SUMMARYObjective: Determine incidence of posttraumatic seizure (PTS) following traumatic brain injury (TBI) among individuals with moderate-to-severe TBI requiring rehabilitation and surviving at least 5 years. Methods: Using the prospective TBI Model Systems National Database, we calculated PTS incidence during acute hospitalization, and at years 1, 2, and 5 postinjury in a continuously followed cohort enrolled from 1989 to 2000 (n = 795). Incidence rates were stratified by risk factors, and adjusted relative risk (RR) was calculated. Late PTS associations with immediate (<24 h), early (24 h-7 day), or late seizures (>7 day) versus no seizure prior to discharge from acute hospitalization was also examined. Results: PTS incidence during acute hospitalization was highest immediately (<24 h) post-TBI (8.9%). New onset PTS incidence was greatest between discharge from inpatient rehabilitation and year 1 (9.2%). Late PTS cumulative incidence from injury to year 1 was 11.9%, and reached 20.5% by year 5. Immediate/early PTS RR (2.04) was increased for those undergoing surgical evacuation procedures. Late PTS RR was significantly greater for individuals who self-identified as a race other than black/white (year 1 RR = 2.22), and for black individuals (year 5 RR = 3.02) versus white individuals. Late PTS was greater for individuals with subarachnoid hemorrhage (year 1 RR = 2.06) and individuals age 23-32 (year 5 RR = 2.43) and 33-44 (year 5 RR = 3.02). Late PTS RR years 1 and 5 was significantly higher for those undergoing surgical evacuation procedures (RR: 3.05 and 2.72, respectively).

SUMMARYObjective: 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-1b) gene, Il-1b levels in cerebral spinal fluid (CSF) and serum, and CSF/serum IL-1b ratios would predict PTE development post-TBI. Methods: We investigated PTE development in 256 Caucasian adults with moderateto-severe TBI. IL-1b tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1b levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1b gene variants, and also PTE. Temporally matched CSF/serum IL-1b ratios were also generated to reflect the relative contribution of serum IL-1b to CSF IL-1b. Results: Multivariate analysis showed that higher CSF/serum IL-1b 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-1b levels (p = 0.014) and higher IL-1b CSF/serum ratios (p = 0.093). Significance: This is the first report implicating IL-1b gene variability in PTE risk and linking (1) IL-1b gene variation with serum IL-1b levels observed after TBI and (2) IL-1b ratios with PTE risk. Given these findings, we propose that genetic and IL-1b 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-1b production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL-1b CSF/serum associations with PTE, and (3) evaluating targeted IL-1b therapies that reduce PTE.

Objective Post-traumatic 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 IL-1β gene, Il-1β levels in cerebral spinal fluid (CSF) and serum, and CSF/serum IL-1β ratios would predict PTE development post-TBI. Methods We investigated PTE development in 256 Caucasian adults with moderate to severe TBI. IL-1β tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1β levels were collected from a subset of subjects (n=59) during first week post injury and evaluated for their associations with IL-1β gene variants and also PTE. Temporally matched CSF/serum IL-1β ratios were also generated to reflect the relative contribution of serum IL-1β to CSF IL-1β. Results Multivariate analysis showed that higher CSF/serum IL-1β 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-1β levels (p=0.014) and higher IL-1β CSF/serum ratios (p=0.093). Significance This is the first report implicating IL-1β gene variability with PTE risk and linking 1) IL-1β gene variation with serum IL-1β levels observed after TBI and 2) IL-1β ratios with PTE risk. Given these findings, we propose that genetic and IL-1β ratio associations with PTE may be attributable to biological 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-1β production after TBI, 2) assessing genetically mediated signaling mechanisms that contribute to IL-1β CSF/serum associations with PTE, and 3) evaluating targeted IL-1β therapies that reduce PTE.

Dopamine (DA) neurotransmission influences cognition and recovery after traumatic brain injury (TBI). We explored whether functional genetic variants affecting the DA transporter (DAT) and D2 receptor (DRD2) impacted in vivo dopaminergic binding with positron emission tomography (PET) using [(11)C]βCFT and [(11)C]raclopride. We examined subjects with moderate/severe TBI (N=12) ∼1 year post injury and similarly matched healthy controls (N=13). The variable number of tandem repeat polymorphism within the DAT gene and the TaqI restriction fragment length polymorphism near the DRD2 gene were assessed. TBI subjects had age-adjusted DAT-binding reductions in the caudate, putamen, and ventral striatum, and modestly increased D2 binding in ventral striatum versus controls. Despite small sample sizes, multivariate analysis showed lower caudate and putamen DAT binding among DAT 9-allele carriers and DRD2 A2/A2 homozygotes with TBI versus controls with the same genotype. Among TBI subjects, 9-allele carriers had lower caudate and putamen binding than 10/10 homozygotes. This PET study suggests a hypodopaminergic environment and altered DRD2 autoreceptor DAT interactions that may influence DA transmission after TBI. Future work will relate these findings to cognitive performance; future studies are required to determine how DRD2/DAT1 genotype and DA-ligand binding are associated with neurostimulant response and TBI recovery.

Objective Post-traumatic 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), 18-75yrs with sTBI, were assessed for genetic relationships with PTS. SNPs within SLC1A1 and SLC1A6 were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure rates from injury to 3yrs post-injury for SNPs by genotype. Hazard ratios were estimated using Cox proportional hazards regression for SNPs significant in Kaplan-Meier analyses adjusting for known PTS risk factors. Results 32 tagging SNPs were examined (SLC1A1: n=28, SLC1A6: n=4). 49 (19.37%) subjects had PTS. Of these, 18 (36.7%) seized within 7days, and 31 (63.3%) seized between 8d-3yrs post-TBI. Correcting for multiple comparisons, genotypes at SNP rs10974620 (SLC1A1) were significantly associated with time-to-first seizure across the full 3yr follow-up (seizure rates: 77.1% minor allele homozygotes, 24.8% heterozygotes, 16.6% major allele homozygotes; p=0.001). When follow-up began day 2, 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). Adjusting for covariates, rs10974620 remained significant (p=0.017, minor allele versus major allele homozygotes HR: 3.4, 95%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.