Corticosteroids Outperform Clobazam on Cognitive Tests in Epileptic Encephalopathy With Spike-Wave Activation in Sleep

Findings from the randomized RESCUE ESES trial showed that treatment with corticosteroids resulted in greater improvements in cognitive outcomes than clobazam in patients with epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS). The trial was terminated prematurely for feasibility reasons; however, the findings complement those from earlier uncontrolled studies supporting the early use of corticosteroids in the treatment of children with EE-SWAS.¹

Published in Lancet Neurology, RESCUE ESES was the first multicenter randomized controlled trial to compare cognitive outcomes in children with EE-SWAS taking 2 of the most commonly prescribed treatments for the disorder. After 6 months of treatment, 25% (5 of 25) of participants assigned to corticosteroids showed a marked improvement of at least 11-25 points in IQ compared with 0% (0 of 18) of those on clobazam. The cognitive sum score responder rate at that time was 5% in both the corticosteroid group (1 of 22) and the clobazam group (1 of 21; rate ratio [RR], 1.0; 95% CI, 0.1-11.7; P = .97).

Between 2014 and 2022, 101 children were assessed for eligibility to the trial, of whom 45 met inclusion criteria and were enrolled. Led by Marleen M.L. van Arhnem, MD, a PhD candidate in the department of pediatric neurology at the University Medical Center Utrecht, the study used IQ responder rate and cognitive sum score responder rate as the 2 coprimary efficacy end points. Treatment was still ongoing at 6 months for 17 children assigned corticosteroids and for 19 children assigned clobazam. At 18 months, treatment was still ongoing for 2 children assigned corticosteroids and for 16 children assigned clobazam.

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Across several different secondary outcomes, which included IQ responder rate and cognitive sum responder rate at 18 months, change in IQ (delta IQ), SWI, and global daily functioning, were similar between the 2 treatment groups, except for mean delta IQ at 6 months. Children assigned to corticosteroids improved on average by 4.9 IQ points compared with baseline, whereas children treated with clobazam showed a decline by 0.7 points (ß = 5.6; 95% CI, 0.3-10.8; P = .039). Using a multivariable regression analysis, investigators observed that an unknown etiology for EE-SWAS was found to be predictive of higher delta IQ (0.3; 95% CI, 0.0-0.6; P = .041).

In terms of safety, 45% (n = 10) of those in the corticosteroid group and 52% (n = 11) of those in the clobazam group had at least 1 adverse event (AE) after 6 months of treatment (RR, 0.8; 95% CI, 0.4-1.4; P = .65). Fatigue, reported in 5 of 21 patients in the clobazam group, and weight gain, found in 3 of the 22 patients on corticosteroids, were the most common AEs observed for each respective group.

In the clobazam group, there were 2 serious AEs recorded: hospitalization because of seizure aggravation in 1 case and respiratory tract infection in another. One patient in the corticosteroid group was hospitalized because of laryngitis, also considered a serious AE. All serious AEs were resolved without sequelae.

After 18 months of treatment, findings showed no between-group differences in IQ responder rates and delta IQ, which investigators concluded could be in part because IQ data were only available for two-thirds of participants in total (31 of 45). "Furthermore, clinical management after 6 months was at the treating physician's discretion and was highly variable across individuals, which might have obscured differences in effectiveness between the treatments allocated initially," van Arhnem et al wrote.

REFERENCE
1. Van Arnhem MML, van den Munckhof B, Arzimanoglou A, et al. Corticosteroids versus clobazam for treatment of children with epileptic encephalopathy with spike-wave activation in sleep (RESCUE ESES): a multicenter randomized controlled trial. Lancet Neurol. Published online December 8, 2023. doi:10.1016/S1474-4422(23)00409-X