Dr. Anne T. Berg is a Research Professor in the Department of Pediatrics, Epilepsy Center, at the Ann&Robert H. Lurie Children's Hospital of Chicago and Northwestern Feinberg School of Medicine.
Childhood absence epilepsy (CAE) is a common form of childhood-onset epilepsy and accounts for approximately 10% of all epilepsies in children 15 years and younger.[1-3] It is generally considered a pharmacologically responsive form of epilepsy, although some children do experience difficulty with seizure control. In about two thirds, CAE completely remits[5, 6]; children can discontinue treatment, and they remain seizure free essentially indefinitely. Because CAE is typically limited to absence seizures, therapy is selected among drugs with known efficacy for that seizure type. In the past, the first-line therapies were ethosuximide (ESM), a drug with a narrow spectrum of efficacy almost entirely limited to absence seizures, and valproic acid (VPA), a broad spectrum drug that is effective in controlling a large number of different seizure types.[7, 8] A recent randomized controlled trial (RCT) demonstrated highly comparable efficacy of ESM and VPA in the short term (at 3 months and at 1 year) for control of absence seizures in children with CAE.[9, 10] Animal studies, however, have suggested that ESM might have disease-modifying properties in two different genetic models of absence epilepsy in rats.[11, 12] We hypothesized that a truly “disease-modifying” impact of ESM (vs. simply seizure suppression), would be seen in long-term epilepsy remission rather than short-term response to medication in children with CAE. To test this hypothesis, we examined complete remission (5 years both seizure free and drug free) and other secondary seizure outcomes in children with CAE who were enrolled in a community-based prospective study of epilepsy. The cohort has been followed into adolescence and early adulthood.
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Our observational results regarding early response to ESM and VPA are entirely consistent with the findings of a definitive head-to-head RCT that concluded ESM and VPA was comparably effective for seizure control in CAE at 3 months and 1 year.[9, 10] They further strengthen and complement the trial findings as our study represents the results of community practice and not the highly selected patient groups who generally enter randomized trials. Our findings suggest, however, that, despite similar short-term efficacy for seizure control, the long-term seizure outcomes may differ for VPA and ESM. Children who initially received ESM were less likely to experience subsequent relapses for any reasons compared to children who received VPA. After ≥5 years of follow-up, children initially treated with ESM were more likely to be at least 5-years seizure free at last follow-up. Specifically, they were much more likely to be in complete remission (both 5-years seizure free and medication free). The difference appeared present even for 10-year remission.
In a nonrandomized study such as ours there are bound to be concerns over confounding by indication, that is, patients with a known poor prognosis are preferentially given one treatment, whereas patients with a better prognosis are preferentially given a different treatment. Any differences in outcomes between the two treatment groups could thus be attributable to baseline differences between the patients in those groups. For these reasons, we a priori excluded children with convulsive seizures for whom the preferred drug would have been VPA. We also considered evidence of school difficulties (special education prior to diagnosis), low IQ, ordering of neuroimaging at initial diagnosis (as indications of heighted concerns), family history of epilepsy, age at onset, and age at diagnosis. None of these factors was associated with treatment selection or seizure outcome. The only factor associated with treatment selection was atypical EEG features.
Atypical features have been discussed by experts in the field as important prognostic factors in CAE, with some suggesting that they be considered exclusion criteria.[15, 16] One study reported atypical features to predict poorer outcomes in a large, heterogeneous range of epilepsies in which absence seizure occurred with age at onset from 0 to 15 years. The series also included individuals with convulsive seizures. Therefore, although in a broader sample of all children with any kind of absence seizure, atypical features may be common in subgroups with poorer outcomes, these other subgroups do not meet criteria for children with the electroclinical syndrome of CAE. A second study reported atypical features (as we have also defined them) to be associated with a poorer outcome. This study targeted a clinical group that more closely resembled CAE but still included patients we would have excluded. It was not clear whether atypical features were prognostic factors within subgroups of patients already excluded from our series (e.g., with other seizure types) or whether they did in fact predict long-term prognosis in children otherwise meeting criteria for CAE. The authors also indicated a strong preference for the use of VPA in that series. Overall, there is little evidence that “atypical” features are prognostic of long-term outcome in CAE, as defined by commonly accepted criteria. A recent series of articles demonstrated that these features occur frequently in CAE but do not meaningfully help define the syndrome itself.[13, 22, 23] In the end, we found, in our fairly “pure” series that, although atypical EEG features were strongly associated with the choice of the initial drug, they were only modestly associated with long-term seizure outcomes and no longer associated after adjustment for initial treatment.
At the time these children were recruited, there was no literature on the comparative effectiveness of these two drugs, so other than the potential concern regarding progression to juvenile myoclonic epilepsy (JME) with multiple seizure types not controlled by ESM, it is unclear what other subtle biases would exist that we have not already addressed as there were, at the time, and still are no data to guide treatment decisions in this regard.
Our findings suggest a hypothesis, that ESM might have disease-modifying properties and may have an impact on the long-term course of CAE. Recent experiments in two different genetic rat models of absence epilepsy provide support for this hypothesis.[11, 12] In these absence models, early treatment with ESM during development reduced the incidence of spike-wave seizures even long after the medication was discontinued. Because the treatment also prevented activity-dependent dysregulation of ion channels and epigenetic changes in DNA-methylation it was proposed that ESM may suppress epileptogenesis in this form of epilepsy. Beyond improvement of seizure outcome, disease-modifying treatment has the potential to improve known absence epilepsy comorbidities such as impaired attention and emotional function.[10, 24-26] Indeed, at least in the animal models, early intervention with ESM was shown to prevent anxiety and depressive behaviors associated with this form of epilepsy.[12, 27]
As acknowledged, the study was not randomized. Randomized controlled trials have severe limitations, however. For example, they rarely are representative of the target population or the large population to which the results may be applied. Furthermore, they are often limited to studying short term, surrogate outcomes. Complete remission after 10–15 years would be a difficult a priori outcome for an RCT. Information from RCTs can be and often is complemented by data from multiple sources. The term “comparative effectiveness” encompasses a range of clinical research endeavors that include but are not limited to RCTs. These different approaches, including observational and qualitative studies, can help fill in gaps left by many RCTs. Furthermore, comparison of well-controlled observational studies to RCTs has shown that observational studies, when carefully considered, yield answers that are comparable to those obtained in randomized trials. Although we would like to see our findings tested independently by others, they represent an initial first step toward examining the potential disease-modifying effect of ESM in this setting. We note that short-term outcomes, the typical target of RCTs, may not be adequate for studying this phenomenon.
EEG tracings, although often centrally read, were not always. Most were recorded on paper and can no longer be retrieved. Regardless, what was written in the reports is what was available to the treating clinicians and was the information that they used when making medication decisions.
VPA is clearly an excellent drug for the treatment of many seizure types and forms of epilepsy, and is a drug of choice in many patients with multiple seizure types. By contrast, ESM's use is narrowly restricted to treatment of absence seizures.[7, 8] Children with CAE usually have only absence seizures. ESM, in the short term, now has class I evidence supporting its use over lamotrigine (LTG) for seizure efficacy and over valproate due to its cognitive profile but not seizure efficacy.[9, 10] Whether benefits extend to the long term is an important question raised by our findings. A definitive study would take years to perform. Our findings, which fall into the growing tradition of comparative effectiveness research, provide clinical evidence to support the novel hypothesis suggested in laboratory studies that there may be disease-modifying properties specific to ESM in the treatment of CAE.