P88. Identification of genome-based biomarkers for response to specific antiepileptic drugs in focal and idiopathic generalized epilepsies

• Published in: Clinical neurophysiology 2015-08, Vol.126 (8), p.e146-e147
• Main Authors: Wolking, S, Becker, F, Rau, S, Weber, Y, Depondt, C, Sisodiya, S, Lerche, H
• Format: Article
• Language: English
• Subjects: Neurology
• ISSN: 1388-2457; 1872-8952
• DOI: 10.1016/j.clinph.2015.04.238

Pharmacoresistance is a major burden in the treatment of epilepsy. The search for an effective and well-tolerated antiepileptic drug (AED) is overall achieved by trial and error. This process often turns out to be challenging and irksome for both, the patient and the clinician. Genetic biomarkers can help in the choice of AEDs in order to individualize the treatment. In the framework of the EpiPGX consortium, a European research project on epilepsy pharmacogenomics, 5000 patients were recruited and meticulously phenotyped. Patient samples were supplied by 10 specialized epilepsy centers. More than 500 phenotype items were assessed. Detailed definitions for pharmacogenomics phenotypes such as multiresistance or late response – i.e. response to a second or later given AED, see below – were created. The consistency of the supplied phenotypes across the participating centers was guaranteed by repeated phenotyping workshops and two rounds of validation exercises on a set of 10 anonymized medical records. Mean inter-rater agreement was 82% for AED outcome classification. True misclassifications accounted for only 5–9% of all cases. We identified and phenotyped patients with focal epilepsies that were late responders to specific AEDs. Late response was defined as 12 months of seizure freedom after failure of at least one well-tolerated AED. We identified 338 late responders to levetiracetam, lamotrigine, or lacosamide. Those are currently being analyzed in the setting of a genome wide association study (GWAS) against a much larger group of non-reponders to the same drugs and to a group of normal controls. For idiopathic generalized epilepsies, we are comparing responders and non-responders to lamotrigine and valproate (VPA). For VPA we identified 487 responders and 164 non-responders; for LTG 158 responders and 217 non-responders. Furthermore we identified 53 subjects that were responders only to the combination of VPA and LTG. The results of the GWAS analysis are pending and are expected in February 2015.