Abstracts

Rationale: The RNS is a closed-loop cortical electrical stimulation system developed as an alternative treatment for patients with drug-resistant epilepsy, who are either refractory to surgery or not surgical candidates. Class IV evidence strongly support RNS as a provider of improved seizure control and quality of life for refractory epilepsy patients. However, no stimulation-induced electrophysiological biomarkers have been described for differentiating responders from non-responders. Methods: 14,394 ECoG files recorded by the RNS System in 11 patients were manually reviewed, corresponding to 157 cumulative months of data across patients, with individual follow-up durations of 6 to 34-months. We marked the onset of electrographic ictal patterns (EPIs) and created 3D time-frequency power plots for each event, which were averaged to highlight the EPIs common spectral features per programming epoch. To describe the association between outcome and the presence of electrophysiological modulation effects, we grouped patients as either responders (Engel class = III) or non-responders (Engel class IV) and calculated the probability of achieving responder status given the presence of modulation effects using two Fisher exact tests. Results: A total of 4,827 ictal-like EPIs were identified. By evaluating spectral characteristics around the onset of EPIs, we identified 2 categories of stimulation event-related modulation effects that occurred immediately following stimulation events: 1) inhibition of EPIs, and 2) modulation of broadband frequencies. The later effect has not been described previously. These direct stimulation effects did not correlate with clinical outcome (odds ratio=0.67; p=1.0). Evaluation of spectral features throughout an EPI's time-course, however, revealed 5 categories of EPI modulation effects that did not occur in the immediate post-stimulation epoch, but that evolved across weeks of stimulation: 1) inhibition, 2) frequency modulation, 3) fine fragmentation, 4) coarse fragmentation, and 5) ictal duration modulation. We defined these effects as indirect, given the absence of any indication that they arose acutely as a direct consequence of a given stimulation event. Importantly, the appearance of indirect stimulation effects was correlated to clinical responsiveness (odds ratio=inf; p=0.02). Conclusions: Direct inhibition of ongoing epileptic activity is thought to act as a neuronal de-synchronizer. Chronic electrical stimulation may progressively disrupt the connectivity of the epileptogenic network by reducing the core synchronized population, resulting in less severe or subclinical seizure manifestation. Our findings of indirect modulation of electrographic ictal patterns may correspond to the progressive nature of documented responsiveness to RNS. Funding: This work was funded by the Walter L. Copeland Fund of the Pittsburgh Foundation.