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RNS System 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;77:1295-1304

Link: https://doi.org/10.1212/WNL.0b013e3182302056

PDF: https://seizure.mgh.harvard.edu/wp-conte...votal-trial.pdf

Clinical Question

Is responsive cortical stimulation safe and effective as adjunctive therapy for reducing partial onset seizures in adults with medically refractory epilepsy who have failed multiple AEDs and have 1-2 localized seizure foci?

Bottom Line

Responsive cortical stimulation significantly reduces disabling partial seizures (37.9% vs 17.3% reduction, P=0.012) in adults with medically intractable epilepsy, with sustained benefit at 2 years (46% responder rate), significant improvements in quality of life, and no adverse effects on mood or cognition. Safety was acceptable compared to alternative neurosurgical procedures. This provides Class I evidence supporting responsive neurostimulation as an adjunctive treatment option.

Major Points

  • First randomized controlled trial of responsive cortical stimulation for partial epilepsy (Class I evidence)
  • 191 adults implanted at 31 US centers; randomized 1:1 to treatment vs sham stimulation
  • Primary endpoint achieved: 37.9% seizure reduction vs 17.3% sham during 12-week blinded period (P=0.012)
  • Treatment effect increased over time during blinded period (month 3: 41.5% vs 9.4%, P=0.008)
  • Transient implant effect observed in both groups during first postoperative month, resolving by month 5 in sham group
  • Responder rate (≥50% reduction) at 1 year: 43% (n=177); at 2 years: 46% (n=102)
  • 7.1% seizure-free over most recent 3 months at data cutoff
  • Significant QOL improvements in both groups at end of blinded period (P=0.040 and P=0.032)
  • SAE rate 12% at 28 days (not worse than 15% comparator); 18.3% at 84 days (not worse than 36% DBS comparator)
  • No difference in neuropsychological function or mood between treatment and sham groups; improvements in cognition at 1-2 years

Design

Study Type: Multicenter, randomized, double-blind, sham-stimulation controlled trial with open-label extension

Randomization: 1

Blinding: Double-blind: Subject blinding maintained via sham programming sessions; blinded physician gathered outcome data, nonblinded physician managed neurostimulator; blinding index 0.572

Enrollment Period: December 2005 to November 2008

Follow-up Duration: 12-week blinded evaluation period (BEP) + 84-week open-label period (OLP); data cutoff June 4, 2010

Centers: 31

Countries: United States

Sample Size: 191

Analysis: Intent-to-treat; Generalized Estimating Equation (GEE) model with group-by-time interaction as primary endpoint variable, accounting for onset zone, number of seizure foci, and prior resection; Fisher exact test for AE comparisons; paired t-test for within-group changes; 2-sample t-test for between-group comparisons

Inclusion Criteria

  • Age 18-70 years
  • Partial onset seizures not controlled with ≥2 trials of AEDs
  • ≥3 disabling seizures per month on average
  • Standard diagnostic testing localized 1 or 2 epileptogenic regions
  • Disabling seizures defined as: simple partial motor, complex partial, or secondarily generalized tonic-clonic seizures

Exclusion Criteria

  • Not explicitly detailed in manuscript
  • More than 2 seizure foci (implied)
  • Non-localizable seizures (implied)

Baseline Characteristics

CharacteristicTreatment (n=97)Sham (n=94)
Sex - female48%47%
Age - mean (SD), years34.0 ± 11.5 (range 18-60)35.9 ± 11.6 (range 18-66)
Years with epilepsy - mean (SD)20.0 ± 11.2 (range 2-57)21.0 ± 12.2 (range 2-54)
Number of AEDs at enrollment - mean (SD)2.8 ± 1.3 (range 1-8)2.8 ± 1.1 (range 0-6)
Baseline seizures per day - mean (SD)1.2 ± 2.0 (range 0.1-10.5)1.2 ± 2.4 (range 0.1-12.1)
Mesial temporal seizure onset49%50%
Two seizure foci (vs one)49%62%
Prior therapeutic surgery for epilepsy35%30%
Prior intracranial EEG monitoring65%53%
Prior VNS31%36%

Arms

FieldControlResponsive Stimulation (Treatment)
InterventionRNS System implanted with neurostimulator programmed to sense and record electrocorticogram but NOT deliver stimulation during blinded periodRNS System implanted with neurostimulator programmed to detect abnormal electrocorticographic activity and deliver responsive cortical stimulation; physician-adjusted detection and stimulation parameters for each patient; stimulation enabled 99% of time
Duration4-week postop stabilization + 4-week stimulation optimization (sham) + 12-week BEP; then stimulation enabled for 84-week OLP4-week postop stabilization + 4-week stimulation optimization + 12-week BEP + 84-week OLP

