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| |  Initial Monotherapy With Ethosuximide Best for Childhood Epilepsy CINCINNATI, Ohio -- March 5, 2010 -- The first comprehensive comparative effectiveness clinical trial of 3 widely used anti-seizure drugs for childhood absence epilepsy has established an evidence-based approach for initial drug therapy. Published in the March 4 issue of the New England Journal of Medicine, data from the double-blind, randomised, comparative clinical trial fill a large information gap in the treatment of childhood absence epilepsy. The research, which identifies important differences between drugs in seizure control and side effects, is expected to impact how physicians select and monitor initial therapy for children with the disorder and ultimately lead to improved outcomes. “Involving 453 children, 32 U.S. medical centers and the National Institutes of Health, this landmark study establishes clinically important differences between the 3 medications most commonly used as initial therapy for childhood absence epilepsy,” said lead investigator Tracy A. Glauser, MD, Comprehensive Epilepsy Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. Although childhood absence epilepsy is common, the comparative efficacy and tolerability of initial therapy with ethosuximide, valproic acid or lamotrigine had not been comprehensively or rigorously assessed. The research team found that ethosuximide provided the best combination of seizure control and fewest attentional side effects over the initial 16- to 20-week period after starting therapy. The researchers concluded ethosuximide is the “sensible choice for initial monotherapy in childhood absence epilepsy.” Children aged 2.5 to 13 years with newly-diagnosed childhood absence epilepsy and free of other medical conditions, such as autism or developmental delay, were randomised to receive ethosuximide (n = 156), valproic acid (n = 148) or lamotrigine (n = 149). Children, their parents and the clinical sites were all blinded to which study medication each child was taking. Study medication doses were incrementally increased until the child was either seizure free (both clinically and by a 1 hour video electroencephalogram [EEG] or the child reached the maximal allowable or highest tolerated dose. The study’s primary outcome goal was to determine the “freedom-from-failure” rate for each medication, defined as being seizure free without intolerable side effects at the 16th week of treatment. A few children who still had seizures but had not yet reached either maximum allowed or tolerated dosage at the 16th week were allowed 1 more dosage increase and re-evaluated at the 20th week of treatment. The study’s secondary outcome examined how the study medications affected attentional abilities in these children. Attentional abilities were measured using the Confidence Index score from the age appropriate computerised Conners’ Continuous Performance Test. Attention dysfunction was defined a Confidence Index of 0.60 or higher. Of the 3 drugs, ethosuximide’s freedom-from-failure rate was 53% compared with 58% for valproic acid and 29% for lamotrigine. The freedom-from-failure rates of ethosuximide and valproic acid were similar to each other and both were significantly higher than that for lamotrigine. A significantly lower percentage of children taking ethosuximide (33%) had abnormal Conners’ confidence index scores compared with those taking valproic acid (49%). Researchers concluded that ethosuximide was preferred as initial therapy because of its improved seizure control compared to lamotrigine and fewer attentional effects compared to valproic acid. Although the clinical trial establishes a rational evidence-based approach for initial drug therapy, the researchers are careful to point out that “even the best empirical therapy fails in almost 50% of newly diagnosed cases.” Also, as patients with childhood absence epilepsy grow into adolescence, they are at risk to develop tonic-clonic seizures, which are resistant to treatment by ethosuximide. “The results of this clinical trial answer important decades old questions and raise new ones” explained Dr. Glauser. “We want to know why specific patients respond differently to different drugs, how we can improve our overall rate of success with initial therapy, and whether those medications that work best in the short-term continue to be the best choice over the long-term.”
SOURCE: Cincinnati Children’s Hospital Medical Center
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