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

Dileep R Nair, Kenneth D Laxer, Peter B Weber, Anthony M Murro, Yong D Park, Gregory L Barkley, Brien J Smith, Ryder P Gwinn, Michael J Doherty, Katherine H Noe, Richard S Zimmerman, Gregory K Bergey, William S Anderson, Christianne Heck, Charles Y Liu, Ricky W Lee, Toni Sadler, Robert B Duckrow, Lawrence J Hirsch, Robert E Wharen Jr, William Tatum, Shraddha Srinivasan, Guy M McKhann, Mark A Agostini, Andreas V Alexopoulos, Barbara C Jobst, David W Roberts, Vicenta Salanova, Thomas C Witt, Sydney S Cash, Andrew J Cole, Gregory A Worrell, Brian N Lundstrom, Jonathan C Edwards, Jonathan J Halford, David C Spencer, Lia Ernst, Christopher T Skidmore, Michael R Sperling, Ian Miller, Eric B Geller, Michel J Berg, A James Fessler, Paul Rutecki, Alica M Goldman, Eli M Mizrahi, Robert E Gross, Donald C Shields, Theodore H Schwartz, Douglas R Labar, Nathan B Fountain, W Jeff Elias, Piotr W Olejniczak, Nicole R Villemarette-Pittman, Stephan Eisenschenk, Steven N Roper, Jane G Boggs, Tracy A Courtney, Felice T Sun, Cairn G Seale, Kathy L Miller, Tara L Skarpaas, Martha J Morrell, RNS System LTT Study, David King-Stephens, Cole A Giller, Ki Hyeong Lee, Mark R Lee, Joseph R Smith, Ellen L Air, David E Burdette, Konstantin V Elisevich, Shailaja Gaddam, Andrea Sneider Hakimi, Madhuri L Koganti, Amit Ray, Jason M Schwalb, Marianna V Spanaki-Varelas, Vibhangini S Wasade, Lisa M Caylor, David G Vossler, Joseph F Drazkowski, Naresh P Patel, Joseph I Sirven, George I Jallo, Eric H Kossoff, Frederick A Lenz, Eva Katharina Ritzl, Rami G Apelian, Vidya P Hawkins, Laura A Kalayjian, Brian Lee, Reed L Levine, George Nune, Ron A Shatzmiller, Parastou Shilian, Aamr A Herekar, Kore K Liow, Andrew D Massey, Nazih Moufarrij, Evan J Fertig, Jason L Gerrard, Alexander M Papanastassiou, Imran Quraishi, Dennis D Spencer, Susan S Spencer, Kenneth P Vives, David R Chabolla, Kent C New, Jerry J Shih, Richard W Byrne, Thomas Hoeppner, Marvin A Rossi, Michael C Smith, Carl W Bazil, Hyunmi Choi, Derek J Chong, Daniel L Friedman, Robert R Goodman, Mona Cheung, Ramon Diaz-Arrastia, Puneet K Gupta, Ryan Hays, Bradley Lega, Christopher J Madden, Pradeep N Modur, Paul C Van Ness, Louis Anthony Whitworth, William E Bingaman, Jehi Lara, Prakash Kotagal, Balu Krishnan, Joshua P Aronson, Krzysztof A Bujarski, Erik J Kobylarz, Richard P Morse, Vijay M Thadani, Nicholas Barbaro, Meridith A Runke, Dragos Sabau, Robert M Worth, Emad N Eskandar, Daniel B Hoch, Jeffrey W Britton, Gregory D Cascino, W R Marsh, Steven Glazier, Justin M Nolte, Mimi Sohn, William A Vandergrift, James J Cereghino, Felicia A Ferguson, Mary M Ransom, Martin C Salinsky, James J Evans, Scott E Mintzer, Maromi Nei, Ashwini D Sharan, Sanjiv Bhatia, Michael S Duchowny, John Ragheb, Werner Doyle, Theodore Schwartz, Peter P Widdess-Walsh, Robert A Gross, John Craig Henry, Lynn C Liu, Webster H Pilcher, Jason M Schwalb, Olga Selioutski, Trent Tollefson, Thomas Wychowski, Azam S Ahmed, John C Jones, Raj D Sheth, Karl A Sillay, Evelyn C Tunnell, Daniel Yoshor, Abdulrahman Alwaki, Charles M Epstein, Rebecca Fasano, Raymond E Faught