant C677T of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The most promising biomarkers identified were IL-1ß rs1143634 and A1AR rs10920573. Both had heterogenous at risk genotypes (CT). Those with IL-1ß rs1143634 CT genotype developed PTE in 47.7% of cases (p=0.008) and those with A1AR rs10920573 CT genotype developed PTE in 19.2% of cases (p=0.022). CONCLUSION: The majority of articles were preliminary with a need for validation of results. There is a need for continued high calibre research in order to validate the currently identified genetic biomarkers as well as to discover new genetic biomarkers in PTE.

NKCC1 up-regulation contributes to early post-traumatic seizures and increased post-traumatic seizure susceptibility.

Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures. Many of the available anti-seizure drugs target gamma-aminobutyric acid (GABAA) receptors. The inhibitory activity of GABAA receptor activation depends on low intracellular Cl-, which is achieved by the opposing regulation of Na+-K+-Cl- cotransporter 1 (NKCC1) and K+-Cl--cotransporter 2 (KCC2). Up-regulation of NKCC1 in neurons has been shown to be involved in neonatal seizures and in ammonia toxicity-induced seizures. Here, we report that TBI-induced up-regulation of NKCC1 and increased intracellular Cl- concentration. Genetic deletion of NKCC1 or pharmacological inhibition of NKCC1 with bumetanide suppresses TBI-induced seizures. TGFß expression was also increased after TBI and competitive antagonism of TGFß reduced NKKC1 expression, ameliorated reactive astrocytosis, and inhibited seizures. Thus, TGFß might be an important pathway involved in NKCC1 up-regulation after TBI. Our findings identify neuronal up-regulation of NKCC1 and its mediation by TGFß, as a potential and important mechanism in the early post-traumatic seizures, and demonstrate the therapeutic potential of blocking this pathway.

Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure.

OBJECTIVE: Posttraumatic seizures (PTS) commonly occur following severe traumatic brain injury (sTBI). Risk factors for PTS have been identified, but variability in who develops PTS remains. Excitotoxicity may influence epileptogenesis following sTBI. Glutamate transporters manage glutamate levels and excitatory neurotransmission, and they have been associated with both epilepsy and TBI. Therefore, we aimed to determine if genetic variation in neuronal glutamate transporter genes is associated with accelerated epileptogenesis and increased PTS risk after sTBI. METHODS: Individuals (N = 253) 18-75 years of age with sTBI were assessed for genetic relationships with PTS. Single nucleotide polymorphisms (SNPs) within SLC1A1 and SLC1A6 were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure rates from injury to 3 years postinjury for SNPs by genotype. Hazard ratios (HRs) were estimated using Cox proportional hazards regression for SNPs significant in Kaplan-Meier analyses adjusting for known PTS risk factors. RESULTS: Thirty-two tagging SNPs were examined (SLC1A1: n = 28, SLC1A6: n = 4). Forty-nine subjects (19.37%) had PTS. Of these, 18 (36.7%) seized within 7 days, and 31 (63.3%) seized between 8 days and 3 years post-TBI. With correction for multiple comparisons, genotypes at SNP rs10974620 (SLC1A1) were significantly associated with time to first seizure across the full 3-year follow-up (seizure rates: 77.1% minor allele homozygotes, 24.8% heterozygotes, 16.6% major allele homozygotes; p = 0.001). When seizure follow-up began day 2 postinjury, genotypes at SNP rs7858819 (SLC1A1) were significantly associated with PTS risk (seizure rates: 52.7% minor allele homozygotes, 11.8% heterozygotes, 21.1% major allele homozygotes; p = 0.002). After adjusting for covariates, we found that rs10974620 remained significant (p = 0.017, minor allele versus major allele homozygotes HR 3.4, 95% confidence interval [CI] 1.3-9.3). rs7858819 also remained significant in adjusted models (p = 0.023, minor allele versus major allele homozygotes HR 3.4, 95%CI 1.1-10.5). SIGNIFICANCE: Variations within SLC1A1 are associated with risk of epileptogenesis following sTBI. Future studies need to confirm findings, but variation within neuronal glutamate transporter genes may represent a possible pharmaceutical target for PTS prevention and treatment.

Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development.

