Dataset Information

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

ABSTRACT:

Objective

To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.

Methods

Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.

Results

Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ²).

Conclusions

Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.

Clinicaltrialsgov identifier

NCT00572195.

Classification of evidence

This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

SUBMITTER: Nair DR

PROVIDER: S-EPMC7538230 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

Nair Dileep R DR Laxer Kenneth D KD Weber Peter B PB Murro Anthony M AM Park Yong D YD Barkley Gregory L GL Smith Brien J BJ Gwinn Ryder P RP Doherty Michael J MJ Noe Katherine H KH Zimmerman Richard S RS Bergey Gregory K GK Anderson William S WS Heck Christianne C Liu Charles Y CY Lee Ricky W RW Sadler Toni T Duckrow Robert B RB Hirsch Lawrence J LJ Wharen Robert E RE Tatum William W Srinivasan Shraddha S McKhann Guy M GM Agostini Mark A MA Alexopoulos Andreas V AV Jobst Barbara C BC Roberts David W DW Salanova Vicenta V Witt Thomas C TC Cash Sydney S SS Cole Andrew J AJ Worrell Gregory A GA Lundstrom Brian N BN Edwards Jonathan C JC Halford Jonathan J JJ Spencer David C DC Ernst Lia L Skidmore Christopher T CT Sperling Michael R MR Miller Ian I Geller Eric B EB Berg Michel J MJ Fessler A James AJ Rutecki Paul P Goldman Alica M AM Mizrahi Eli M EM Gross Robert E RE Shields Donald C DC Schwartz Theodore H TH Labar Douglas R DR Fountain Nathan B NB Elias W Jeff WJ Olejniczak Piotr W PW Villemarette-Pittman Nicole R NR Eisenschenk Stephan S Roper Steven N SN Boggs Jane G JG Courtney Tracy A TA Sun Felice T FT Seale Cairn G CG Miller Kathy L KL Skarpaas Tara L TL Morrell Martha J MJ

Neurology 20200720 9

<h4>Objective</h4>To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.<h4>Methods</h4>Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficac ...[more]

PMID: 32690786

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Project description:Responsive neurostimulation is a promising treatment for drug-resistant focal epilepsy; however, clinical outcomes are highly variable across individuals. The therapeutic mechanism of responsive neurostimulation likely involves modulatory effects on brain networks; however, with no known biomarkers that predict clinical response, patient selection remains empiric. This study aimed to determine whether functional brain connectivity measured non-invasively prior to device implantation predicts clinical response to responsive neurostimulation therapy. Resting-state magnetoencephalography was obtained in 31 participants with subsequent responsive neurostimulation device implantation between 15 August 2014 and 1 October 2020. Functional connectivity was computed across multiple spatial scales (global, hemispheric, and lobar) using pre-implantation magnetoencephalography and normalized to maps of healthy controls. Normalized functional connectivity was investigated as a predictor of clinical response, defined as percent change in self-reported seizure frequency in the most recent year of clinic visits relative to pre-responsive neurostimulation baseline. Area under the receiver operating characteristic curve quantified the performance of functional connectivity in predicting responders (≥50% reduction in seizure frequency) and non-responders (<50%). Leave-one-out cross-validation was furthermore performed to characterize model performance. The relationship between seizure frequency reduction and frequency-specific functional connectivity was further assessed as a continuous measure. Across participants, stimulation was enabled for a median duration of 52.2 (interquartile range, 27.0-62.3) months. Demographics, seizure characteristics, and responsive neurostimulation lead configurations were matched across 22 responders and 9 non-responders. Global functional connectivity in the alpha and beta bands were lower in non-responders as compared with responders (alpha, pfdr < 0.001; beta, pfdr < 0.001). The classification of responsive neurostimulation outcome was improved by combining feature inputs; the best model incorporated four features (i.e. mean and dispersion of alpha and beta bands) and yielded an area under the receiver operating characteristic curve of 0.970 (0.919-1.00). The leave-one-out cross-validation analysis of this four-feature model yielded a sensitivity of 86.3%, specificity of 77.8%, positive predictive value of 90.5%, and negative predictive value of 70%. Global functional connectivity in alpha band correlated with seizure frequency reduction (alpha, P = 0.010). Global functional connectivity predicted responder status more strongly, as compared with hemispheric predictors. Lobar functional connectivity was not a predictor. These findings suggest that non-invasive functional connectivity may be a candidate personalized biomarker that has the potential to predict responsive neurostimulation effectiveness and to identify patients most likely to benefit from responsive neurostimulation therapy. Follow-up large-cohort, prospective studies are required to validate this biomarker. These findings furthermore support an emerging view that the therapeutic mechanism of responsive neurostimulation involves network-level effects in the brain.

