Effectiveness of Responsive Neurostimulation Modulated by Seizure Network Activity

Responsive neurostimulation (RNS) effectiveness may be explained by long-term, stimulation-induced modulation of seizure network activity instead of direct effects on each detected seizure, according to study results published in JAMA Neurology. The therapeutic outcomes of closed-loop RNS seem to emerge from the seizure network modulation over time rather than from the individual seizure events’ acute interruption.

In this study, the investigators aimed to test whether RNS clinical effectiveness arises from successful detection-triggered electrical stimulation and subsequent, direct termination of seizure activity. They retrospectively reviewed electrocorticography (ECOG) recordings and clinical data from 11 consecutive patients with focal epilepsy who were implanted with an RNS system between January 28, 2015 and June 6, 2017, with 22 to 112 weeks of follow-up.

Recorded ECOG data were obtained from the manufacturer; additional data, including recording and detection settings, were collected directly from the manufacturer’s management system. Electrographic seizure patterns were identified in RNS recordings and evaluated in the time-frequency domain, which was locked to the onset of the seizure pattern.

The patterns of electrophysiological modulation were classified according to their latency of onset concerning triggered stimulation events. Three variables assessed seizure control after RNS implantation: seizure occurrence mean frequency, seizures’ estimated mean severity, and seizures’ mean duration.

Overall seizure outcomes were evaluated by the extended Personal Impact of Epilepsy Scale questionnaires, a patient-reported measure of 3 domains (seizure characteristics, medication adverse effects, and quality of life), with a range from 0 to 300 in which lower scores indicate worse status, and the Engel scale, which consists of 4 classes in which lower numbers indicate greater improvement.

Researchers found 2 main categories of electrophysiological signatures of stimulation-induced modulation of the seizure network: direct and indirect effects. Direct effects included ictal inhibition and early frequency modulation but were not associated with improved clinical outcomes (odds ratio 0.67; 95% CI, 0.06-7.35; P >.99). Only indirect effects — those occurring remotely from triggered stimulation — were associated with improved clinical outcomes (OR infinity; 95% CI, negative infinity to infinity; P =.02). These indirect effects included spontaneous ictal inhibition, frequency modulation, fragmentation, and ictal duration modulation.

Among the study limitations, the investigators believe that patient nonadherence to the data uploads and limited data storage led to the preservation of a small subset of ECOGs concerning the continuous neural signal analyzed by the device. Also, the evaluation of direct inhibitory modulation on clinical rather than electrographic events remains limited without the confirmed presence of clinical seizures during modulated electrographic events. Lastly, the researchers did not control for changes in antiepileptic medication.

The fact that indirect modulation effects were associated with improved seizure control rather than the effects of direct stimulation being associated with triggered seizures indicates that neuroplasticity may be required for a therapeutic response. It may be possible to improve the therapeutic speed and efficacy of closed-loop brain stimulation by identifying the specific modulation scenarios that produce these modulatory effects.

Reference

Kokkinos V, Sisterson ND, Wozny TA, Richardson RM. Association of closed-loop brain stimulation neurophysiological features with seizure control among patients with focal epilepsy [published online April 15, 2019]. JAMA Neurol. doi: 10.1001/jamaneurol.2019.0658