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Difference between treatment and sham groups in mean percentage reduction of seizure frequency during blinded evaluation period (BEP) relative to preimplant period (12 weeks); measured by group-by-time interaction term in GEE modelPrimary-17.3% (95% CI: -29.9%, -2.3%)-37.9% (95% CI: -46.7%, -27.7%)20.60%0.012
Seizure reduction - Month 1 of BEP (3rd month postop)Secondary-25.2% (95% CI: -37.1%, -11.1%)-34.2% (95% CI: -44.1%, -22.6%)0.279
Seizure reduction - Month 2 of BEP (4th month postop)Secondary-17.2% (95% CI: -30.5%, -1.3%)-38.1% (95% CI: -47.3%, -27.3%)0.016
Seizure reduction - Month 3 of BEP (5th month postop)Secondary-9.4% (95% CI: -29.5%, +16.4%)-41.5% (95% CI: -52.0%, -28.7%)0.008
≥50% responder rate during BEPSecondary27%29%
Seizure-free during 12-week BEPSecondary0%2.1% (2 subjects)
Change in proportion of seizure-free days (month 3 of BEP)Secondary16% fewer days with seizures27% fewer days with seizures0.048
≥50% responder rate at 1 year postimplant (all subjects)SecondaryN/A (combined)43% (n=177)
≥50% responder rate at 2 years postimplantSecondaryN/A (combined)46% (n=102)
Seizure-free over most recent 3 months at data cutoffSecondaryN/A7.1% (13 subjects)
Sham group seizure reduction when stimulation began in OLPSecondarySignificant reduction vs preimplantN/A0.04
QOLIE-89 overall t-score improvement at end of BEP - TreatmentSecondaryImproved (P=0.032)Improved (P=0.040)
QOLIE-89 overall improvement at 1 year (all subjects)SecondaryN/A (combined)Improved<0.001
QOLIE-89 overall improvement at 2 years (all subjects)SecondaryN/A (combined)Improved0.016
QOLIE-89 Language subscale improvement at 1 year/2 yearsSecondaryN/AImproved<0.001 / 0.025
QOLIE-89 Memory subscale improvement at 1 year/2 yearsSecondaryN/AImproved<0.001 / 0.004
QOLIE-89 Attention/Concentration improvement at 1 year/2 yearsSecondaryN/AImproved<0.001 / 0.019
QOLIE-89 Work/Driving/Social Function at 1 year/2 yearsSecondaryN/AImproved0.001 / 0.002
SAE rate - first 28 daysAdverseN/A (combined)12% (vs 15% literature comparator)
SAE rate - first 84 daysAdverseN/A (combined)18.3% (vs 36% DBS comparator)
Intracranial hemorrhage (overall)AdverseN/A4.7% (9/191 subjects)
Serious intracranial hemorrhage (not seizure-related)AdverseN/A2.1% (no permanent sequelae)
Implant/incision site infection (SAEs)AdverseN/A5.2% (10/191); 4 explanted; all soft tissue only
Device-related SAEs during BEPAdverse1 subject (3 events - change in seizures)1 subject (1 event - change in seizures)NS
Implant site pain (through 1 year)AdverseN/A (combined)15.7% (30 subjects)
Headache (through 1 year)AdverseN/A10.5% (20 subjects)
Procedural headacheAdverseN/A9.4% (18 subjects)
DysesthesiaAdverseN/A6.3% (12 subjects)
Memory impairmentAdverseN/A4.2% (8 subjects)
Depression AEs (all mild)AdverseN/A13.6% (26 subjects; 16 had history of depression)
Suicidality AEsAdverseN/A6.8% (13 subjects); 3.1% SAEs; all had history of depression/anxiety
DeathsAdverseN/A6 total: lymphoma (1), suicide (1 - history of depression), SUDEP (4; 3 had stimulation enabled)
SUDEPAdverseN/A4 deaths over 340 patient-years (within expected range for population)

Subgroup Analysis

Treatment response did not depend on: mesial temporal vs other brain region seizure onset, 1 vs 2 seizure foci, or prior epilepsy surgery or VNS (GEE interaction terms). Preimplant neuropsychological assessment showed 52.7% had verbal memory dysfunction and 56.2% had visuospatial memory dysfunction. At baseline, 49.7% had history of depression, 5.2% history of suicidality, 42.0% met criteria for depression (BDI-II or CES-D), and 10.2% endorsed passive suicidality. No deterioration in any neuropsychological measure at BEP end or at 1-2 years; significant improvements in verbal functioning, visuospatial ability, and memory at 1-2 years (P<0.05). No adverse changes in mood inventories at any timepoint.

Criticisms

  • Sponsored by NeuroPace, Inc., with company involvement in data acquisition, statistical analysis, study supervision, and manuscript approval
  • Lead author is NeuroPace employee with stock options
  • Modest difference in responder rates during blinded period (29% vs 27%)
  • Transient implant/surgical effect complicates interpretation of early results
  • Open-label extension lacks placebo control for long-term efficacy assessment
  • Patient experience (340 years) insufficient to calculate confident SUDEP rate
  • Blinding success was only moderate (blinding index 0.572); 43% guessed correctly
  • Primary endpoint comparison based on percentage change rather than absolute seizure reduction
  • Predominantly US-based population limits generalizability
  • High baseline rate of psychiatric comorbidity (50% depression history) may limit generalizability
  • 32% had prior epilepsy surgery, 34% prior VNS - highly selected population
  • Device lead damage occurred in 2.6% by 1 year

Funding

NeuroPace, Inc. (Mountain View, CA)

Based on: RNS System Pivotal Trial (Neurology, 2011)

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

Citation: Neurology. 2011;77:1295-1304

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