Jr, Sandra L Helmers, Ioannis Karakis, Suzette M LaRoche, Kimford J Meador, Andres A Rodriguez Ruiz, Hannah Villarreal, Jon T. Willie, James W Leiphart, Samuel J Potolicchio Jr, Cynthia L Harden, Erik J Kobylarz, Mark S Quigg, Edward Mader, Jean E Cibula, William L Bell, Daniel E Couture, Thomas L Ellis, Cormac A O'Donovan, Maria C Sam, Dileep R Nair, Kenneth D Laxer, Peter B Weber, Anthony M Murro, Yong D Park, Gregory L Barkley, Brien J Smith, Ryder P Gwinn, Michael J Doherty, Katherine H Noe, Richard S Zimmerman, Gregory K Bergey, William S Anderson, Christianne Heck, Charles Y Liu, Ricky W Lee, Toni Sadler, Robert B Duckrow, Lawrence J Hirsch, Robert E Wharen Jr, William Tatum, Shraddha Srinivasan, Guy M McKhann, Mark A Agostini, Andreas V Alexopoulos, Barbara C Jobst, David W Roberts, Vicenta Salanova, Thomas C Witt, Sydney S Cash, Andrew J Cole, Gregory A Worrell, Brian N Lundstrom, Jonathan C Edwards, Jonathan J Halford, David C Spencer, Lia Ernst, Christopher T Skidmore, Michael R Sperling, Ian Miller, Eric B Geller, Michel J Berg, A James Fessler, Paul Rutecki, Alica M Goldman, Eli M Mizrahi, Robert E Gross, Donald C Shields, Theodore H Schwartz, Douglas R Labar, Nathan B Fountain, W Jeff Elias, Piotr W Olejniczak, Nicole R Villemarette-Pittman, Stephan Eisenschenk, Steven N Roper, Jane G Boggs, Tracy A Courtney, Felice T Sun, Cairn G Seale, Kathy L Miller, Tara L Skarpaas, Martha J Morrell, RNS System LTT Study, David King-Stephens, Cole A Giller, Ki Hyeong Lee, Mark R Lee, Joseph R Smith, Ellen L Air, David E Burdette, Konstantin V Elisevich, Shailaja Gaddam, Andrea Sneider Hakimi, Madhuri L Koganti, Amit Ray, Jason M Schwalb, Marianna V Spanaki-Varelas, Vibhangini S Wasade, Lisa M Caylor, David G Vossler, Joseph F Drazkowski, Naresh P Patel, Joseph I Sirven, George I Jallo, Eric H Kossoff, Frederick A Lenz, Eva Katharina Ritzl, Rami G Apelian, Vidya P Hawkins, Laura A Kalayjian, Brian Lee, Reed L Levine, George Nune, Ron A Shatzmiller, Parastou Shilian, Aamr A Herekar, Kore K Liow, Andrew D Massey, Nazih Moufarrij, Evan J Fertig, Jason L Gerrard, Alexander M Papanastassiou, Imran Quraishi, Dennis D Spencer, Susan S Spencer, Kenneth P Vives, David R Chabolla, Kent C New, Jerry J Shih, Richard W Byrne, Thomas Hoeppner, Marvin A Rossi, Michael C Smith, Carl W Bazil, Hyunmi Choi, Derek J Chong, Daniel L Friedman, Robert R Goodman, Mona Cheung, Ramon Diaz-Arrastia, Puneet K Gupta, Ryan Hays, Bradley Lega, Christopher J Madden, Pradeep N Modur, Paul C Van Ness, Louis Anthony Whitworth, William E Bingaman, Jehi Lara, Prakash Kotagal, Balu Krishnan, Joshua P Aronson, Krzysztof A Bujarski, Erik J Kobylarz, Richard P Morse, Vijay M Thadani, Nicholas Barbaro, Meridith A Runke, Dragos Sabau, Robert M Worth, Emad N Eskandar, Daniel B Hoch, Jeffrey W Britton, Gregory D Cascino, W R Marsh, Steven Glazier, Justin M Nolte, Mimi Sohn, William A Vandergrift, James J Cereghino, Felicia A Ferguson, Mary M Ransom, Martin C Salinsky, James J Evans, Scott E Mintzer, Maromi Nei, Ashwini D Sharan, Sanjiv Bhatia, Michael S Duchowny, John Ragheb, Werner Doyle, Theodore Schwartz, Peter P Widdess-Walsh, Robert A Gross, John