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      Early detection rate changes from a brain‐responsive neurostimulation system predict efficacy of newly added antiseizure drugs

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          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).


          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.


          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%.


          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.

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          Most cited references 23

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          Responsive cortical stimulation for the treatment of medically intractable partial epilepsy.

           Lesley Morrell,   (2011)
          This multicenter, double-blind, randomized controlled trial assessed the safety and effectiveness of responsive cortical stimulation as an adjunctive therapy for partial onset seizures in adults with medically refractory epilepsy. A total of 191 adults with medically intractable partial epilepsy were implanted with a responsive neurostimulator connected to depth or subdural leads placed at 1 or 2 predetermined seizure foci. The neurostimulator was programmed to detect abnormal electrocorticographic activity. One month after implantation, subjects were randomized 1:1 to receive stimulation in response to detections (treatment) or to receive no stimulation (sham). Efficacy and safety were assessed over a 12-week blinded period and a subsequent 84-week open-label period during which all subjects received responsive stimulation. Seizures were significantly reduced in the treatment (-37.9%, n = 97) compared to the sham group (-17.3%, n = 94; p = 0.012) during the blinded period and there was no difference between the treatment and sham groups in adverse events. During the open-label period, the seizure reduction was sustained in the treatment group and seizures were significantly reduced in the sham group when stimulation began. There were significant improvements in overall quality of life (p < 0.02) and no deterioration in mood or neuropsychological function. Responsive cortical stimulation reduces the frequency of disabling partial seizures, is associated with improvements in quality of life, and is well-tolerated with no mood or cognitive effects. Responsive stimulation may provide another adjunctive treatment option for adults with medically intractable partial seizures. This study provides Class I evidence that responsive cortical stimulation is effective in significantly reducing seizure frequency for 12 weeks in adults who have failed 2 or more antiepileptic medication trials, 3 or more seizures per month, and 1 or 2 seizure foci.
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            Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study.

            Seizure prediction would be clinically useful in patients with epilepsy and could improve safety, increase independence, and allow acute treatment. We did a multicentre clinical feasibility study to assess the safety and efficacy of a long-term implanted seizure advisory system designed to predict seizure likelihood and quantify seizures in adults with drug-resistant focal seizures. We enrolled patients at three centres in Melbourne, Australia, between March 24, 2010, and June 21, 2011. Eligible patients had between two and 12 disabling partial-onset seizures per month, a lateralised epileptogenic zone, and no history of psychogenic seizures. After devices were surgically implanted, patients entered a data collection phase, during which an algorithm for identification of periods of high, moderate, and low seizure likelihood was established. If the algorithm met performance criteria (ie, sensitivity of high-likelihood warnings greater than 65% and performance better than expected through chance prediction of randomly occurring events), patients then entered an advisory phase and received information about seizure likelihood. The primary endpoint was the number of device-related adverse events at 4 months after implantation. Our secondary endpoints were algorithm performance at the end of the data collection phase, clinical effectiveness (measures of anxiety, depression, seizure severity, and quality of life) 4 months after initiation of the advisory phase, and longer-term adverse events. This trial is registered with, number NCT01043406. We implanted 15 patients with the advisory system. 11 device-related adverse events were noted within four months of implantation, two of which were serious (device migration, seroma); an additional two serious adverse events occurred during the first year after implantation (device-related infection, device site reaction), but were resolved without further complication. The device met enabling criteria in 11 patients upon completion of the data collection phase, with high likelihood performance estimate sensitivities ranging from 65% to 100%. Three patients' algorithms did not meet performance criteria and one patient required device removal because of an adverse event before sufficient training data were acquired. We detected no significant changes in clinical effectiveness measures between baseline and 4 months after implantation. This study showed that intracranial electroencephalographic monitoring is feasible in ambulatory patients with drug-resistant epilepsy. If these findings are replicated in larger, longer studies, accurate definition of preictal electrical activity might improve understanding of seizure generation and eventually lead to new management strategies. NeuroVista. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Long-term treatment with responsive brain stimulation in adults with refractory partial seizures

              Objective: The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. Methods: All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. Results: The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). Conclusions: The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. Classification of evidence: This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

                Author and article information

                John Wiley and Sons Inc. (Hoboken )
                17 December 2019
                January 2020
                : 61
                : 1 ( doiID: 10.1111/epi.v61.1 )
                : 138-148
                [ 1 ] Comprehensive Epilepsy Center Department of Neurology Yale University School of Medicine New Haven Connecticut
                [ 2 ] NeuroPace Mountain View California
                Author notes
                [* ] Correspondence

                Imran H. Quraishi, Comprehensive Epilepsy Center, Department of Neurology, Yale University School of Medicine, PO Box 208018, New Haven, CT 06520‐8018.

                Email: imran.quraishi@

                © 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy

                This is an open access article under the terms of the License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 5, Tables: 1, Pages: 11, Words: 6444
                Full‐length Original Research
                Full‐length Original Research
                Custom metadata
                January 2020
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