Second monotherapy in childhood absence epilepsy

Abstract

Objective: To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure.Methods: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16-20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits.Results: A total of 208 children were enrolled, randomized, and received second therapy. At both week 16-20 visit and month 12 visit, ethosuximide's (63%, 57%) and valproic acid's (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine's (45%, 36%, p 5 0.051 and p 5 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine (p , 0.0001). At both the week 16-20 and month 12 visits, attentional dysfunction was numerically more common with valproic acid than with ethosuximide or lamotrigine. For each medication, second monotherapy freedom from failure proportions demonstrated noninferiority to initial monotherapy freedom from failure proportions.Conclusions: As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications. ClinicalTrials.gov identifier: NCT00088452.Classification of evidence: This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with ethosuximide or valproic acid is superior to lamotrigine. Neurology ® 2017;88:182-190 GLOSSARY AED 5 antiepileptic drug; CAE 5 childhood absence epilepsy; CI 5 confidence interval; CPT 5 Continuous Performance Test; FFF 5 freedom from treatment failure; GTC 5 generalized tonic-clonic; ILAE 5 International League Against Epilepsy; OR 5 odds ratio; RCT 5 randomized clinical trial.A double-blind randomized clinical trial (RCT) compared ethosuximide, lamotrigine, and valproate as initial monotherapy for children with newly diagnosed childhood absence epilepsy (CAE).1,2 Freedom from treatment failure (FFF) was assessed at week 16-20 and at month 12 of therapy. The FFF rates at these 2 timepoints for ethosuximide were 53% and 45%, valproate 58% and 44%, and lamotrigine 29% and 21%.1,2 Ethosuximide was identified as the optimal initial therapy due to superior efficacy compared with lamotrigine and similar efficacy but fewer attentional side effects when compared to valproate. However, initial monotherapy failed in a substantial proportion of children with CAE.

Cognitive development in absence epilepsy during long-term follow-up

“…On the contrary, improvement in sustained attention in this study did not coincide with similar improvement in other cognitive domains. Furthermore, although attentional deficits in this RCT were associated with the use of Valproate, the overall prevalence of attentional deficits from baseline up to 12 months of follow-up remained roughly the same, while some improved and some worsened (Cnaan et al, 2017;Glauser et al, 2013;Masur et al, 2013). However, in line with our results, modest improvements in attention were reported in a by proxy questionnaire in the same RCT after 1 year (Shinnar et al, 2017).…”

“…Furthermore, although attentional deficits in this RCT were associated with the use of Valproate, the overall prevalence of attentional deficits from baseline up to 12 months of follow-up remained roughly the same, while some improved and some worsened (Cnaan et al, 2017;Glauser et al, 2013;Masur et al, 2013). However, in line with our results, modest improvements in attention were reported in a by proxy questionnaire in the same RCT after 1 year (Shinnar et al, 2017). Based on the data in our study with a longer follow-up time, it seems that an improvement in attention becomes apparent after a follow-up time of more than 12 months and occurs in both children with and without seizure freedom.…”

“…This study was performed in a tertiary epilepsy center, in which the AE patients were closely monitored regarding clinical, cognitive, and EEG aspects during follow-up. Importantly, a large proportion of the AE patients were difficult to treat in this population; however, previously it has been shown that about half of CAE patients fail treatment on the first and second monotherapies (Cnaan et al, 2017;Glauser et al, 2013Glauser et al, , 2010Tenney & Glauser, 2013). Furthermore, as this study focused on cognitive development, only children with two neuropsychological assessments were included.…”

“…Ethosuximide has been associated with lower performance on simple reaction times but does not seem to affect measures on intelligence, processing speed, sustained attention with the Bourdon- Vos, visual motor integration, or verbal memory (IJff et al, 2016). Valproate has been associated with additional numbers of attentional deficits on the continuous performance task compared to monotherapy with Ethosuximide or Lamotrigine (Cnaan et al, 2017;Glauser et al, 2013Glauser et al, , 2010. In this study, some children showed an improvement in sustained attention despite the use of Valproic acid.…”

“…These attentional deficits persisted after 1-year follow-up despite successful treatment or the randomly allocated treatment (Cnaan et al, 2017;Glauser et al, 2013Glauser et al, , 2010Masur et al, 2013). Based on behavioral questionnaires from the same trial, attentional problems seem to improve during 1 year of follow-up (Shinnar et al, 2017). Nevertheless, follow-up data within other cognitive domains were not available.…”