Abstracts

Rationale: Animal models have implicated inflammatory cytokines in the pathogenesis of febrile status epilepticus (FSE) and the development of epilepsy. It has been proposed that the IL-1 system (IL-1β and its antagonist IL-1RA, both competing for binding on the IL-1 receptor) may play a pivotal role in the development of FSE, as well as subsequent temporal lobe epilepsy. Manipulation of this system results in a substantially higher seizure threshold and has anti-epileptogenic effects. The IL-1 system is activated during periods of stress such as seizures, febrile illnesses, and trauma. Induction of IL-1β following one of these stressors triggers a massive release of IL-1RA which plays an important auto regulatory role in dampening the inflammatory response. IL-1RA has been found to have potent anti-convulsant properties. As such inadequate IL-1RA response following IL-1β activation could predispose one to prolonged seizures and may be proposed as a possible mechanism leading to the development of FSE. As the inflammatory cytokine system is one of many complex interactions, more than one system certainly may be involved. Using a sub cohort of the FEBSTAT study, our aim was to evaluate the potential association between inflammatory cytokines and the development of in children with FSE.Methods: Cytokine analysis was performed on plasma samples obtained from children with FSE as part of the FEBSTAT study(n=33) using a multi-plex protein array assay for the following: IL-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40/p70, IL-13, IL-15, IL-17, TNF-α, IFN-α, IFN-ϒ,GM-CSF, MIP-1α, MIP-1β, IP-10, MIG, Eotaxin, RANTES, MCP-1, VEGF, G-CSF, EGF, FGF-basic, and HGF. Age matched control samples were also analyzed (n=17). Data was summarized using mean and standard deviation for each. As the results did not have a normal distribution, nonparametric statistics using the Wilcoxon rank sum test was performed for all comparisons. A Bonferoni correction was performed to account for multiple comparisons (critical p value <0.003846).Results: Although IL-1β plasma levels trended higher in children with FSE (mean 270.8 + 1171.7 SD vs. control 25.2+ 29.2 SD), this did not reach statistical significance (p=0.0633, critical p<0.05). Inflammatory cytokines IL-8 (p=0.0012) and EGF (p= <0.0001) were elevated in children with FSE in comparison to controls. IL-1RA was found to be lower in children with FSE (p= 0.0031), as was VGEF (p=<0.0001) and IL-2R (p=<0.0001). Furthermore, children with FSE were also found to have lower IL-1RA/IL-1B ratios (mean 30.22+25.37 vs. 119.85+107.23, p=0.0039).Conclusions: Our data supports involvement of the IL-1 cytokine system in association with FSE in children. In some children, the IL-1RA auto regulatory response may be inadequate to suppress the pro-convulsant effects of IL-1β, thus creating the propensity for status epilepticus. Elevations of pro-inflammatory cytokines IL-8 and EGF, as well as low levels of VEGF and IL-2R were also associated with FSE. These cytokines may contribute to the pro-convulsant environment created by the IL-1 system in FSE.