Investigating the genetic component of drug resistance in mesial temporal lobe epilepsy: an international multicenter study

• Grant number: 17/04891-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2017
• End date: May 31, 2019
• Field of knowledge: Health Sciences - Medicine
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Iscia Teresinha Lopes Cendes
• Grantee: Miriam Coelho Molck
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07559-3 - BRAINN - The Brazilian Institute of Neuroscience and Neurotechnology, AP.CEPID

Abstract

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy in the adult population, and many of these patients have epileptic seizures refractory to treatment with antiepileptic drugs (AEDs). For these patients, surgical indication is an option to control seizures. However, due to the numerous tests with different combinations of AEDs, the indication of surgery may take many years. In a recent study, our group demonstrated that it is possible to use a prediction algorithm to determine which patient with MTLE will likely to be refractory to AED treatment. This model includes 56 SNPs in candidate genes and the presence of hippocampal sclerosis, leading to and accuracy of prediction of 0.8177. This was the first evidence presented in the literature indicating that genetic information may help predictive drug response in patients with MTLE, reducing the time to propose a more effective alternative of treatment. However, our study was performed in only one clinical center and had a cross-sectional design, where outcome was determined retrospectively. Therefore, the present proposal aims to validate and expand the previous work by evaluating patients from multiple clinical centers in several countries, and accessing outcome (drug response) prospectively. To this end, we propose to carry out an international collaborative study within the International Consortium of Complex Epilepsies, which is housed in the International League Against Epilepsy (ILAE) classification committee. Our proposal is a study carried out in two phases: i) the first phase will have a cross-sectional designed, including patients from various international collaborating groups. We will include at least 300 patients divided into two groups. The same SNPs that had a significant contribution to the prediction of drug response in our previously published study will be genotyped, as well as GWAS-SNPs. ii) The second phase will be a prospective study including at least 500 patients with MTLE divided into two groups. In this phase the same SNPs of phase I will be genotyped. We hope with this strategy to be able to propose a validated algorithm of investigation which can be applied to clinical practice, helping to determine which patients should be sent to epilepsy surgery sooner. In addition, these results my lead to a better knowledge of the molecular mechanisms leading to failure in AED treatment of patients with MTLE. (AU)