Childhood absence epilepsy (CAE) is the most common pediatric epilepsy syndrome, occurring in 10–17% of all children with epilepsy with an annual incidence of 6.3–8/100,000 in children <15 years of age (Berg et al., 2000; Jallon et al., 2001). The classic characteristics include very frequent (several to many per day) absence seizures in an otherwise normal-appearing child with 3-Hz bilateral, synchronous, symmetrical spike-wave pattern with normal background activity on electroencephalography (EEG) (International League Against Epilepsy, 1989). Previously considered benign, growing evidence indicates that children with CAE have a high rate of baseline attentional deficits unrelated to seizure frequency, along with long-term psychosocial difficulties and variable remission rates (Bouma et al., 1996; Wirrell et al., 1997; Pavone et al., 2001).
There have been no published class I or class II initial monotherapy clinical trials for the three most commonly used antiepileptic medications (ethosuximide, lamotrigine, and valproic acid) in this population (Glauser et al., 2006). In 2003, the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) funded a trial to compare the efficacy and effectiveness of these three medications. The primary endpoint was at 16–20 weeks, but built into the trial was an examination of longer-term outcomes. The short-term data showed that ethosuximide and valproic acid were more effective than lamotrigine in controlling the absence seizures and that ethosuximide was associated with fewer adverse attentional effects compared to valproic acid. These short-term data indicated that ethosuximide was a “sensible choice for initial empirical monotherapy in childhood absence epilepsy” (Glauser et al., 2010).
Ideally, optimal initial monotherapy is the medication that provides the best short- (4–5 months), medium- (1-year postdiagnosis), and long-term (>2 years postdiagnosis) outcomes. For multiple reasons, it is not guaranteed that the short-term initial monotherapy results of the CAE trial would match medium- and long-term outcomes. For example, as children with CAE get older, there is an increased risk of generalized tonic–clonic seizures (Currier et al., 1963; Livingston et al., 1965; Charlton & Yahr, 1967; Loiseau et al., 1983; Dieterich et al., 1985; Wirrell et al., 2001; Trinka et al., 2004; Grosso et al., 2005; Callenbach et al., 2009), and ethosuximide has previously been reported to be ineffective in preventing these types of seizures (Glauser, 2002). Second, chronic drug toxicities, such as weight gain with valproic acid, may become treatment limiting later rather than in the short term (16–20 week) period (Glauser, 2007). Medium- and long-term outcomes need to be combined with short-term results to determine the optimal initial monotherapy. The main purpose of this report is to expand the 16–20 week initial monotherapy data for CAE to outcomes at 12 months of initial therapy in subjects participating in a long-term double-blind, randomized comparative trial. A secondary purpose is to provide sufficient methodologic detail and data to qualify this study as a class I study using the 2006 International League Against Epilepsy (ILAE) classification criteria (Glauser et al., 2006). These medium-term (12 month) results will be combined with the short-term (16–20 weeks) results to help better determine the optimal initial empirical monotherapy for children with CAE.