OBJECTIVE: Determine if genetic variation in enzymes/transporters influencing extracellular adenosine homeostasis, including adenosine kinase (ADK), [ecto-5'-nucleotidase (NT5E), cluster of differentiation 73 (CD73)], and equilibrative nucleoside transporter type-1 (ENT-1), is significantly associated with epileptogenesis and posttraumatic epilepsy (PTE) risk, as indicated by time to first seizure analyses. METHODS: Nine ADK, three CD73, and two ENT-1 tagging single nucleotide polymorphisms (SNPs) were genotyped in 162 white adults with moderate/severe traumatic brain injury (TBI) and no history of premorbid seizures. Kaplan-Meier models were used to screen for genetic differences in time to first seizure occurring >1 week post-TBI. SNPs remaining significant after correction for multiple comparisons were examined using Cox proportional hazards analyses, adjusting for subdural hematoma, injury severity score, and isolated TBI status. SNPs significant in multivariate models were then entered simultaneously into an adjusted Cox model. RESULTS: Comparing Kaplan-Meier curves, rs11001109 (ADK) rare allele homozygosity and rs9444348 (NT5E) heterozygosity were significantly associated with shorter time to first seizure and an increased seizure rate 3 years post-TBI. Multivariate Cox proportional hazard models showed that these genotypes remained significantly associated with increased PTE hazard up to 3 years post-TBI after controlling for variables of interest (rs11001109: hazard ratio (HR) 4.47, 95% confidence interval (CI) 1.27-15.77, p = 0.020; rs9444348: HR 2.95, 95% CI 1.19-7.31, p = 0.019) . SIGNIFICANCE: Genetic variation in ADK and NT5E may help explain variability in time to first seizure and PTE risk, independent of previously identified risk factors, after TBI. Once validated, identifying genetic variation in adenosine regulatory pathways relating to epileptogenesis and PTE may facilitate exploration of therapeutic targets and pharmacotherapy development.

IL-1ß associations with posttraumatic epilepsy development: a genetics and biomarker cohort study.

OBJECTIVE: Posttraumatic epilepsy (PTE) is a significant complication following traumatic brain injury (TBI), yet the role of genetic variation in modulating PTE onset is unclear. We hypothesized that TBI-induced inflammation likely contributes to seizure development. We assessed whether genetic variation in the interleukin-1beta (IL-1ß) gene, IL-1ß levels in cerebrospinal fluid (CSF) and serum, and CSF/serum IL-1ß ratios would predict PTE development post-TBI. METHODS: We investigated PTE development in 256 Caucasian adults with moderate-to-severe TBI. IL-1ß tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1ß levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1ß gene variants, and also PTE. Temporally matched CSF/serum IL-1ß ratios were also generated to reflect the relative contribution of serum IL-1ß to CSF IL-1ß. RESULTS: Multivariate analysis showed that higher CSF/serum IL-1ß ratios were associated with increased risk for PTE over time (p = 0.008). Multivariate analysis for rs1143634 revealed an association between the CT genotype and increased PTE risk over time (p = 0.005). The CT genotype group also had lower serum IL-1ß levels (p = 0.014) and higher IL-1ß CSF/serum ratios (p = 0.093). SIGNIFICANCE: This is the first report implicating IL-1ß gene variability in PTE risk and linking (1) IL-1ß gene variation with serum IL-1ß levels observed after TBI and (2) IL-1ß ratios with PTE risk. Given these findings, we propose that genetic and IL-1ß ratio associations with PTE may be attributable to biologic variability with blood-brain barrier integrity during TBI recovery. These results provide a rationale for further studies (1) validating the impact of genetic variability on IL-1ß production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL-1ß CSF/serum associations with PTE, and (3) evaluating targeted IL-1ß therapies that reduce PTE.

Hippocampal gene expression profiling in a rat model of posttraumatic epilepsy reveals temporal upregulation of lipid metabolism-related genes.

Traumatic brain injury occasionally causes posttraumatic epilepsy. To elucidate the molecular events responsible for posttraumatic epilepsy, we established a rodent model that involved the injection of microliter quantities of FeCl3 solution into the amygdalar nuclear complex. We previously compared hippocampal gene expression profiles in the traumatic epilepsy model and normal rats at 5 days after brain injury (acute phase) to determine the role of inflammation. In this study, we focused on later stages of epileptogenesis. We compared gene expression profiles at 5, 15 (sub-chronic phase), and 30 days (chronic phase) after brain injury to identify temporal changes in molecular networks involved in epileptogenesis. A total of 81 genes were significantly (at least twofold) up- or downregulated over the course of disease progression. We found that genes related to lipid metabolism, namely, Apoa1, Gh, Mc4r, Oprk1, and Pdk4, were temporarily upregulated in the sub-chronic phase. Changes in lipid metabolism regulation might be related to seizure propagation during epileptogenesis. This temporal description of hippocampal gene expression profiles throughout epileptogenesis provides clues to potential markers of disease phases and new therapeutic targets.

