Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: Initial monotherapy outcomes at 12 months

Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A. Children's National Medical Center, Washington, District of Columbia, U.S.A. Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York, U.S.A. National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A. The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.
Epilepsia (Impact Factor: 4.57). 11/2012; 54(1). DOI: 10.1111/epi.12028
Source: PubMed


Purpose: Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy (CAE) based on 12 months of double-blind therapy.
Methods: A double-blind, randomized controlled clinical trial compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed CAE. Study medications were titrated to clinical response, and subjects remained in the trial unless they reached a treatment failure criterion. Maximal target doses were ethosuximide 60 mg/kg/day or 2,000 mg/day, valproic acid 60 mg/kg/day or 3,000 mg/day, and lamotrigine 12 mg/kg/day or 600 mg/day. Original primary outcome was at 16–20 weeks and included a video–electroencephalography (EEG) assessment. For this report, the main effectiveness outcome was the freedom from failure rate 12 months after randomization and included a video-EEG assessment; differential drug effects were determined by pairwise comparisons. The main cognitive outcome was the percentage of subjects experiencing attentional dysfunction at the month 12 visit.
Key Findings: A total of 453 children were enrolled and randomized; 7 were deemed ineligible and 446 subjects comprised the overall efficacy cohort. There were no demographic differences between the three cohorts. By 12 months after starting therapy, only 37% of all enrolled subjects were free from treatment failure on their first medication. At the month 12 visit, the freedom-from-failure rates for ethosuximide and valproic acid were similar (45% and 44%, respectively; odds ratio [OR]with valproic acid vs. ethosuximide 0.94; 95% confidence interval [CI] 0.58–1.52; p = 0.82) and were higher than the rate for lamotrigine (21%; OR with ethosuximide vs. lamotrigine 3.08; 95% CI 1.81–5.33; OR with valproic acid vs. lamotrigine 2.88; 95% CI 1.68–5.02; p < 0.001 for both comparisons). The frequency of treatment failures due to lack of seizure control (p < 0.001) and intolerable adverse events (p < 0.037) was significantly different among the treatment groups. Almost two thirds of the 125 subjects with treatment failure due to lack of seizure control were in the lamotrigine cohort. The largest subgroup (42%) of the 115 subjects discontinuing due to adverse events was in the valproic acid group. The previously reported higher rate of attentional dysfunction seen at 16–20 weeks in the valproic acid group compared with the ethosuximide or lamotrigine groups persisted at 12 months (p < 0.01).
Significance: As initial monotherapy, the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine in controlling seizures without intolerable adverse events noted at 16–20 weeks persisted at 12 months. The valproic acid cohort experienced a higher rate of adverse events leading to drug discontinuation as well as significant negative effects on attentional measures that were not seen in the ethosuximide cohort. These 12-month outcome data coupled with the study’s prespecified decision-making algorithm indicate that ethosuximide is the optimal initial empirical monotherapy for CAE. This is the first randomized controlled trial meeting International League Against Epilepsy (ILAE) criteria for class I evidence for CAE (or for any type of generalized seizure in adults or children). (NCT00088452.)

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    • "Studies focusing on early pre-ictal sources have demonstrated that spike and wave discharges (SWDs) do not suddenly increase but gradually build up over a dynamic network and are preceded by low-frequency occipital and frontal sources (Gupta et al., 2011). Children with CAE commonly present with psychological problems, even if their seizures are controlled (Cerminara et al., 2013; Glauser et al., 2013). "
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    ABSTRACT: Objective: This study quantified the clinical correlation of interictal and ictal neuromagnetic activities from low- to very-high-frequency ranges in childhood absence epilepsy (CAE). Methods: Twelve patients with clinically diagnosed drug-naïve CAE were studied using a 275-channel whole-head magnetoencephalography (MEG) system. MEG data were digitized at 6000Hz and analyzed at both sensor and source levels with multi-frequency analyses. Results: Neuromagnetic changes from interictal to ictal periods predominantly occurred in medial prefrontal cortex and parieto-occipito-temporal junction in absence seizures. The changes were statistically significant in low-frequency bands only (<30Hz, p<0.0001). There was a significant correlation between the source strength of ictal high-frequency oscillations (HFOs) in 200-1000Hz and the number of daily seizures (r=0.734, p<0.01). Conclusions: CAE has focal neuromagnetic sources. The transition from interictal to ictal periods is associated with the elevation of low-frequency brain activities. The strength of HFOs reflects the severity of absence seizures. Significance: Low- and high-frequency MEG signals reveal distinct brain activities in CAE. HFOs is a new biomarker for the study of absence seizures.
    Full-text · Article · Sep 2015 · Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology
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    • "Lowering seizure frequency is the main evaluation criterion in the clinical studies that have been published.23 This objective makes it possible, of course, to reduce accident risk and embarrassment that the seizures cause directly. "
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