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Shinnar S, Cnaan A, Hu F, Clark P, Dlugos D, Hirtz DG, Masur D, Mizrahi EM, Moshé SL, Glauser TA; for Childhood Absence Epilepsy Study Group. Neurology 2015;85:1108–1114 [PubMed].
OBJECTIVE: To determine incidence and early predictors of generalized tonic-clonic seizures (GTCs) in children with childhood absence epilepsy (CAE). METHODS: Occurrence of GTCs was determined in 446 children with CAE who participated in a randomized clinical trial comparing ethosuximide, lamotrigine, and valproate as initial therapy for CAE. RESULTS: As of June 2014, the cohort had been followed for a median of 7.0 years since enrollment and 12% (53) have experienced at least one GTC. The median time to develop GTCs from initial therapy was 4.7 years. The median age at first GTC was 13.1 years. Fifteen (28%) were not on medications at the time of their first GTC. On univariate analysis, older age at enrollment was associated with a higher risk of GTCs (p = −0.0009), as was the duration of the shortest burst on the baseline EEG (p = 0.037). Failure to respond to initial treatment (p < 0.001) but not treatment assignment was associated with a higher rate of GTCs. Among patients initially assigned to ethosuximide, 94% (15/16) with GTCs experienced initial therapy failure (p < 0.0001). A similar but more modest effect was noted in those initially treated with valproate (p = 0.017) and not seen in those initially treated with lamotrigine. CONCLUSIONS: The occurrence of GTCs in a well-characterized cohort of children with CAE appears lower than previously reported. GTCs tend to occur late in the course of the disorder. Children initially treated with ethosuximide who are responders have a particularly low risk of developing subsequent GTCs.
Childhood absence epilepsy (CAE) is the most common type of childhood-onset epilepsy syndrome. CAE was often considered a “benign” syndrome because of the perception of normal cognition in affected children, excellent remission with treatment, and the high rate of outgrowing epilepsy later in life. However, one issue of concern was the often quoted 30 to 50 percent risk of generalized tonic-clonic seizures (GTCs) based on retrospective series (1–4). In 2016, the news is exactly the opposite. CAE is not really as benign a syndrome as we thought. And, the risk of GTCs is quite lower than what we believed. It all began in 2010 when a randomized clinical trial (RCT) studied a cohort of 446 children with CAE to compare ethosuximide (ESM), lamotrigine (LTG), and valproate (VPA) for initial therapy (5). After 16 weeks of treatment, only 53% of children on ESM, 58% on VPA, and 29% on LTG were seizure free, much lower than previously expected (5). After 12 months of follow-up, seizure-freedom rates were even more sobering. Only 37% of CAE patients were seizure free at the 12-month visit. Forty-five percent of children on ESM, 44% of those on VPA, and a meager 21% of the LTG cohort were seizure free (6). Children with CAE were also found to be at risk of academic failure, as there was a high rate of pretreatment attentional deficits that persisted despite seizure freedom (7). The RCT identified ESM to have superior efficacy compared with LTG and similar efficacy but fewer cognitive side effects compared with VPA. This finding led to the recommendation of ESM being the drug of choice for CAE (8). However, concerns were then raised for a higher risk of GTCs, as ESM is not considered to be effective against GTCs. The current study clarifies the incidence of GTCs after a long-term follow-up of the RCT cohort and attempts to find early predictors of GTCs in CAE.
The most important finding of this study is the low incidence of GTCs in CAE. At a median follow-up of 7 years, only 12% (53 of 446) of children with CAE were reported to have had a GTC, a significantly lower incidence compared with what was previously thought. The only demographic risk factor for the occurrence of GTCs in CAE was older age at the time of randomization (study entry). Five years after randomization, the highest cumulative risk of GTCs was 19% in children aged 9 years and above compared with the lowest risk of 6% in children 6 years or under at the time of study entry. Regression analysis showed that the onset of GTCs was typically late into the course of CAE regardless of the age of onset, but older children developed GTCs after a shorter period of time from the onset compared with younger children. The median age of first GTC in the CAE cohort was 13.1 years. One confounding factor must be noted in determining the true incidence of GTCs in this study. The RCT (5), in an effort to recruit a homogeneous CAE cohort, excluded enrollment of children who reported prior GTC, and this could have led to low GTCs incidence and a later age of occurrence of GTCs. However, authors claim that GTCs at the time of CAE presentation are a rare event both in their study and in the review of the literature, and therefore excluding GTCs in the RCT enrollment would have been unlikely to have significantly altered the results. Another factor to be considered is the inability to separate CAE from juvenile absence epilepsy (JAE). JAE is an overlapping syndrome that has a later age of onset of 7 to 17 years and a higher risk of GTCs, and it could electroclinically mimic CAE. The authors claim that the cohort has been followed long enough that the risk of GTCs is a function of the age of onset of CAE rather than primarily the older age and a diagnosis of JAE per se. Another characteristic in the CAE cohort associated with higher risk of GTCs was a baseline EEG marker having a shorter duration of the shortest spike and wave burst. Of interest, children with this EEG marker also had lower treatment success rate, and the authors suggest that this EEG trait could be a subtype of CAE, predictive of poor response to treatment and higher risk of subsequent GTCs. However, the effect of this EEG variable disappeared in a multivariate analysis after accounting for the effect of treatment response. Of note, neuropsychologic variables such as full-scale IQ had no association with the risk of developing GTCs.
The current study showed no differences in the GTCs incidence in children assigned to ESM, LTG, or VPA initial treatment but showed that the risk of GTCs is a strong function of treatment response at the 16- to 20-week visit, with nonresponders most likely to be at risk of GTCs. A closer look at the data showed that the rate of development of GTCs was strikingly lower in treatment responders than nonresponders in the ESM group, moderately lower in the VPA group, but not different in the LTG group. Ninety-four percent (15 of 16) of children with GTCs in the ESM group were nonresponders (p < 0.0001) compared with 71% (12 of 17) in the VPA group (p = 0.017) and 70% (14 of 20) in the LTG group (p = 1.0). Hence, the study convincingly discounted the concerns of ESM initial therapy being associated with a higher risk of GTCs.
Of 53 patients who had GTCs, 15 were not on any treatment at the time of first GTC. Sixty percent (9 of 15) completed 2 years of successful treatment and were weaned off medication per study protocol. In 37 children, GTC occurred despite being on treatment including monotherapy or polytherapy of RCT as well as non-RCT antiepileptic drugs. It is not clear if any of the GTCs patients were on antiepileptic agents that could worsen CAE and perhaps posed additional risk of GTCs. It is also not clear if the patients on long-term follow-up (on or off antiepileptic drugs) underwent any periodic EEGs systematically to know the recurrence of unwitnessed absence seizures before GTCs brought them back to attention.
The story of CAE continues to evolve from the RCT cohort (5). After the findings from RCT shattered the benign perception of CAE, this current study offers much better news in that the risk of GTCs in a well-differentiated CAE cohort is much lower than previously thought and is particularly low if a child responds to ESM initial therapy. For now, ESM will retain its place as the drug of choice for CAE.
Editor's Note: Authors have a Conflict of Interest disclosure which is posted under the Supplemental Materials link.