Abstracts

Rationale: Elevated plasma total homocysteine (tHcy) is an independent risk factor for developing vascular disease. We investigated the relationship between elevated tHcy concentrations, caused by both valproic acid (VPA) therapy, 5-methylenetetrahydrofolate reductase (MTHFR) genotype, and indirect measures of endothelial function in epileptic children and adolescents. Methods: Patients with epilepsy treated with VPA and controls without epilepsy (VPA naïve) were recruited. Endothelial function was assessed via peripheral arterial tonometry (PAT) in all participants at baseline. Overnight fasting blood samples were obtained from the epileptic group to assess plasma tHcy, erythrocyte folic acid and serum vitamin B12 concentrations via high-performance liquid chromatography (HPLC) and core lab procedures, while MTHFR genotypes were determined via Genotype-specific Approaches to Therapy in Childhood (GATC) protocol. Serum samples provided from controls were used to assess serum tHcy concentration via HPLC. Within 6 months the same parameters were assessed again in the epileptic group. Results: Nine epileptic patients (78% male; ages 7-16 years) and 31 controls (39% male; ages 11-16 years) were recruited. tHcy concentration significantly increased in epileptic patients after follow-up compared to controls (+29%; P=0.016) while vitamin B12 concentration demonstrated a trend towards a gradual decline. Epileptic patients expressing the 677CT genotype had elevated tHcy and reduced folic acid concentrations compared to patients expressing the 677CC genotype. Endothelial function was affected in epileptic patients, indicated by a significant reduction in the reactive hyperemia-PAT index at baseline and follow-up in epileptic patients compared to controls (-20%; P=0.018 and -23%; P=0.012, respectively), with a corresponding increase in tHcy and decrease in vitamin B12 concentrations. Conclusions: This pilot study prospectively documents an association between elevated tHcy concentration and endothelial dysfunction assessed by PAT in children with diagnosed epilepsy expressing the MTHFR 677CT polymorphism when treated with VPA. Further studies are required to confirm these findings and evaluate long-term cardiovascular risk for children and adolescence with epilepsy on long-term VPA treatment.