EEC 2022 | ESTEL: DBS for Lennox-Gastaut syndrome

At the moment, we don’t have approval to use neuromodulation for Lennox-Gastaut syndrome, but there has been a lot of evidence over the years, mainly uncontrolled trials that have reported seizure reductions using deep brain stimulation in Lennox-Gastaut syndrome. And one of the seminal papers by the Velasco group reported an 80% seizure reduction. We were quite excited by this, and we set about performing a randomized control trial, which is essentially what the ESTEL trial was.

And so we took 20 patients with Lennox-Gastaut syndrome, and we performed bilateral deep brain stimulation to the bilateral CM or the centromedian nucleus. The trial was conducted at a single site in Australia at our Austin hospital. And we focused on recruiting young adults that had Lennox-Gastaut syndrome. And we recruited 20 patients to the study, and over a two year period, we performed bilateral deep brain stimulation surgery to the centromedian nucleus of the thalamus.

And the reason we chose this target was mainly based on work by the Velasco group, which reported quite a remarkable reduction in the number of seizures, but there hasn’t to date been a randomized control trial for this. Patients initially entered a three-month baseline period. They had their surgery. We monitored them for another three months and then they were randomized into either having treatment or not having treatment, so the blinded phase which is where the primary outcome data came from. And then at the end of the three months of the study, the people that had not yet received stimulation, they then received stimulation. By the end of it, you had the two groups of patients. You had the first group who had received six months of stimulation, and the second group who had received delayed treatment in the final three months.

And we also, in addition to having seizure diaries kept by the families and the caregivers, which recorded seizures in a diary, we also had four 24-hour ambulatory EEGs, where we could assess more objectively markers of seizures, so both the burden of interictal discharges, but also the number of electrographic seizures. And although we didn’t meet our primary outcome with respect to the seizure diary reduction, 50% of patients did receive a 50% reduction in the number of seizures. Actually 89% of them were in this group. That was quite encouraging. And then at the end of the study, there was a median 50% reduction in all seizure types, across all patients. That was really encouraging and exciting. And certainly we’ve been following up these patients after the study now, and we are seeing suggestions of progressive benefit, but that work is still underway.

We were expecting the results, given the success of the Velasco group’s work and other previous CM stimulation studies. I think it was quite a small cohort of patients, so obviously a large trial will be needed, but it definitely was encouraging that we saw both a reduction in the overall number of seizures on the seizure diaries at the end of the study, and also electrographically, we saw that there was a clear treatment effect in the treatment group at the end of the blinded phase, with respect to the electrographic seizures. I think with respect to your question about the, I guess, mechanism of why we see this change, we conceptualize Lennox-Gastaut syndrome as a secondary network epilepsy. In a way it doesn’t really matter what the cause of Lennox-Gastaut syndrome is. All patients have the same electro-clinical phenotype and neuromodulation is really just targeting this network. And this is a network disease, and this is the network-based approach. That’s the more simplistic way that I think about it.