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Association of Closed-Loop Brain Stimulation Neurophysiological Features With Seizure Control Among Patients With Focal Epilepsy

Educational Objective
To determine the association of closed-loop invasive brain stimulation with seizure control in patients with epilepsy.
1 Credit CME
Key Points

Question  What is the association of closed-loop invasive brain stimulation with seizure control in patients with epilepsy?

Finding  In this cohort study of 11 patients with focal epilepsy, seizure reduction was not associated with the direct effects of acute responsive stimulation events. Indirect effects on seizure electrophysiology, which occurred remotely to individual stimulation events, were associated with improved seizure control.

Meaning  Therapeutic outcomes of closed-loop stimulation appear to emerge from modulation of the seizure network over time rather than from the acute interruption of individual seizure events.


Importance  A bidirectional brain-computer interface that performs neurostimulation has been shown to improve seizure control in patients with refractory epilepsy, but the therapeutic mechanism is unknown.

Objective  To investigate whether electrographic effects of responsive neurostimulation (RNS), identified in electrocorticographic (ECOG) recordings from the device, are associated with patient outcomes.

Design, Setting, and Participants  Retrospective review of ECOG recordings and accompanying clinical meta-data from 11 consecutive patients with focal epilepsy who were implanted with a neurostimulation 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 system-generated meta-data, including recording and detection settings, were collected directly from the manufacturer’s management system using an in-house, custom-built platform. 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.

Main Outcomes and Measures  Patterns of electrophysiological modulation were identified and then classified according to their latency of onset in relation to triggered stimulation events. Seizure control after RNS implantation was assessed by 3 main variables: mean frequency of seizure occurrence, estimated mean severity of seizures, and mean duration of seizures. Overall seizure outcomes were evaluated by the extended Personal Impact of Epilepsy Scale questionnaires, a patient-reported outcome measure of 3 domains (seizure characteristics, medication adverse effects, and quality of life), with a range of possible scores from 0 to 300 in which lower scores indicate worse status, and the Engel scale, which comprises 4 classes (I-IV) in which lower numbers indicate greater improvement.

Results  Electrocorticographic data from 11 patients (8 female; mean [range] age, 35 [19-65] years; mean [range] duration of epilepsy, 19 [5-37] years) were analyzed. Two main categories of electrophysiological signatures of stimulation-induced modulation of the seizure network were discovered: direct and indirect effects. Direct effects included ictal inhibition and early frequency modulation but were not associated with improved clinical outcomes (odds ratio [OR], 0.67; 95% CI, 0.06-7.35; P > .99). Only indirect effects—those occurring remote from triggered stimulation—were associated with improved clinical outcomes (OR, infinity; 95% CI, –infinity to infinity; P = .02). These indirect effects included spontaneous ictal inhibition, frequency modulation, fragmentation, and ictal duration modulation.

Conclusions and Relevance  These findings suggest that RNS effectiveness may be explained by long-term, stimulation-induced modulation of seizure network activity rather than by direct effects on each detected seizure.

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Article Information

Accepted for Publication: January 11, 2019.

Corresponding Author: R. Mark Richardson, MD, PhD, Department of Neurological Surgery, School of Medicine, University of Pittsburgh, 200 Lothrop St, Ste B400, Pittsburgh, PA 15213 (richardsonrm@upmc.edu).

Published Online: April 15, 2019. doi:10.1001/jamaneurol.2019.0658

Author Contributions: Dr Kokkinos and Mr Sisterson had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kokkinos.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kokkinos, Sisterson.

Obtained funding: Richardson.

Administrative, technical, or material support: All authors.

Supervision: Richardson.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was partly funded by the Walter L. Copeland Fund of the Pittsburgh Foundation (Mr Sisterson and Dr Richardson) and grant R01 NS110424 from the National Institute of Neurological Disorders and Stroke (Dr Richardson).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The authors thank NeuroPace, Inc, for assistance with data transfer. NeuroPace, Inc, was not compensated for this work.

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