Abstracts

Rationale: The mechanism of cellular injury in MTS and its relationship to clinical presentation and severity is incompletely understood. Up regulation of "injury oxidative mechanisms", apoptosis and protein synthesis inhibition have been proposed. We inquired whether specific gene expression profiles could be identified in the hippocampus and predict the post-surgical outcome. Methods: Patients with TLE and candidates for temporal lobectomy were asked to participate and sign an informed consent. Demographic data, seizure history and post temporal lobectomy outcome were reviewed. Patients were divided in 2 groups: seizure onset at or before age 3(early onset group) and after age 3(late onset group). The removed hippocampus (HPC) were labeled and evaluated for specific pathology and for gene expression. The GeneFilters GF211 DNA array containing known named human genes were used (5184 total spots each containing 0.5 ng of approx. 1000 base long, 3' end-derived PCR fragment). The data analysis was conducted in MeV 4.0. We conducted t-tests to compare the two groups. Significant genes were identified if their permutation-based p-values were 0.01 with an adjusted Bonferroni correction. The EASE program with Gene Ontology annotations for Biological Process, Molecular Function and Cellular Location was used to identify the functions that were over-represented among the significantly different genes. Results: Brain tissue was available from 8 consecutive patients (4 M and 4 F) with TLE secondary to MTS. Mean age was 15 years (range 7-23), and mean disease duration was 9.4 years (range 4-16). There were 4 patients in the early onset group (2 M, 2 F; mean age 11, range 7-19 yrs, age of seizure onset 10 days-3 yrs,) and 4 patients in the late onset group (2 M, 2 F mean age 19, range 15-23yrs, age of seizure onset 5 yrs-11 yrs,). Pre-surgical evaluation revealed that the early onset group had more frequent seizures (1x/week- several daily) than the latter onset group (1-3x/ month) and full seizure freedom was obtained in only 2 out of the 4 patients; in the late onset group all 4 patients were seizure free post-surgery after 5 F/U years. There were 111 genes that were significantly different between the two groups. Genes involved in lymphocyte activation (e.g., nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, pre-B-cell colony-enhancing factor, CD3G antigen and others) and genes involved in cell-cell interactions, cytoskeletal function and microtubule function (e.g., integrin beta4, keratin 1 and kinesin family member 5B and others), in particular were over-represented in the late onset seizure group. Conclusions: Our microarray data suggests the presence of an increased immune activation process in children who presented with seizures later than three years of age, as compared to a younger seizure onset age group. This may indicate that these patients were able to mount a protective inflammatory process that can be involved in tissue recovery. There also appears to be altered expression of genes involved in cell-cell interactions and cytoskeletal function.