Epilepsy in adult X-linked adrenoleucodystrophy due to the deletion c.1415-1416delAG in exon 5 of the ABCD1-gene.

Seizures in cerebral X-linked adrenoleucodystrophy (X-ALD) more frequently occur in the early-onset compared to the late-onset form. Here we describe an adult in whom X-ALD deteriorated after head trauma and who developed epilepsy with progression of X-ALD. In a 50 year-old Caucasian male, cerebral X-ALD was diagnosed upon progressive gait disturbance, intellectual decline, elevated very-long chain fatty acids in the serum or leucocytes, cerebral MRI, showing extensive, symmetric, homogenous demyelination in the parieto-occipital areas, the splenium corporis callosum, the thalamus, the crura cerebri, the brain stem, and the pedunculi cerebelli, and the deletion c.1415-1416delAG in the ABCD1-gene. After a head trauma the phenotype deteriorated to mutism, dysphagia, and severe spastic quadruparesis. At an age of 50 years the patient experienced his first, self-limiting, tonic-clonic seizure during an infection, which is why valproic acid was started. Recurrence of seizures after discharge required repeated adaptation of the valproic acid-dosage. Adult X-ALD may be associated with late-onset seizures, which respond favourably to valproic acid. Since any type of seizure episode in adult-onset cerebral X-ALD is usually followed by neurological decline, prophylactic treatment with antiepileptic drugs should be considered not only in early-onset but also in adult-onset epilepsy in X-ALD.

MTHFR C677T genotype as a risk factor for epilepsy including post-traumatic epilepsy in a representative military cohort.

The well-studied C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme is a biologically plausible genetic risk factor for seizures or epilepsy. First, plasma/serum levels of homocysteine, a pro-convulsant, are moderately elevated in individuals with the homozygote TT genotype. Furthermore, the TT genotype has been previously linked with migraine with aura-a comorbid condition-and with alcohol withdrawal seizures. Finally, several small studies have suggested that the TT genotype may be overrepresented in epilepsy patients. In this study, we consider whether the MTHFR C677T or A1298C variants are associated with risk of epilepsy including post-traumatic epilepsy (PTE) in a representative military cohort. Study subjects were selected from the cohort of military personnel on active duty during the years 2003 through 2007 who had archived serum samples at the DoD Serum Repository, essentially all active duty personnel during this time frame. We randomly selected 800 epilepsy patients and 800 matched controls based on ICD-9-CM diagnostic codes. We were able to isolate sufficient genetic material from the archived sera to genotype approximately 85% of our study subjects. The odds of epilepsy were increased in subjects with the TT versus CC genotype (crude OR=1.52 [1.04-2.22], p=0.031; adjusted OR=1.57 [1.07-2.32], p=0.023). In our sensitivity analysis, risk was most evident for patients with repeated rather than single medical encounters for epilepsy (crude OR=1.85 [1.14-2.97], p=0.011, adjusted OR=1.95 [1.19-3.19], p=0.008), and particularly for PTE (crude OR=3.14 [1.41-6.99], p=0.005; adjusted OR=2.55 [1.12-5.80], p=0.026). Our early results suggest a role for the common MTHFR C677T variant as a predisposing factors for epilepsy including PTE. Further exploration of baseline homocysteine and folate levels as predictors of seizure risk following traumatic brain injury is warranted.

Alterations of GABA(A) and glutamate receptor subunits and heat shock protein in rat hippocampus following traumatic brain injury and in posttraumatic epilepsy.

Traumatic brain injury (TBI) can result in the development of posttraumatic epilepsy (PTE). Recently, we reported differential alterations in tonic and phasic GABA(A) receptor (GABA(A)R) currents in hippocampal dentate granule cells 90 days after controlled cortical impact (CCI) (Mtchedlishvili et al., 2010). In the present study, we investigated long-term changes in the protein expression of GABA(A)R α1, α4, γ2, and δ subunits, NMDA (NR2B) and AMPA (GluR1) receptor subunits, and heat shock proteins (HSP70 and HSP90) in the hippocampus of Sprague-Dawley rats evaluated by Western blotting in controls, CCI-injured animals without PTE (CCI group), and CCI-injured animals with PTE (PTE group). No differences were found among all three groups for α1 and α4 subunits. Significant reduction of γ2 protein was observed in the PTE group compared to control. CCI caused a 194% and 127% increase of δ protein in the CCI group compared to control (p<0.0001), and PTE (p<0.0001) groups, respectively. NR2B protein was increased in CCI and PTE groups compared to control (p=0.0001, and p=0.011, respectively). GluR1 protein was significantly decreased in CCI and PTE groups compared to control (p=0.003, and p=0.001, respectively), and in the PTE group compared to the CCI group (p=0.036). HSP70 was increased in CCI and PTE groups compared to control (p=0.014, and p=0.005, respectively); no changes were found in HSP90 expression. These results provide for the first time evidence of long-term alterations of GABA(A) and glutamate receptor subunits and a HSP following CCI.