Craig Henry, Lynn C Liu, Webster H Pilcher, Jason M Schwalb, Olga Selioutski, Trent Tollefson, Thomas Wychowski, Azam S Ahmed, John C Jones, Raj D Sheth, Karl A Sillay, Evelyn C Tunnell, Daniel Yoshor, Abdulrahman Alwaki, Charles M Epstein, Rebecca Fasano, Raymond E Faught Jr, Sandra L Helmers, Ioannis Karakis, Suzette M LaRoche, Kimford J Meador, Andres A Rodriguez Ruiz, Hannah Villarreal, Jon T. Willie, James W Leiphart, Samuel J Potolicchio Jr, Cynthia L Harden, Erik J Kobylarz, Mark S Quigg, Edward Mader, Jean E Cibula, William L Bell, Daniel E Couture, Thomas L Ellis, Cormac A O'Donovan, Maria C Sam

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.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. RNS System
Figure 1. RNS System
Left, RNS neurostimulator and NeuroPace cortical strip and depth leads. Top right, record of the number of electrographic events detected by the neurostimulator over time for an individual patient. Bottom right, snapshots of electrographic activity recorded by the RNS System for an individual patient. Copyright © 2020 NeuroPace, Inc.
Figure 2. RNS System studies, participant accountability
Figure 2. RNS System studies, participant accountability
aFeasibility study: 6 participants discontinued before completing the study; 2 participants completed the study but elected not to enroll in the long-term treatment (LTT) study. Thus, 57 participants in the feasibility study enrolled in the LTT study. bPivotal study: 16 participants discontinued before completing the study; 4 participants completed the study but elected not to enroll in the LTT study. Two participants who discontinued early were granted waivers and were allowed to enroll, resulting in 173 pivotal participants enrolling into LTT. A total of 230 participants chose to enroll in the LTT study, and 162 participants completed the study. cReasons for early withdrawal from the LTT study included the following: chose not to replace neurostimulator (n = 20); to pursue other treatment options (n = 10); insufficient efficacy (n = 8); study noncompliance (n = 7); and to receive medical care at a nonstudy center (n = 5).
Figure 3. RNS System long term clinical…
Figure 3. RNS System long term clinical response
Plot showing the median percent reduction ± IQR in seizure frequency for the last 6 months of each year in the long-term treatment study (years 3 through 9 of treatment) compared to baseline for the 91-day minimum diary requirement population, the constant cohort population, and the last observation carried forward (LOCF) population. (A) Median percent reduction ± interquartile range (IQR) over time. (B) Individual changes in clinical seizure frequency. Changes in clinical seizure frequency during the last 6 months of follow-up before the year 9 visit for each participant who had at least 91 days of seizure diary data. Negative values indicate a seizure frequency reduction compared with baseline. (C) Bar graph showing the percent of all participants (All) and participants with onsets in the mesial temporal lobe (MTL) or neocortex (Neo) with at least 1 period of seizure freedom lasting at least 3, 6, and 12 months.

