COLUMBUS, OHIO—Evidence for the safety and efficacy of antiepileptic drugs (AEDs) in children has become more robust in the past 20 years, but the data remain insufficient to answer certain questions, according to research presented at the 43rd Annual Meeting of the Child Neurology Society. “We are still catching up,” said Sudha K. Kessler, MD, a neurologist at the Children’s Hospital of Philadelphia.

To date, investigators have accumulated little class I evidence of drug efficacy in children with new-onset epilepsy. Exceptions include a trial of topiramate and a study of childhood absence epilepsy. Comparative effectiveness data for new-onset focal epilepsy consist of little more than expert opinion, “which is a key gap,” said Dr. Kessler. But by including children in new regulatory trials of AEDs, researchers have gathered more evidence about refractory pediatric epilepsy.

Regulatory Trials Leave Unanswered Questions
Pediatric neurologists must decide which therapy among a large pool of available AEDs is the most appropriate for each patient. The first source that most neurologists consult is the series of studies submitted when a medication undergoes regulatory review, said Dr. Kessler.

In the past, most studies of new AEDs were conducted in adults, although this tendency is changing. Most of these medications are tested in patients with medication-resistant epilepsy. AEDs often are studied as supplements to patients’ existing regimens, rather than as monotherapies, and the primary outcome is almost always efficacy, which usually is defined in terms of the number of seizures. Many studies also examine a drug’s 50% responder rate, which is the percentage of study participants that have at least a 50% reduction in seizures. The studies cover a relatively short term and generally last from 12 to 15 weeks.

Regulatory trials do not “necessarily tell us everything that we want to know,” said Dr. Kessler. In addition to focusing on adults, rather than children, AED studies rarely provide information about new-onset epilepsy. The studies also do not gather comparative effectiveness data; instead, they compare the study drug with placebo. Furthermore, neurologists may not gain much information about drugs’ tolerability or long-term effects from regulatory trials.

Comparative Effectiveness Studies of AEDs
The literature contains studies that address some of the questions about AEDs that regulatory studies leave unanswered. For example, the Standard and New AED Studies conducted in Europe were comparative effectiveness trials that examined focal epilepsy and idiopathic generalized epilepsy. The inclusion criteria and study design were developed to approximate the conditions of clinical practice. After randomization, clinicians’ treatment decisions were not limited by the protocol, and the follow-up lasted for years.

The studies’ primary outcomes were time to treatment failure and time to one-year seizure remission. Treatment failure was defined as lack of seizure reduction or insufficient tolerability. Seizure remission is a valuable outcome because several studies now indicate that people with refractory epilepsy can achieve meaningful remissions, said Dr. Kessler. Among the investigators’ conclusions was that lamotrigine may be a clinically effective and cost-effective alternative to carbamazepine for patients with partial seizures.

Another source of comparative effectiveness data is a study by Glauser and colleagues that examined ethosuximide, valproate, and lamotrigine as treatments for childhood absence epilepsy. The trial’s primary outcome was freedom from treatment failure, which was defined as the discontinuation of treatment for lack of efficacy or for lack of tolerability. The secondary outcome was attentional dysfunction, which made the study one of relatively few to analyze AEDs’ effects on cognition and behavior. Ethosuximide and valproate had similar rates of freedom from treatment failure, and these rates were higher than that for lamotrigine. Attentional dysfunction was less common with ethosuximide than with valproate.

Dr. Kessler and colleagues studied children with new-onset focal epilepsy who were diagnosed between 2008 and 2010 to compare the efficacies of levetiracetam and oxcarbazepine. The primary outcome was time to drug failure, which was defined as the discontinuation of an AED or the initiation of a new AED. At six months, approximately three-quarters of participants were still taking their first AED. The difference in efficacy between the two drugs was not statistically significant.

Cognitive and Behavioral Effects of AEDs
Loring and colleagues are recruiting patients for a study of the cognitive outcomes of AEDs in pediatric localization-related epilepsy. The multisite study will compare the cognitive and behavioral effects of lamotrigine, levetiracetam, and oxcarbazepine. A population of 300 children will be tested at baseline, randomized to one of the drugs, and tested again at three months and six months.

Dr. Kessler and colleagues also examined the effectiveness of rufinamide among patients with Lennox–Gastaut syndrome and patients with other forms of epilepsy. The primary outcome was either discontinuation of rufinamide or initiation of additional therapy. The study included approximately 135 participants. At 12 months, about half of participants “found enough value in rufinamide that they continued to be on it without having added anything else,” said Dr. Kessler.

—Erik Greb

Can the Literature Guide Treatment of Pediatric Epilepsy?