DBS of Thalamic Centromedian Nucleus for Lennox–Gastaut Syndrome (ESTEL Trial)

Abstract

Objective Prior uncontrolled studies have reported seizure reductions following deep brain stimulation (DBS) in patients with Lennox–Gastaut syndrome (LGS), but evidence from randomized controlled studies is lacking. We aimed to formally assess the efficacy and safety of DBS to the centromedian thalamic nucleus (CM) for the treatment of LGS. Methods We conducted a prospective, double‐blind, randomized study of continuous, cycling stimulation of CM‐DBS, in patients with LGS. Following pre‐ and post‐implantation periods, half received 3 months of stimulation (blinded phase), then all received 3 months of stimulation (unblinded phase). The primary outcome was the proportion of participants with ≥50% reduction in diary‐recorded seizures in stimulated versus control participants, measured at the end of the blinded phase. A secondary outcome was the proportion of participants with a ≥50% reduction in electrographic seizures on 24‐hour ambulatory electroencephalography (EEG) at the end of the blinded phase. Results Between November 2017 and December 2019, 20 young adults with LGS (17–37 years;13 women) underwent bilateral CM‐DBS at a single center in Australia, with 19 randomized (treatment, n = 10 and control, n = 9). Fifty percent of the stimulation group achieved ≥50% seizure reduction, compared with 22% of controls (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 0.44–21.45, p = 0.25). For electrographic seizures, 59% of the stimulation group had ≥50% reduction at the end of the blinded phase, compared with none of the controls (OR= 23.25, 95% CI = 1.0–538.4, p = 0.05). Across all patients, median seizure reduction (baseline vs study exit) was 46.7% (interquartile range [IQR] = 28–67%) for diary‐recorded seizures and 53.8% (IQR = 27–73%) for electrographic seizures. Interpretation CM‐DBS in patients with LGS reduced electrographic rather than diary‐recorded seizures, after 3 months of stimulation. Fifty percent of all participants had diary‐recorded seizures reduced by half at the study exit, providing supporting evidence of the treatment effect. ANN NEUROL 2022;91:253–267

Deep Brain Stimulation of the Centromedian Nucleus of the Thalamus for Lennox-Gastaut Syndrome: A Systematic Review and Individual Patient Data Analysis

“…34 Eighty-nine percent of the stimulation group had a ≥50% reduction in electrographic seizures relative to 0% of controls (odds ratio 23.25, 95% CI: 1.0-538.4, P = .05). 34 Most studies reported that <10% of patients experienced seizure freedom.…”

“…As medications are typically unsuccessful at controlling seizures, disconnection procedures and vagus nerve stimulation have been used. 1a The recent Electrical Stimulation of Thalamus for Epilepsy of Lennox-Gastaut phenotype (ESTEL) trial investigated the benefits of centromedian nucleus deep brain stimulation (CMN DBS), building on efficaciousness reported in primarily case series 2a. However, analysis of these prior studies, which contain important clinical data and experience, has not been fully reported.…”

Could We Generalize Surgical Candidacy Beyond Focal Epilepsy With Neurostimulation?

“…A prospective, randomized study of CM DBS in 20 patients with Lennox-Gastaut syndrome was recently reported, with 50% of the stimulation group achieving ≥50% seizure reduction, compared with 22% of controls. 6 In a recent retrospective case series of bilateral CM DBS in 12 patients with symptomatic generalized epilepsy (including Lennox-Gastaut syndrome) or IGE, 10 individuals achieved at least 50% decrease in seizure frequency at last follow-up. 7 Moving forward, it will be worthwhile to compare results with closed-loop responsive vs open-loop cycling CM stimulation in generalized epilepsies, although there is likely significant overlap in the mechanistic effects of these 2 stimulation paradigms.…”

Medial Pulvinar Stimulation in Temporal Lobe Epilepsy: A Literature Review and a Hypothesis Based on Neuroanatomical Findings

“…Following the publication of promising reports [13], two RCTs were conducted in 1992 and 2000 showing some success for patients with Lennox-Gastaut syndrome and generalized tonic-clonic seizures [14,15]. Since then, CMT DBS has been investigated in multiple studies [16][17][18]. Notably, the electrical stimulation of thalamic centromedian nucleus for epilepsy of Lennox-Gastaut syndrome (ESTEL) trial, reported a reduction of electrographic seizures in patients with Lennox-Gastaut after CMT DBS [16].…”

“…Since then, CMT DBS has been investigated in multiple studies [16][17][18]. Notably, the electrical stimulation of thalamic centromedian nucleus for epilepsy of Lennox-Gastaut syndrome (ESTEL) trial, reported a reduction of electrographic seizures in patients with Lennox-Gastaut after CMT DBS [16]. Recently, a retrospective case series reported promising results with the combination of CMT and ATN DBS for the management of patients with generalized, multifocal, posterior origin and poorly localized drug-resistant epilepsy [17].…”