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Association of Closed-Loop Brain Stimulation Neurophysiological Features With Seizure Control Among Patients With Focal Epilepsy

Educational Objective
To determine the association of closed-loop invasive brain stimulation with seizure control in patients with epilepsy.
1 Credit CME
Key Points

Question  What is the association of closed-loop invasive brain stimulation with seizure control in patients with epilepsy?

Finding  In this cohort study of 11 patients with focal epilepsy, seizure reduction was not associated with the direct effects of acute responsive stimulation events. Indirect effects on seizure electrophysiology, which occurred remotely to individual stimulation events, were associated with improved seizure control.

Meaning  Therapeutic outcomes of closed-loop stimulation appear to emerge from modulation of the seizure network over time rather than from the acute interruption of individual seizure events.

Abstract

Importance  A bidirectional brain-computer interface that performs neurostimulation has been shown to improve seizure control in patients with refractory epilepsy, but the therapeutic mechanism is unknown.

Objective  To investigate whether electrographic effects of responsive neurostimulation (RNS), identified in electrocorticographic (ECOG) recordings from the device, are associated with patient outcomes.

Design, Setting, and Participants  Retrospective review of ECOG recordings and accompanying clinical meta-data from 11 consecutive patients with focal epilepsy who were implanted with a neurostimulation system between January 28, 2015, and June 6, 2017, with 22 to 112 weeks of follow-up. Recorded ECOG data were obtained from the manufacturer; additional system-generated meta-data, including recording and detection settings, were collected directly from the manufacturer’s management system using an in-house, custom-built platform. Electrographic seizure patterns were identified in RNS recordings and evaluated in the time-frequency domain, which was locked to the onset of the seizure pattern.

Main Outcomes and Measures  Patterns of electrophysiological modulation were identified and then classified according to their latency of onset in relation to triggered stimulation events. Seizure control after RNS implantation was assessed by 3 main variables: mean frequency of seizure occurrence, estimated mean severity of seizures, and mean duration of seizures. Overall seizure outcomes were evaluated by the extended Personal Impact of Epilepsy Scale questionnaires, a patient-reported outcome measure of 3 domains (seizure characteristics, medication adverse effects, and quality of life), with a range of possible scores from 0 to 300 in which lower scores indicate worse status, and the Engel scale, which comprises 4 classes (I-IV) in which lower numbers indicate greater improvement.

Results  Electrocorticographic data from 11 patients (8 female; mean [range] age, 35 [19-65] years; mean [range] duration of epilepsy, 19 [5-37] years) were analyzed. Two main categories of electrophysiological signatures of stimulation-induced modulation of the seizure network were discovered: direct and indirect effects. Direct effects included ictal inhibition and early frequency modulation but were not associated with improved clinical outcomes (odds ratio [OR], 0.67; 95% CI, 0.06-7.35; P > .99). Only indirect effects—those occurring remote from triggered stimulation—were associated with improved clinical outcomes (OR, infinity; 95% CI, –infinity to infinity; P = .02). These indirect effects included spontaneous ictal inhibition, frequency modulation, fragmentation, and ictal duration modulation.

Conclusions and Relevance  These findings suggest that RNS effectiveness may be explained by long-term, stimulation-induced modulation of seizure network activity rather than by direct effects on each detected seizure.

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Article Information

Accepted for Publication: January 11, 2019.

Corresponding Author: R. Mark Richardson, MD, PhD, Department of Neurological Surgery, School of Medicine, University of Pittsburgh, 200 Lothrop St, Ste B400, Pittsburgh, PA 15213 (richardsonrm@upmc.edu).

Published Online: April 15, 2019. doi:10.1001/jamaneurol.2019.0658

Author Contributions: Dr Kokkinos and Mr Sisterson had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kokkinos.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kokkinos, Sisterson.

Obtained funding: Richardson.

Administrative, technical, or material support: All authors.

Supervision: Richardson.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was partly funded by the Walter L. Copeland Fund of the Pittsburgh Foundation (Mr Sisterson and Dr Richardson) and grant R01 NS110424 from the National Institute of Neurological Disorders and Stroke (Dr Richardson).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The authors thank NeuroPace, Inc, for assistance with data transfer. NeuroPace, Inc, was not compensated for this work.

