A clinical trial of bilateral deep brain stimulation (DBS) of the thalamic centromedian nucleus has identified the optimal target area for reducing seizures in Lennox-Gastaut epilepsy.

Stimulation was most efficacious on average when targeting the anterior and inferolateral “parvocellular” border of the thalamic centromedian nucleus (CN) and the adjacent ventral lateral nucleus, the study found.

That target area was also associated with connectivity to the secondary epilepsy network that underlies the electrical and clinical manifestations of Lennox-Gastaut epilepsy (LGE).

Because the study included patients with structural brain abnormalities and previous neurosurgery, the authors concluded, “We anticipate that large, multi-center collaborations will be required to disentangle these factors, and to assess the predictive value of our findings at the patient level.”

The first author of the study from Australia was Aaron E.L. Warren, PhD, a postdoctoral fellow studying epilepsy, brain imaging, and neuromodulation in the Department of Medicine at the University of Melbourne in Heidelberg, the Murdoch Children’s Research Institute in Parkville, and the Florey Institute of Neuroscience and Mental Health in Heidelberg.

The study drew on data from the group’s randomized controlled trial, named ESTEL (Electrical Stimulation of Thalamus for Epilepsy of Lennox–Gastaut phenotype). That trial, published in December online ahead of print in Annals of Neurology,  involved 10 treated patients and nine controls. As measured by electrographic seizures, 89 percent of the stimulation group had at least a 50 percent reduction in seizures after three months of blinded treatment, compared with none of the controls (p =0.05). ​

The new study, published in the Annals of Neurology on April 15, involved a total of 20 LGS patients who underwent bilateral DBS of the CM. The outcome measure was the percentage of seizure reduction from baseline after three months of DBS. Seizure activity was defined with three measures: monthly seizure diaries, 24-hour scalp EEG, and a novel diary-EEG composite.

Two diffusion MRI datasets—one from healthy subjects and another from disease-matched LGS patients—were used “to calculate the structural connectivity between DBS sites and a map of areas known to express epileptic activity in LGS, derived from our previous EEG-fMRI research,” the paper stated.

Across all 20 patients, the median reduction in seizure activity after three months was relatively similar whether measured by diaries, EEG, or diary-EEG average: 52 percent, 57 percent, and 44 percent, respectively.

But seizure reduction varied widely among patients, ranging from 0.2 to 90 percent as measured by diaries, 1 to 100 percent measured by EEG, and 22 to 83 percent measured by the diary-EEG average.
The peak “sweet-spot” coordinates associated with the greatest mean reduction in seizures as measured by both the EEG and diary-EEG turned out to be located outside the CM, in the posterior of the adjacent ventral lateral nucleus.

As for structural connectivity, the study found, the reduction in seizures was most strongly correlated with connectivity to the premotor cortex/Brodmann’s area 6, frontal operculum, dorsoposterior putamen, globus pallidus, right hippocampal head, right inferoposterior cerebellum, and pontine locus coeruleus of the brainstem.

The findings, the authors concluded, “suggest therapeutic mechanisms of CM-DBS and have implications for planning future trials, optimizing stimulation in patients with existing devices, and developing new treatments.”

In particular, the study’s identification of a peak sweet spot in the ventral lateral nucleus (posterior subdivision) offers a novel stimulation target for LGS, the authors concluded.


Source: journals.lww.com, Dan Hurley