IL‐1β associations with posttraumatic epilepsy development: A genetics and biomarker cohort study

Abstract

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.

Acute CSF interleukin-6 trajectories after TBI: Associations with neuroinflammation, polytrauma, and outcome

“…Many studies have shown that genetic variation is associated with outcomes and conditions following TBI (Hoh et al, 2010;Weaver et al, 2012;Wagner et al, 2012;Garringer et al, 2013;Diamond et al, 2014;Failla et al, 2014). Of note, an IL-6 polymorphism (À174 G/C) has been reported as associated with mortality after severe TBI (Dalla Libera et al, 2011) and the development of Alzheimer's disease in non-TBI populations (Qi et al, 2012).…”

Update on Cysticercosis Epileptogenesis: the Role of the Hippocampus

“…Moreover, compared to the existent traumatic brain injury model [54, 55], parenchymal brain calcified cysticerci have the advantage of being much more homogeneous and predictable in their structure and evolution than are traumatic brain lesions. Knowledge provided from these suggested cohort studies might also allow the development of novel interventions to prevent chronic epilepsy in NCC and perhaps in other forms of acquired epilepsy.…”

Principal components derived from CSF inflammatory profiles predict outcome in survivors after severe traumatic brain injury

“…Studies have characterized certain candidate cytokines, chemokines, cell-surface markers, and microglia as elevated early after injury compared to uninjured controls (Woodcock and Morganti-Kossmann, 2013). Contemporary concepts contend that controlled inflammation is necessary to clear debris and damaged cells early following TBI, while sustained elevations of inflammatory markers, such as IL-1β, TNFα, and IL-6, are deleterious if not physiologically regulated and can lead to an increased risk of depression (Juengst et al , 2014), epilepsy (Diamond et al , 2014), cognitive deficits (Clausen et al , 2009, 2011) and poor global outcomes (Kumar et al , 2014). …”