Abstract
Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC; Childhood Absence Epilepsy Study Group. N Engl J Med. 2010 Mar 4;362(9):790-9. doi:10.1056/NEJMoa0902014. PMID: 20200383 https://pubmed.ncbi.nlm.nih.gov/20200383 Background: Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined. Methods: In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug doses were incrementally increased until the child was free of seizures, the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. Differential drug effects were determined by means of pairwise comparisons. Results: The 453 children who were randomly assigned to treatment with ethosuximide (156), lamotrigine (149), or valproic acid (148) were similar with respect to their demographic characteristics. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar (53% and 58%, respectively; odds ratio with valproic acid vs ethosuximide, 1.26; 95% confidence interval [CI], 0.80 to 1.98; P = .35) and were higher than the rate for lamotrigine (29%; odds ratio with ethosuximide vs lamotrigine, 2.66; 95% CI, 1.65 to 4.28; odds ratio with valproic acid vs lamotrigine, 3.34; 95% CI, 2.06 to 5.42; P < .001 for both comparisons). There were no significant differences among the three drugs with regard to discontinuation because of adverse events. Attentional dysfunction was more common with valproic acid than with ethosuximide (in 49% of the children vs 33%; odds ratio, 1.95; 95% CI, 1.12 to 3.41; P = .03). Conclusions: Ethosuximide and valproic acid are more effective than lamotrigine in the treatment of childhood absence epilepsy. Ethosuximide is associated with fewer adverse attentional effects. (ClinicalTrials.gov number, NCT00088452.)
Commentary
Drs Strozzi and Joshi have the distinct honor and privilege to write a commentary on an NINDS sponsored study, published in NEJM in 2010 by Dr Tracy Glauser. 1 The question asked was simple; the trial design was elegant and the results eye-opening. We write this editorial from the viewpoints of a current epilepsy fellow (IS) and their attending (CJ).
The Question: Among Available Medications to Treat Childhood Absence Epilepsy (CAE) Which is the Best First Empirical Choice?
CAE is second only to self-limited epilepsy of childhood with centrotemporal spikes 2 in terms of incidence and prevalence. CAE is treated with either ethosuximide, valproic acid or lamotrigine which were approved in 1960, 1983 and 1994, respectively. A physician typically assesses known information about treatment effectiveness (a combination of efficacy and tolerability) and matches their patient to chosen antiseizure medication (ASM). Additionally, for two equally effective ASMs, evolving cognitive side effects at target dose might further narrow ASM choice. In the early part of the 21st century there seemed to be a “race” with new studies (NCT00144872) or publications suggesting lamotrigine as the new ASM to consider in CAE treatment. 3 In 2006, Dr Glauser had previously published evidence (or lack thereof) about existing ASMs to treat CAE and identified a treatment gap. 4 Similarly, a Cochrane review 5 identified the need for better trial design and called for a pragmatic trial comparing ASMs in CAE. 6 The only other published comparative effectiveness trial in generalized epilepsy, at the time 7 , excluded patients under age 4 years and primarily compared valproate, lamotrigine and topiramate for generalized or unclassified epilepsy in an open label phase 4 study.
Study Design
This randomized, double-blind controlled study took 2.5 years to design (personal communication with Dr Glauser). Outcomes and statistical analyses chosen were predetermined. Dosing and titration of each medication according to pharmacodynamic and pharmacokinetic models ensured an appropriate titration without exceeding therapeutic thresholds.
Authors looked at primary endpoint of freedom from treatment failure at 16 weeks (or 20 weeks if target dose had not been achieved by 16 weeks) using either ethosuximide, valproic acid or lamotrigine using a double blind, stratified randomization technique with an open label extension. Prespecified criteria for treatment failure included persistence of absence seizures at week 16 (or 20 to allow for target dose achievement), generalized tonic-clonic seizure at any time or excessive drug-related systemic toxicity. Thus, primary outcome assessed treatment effectiveness (efficacy and tolerability). Secondary outcome was an assessment of attentional deficit using the confidence index of 0.6 or higher on age-appropriate Conners’ Continuous Performance Test outcomes. This secondary outcome enabled comparison between ASMs with potentially equivalent effectiveness based on cognitive outcomes.
