Current challenges in the management of epilepsy.

A series of conceptual reconsiderations and therapeutic advances in recent years has resulted in meaningful changes in the classification, diagnosis, and treatment of epilepsy. The first step in evaluation of the person with epilepsy is determining whether the seizures are partial or generalized in onset; this determination will guide further evaluation and is mandatory in choosing an antiepileptic drug (AED). With 12 new AEDs and 1 device approved for use in epilepsy by the US Food and Drug Administration since 1993, the choice of AED has become more complex and it is impossible to predict whether a patient will respond favorably to a drug based on clinical features or clinical laboratory results. AEDs have many different mechanisms of action, but there does not seem to be a strong base of evidence to demonstrate that AED choice should be based on mechanism of action. Yet, a new secondary analysis of data from clinical trials of the new AED lacosamide suggests that combining this AED with another AED that has minimal or no activity at the sodium channel may lead to better tolerability and efficacy. The new AEDs have been tested in randomized controlled trials and compared with placebo; however, there are few head-to-head trials assessing the efficacy of various AEDs, and none of them provide evidence of a clear first choice drug or first add-on drug. Adverse effect profiles of the new generation of AEDs generally show better overall tolerability, but the choice of AED must be individualized (often based on comorbidities) because the adverse effect profiles of the newer AEDs differ widely. One area where the new AEDs consistently outperform the older AEDs is pharmacokinetic profile. Three new AEDs have no hepatic metabolism or protein binding, and others have minimal drug-drug interactions. Ultimately, selection of an appropriate agent involves matching a patient to a medication, or combination of medications, with the best record of efficacy while avoiding issues of tolerability and unwanted drug interactions (specifically tied to the needs of a given patient). Despite major advances in AED development, approximately one-third of people with epilepsy will have incomplete control of seizures no matter which AED is used alone or in combination, emphasizing the need for more effective AEDs. Patients with medication-resistant epilepsy may be candidates for epilepsy surgery, a highly effective treatment that is underutilized in this population.