Abstracts

Rationale: The aim of this study was to determine if valproate (VPA) therapy is associated with increased levels of autoantibodies to the folate receptor, in order to further explore the hypothesis that immune-mediated folate receptor dysfunction is a mechanism of VPA teratogenesis. Methods: Female subjects aged 18-50 who were taking either VPA or lamotrigine (LTG) as monotherapy or as part of polytherapy, and had never taken the other medication. LTG was intended as a comparator since it is associated with a much lower risk of teratogenesis than VPA. Subjects were enrolled at the Hosftra North Shore-LIJ School of Medicine and the analysis was performed in the laboratory of Dr. Richard Finnell at the University of Texas in Austin. The analyses performed were IgG and IgM , and combined IgG and IgM autoantibodies binding to the alpha type folate receptor. Additionally, a folate blocking assay measuring the competitive inhibition of folate binding between serum and immobilized folate receptor, alpha type, was performed. Results: Thirty-seven women were enrolled, of which 27 were in the LTG arm and 10 were in the VPA arm. Twenty-eight subjects were taking monotherapy. Across groups, there were no baseline differences in age, use of vitamins or folate supplementation, family history of birth defects, or reason for antiepileptic drug (AED) use (epilepsy, migraine or psychiatric condition). Body mass index (BMI) was significantly higher in the VPA group compared to the LTG group. There was no difference in the results when analyzed by parametric and nonparametric methods. The p values were close to 1 for differences between IgG, IgM and IgGIgM combined. T-tests for means of immune parameters between groups showed no differences, with small differences in means and standard deviations between groups. However, a potentially significant effect cannot be ruled out as evidenced by the fairly wide 95% confidence intervals (Table 1). These data were unchanged when the analysis was performed on the 28 monotherapy subjects only. There was no correlation between any immune parameters and factors within treatment groups including BMI, use of vitamins or folate, AED dose, duration of therapy or AED level. Further, across the entire group, there was no correlation between BMI and antibodies or tissue blocking to the alpha type folate receptor. However, age was negatively correlated with blocking at the alpha type folate receptor (p=0.037) and this correlation was present in the LTG group. Conclusions: The negative result of this small study suggests that the folate receptor auto-antibody mechanism of possible teratogenesis must be studied with a larger study group or with subjects who bore children with birth defects. However, a sample size analysis using the means and an average of the SDs for the IgGIgM levels in each group shows that 5800 subjects would be needed to find a difference in means between the two groups with 80% power and a 0.05 significance level. This large number suggests that this avenue of research may not be clinically relevant and supports futility of furthering this work. Sponsored by the Epilepsy Foundation