Protein biomarkers of epileptogenicity after traumatic brain injury.

Traumatic brain injury (TBI) is a major risk factor for acquired epilepsy. Post-traumatic epilepsy (PTE) develops over time in up to 50% of patients with severe TBI. PTE is mostly unresponsive to traditional anti-seizure treatments suggesting distinct, injury-induced pathomechanisms in the development of this condition. Moderate and severe TBIs cause significant tissue damage, bleeding, neuron and glia death, as well as axonal, vascular, and metabolic abnormalities. These changes trigger a complex biological response aimed at curtailing the physical damage and restoring homeostasis and functionality. Although a positive correlation exists between the type and severity of TBI and PTE, there is only an incomplete understanding of the time-dependent sequelae of TBI pathobiologies and their role in epileptogenesis. Determining the temporal profile of protein biomarkers in the blood (serum or plasma) and cerebrospinal fluid (CSF) can help to identify pathobiologies underlying the development of PTE, high-risk individuals, and disease modifying therapies. Here we review the pathobiological sequelae of TBI in the context of blood- and CSF-based protein biomarkers, their potential role in epileptogenesis, and discuss future directions aimed at improving the diagnosis and treatment of PTE.

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.

Cerebrospinal fluid gamma-aminobutyric acid in neurologic disease.

Cerebrospinal fluid gamma-aminobutyric acid (CSF GABA) was analyzed in 151 patients who underwent evaluation for central nervous system disease. CSF GABA was not detected in 19 of these patients, who had no evidence of neurologic disease and who served as controls. GABA was most frequently detected in patients with cerebrovascular disease, and was detected only in Parkinson's syndrome of atherosclerotic origin and dementia of multi-infarct type. CSF GABA was not detected in Alzheimer's disease or Huntington's disease. Patients with grand mal seizures exhibited CSF GABA elevation within 24 hours of the ictus. In patients with multiple sclerosis GABA detection was related to the presence or exacerbation of spinal cord lesions. Further study is necessary to evaluate the significance of elevated CSF GABA in central nervous system disease.