How to explain multidrug resistance in epilepsy?

Despite advancements in antiepileptic therapy, about one third of people with epilepsy will remain intractable to medication. The initial response to antiepileptic drug therapy is highly predictive of long-term outcome. However, the mechanisms of medical intractability of epilepsy are only incompletely understood. Current interest is focused on two hypotheses: overexpression of drug efflux transporters and alterations in drug targets in the brain, with the most relevant causative mechanism(s) still to be elucidated.