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RNS Pivotal Trial

Responsive Cortical Stimulation for the Treatment of Medically Intractable Partial Epilepsy

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Year of Publication: 2011

Authors: Martha J. Morrell, on behalf of the RNS System in Epilepsy Study Group

Journal: Neurology

Citation: Neurology. 2011;77(13):1295-1304.

Link: https://pubmed.ncbi.nlm.nih.gov/21917777/

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PMC4233950/

Clinical Question

In adults with medically intractable partial epilepsy (failed ≥2 AEDs, 1-2 foci), does responsive cortical stimulation (RNS) reduce disabling seizure frequency vs sham stimulation?

Bottom Line

RNS significantly reduced seizures by 37.9% vs 17.3% sham over 12 weeks (P=0.012), with improving response through 2 years (46% responder rate, 7.1% seizure-free at last 3-month period). No adverse cognitive or mood effects. Serious hemorrhage 2.1%, serious infection 4.2%. First Class I evidence for responsive (closed-loop) cortical stimulation. 191 patients, 32 US centers.

        Major Points
        Primary endpoint met: seizure reduction 37.9% vs 17.3% sham (P=0.012). Effect grew each month: Month 3 -41.5% vs -9.4% (P=0.008).
Responder rate improved over time: 29% at 12-week BEP → 43% at 1 year → 46% at 2 years. 7.1% seizure-free at last 3-month period.
Sham crossover confirmed stimulation effect: when sham group received active stimulation in OLP, seizures reduced (P=0.04).
No adverse cognitive effects — improvements in verbal, visuospatial, and memory at 1-2 years. QOLIE-89 improved significantly.
Safety: serious hemorrhage 2.1%, serious infection 4.2% (4 explants). 4 SUDEP deaths over 340 patient-years (within expected range).
Subgroup consistency: benefit regardless of mesial temporal vs neocortical, 1 vs 2 foci, prior VNS or surgery.
Closed-loop mechanism: continuous ECoG sensing → detection of abnormal activity → responsive stimulation to seizure focus.
191 patients, 32 US centers. Double-blind, sham-controlled (12-week BEP) then open-label.
49.7% had prior depression; no increase in depression or suicidality with RNS — important safety distinction from some AEDs.
First FDA-approved responsive neurostimulation device for epilepsy. Led to NeuroPace RNS System approval.

      

Design

Study Type: Multicenter, double-blind, randomized, sham-stimulation controlled trial

Randomization: 1

Blinding: Double-blind. Blinded physician gathered outcomes; separate unblinded physician managed device. Adaptive 1:1 randomization.

Enrollment Period: December 2005 to November 2008

Follow-up Duration: 12-week blinded period + 84-week open-label (total ~2 years). Data cutoff June 2010.

Centers: 32

Countries: United States

Sample Size: 191

Analysis: Intention-to-treat. GEE model with group-by-time interaction. 340 patient-years experience.

Inclusion Criteria

Age 18-70 years.
Partial onset seizures not controlled by ≥2 AED trials.
≥3 disabling seizures per month on average.
1 or 2 localized epileptogenic regions on standard testing.
Stable AED regimen for 12 weeks.

Exclusion Criteria

Did not meet/maintain inclusion criteria.
Physician or subject preference not to proceed.
Subject compliance failure.

Baseline Characteristics

Characteristic	Treatment (N=97)	Sham (N=94)
Mean age	34.0±11.5	35.9±11.6
Female	48%	47%
Mean years with epilepsy	20.0±11.2	21.0±12.2
Mean AEDs	2.8±1.3	2.8±1.1
Mean seizures/day	1.2±2.0	1.2±2.4
Mesial temporal onset	49%	50%
Two foci	49%	62%
Prior epilepsy surgery	35%	30%
Prior VNS	31%	36%
History of depression	~50%	~50%

Arms

Field	Responsive Stimulation (Treatment)	Control
Intervention	RNS System (NeuroPace) implanted cranially with 1-2 depth/cortical strip leads at seizure foci. Responsive stimulation enabled from week 4. Device continuously senses ECoG, detects abnormal patterns, delivers targeted stimulation. Parameters individualized per physician programming.	Same RNS System implanted but NOT programmed to deliver stimulation during 12-week blinded period. Device sensed and recorded but did not stimulate. Crossed to active stimulation at week 20.
Duration	Blinded 12 weeks + open-label 84 weeks	12 weeks sham, then active

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Reduction in mean seizure frequency during 12-week BEP vs preimplant	Primary	-17.3% (95% CI -29.9 to -2.3%)	-37.9% (95% CI -46.7 to -27.7%)	20.60%	0.012
BEP Month 3 seizure reduction	Secondary	-9.4% (-29.5 to +16.4%)	-41.5% (-52.0 to -28.7%)		0.008
≥50% responder rate (BEP)	Secondary	27%	29%
Responder rate at 1 year (OLP)	Secondary		43% (n=177)
Responder rate at 2 years (OLP)	Secondary		46% (n=102)
Seizure-free (last 3 months at cutoff)	Secondary		13/191 (7.1%)
QOLIE-89 at 1 year	Secondary		Significant improvement (P<0.001)
QOLIE-89 at 2 years	Secondary		Significant improvement (P=0.016)
Serious hemorrhage (non-trauma)	Adverse		4/191 (2.1%)
Serious infection	Adverse		8/191 (4.2%); 4 explants
SUDEP	Adverse		4 deaths over 340 patient-years (within expected)
Depression AEs	Adverse		13.6% (all mild); no between-group difference
Suicidality AEs	Adverse		6.8%; 3.1% SAEs. All had prior psych history

Subgroup Analysis

No significant interaction by seizure onset location (mesial temporal vs neocortical), number of foci (1 vs 2), or prior VNS/surgery — benefit consistent across all subgroups.

Criticisms

Industry-sponsored (NeuroPace). Lead author is NeuroPace employee with stock options.
Short 12-week blinded period. Long-term data are open-label/uncontrolled.
Implant effect: both groups had early post-implant reduction (confounded Month 1, P=0.279).
Moderate effect size: only 2.1% seizure-free during BEP.
Responder rates similar during BEP (29% vs 27%) — difference driven by degree of reduction.
No active comparator (VNS or DBS).
Stimulation parameters not specified in publication.
High baseline psychiatric comorbidity (50% depression) limits generalizability.

Funding

NeuroPace, Inc.

Based on: RNS Pivotal Trial (Neurology, 2011)