References

    1. Engel J Jr, Wiebe S, French J, et al. . Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Epilepsia 2003;44:741–751.
    1. Shimamoto S, Wu C, Sperling MR. Laser interstitial thermal therapy in drug-resistant epilepsy. Curr Opin Neurol 2019;32:237–245.
    1. West S, Nolan SJ, Cotton J, et al. . Surgery for epilepsy. Cochrane Database Syst Rev 2015;7:CD010541.
    1. DeGiorgio CM, Schachter SC, Handforth A, et al. . Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures. Epilepsia 2000;41:1195–1200.
    1. Ramsay RE, Uthman BM, Augustinsson LE, et al. . Vagus nerve stimulation for treatment of partial seizures, 2: safety, side effects, and tolerability: First International Vagus Nerve Stimulation Study Group. Epilepsia 1994;35:627–636.
    1. Fisher R, Salanova V, Witt T, et al. . Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51:899–908.
    1. Salanova V, Witt T, Worth R, et al. . Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology 2015;84:1017–1025.
    1. Bergey GK, Morrell MJ, Mizrahi EM, et al. . Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology 2015;84:810–817.
    1. Heck CN, King-Stephens D, Massey AD, et al. . Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System pivotal trial. Epilepsia 2014;55:432–441.
    1. Morrell MJ. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011;77:1295–1304.
    1. Sun FT, Morrell MJ. The RNS System: responsive cortical stimulation for the treatment of refractory partial epilepsy. Expert Rev Med Devices 2014;11:563–572.
    1. Devinsky O, Vickrey BG, Cramer J, et al. . Development of the quality of life in epilepsy inventory. Epilepsia 1995;36:1089–1104.
    1. Weber PB, Kapur R, Gwinn RP, Zimmerman RS, Courtney TA, Morrell MJ. Infection and erosion rates in trials of a cranially implanted neurostimulator do not increase with subsequent neurostimulator placements. Stereotact Funct Neurosurg 2017;95:325–329.
    1. Wei Z, Gordon CR, Bergey GK, Sacks JM, Anderson WS. Implant site infection and bone flap osteomyelitis associated with the NeuroPace responsive neurostimulation system. World Neurosurg 2016;88:687.e1–687.e6.
    1. Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials. Lancet Neurol 2011;10:961–968.
    1. Loscher W, Schmidt D. Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs. Epilepsia 2006;47:1253–1284.
    1. Hessen E, Lossius MI, Gjerstad L. Health concerns predicts poor quality of life in well-controlled epilepsy. Seizure 2009;18:487–491.
    1. Loring DW, Meador KJ, Lee GP. Determinants of quality of life in epilepsy. Epilepsy Behav 2004;5:976–980.
    1. Behrens E, Schramm J, Zentner J, Konig R. Surgical and neurological complications in a series of 708 epilepsy surgery procedures. Neurosurgery 1997;41:1–9.
    1. Silberbusch MA, Rothman MI, Bergey GK, Zoarski GH, Zagardo MT. Subdural grid implantation for intracranial EEG recording: CT and MR appearance. AJNR Am J Neuroradiol 1998;19:1089–1093.
    1. Wong CH, Birkett J, Byth K, et al. . Risk factors for complications during intracranial electrode recording in presurgical evaluation of drug resistant partial epilepsy. Acta Neurochir (Wien) 2009;151:37–50.
    1. Engel J Jr, Wiebe S, French J, et al. . Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons. Neurology 2003;60:538–547.
    1. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001;345:311–318.
    1. Weaver FM, Follett K, Stern M, et al. . Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA 2009;301:63–73.
    1. Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet 2011;378:2028–2038.
    1. Dasheiff RM. Sudden unexpected death in epilepsy: a series from an epilepsy surgery program and speculation on the relationship to sudden cardiac death. J Clin Neurophysiol 1991;8:216–222.
