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Ethosuximide Found to be the Best Treatment for Childhood Absence Epilepsy


An older, less expensive drug, ethosiximide proved to be as effective with fewer adverse events compared with two newer drugs for childhood absence epilepsy.

In a double-blind randomized clinical trial, the anticonvulsant ethosuximide (available since the 1950s) was found to be the optimal treatment for childhood absence epilepsy — the most common form of childhood onset epilepsy syndrome — because it was effective and had fewer adverse cognitive side effects than two other therapies.

Researchers performed a head-to-head trial with ethosuximide, lamotrigine, and valproic acid, the three most effective and commonly used drugs to treat childhood absence epilepsy. Ethosuximide and valproic acid were found to be more effective than lamotrigine at the end of the 16-week trial; however, ethosuximide had fewer attentional side effects compared to valproic acid, according to the March 4 study in The New England Journal of Medicine (NEJM).

One of the study authors, Shlomo Shinnar, MD, PhD, professor of neurology, pediatrics, and epidemiology and director of the Comprehensive Epilepsy Management Center at Albert Einstein College of Medicine-Montefiore Medical Center, told Neurology Today that there is a need for additional head-to-head trials among first-line agents to determine which is the most efficacious; against placebo all the drugs win. Dr. Shinnar added that these types of trials “are critical to guide choice of drugs for these common disorders.”


Investigators randomized 453 patients between ages 2.5 and 13 years to ethosuximide, lamotrigine, and valproic acid. Doses were increased every one to two weeks over the 16-week trial until either freedom-from-failure was achieved — that is, patients still had seizures when the dose limit was reached — or adverse side effects prohibited a dose increase. The maximum allowable daily dose for the medications was 2000 mg for ethosuximide, 3000 mg for valproic acid, and 600 mg for lamotrigine.

Researchers also tested for attentional dysfunction as a secondary outcome. The physician's goal is to help children outgrow their seizures with limited morbidities; however, attentional deficits are a “hallmark of the disease” and the medications themselves can compound that problem, said Dr. Shinnar.

Participants ages 6 years and older underwent baseline neuropsychological testing within seven days of beginning medication. The Conners' Continuous Performance Test assessed attention, verbal and non-verbal intelligence, learning skills, visuomotor integration, executive function, vocabulary, and memory. A confidence index of 0.60 was used as an indicator of clinically significant attention difficulties.

Patients were evaluated every four weeks during the first 16 weeks of the trial. If seizures were reported, researchers increased the dosage. In the absence of seizures, researchers performed bedside hyperventilation in five-minute intervals. The dosage was increased if a seizure occurred; if no seizure occurred, a one-hour video EEG was obtained.


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Those who had not reached the drug-dose limit at 16 weeks had their medications adjusted a final time and were re-evaluated four weeks later. Forty-seven percent of participants no longer experienced absence seizures after five months. Patients who were treated with valproic acid had the highest freedom-from-failure rate — 58 percent — compared to 53 percent of patients treated with ethosuximide (p<0.001). Twenty-nine percent finished seizure free on lamotrigine (p<0.001).

There were two main causes of treatment failure: lack of seizure control (24 percent) and intolerable adverse side effects (22 percent).

At the end of the trial, the results were also available for the 316 participants in the Conners' Continuous Performance Test. Patients on valproic acid experienced more adverse cognitive side effects than those on the other treatments. Forty-nine percent of patients in the valproic acid cohort scored at or above the confidence index score of 0.60, which indicates attentional dysfunction, compared to 33 percent taking ethosuximide (p=0.03) and 24 percent taking lamotrigine (p<0.001).

Eight participants had to discontinue treatment because they had generalized tonic-clonic seizures: three were taking ethosuximide; four, valproic acid; and one, lamotrigine.


DR. SHLOMO SHINNAR said there is a need for additional head-to-head trials among first-line agents to determine which is the most efficacious.


Orrin Devinsky, MD, director of the New York University Epilepsy Center in New York City, praised the study authors for what he called an “outstanding and incredibly effective and helpful [study].”

“I think there's a relative paucity of head-to-head trials on medications with large numbers of patients with excellent methodologies,” Dr. Devinsky said. “This is a very important study because there is very little class 1 data on the treatment of epilepsy.” Of equal importance was the trial's comparison of the relatively newer drugs to ethosuximide, he added.

“Many people automatically assume that newer drugs are better,” said Marc Patterson, MD, chair of the Division of Child and Adolescent Neurology and program director of the Child Neurology Training Program at the Mayo Clinic in Rochester, MN. “[Newer drugs] do have some pharmacological [and pharmacodynamic] advantages, but their superior clinical efficacy just an assumption [until it is proven in clinical trials].”

However, both Drs. Devinsky and Patterson acknowledged the study's limitations. In this particular population the patients are treated for years, so the researchers need to determine the efficacy of these drugs at six months, two years, and longer, said Dr. Patterson. But this is still a great starting point, he added. He hopes that this study group continues on with longer studies.

“The primary outcome was at 16 weeks but we continued to follow the children in a double blind fashion until two years of treatment,” Dr. Shinnar said. The longer term outcomes are being analyzed and a study of the long term outcomes of this cohort and the impact of the initial therapy is in progress, according to Dr. Shinnar.

Dr. Devinsky also warns neurologists against adhering exclusively to the results of the study when treating their patients. “Anyone who treats these types of seizures realizes that individual variability is enormous,” said Dr. Devinsky. “For any patient a different medication may be more suitable.”


Neurology Today Editor-in-Chief Steven P. Ringel, MD, Comments:


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Neurologists are tempted to offer patients newer, more costly medications. Consciously or subconsciously, we assume that the “latest greatest drug is more effective and causes fewer side effects than older standby treatments. Unfortunately there are few head-to-head comparisons of existing therapies to counter that thinking process. That's why it does my heart good to see that ethosuximide, a drug that was available since the 1960s, outperformed valproic acid and lamotrigine in controlling childhood absence seizures with fewer adverse attentional effects. [Disclosure – I take hydrochlorthiazide; a 2002 comparative effectiveness trial demonstrated this 1950s drug to be the most effective and least expensive antihypertensive treatment.]

In the future, neurologists can expect to see more comparative effectiveness trials to help guide treatment decisions. The American Recovery and Reinvestment Act included $1.1 billion for studies that compare drugs, medical devices, surgery and other ways of treating specific conditions. The Institute of Medicine research priority list of 100 topics includes 14 in the clinical neurosciences, six of which are primarily categorized as neurological disorders. Because of rapidly increasing health care costs, Congress and health policy experts hope that these studies will save money by discouraging the use of costly, less effective treatments.

Pharmaceutical and medical device makers, fearful that comparative effectiveness studies will be used to deny coverage for more expensive care, have signaled that these efforts are a means of rationing care and limiting physician choice. Neurologists would be wise to disregard such alarmist views and should embrace studies that help us improve both the quality and cost effectiveness of the care we provide our patients.•


• Glauser TA, Cnaan A, Adamson PC, et al, for the Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 2010;362(9):790–799.