Old drug may be first choice for childhood petit mal epilepsy

Effectiveness and modest side effects tilt comparison toward ethosuximide

In a three-way test, a 50-year-old drug has edged out two newer ones for treatment of a kind of epilepsy that causes children to gaze off into space.

The new study provides much-needed data for doctors, since all three medications have been used for years without being compared against one another in a controlled trial. The drug that came out on top, ethosuximide, gave the best balance of effectiveness and side effects, researchers report in the March 4 New England Journal of Medicine.

In the aptly named childhood absence epilepsy, or petit mal epilepsy, a child stops in the middle of an activity and stares blankly for 15 seconds or longer. “You can’t snap them out of it,” says study coauthor Tracy Glauser, a pediatric neurologist at the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital. ”The kid is just like a statue.” Although appearing frozen, such a child is undergoing “an electrical storm on the surface of the brain,” he says.

The top three drugs prescribed for childhood absence epilepsy are ethosuximide (also sold as Zarontin), valproate (Depakote), and lamotrigine (Lamictal). Glauser and his colleagues randomly assigned 453 children with this form of epilepsy to receive one of these drugs for several months. The children ranged in age from 2 to 13 years and were seen at 32 medical centers across the United States.

During the trial, parents reported any seizures their children had, and doctors checked for hidden seizures using electroencephalograms. Another test required children to blow on a pinwheel and become slightly hyperventilated, which can bring on pediatric absence epilepsy seizures. This test is designed to detect whether children who appear normal while on medication for petit mal epilepsy are still at risk of seizures during rigorous playground activities.

Doctors also recorded any side effects the children had and watched for signs of attention loss, a problem that affects a child’s in-school performance. Doctors increased medication dosage gradually until children either stopped having seizures, reached a preset maximum dose or reached 20 weeks of treatment.

Treatment was considered a failure if it did not stop seizures or caused intolerable drug side effects. Overall, nearly as many children in the trial failed treatment because of side effects as from failure to stop seizures.

At the final checkups, 58 percent of the valproate children had successful treatment, as did 53 percent of those on ethosuximide and 29 percent of those on lamotrigine. But about half of the children taking valproate experienced attention problems, compared with one-third of those getting ethosuximide and one-fourth of those on lamotrigine.

“Even though valproate was good at getting rid of the kids’ seizures, it appears it was doing so at the expense of mildly dulling the brain in some cases,” says neurologist Jacqueline French of the New York University School of Medicine.

“Ethosuximide came out the winner,” says Glauser, since its effectiveness was comparable to valproate and it was well tolerated, meaning it had fewer side effects such as weight gain, hostility, and attention problems.

“This is a beautifully done study,” French says, but she sees the results as open to interpretation. “When efficacy and side effects go in two different directions, comparative effectiveness becomes very complicated,” she says. “Lamotrigine was well tolerated but not as effective. Valproate is effective but poorly tolerated. Ethosuximide is pretty effective and pretty well tolerated,” she says.

In the past, doctors have tended to favor one drug over another for all their patients. Now they have better information, French says. “They’ll be able to sit down with parents and children and discuss the risks and benefits of each therapy.”

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