Abstracts

Rationale: Valproic Acid (VPA) is reported to be the most effective drug for the control of absence seizures (AS). However, only 75% of children with Childhood Absence Epilepsy (CAE) are controlled. It has been hypothesized that patients who are refractory to VPA might have a different clinical profile or pathophysiology. The aim of this study was to evaluate the frequency of refractory CAE in our population and to determine clinical, socio-demographic and genetic factors associated with absence seizures that are refractory to VPA. Methods: Medical charts of children with CAE followed at the CHU Sainte Justine were reviewed. Clinical, electroencephalographic (EEG) and imaging findings were recorded to correlate with complete VPA response. Factors associated with non-responsiveness were identified through univariate and a multivariable logistic regression analyses. DNA samples of the patients were also collected in order to test for single nucleotide polymorphisms (SNP) in two Cytochrome P450 isoforms: CYP2C9 and CYP2C19. The genotypes were then correlated with responsiveness to VPA. This research was approved by both ethical committees of the CHU Sainte Justine and of the CHU Sherbrooke. Results: VPA led to seizure freedom in 59.1% of patients. Compared to those who responded to VPA, more children with refractory CAE experienced generalized tonic-clonic seizures (GTCS) (36.4% vs. 13.9%; p=0.001) and 48.5% had a pre-treatment seizure frequency greater than 10/day (vs. 26.2% for responders; p=0.003). Past history of febrile convulsions was present in 14.8% of the responders compared to only 4.6% of non-responders (p=0.045). All these factors continued to be significant when combined in a multiple logic regression model. Finally, patients who responded were older at time of seizure onset versus patients who did not respond (p<0.013). VPA non-response was also positively correlated with the presence of the CYP2C19*2 allele (G681A) with an odds ratio of 3.77 (p=0.020). When we inserted this variable in our clinical regression model, beside CYP2C19 genotype (p=0.008), only the age at seizure onset continued to be significant (p=0.006). Conclusions: VPA treatment outcome is therefore associated with certain variables which would allow us to know beforehand which types of patients might or might not respond to the treatment. Our results suggest that certain clinical phenotypes are associated with a reduced response rate to VPA. But most interestingly, these clinical phenotypes seem to play a very minor role in the modulation of the response to VPA compared to the CYP2C19 genotype.