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.)

Download full-text


Available from: Avital Cnaan, Nov 27, 2014
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 09/2015; DOI:10.1016/j.clinph.2015.08.016 · 3.10 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this report, we review the pharmacological and non-pharmacological treatments of the different absence seizure types as recently recognized by the International League Against Epilepsy: typical absences, atypical absences, myoclonic absences, and eyelid myoclonia with absences. Overall, valproate and ethosuximide remain the principal anti-absence drugs. Typical absence seizures exhibit a specific electroclinical semiology, pathophysiology, and pharmacological response profile. A large-scale comparative study has recently confirmed the key role of ethosuximide in the treatment of childhood absence epilepsy, more than 50 years after its introduction. No new antiepileptic drug has proven major efficacy against typical absences. Of the medications under development, brivaracetam might be an efficacious anti-absence drug. Some experimental drugs also show efficacy in animal models of typical absence seizures. The treatment of other absence seizure types is not supported with a high level of evidence. Rufinamide appears to be the most promising new antiepileptic drug for atypical absences and possibly for myoclonic absences. The efficacy of vagal nerve stimulation should be further evaluated for atypical absences. Levetiracetam appears to display a particular efficacy in eyelid myoclonia with absences. Finally, it is important to remember that the majority of antiepileptic drugs, whether they be old or new, may aggravate typical and atypical absence seizures.
    Neuropsychiatric Disease and Treatment 07/2013; 9:963-75. DOI:10.2147/NDT.S30991 · 1.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The story began on 11th May 1857 when Charles Locock commented in the Lancet on his use of potassium bromide in 15 cases of "hysterical" epilepsy in young women. The next development was the serendipitous discovery of the anticonvulsant properties of phenobarbital by Alfred Hauptmann in 1912. This predated by more than 20 years the screening of potential therapeutic agents against "electrical seizures" in cats by Houston Merritt and Tracy Putnam. The result was the launching of phenytoin in 1938. Next came primidone, ethosuximide, carbamazepine and valproic acid, all of which can be regarded as first generation antiepileptic drugs (AEDs). Shortly after their synthesis, the benzodiazepines were rapidly recognised as having anticonvulsant activity. The modern era focused on the systematic screening of many thousands of compounds against rodent seizure models under the Anticonvulsant Drug Development Program in the US. This resulted in the global licensing, in chronological order, of vigabatrin, zonisamide, oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam, pregabalin and lacosamide. Rufinamide is available in the US and Europe for Lennox-Gastaut syndrome and stiripentol has been made available for Dravet syndrome under the European orphan drug scheme. Eslicarbazepine can be prescribed in Europe for partial seizures, but not in the US. Has all this activity improved the lives of people with epilepsy? The short answer is-probably yes, but not by very much! This paper will conclude with a précis of the views of a selected group of paediatric and adult epileptologists on the advances in pharmacological management achieved over the last 20 years.
    Seizure 11/2010; 19(10):650-5. DOI:10.1016/j.seizure.2010.10.027 · 1.82 Impact Factor
Show more