Project description:ObjectiveThe RNS System is a direct brain-responsive neurostimulation system that is US Food and Drug Administration-approved for adults with medically intractable focal onset seizures based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real-world safety and effectiveness of the RNS System.MethodsEight comprehensive epilepsy centers conducted a chart review of patients treated with the RNS System for at least 1 year, in accordance with the indication for use. Data included device-related serious adverse events and the median percent change in disabling seizure frequency from baseline at years 1, 2, and 3 of treatment and at the most recent follow-up.ResultsOne hundred fifty patients met the criteria for analysis. The median reduction in seizures was 67% (interquartile range [IQR] = 33%-93%, n = 149) at 1 year, 75% (IQR = 50%-94%, n = 93) at 2 years, 82% (IQR = 50%-96%, n = 38) at ≥3 years, and 74% (IQR = 50%-96%, n = 150) at last follow-up (mean = 2.3 years). Thirty-five percent of patients had a ≥90% seizure frequency reduction, and 18% of patients reported being clinically seizure-free at last follow-up. Seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, seizure onset in mesial temporal or neocortical foci, magnetic resonance imaging findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment. The infection rate per procedure was 2.9% (6/150 patients); five of the six patients had an implant site infection, and one had osteomyelitis. Lead revisions were required in 2.7% (4/150), and 2.0% (3/150) of patients had a subdural hemorrhage, none of which had long-lasting neurological consequences.SignificanceIn this real-world experience, safety was similar and clinical seizure outcomes exceeded those of the prospective clinical trials, corroborating effectiveness of this therapy and suggesting that clinical experience has informed more effective programming.

Project description:IntroductionOne-third of patients with epilepsy continue to have seizures despite antiepileptic medications. Some of these refractory patients may not be candidates for surgical resection primarily because the seizure onset zones (SOZs) involve both hemispheres or are located in eloquent areas. The NeuroPace Responsive Neurostimulation System (RNS) is a closed-loop device that uses programmable detection and stimulation to tailor therapy to a patient's individual neurophysiology. Here, we present our single-center experience with the use of RNS in thalamic nuclei to provide long-term seizure control in patients with refractory epilepsy.MethodsWe performed a prospective single-center study of consecutive refractory epilepsy patients who underwent RNS system implantation in the anterior (ANT) and centromedian (CM) thalamic nuclei from September 2015 to December 2020. Patients were followed postoperatively to evaluate seizure freedom and complications.ResultsTwenty-three patients underwent placement of 36 RNS thalamic leads (CM = 27 leads, ANT = 9 leads). Mean age at implant was 18.8 ± 11.2 years (range 7.8-62 years-old). Two patients (8.7%) developed infections: 1 improved with antibiotic treatments alone, and 1 required removal with eventual replacement of the system to recover the therapeutic benefit. Mean time from RNS implantation to last follow-up was 22.3 months. Based on overall reduction of seizure frequency, 2 patients (8.7%) had no- to <25% improvement, 6 patients (26.1%) had 25-49% improvement, 14 patients (60.9%) had 50-99% improvement, and 1 patient (4.3%) became seizure-free. All patients reported significant improvement in seizure duration and severity, and 17 patients (74%) reported improved post-ictal state. There was a trend for subjects with SOZs located in the temporal lobe to achieve better outcomes after thalamic RNS compared to those with extratemporal SOZs. Of note, seizure etiology was syndromic in 12 cases (52.2%), and 7 patients (30.4%) had undergone resection/disconnection surgery prior to thalamic RNS therapy.ConclusionThalamic RNS achieved ≥50% seizure control in ~65% of patients. Infections were the most common complication. This therapeutic modality may be particularly useful for patients affected by aggressive epilepsy syndromes since a young age, those whose seizure foci are located in the mesial temporal lobe, and those who have failed prior surgical interventions.

Project description:OBJECTIVE:Brain-responsive neurostimulation (RNS System, NeuroPace) is used to treat medically refractory focal epilepsy and also provides long-term ambulatory neurophysiologic data. We sought to determine whether these data could predict the clinical response to antiseizure drugs (ASDs). METHODS:First, newly added medications were identified in RNS System patients followed at a single epilepsy center. Daily detection rates including "episode starts" (predominantly interictal activity) and "long episodes" (often electrographic seizures) were compared before and after ASD initiation. Efficacy was determined from documentation of clinical improvement and medication retention. Next, the analysis was repeated on an independent sample of patients from a multicenter long-term treatment trial, using an efficacy measure of ?50% reduction in diary-recorded seizure frequency after 3 months. RESULTS:In the single center cohort, long episodes, but not episode starts, had a significantly greater reduction in the first week for clinically efficacious compared to inefficacious medications. In this cohort, having no long episodes in the first week was highly predictive of ASD efficacy. In the multicenter cohort, both long episodes and episode starts had a significantly greater reduction for effective medications starting in the first 1-2 weeks. In this larger dataset, a ?50% decrease in episode starts was 90% specific for efficacy with a positive predictive value (PPV) of 67%, and a ?84% decrease in long episodes was 80% specific with a PPV of 48%. Conversely, a <25% decrease in long episodes (including any increase) or a <20% decrease in episode starts had a predictive value for inefficacy of >80%. SIGNIFICANCE:In RNS System patients with stable detection settings, when new ASDs are started, detection rates within the first 1-2 weeks may provide an early, objective indication of efficacy. These data could be used to identify responses to medication trials early to allow more rapid medication adjustments than conventionally possible.

Dataset Information

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

Objective

Methods

Results

Conclusions

Clinicaltrialsgov identifier

Classification of evidence

Publications

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

Similar Datasets

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