APOE genetic associations with seizure development after severe traumatic brain injury.

PRIMARY OBJECTIVE: The purpose of the current study is to assess the role of the APOE genotype in post-traumatic seizure (PTS) development. RESEARCH DESIGN: A retrospective study of 322 adult Caucasians with a severe TBI and APOE genotype. METHODS AND PROCEDURES: Medical records were searched for PTS. Time to first seizure was categorized as early, late or delayed-onset PTS. Potential PTS associations by genotype, grouped genotype and allele were investigated. MAIN OUTCOME AND RESULTS: No statistically significant associations were found. However, two out of the four individuals (50%) with the E4/E4 genotype had late/delayed-onset PTS. Furthermore, none with a E2/E2 or E2/E4 genotype seized in the late periods. CONCLUSIONS: The results of this study may suggest 4/4 as a risk genotype for late/delayed onset PTS and a potential neuroprotective role of the E2 allele. However, this study did not definitively support a role for the APOE genotype in PTS susceptibility and indicates that larger populations are needed to fully evaluate the potential impact of APOE on PTS.

Correlates of posttraumatic epilepsy 35 years following combat brain injury.

BACKGROUND: The Vietnam Head Injury Study (VHIS) is a prospective, longitudinal follow-up of 1,221 Vietnam War veterans with mostly penetrating head injuries (PHIs). The high prevalence (45%-53%) of posttraumatic epilepsy (PTE) in this unique cohort makes it valuable for study. METHODS: A standardized multidisciplinary neurologic, cognitive, behavioral, and brain imaging evaluation was conducted on 199 VHIS veterans plus uninjured controls, some 30 to 35 years after injury, as part of phase 3 of this study. RESULTS: The prevalence of seizures (87 patients, 43.7%) was similar to that found during phase 2 evaluations 20 years earlier, but 11 of 87 (12.6%) reported very late onset of PTE after phase 2 (more than 14 years after injury). Those patients were not different from patients with earlier-onset PTE in any of the measures studied. Within the phase 3 cohort, the most common seizure type last experienced was complex partial seizures (31.0%), with increasing frequency after injury. Of subjects with PTE, 88% were receiving anticonvulsants. Left parietal lobe lesions and retained ferric metal fragments were associated with PTE in a logistic regression model. Total brain volume loss predicted seizure frequency. CONCLUSIONS: Patients with PHI carry a high risk of PTE decades after their injury, and so require long-term medical follow-up. Lesion location, lesion size, and lesion type were predictors of PTE.

Adenosine A1 receptor gene variants associated with post-traumatic seizures after severe TBI.

Post-traumatic seizures (PTS) are a significant complication from traumatic brain injury (TBI). Adenosine, a major neuroprotective and neuroinhibitory molecule, is important in experimental epilepsy models. Thus, we investigated the adenosine A1 receptor (A1AR) gene and linked it with clinical data extracted for 206 subjects with severe TBI. Tagging SNPs rs3766553, rs903361, rs10920573, rs6701725, and rs17511192 were genotyped, and variant and haplotype associations with PTS were explored. We investigated further genotype, grouped genotype, and allelic associations with PTS for rs3766553 and rs10920573. Multivariate analysis of rs3766553 demonstrated an association between the AA genotype and increased early PTS incidence. In contrast, the GG genotype was associated with increased late and delayed-onset PTS rates. Multivariate analysis of rs10920573 revealed an association between the CT genotype and increased late PTS. Multiple risk genotype analysis showed subjects with both risk genotypes had a 46.7% chance of late PTS. To our knowledge, this is the first report implicating genetic variability in the A1AR with PTS, or any type of seizure disorder. These results provide a rationale for further studies investigating how adenosine neurotransmission impacts PTS, evaluating anticonvulsants in preventing and treating PTS, and developing and testing targeted adenosinergic therapies aimed at reducing PTS.