Chronic Subthreshold Cortical Stimulation to Treat Focal Epilepsy

Approximately 1 to 3 in 1000 people have drug-resistant focal epilepsy.¹ Resective surgical procedures are the most effective treatments for patients with epilepsy but are not feasible when seizures originate from critical cortical areas, ie, the eloquent cortex. Despite evidence for efficacy, current approaches to focal brain stimulation rarely yield seizure-free outcomes.² We report on 13 patients treated with continuous subthreshold electrical cortical stimulation, which led to the suppression of interictal epileptiform discharges (IEDs) and improvement in clinical seizures (ie, reduced frequency, with some experiencing reduced intensity and duration).

The Mayo Clinic Institutional Review Board approved this study, and informed consent was waived, as data were obtained through a deidentified database. Thirteen patients with drug-resistant focal epilepsy were deemed unsuitable for resective surgical procedures following intracranial electroencephalography monitoring with surgically implanted subdural grid and depth electrodes (Figure, A). To accurately estimate the seizure focus, prestimulation monitoring was typically several days, as clinically determined. If they were not a surgical candidate, patients were offered a therapeutic trial of continuous cortical stimulation (biphasic; frequency, 2-100 Hz; pulse width, 90-450 μs; amplitude, 1-6 V in voltage mode) via adjacent strip and occasional depth electrodes in the region of seizure onset. Permanent stimulation hardware (16-contact Medtronic PrimeAdvanced Neurostimulator with Medtronic 6-mm² platinum-iridium 2×8 surgical leads or Medtronic DBS electrodes [model 3387, 3389, or 3391]) was implanted when intracranial electroencephalography electrodes were explanted.

Data were analyzed retrospectively. Rates of IED were quantified for 6 patients who underwent stimulation at 2 Hz and had 24 hours of pre- and poststimulation intracranial electroencephalography data available for analysis; the 7 patients who were stimulated at greater than 2 Hz were excluded from IED rate analysis because of stimulation artifact. Six 15-minute blocks from a 24-hour period of 500-Hz sampled data were analyzed before and during stimulation. Interictal epileptiform discharges were automatically detected in 5 electrodes per patient (electrode with the highest IED rate and 4 background electrodes) using a previously validated method³ (Figure, B). Within a 4 millisecond window, spikes that occurred at a frequency of 2, 1, or 0.5 Hz were excluded to account for stimulation artifact. Results from IED rates calculated via manual detection for 3 patients using 1 hour of data were similar. Assessments of epilepsy severity and life satisfaction (on a scale from 1 to 10) as well as frequency of disabling seizures were based on retrospective patient report. Statistical significance was set at P < .05.

Ten of the 13 patients (76.9%) reported improvement for both epilepsy severity and life satisfaction following chronic stimulation (Table). According to patient self-report, the mean (range) decrease in disabling seizures was 80% (33-100), mean (SD) epilepsy severity decreased from 7.2 (2.0) to 2.4 (2.6; P < .001), and mean (SD) life satisfaction increased from 4.5 (2.2) to 7.3 (1.6; P = .003). Patients tolerated permanent implantation without serious adverse effects. Rates of IED decreased significantly for all analyzed patients, with 3 patients achieving near-complete cessation of IEDs (Figure, C). The reduction in IED rate occurred within minutes of initiating stimulation. The mean IED rate decreased from 0.61 to 0.08 IEDs per second (P = .002) (Figure, D).

These results suggest a clinical benefit and quantitative reduction in IED rates following subthreshold cortical stimulation. Prior work, including time-limited cortical stimulation,⁴ long-term cortical stimulation in 2 patients,⁵ and initial case reports from 3 patients,⁶ has suggested a clinical benefit with this approach. Most patients experienced more than a 50% reduction in seizure frequency, and the reduction in IED rate with cortical stimulation was pronounced. The immediate reduction in IED rate at the time of stimulation in conjunction with clinical improvement suggests that IED rate is associated with seizure probability. Clinically, IED rate could be a useful biomarker for treatment efficacy.

Further investigation is needed to quantify treatment effects and examine the effect mechanism. Limitations in the current retrospective data include suboptimal pre- and poststimulation assessments of seizure frequency, epilepsy severity, and quality of life. In sum, continuous subthreshold cortical stimulation may be a suitable treatment for patients with focal epilepsy with lesions involving critical cortical areas or for whom a potentially reversible procedure is attractive.

Corresponding Author: Matt Stead, MD, PhD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (stead.squire@mayo.edu).

Published Online: September 19, 2016. doi:10.1001/jamaneurol.2016.2857

Author Contributions: Drs Lundstrom and Stead had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lundstrom, Worrell, Stead.

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

Drafting of the manuscript: Lundstrom, Stead.

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

Statistical analysis: Lundstrom, Stead.

Obtained funding: Worrell, Stead.

Administrative, technical, or material support: Britton, Nickels, Worrell, Stead.

Study supervision: Worrell, Stead.

Conflict of Interest Disclosures: None reported.

Funding/Support: Data collection was supported by grants R01 NS092882 (Dr Worrell) and R01 NS078136 (Dr Stead) from the National Institutes of Health.

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

Additional Contributions: We thank a number of colleagues at the Mayo Clinic, including Deb Gorman, RN (Department of Neurologic Surgery), for assistance collecting clinical data, Ben Brinkman, PhD (Department of Neurology), and Hyuck J. Choi, MS (Department of Neurology), for technical assistance, and Dave McFadden, MD (Department of General Internal Medicine), and Laura Miller, AA (Department of Neurology), for thoughtful comments. The contributors were not compensated for their work.