Patients experiencing treatment failure were invited to enter a randomized open label extension lasting 2 years after the initial 20 weeks (thus maintaining the initial double blind) allowing for long-term efficacy results that were published later. 8
Study Results
Of the 446 enrolled participants 209 (47%) were free from treatment failure at the end of final follow-up visit, higher for ethosuximide (53%) and valproic acid (58%) group compared to lamotrigine (29%). Majority of treatment failure involved intolerable side effects or lack of seizure control, the latter having higher prevalence in the lamotrigine group, which also required higher drug levels.
Greater number of patients receiving valproic acid (49%) had attentional dysfunction (Conner's continuous performance test with confidence index of 0.60 or higher) compared to ethosuximide (33%) and lamotrigine (24%). These results were independent of seizure freedom within treatment groups.
Implications and Lessons Learned From This Landmark Study
From the Perspective of a Pediatric Epilepsy Fellow (IS)
As a pediatric epileptologist in training, I have the privilege of having most basic clinical questions addressed before entering practice. This landmark paper represents the source of many “knowable facts” which are passed along from attending to trainees, regarding CAE.
Some important points, however, stand out.
Three second rule as a convention to determine clinically actionable seizures in CAE: In addition to bedside hyperventilation in the clinic, an objective, reliable, reproducible test/biomarker in the form of electrographic seizure lasting greater than or equal to 3 s was used as a criterion for both inclusion as well as treatment failure. The operational definition of 3 s of electrographic discharge in CAE was previously published by Holmes et al 9 ; however, it was this NEJM study that established the 3-s rule as a standard for future clinical practice.
Newer is not always better: Ethosuximide and valproic acid had a significantly better efficacy profile compared to the newer lamotrigine, which on the other hand had a slightly better safety profile and lower cognitive side effects.
The comorbidities of CAE are separate from treatment response: The misperception of uncontrolled absence seizures contributing to cognitive difficulties were clarified in this study. Attentional deficits in CAE are independent of seizure burden or control. In all treatment groups, the confidence index results between seizure free patients and those with continued seizures was no different.
Durability: This study has also stood the test of time. Upon review of the latest 2021 Cochrane guidelines for treatment of CAE, 10 eight studies published between 1982 and 2013 were included. The 2010 Glauser study was determined to have the lowest risk of bias and the most robust set of results to date.
From the Perspective of the Attending (CJ)
CAE can be a challenge to treat, and it is important to counsel patients accordingly: As a junior attending in 2008, I was under the impression that absence epilepsy was one of the more benign and easy epilepsy syndromes to treat. This information was based on retrospective studies of chart review and patient questionnaires. 11 Other retrospective studies at the time had indicated a much higher percentage of response to lamotrigine. However, Glauser et al proved that only around 50% of children will respond to the first ASM in the short term.
This was the first randomized, double blind, comparative effectiveness trial in pediatric epilepsy using time to event trial design.
All of us participating in pharmaceutical trials have experienced the challenges of enrolling young patients into placebo-controlled trials. 12 I have also become acutely sensitive to the cost of running such trials and the need to enroll a large number of patients to obtain the statistical power necessary to differentiate true drug effect from placebo. There is increased medical risk to a patient from being exposed to placebo while not getting the benefit of an effective medication in randomized double-blind placebo-controlled trial. Lastly the long treatment ramp-up and maintenance phases of up to 20 weeks prolong trial duration. Time to treatment failure is a type of time to event trial. Despite perceived challenges, time to event trials are the need of the hour 13 especially in younger patients with motor seizures.
Snowball Effect
The childhood absence epilepsy study group continued their work for more than a decade after the initial study resulting in more than 10 follow-up papers from this initial cohort of patients that ranged from topics on cognitive deficits in CAE and pharmacogenetic profiles in responders, to a machine learning approach for predicting impairment of consciousness in CAE.
Prototype of NINDS's Epilepsy Centers Without Walls?
Dr Glauser effectively brought together 32 centers and a team with a common goal in mind that overcame geographic barriers. Key stakeholders included an executive core (clinician/s, clinical pharmacologist/s, bio statistician/s, expert/s in translational medicine), pharmacogenetics core, pharmacokinetic core, data safety monitoring board, and a separately appointed medical safety monitor. Enrollment and study completion required nearly 3 years starting in July 2004 until the first publication in March 2010. One could consider this to be the prototype of NINDS's Epilepsy Centers Without Walls that later came to prominence with SUDEP research.
Conclusion
We are grateful to NINDS for funding this pediatric epilepsy study that was one of the first studies among others including the FEBSTAT study, PREVeNT trial as examples of practice changing seminal work.
Footnotes
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.