    1. Devinsky O, Friedman D, Duckrow RB, et al. . Sudden unexpected death in epilepsy in patients treated with brain-responsive neurostimulation. Epilepsia 2018;59:555–561.
    1. Kahlow H, Olivecrona M. Complications of vagal nerve stimulation for drug-resistant epilepsy: a single center longitudinal study of 143 patients. Seizure 2013;22:827–833.
    1. Lambert MV, Robertson MM. Depression in epilepsy: etiology, phenomenology, and treatment. Epilepsia 1999;40(suppl 10):S21–S47.
    1. Meador KJ, Kapur R, Loring DW, Kanner AM, Morrell MJ. Quality of life and mood in patients with medically intractable epilepsy treated with targeted responsive neurostimulation. Epilepsy Behav 2015;45:242–247.
    1. Loring DW, Kapur R, Meador KJ, Morrell MJ. Differential neuropsychological outcomes following targeted responsive neurostimulation for partial-onset epilepsy. Epilepsia 2015;56:1836–1844.
    1. Gleissner U, Helmstaedter C, Schramm J, Elger CE. Memory outcome after selective amygdalohippocampectomy: a study in 140 patients with temporal lobe epilepsy. Epilepsia 2002;43:87–95.
    1. Helmstaedter C, Kurthen M, Lux S, Reuber M, Elger CE. Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy. Ann Neurol 2003;54:425–432.
    1. Donos C, Breier J, Friedman E, et al. . Laser ablation for mesial temporal lobe epilepsy: surgical and cognitive outcomes with and without mesial temporal sclerosis. Epilepsia 2018;59:1421–1432.
    1. RNS System User Manual (RNS-300M). Mountain View: NeuroPace, Inc; 2018.
    1. Sette AL, Seigneuret E, Reymond F, et al. . Battery longevity of neurostimulators in Parkinson disease: a historic cohort study. Brain Stimul 2019;12:851–857.
    1. DiLorenzo DJ, Mangubat EZ, Rossi MA, Byrne RW. Chronic unlimited recording electrocorticography-guided resective epilepsy surgery: technology-enabled enhanced fidelity in seizure focus localization with improved surgical efficacy. J Neurosurg 2014;120:1402–1414.
    1. Enatsu R, Alexopoulos A, Bingaman W, Nair D. Complementary effect of surgical resection and responsive brain stimulation in the treatment of bitemporal lobe epilepsy: a case report. Epilepsy Behav 2012;24:513–516.
    1. Ma BB, Rao VR. Responsive neurostimulation: candidates and considerations. Epilepsy Behav 2018;88:388–395.
    1. Skarpaas TL, Tcheng TK, Morrell MJ. Clinical and electrocorticographic response to antiepileptic drugs in patients treated with responsive stimulation. Epilepsy Behav 2018;83:192–200.
    1. Mackow MJ, Krishnan B, Bingaman WE, Najm IM, Alexopoulos AV, Nair DR. Increased caffeine intake leads to worsening of electrocorticographic epileptiform discharges as recorded with a responsive neurostimulation device. Clin Neurophysiol 2016;127:2341–2342.
    1. Arcot DS, Tcheng TK, Morrell MJ. Quantitative electrocorticographic biomarkers of clinical outcomes in mesial temporal lobe epileptic patients treated with the RNS® system. Clin Neurophysiol 2019;130:1364–1374.
    1. Kokkinos V, Sisterson ND, Wozny TA, Richardson RM. Association of closed-loop brain stimulation neurophysiological features with seizure control among patients with focal epilepsy. JAMA Neurol 2019;76:800–808.
    1. Baud MO, Rao VR. Gauging seizure risk. Neurology 2018;91:967–973.
    1. Baud MO, Kleen JK, Mirro EA, et al. . Multi-day rhythms modulate seizure risk in epilepsy. Nat Commun 2018;9:88.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever