Abstracts

Rationale: Status epilepticus (SE) is a common cause of hippocampal neurodegeneration and synaptic reorganization that ultimately may, or may not lead to the development of epilepsy. No effective prognostic tools exist that would reliably predict whether chronic epilepsy would indeed develop in post-SE patients. No reliable diagnostic markers detecting epileptogenesis during the latent period currently exist. For this reason it is not known whether post-SE patients should undergo antiepileptogenic preventive therapy, and in which case, the effectiveness of such therapy is difficult to assess. We attempted to identify prognostic peripheral biomarkers of epilepsy applying a microarray-based approach for the analysis of expression changes in the blood of two rat models of chronic epilepsy. Methods: Adult Wistar male rats (postnatal day 90) were subjected to SE induced by either systemic pilocarpine (n=25) or intrahippocampal kainic acid (KA; n=19). Samples of peripheral blood were collected before status epilepticus to establish a baseline and one, three, seven and thirty days after SE. Isolated RNA was used for global transcriptome analysis using Agilent Rat Whole Genome microarrays. After SE, animals were continuously monitored using both EEG and video for the occurrence, frequency and severity of spontaneous recurrent limbic seizures for a period of six weeks. Seizure syndrome was retrospectively correlated with the changes in blood transcriptome profile. Identified gene expression changes were confirmed using semi quantitative RT-PCR and tested in independent group of post-SE kainic acid rats (n=6) using custom microarrays. Results: Analysis of microarray data revealed that nearly 100 genes in each model were associated with later occurring epilepsy. Approximately 20% of identified genes were regulated in a similar fashion, independent of the model. This gene set provides an initial class predictor/biomarker associated with later occurring chronic seizures. To further evaluate the effectiveness of the identified biomarkers, an additional group of post-SE animals was tested using a custom designed prognostic microarray. Conclusions: This initial analysis demonstrated that the molecular signature preceding the development of epilepsy is present in the peripheral blood transcriptome, allowing the design of a prognostic biomarker chip that can be used both to screen and diagnose potential epilepsy patients, and to prospectively evaluate the effectiveness of antiepileptogenic therapy.