References
1.
Penfield  W, Jasper  H. Electrocorticography. In:  Epilepsy and the Functional Anatomy of the Human Brain. Boston, MA: Little Brown; 1954.
2.
Kossoff  EH, Ritzl  EK, Politsky  JM,  et al.  Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring.  Epilepsia. 2004;45(12):1560-1567. doi:10.1111/j.0013-9580.2004.26104.xPubMedGoogle Scholar
3.
Stacey  WC, Litt  B.  Technology insight: neuroengineering and epilepsy-designing devices for seizure control.  Nat Clin Pract Neurol. 2008;4(4):190-201. doi:10.1038/ncpneuro0750PubMedGoogle Scholar
4.
Velasco  M, Velasco  F, Velasco  AL,  et al.  Subacute electrical stimulation of the hippocampus blocks intractable temporal lobe seizures and paroxysmal EEG activities.  Epilepsia. 2000;41(2):158-169. doi:10.1111/j.1528-1157.2000.tb00135.xPubMedGoogle Scholar
5.
Yamamoto  J, Ikeda  A, Satow  T,  et al.  Low-frequency electric cortical stimulation has an inhibitory effect on epileptic focus in mesial temporal lobe epilepsy.  Epilepsia. 2002;43(5):491-495. doi:10.1046/j.1528-1157.2002.29001.xPubMedGoogle Scholar
6.
Kinoshita  M, Ikeda  A, Matsumoto  R,  et al.  Electric stimulation on human cortex suppresses fast cortical activity and epileptic spikes.  Epilepsia. 2004;45(7):787-791. doi:10.1111/j.0013-9580.2004.60203.xPubMedGoogle Scholar
7.
Kinoshita  M, Ikeda  A, Matsuhashi  M,  et al.  Electric cortical stimulation suppresses epileptic and background activities in neocortical epilepsy and mesial temporal lobe epilepsy.  Clin Neurophysiol. 2005;116(6):1291-1299. doi:10.1016/j.clinph.2005.02.010PubMedGoogle Scholar
8.
Yamamoto  J, Ikeda  A, Kinoshita  M,  et al.  Low-frequency electric cortical stimulation decreases interictal and ictal activity in human epilepsy.  Seizure. 2006;15(7):520-527. doi:10.1016/j.seizure.2006.06.004PubMedGoogle Scholar
9.
Elisevich  K, Jenrow  K, Schuh  L, Smith  B.  Long-term electrical stimulation-induced inhibition of partial epilepsy: case report.  J Neurosurg. 2006;105(6):894-897. doi:10.3171/jns.2006.105.6.894PubMedGoogle Scholar
10.
Velasco  AL, Velasco  F, Velasco  M, María Núñez  J, Trejo  D, García  I.  Neuromodulation of epileptic foci in patients with non-lesional refractory motor epilepsy.  Int J Neural Syst. 2009;19(3):139-147. doi:10.1142/S0129065709001914PubMedGoogle Scholar
11.
Child  ND, Stead  M, Wirrell  EC,  et al.  Chronic subthreshold subdural cortical stimulation for the treatment of focal epilepsy originating from eloquent cortex.  Epilepsia. 2014;55(3):e18-e21. doi:10.1111/epi.12525PubMedGoogle Scholar
12.
Lundstrom  BN, Van Gompel  J, Britton  J,  et al.  Chronic subthreshold cortical stimulation to treat focal epilepsy.  JAMA Neurol. 2016;73(11):1370-1372. doi:10.1001/jamaneurol.2016.2857PubMedGoogle Scholar
13.
Lundstrom  BN, Worrell  GA, Stead  M, Van Gompel  JJ.  Chronic subthreshold cortical stimulation: a therapeutic and potentially restorative therapy for focal epilepsy.  Expert Rev Neurother. 2017;17(7):661-666. doi:10.1080/14737175.2017.1331129PubMedGoogle Scholar
14.
Valentin  A, Ughratdar  I, Venkatachalam  G,  et al.  Sustained seizure control in a child with drug resistant epilepsy after subacute cortical electrical stimulation (SCES).  Brain Stimul. 2016;9(2):307-309. doi:10.1016/j.brs.2015.12.004PubMedGoogle Scholar
15.
Kerezoudis  P, Grewal  SS, Stead  M,  et al.  Chronic subthreshold cortical stimulation for adult drug-resistant focal epilepsy: safety, feasibility, and technique.  J Neurosurg. 2018;129(2):533-543. doi:10.3171/2017.5.JNS163134PubMedGoogle Scholar
16.
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(3):432-441. doi:10.1111/epi.12534PubMedGoogle Scholar
17.
Bergey  GK, Morrell  MJ, Mizrahi  EM,  et al.  Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.  Neurology. 2015;84(8):810-817. doi:10.1212/WNL.0000000000001280PubMedGoogle Scholar
18.
Geller  EB, Skarpaas  TL, Gross  RE,  et al.  Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.  Epilepsia. 2017;58(6):994-1004. doi:10.1111/epi.13740PubMedGoogle Scholar
19.
Jobst  BC, Kapur  R, Barkley  GL,  et al.  Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.  Epilepsia. 2017;58(6):1005-1014. doi:10.1111/epi.13739PubMedGoogle Scholar
20.
Lesser  RP, Kim  SH, Beyderman  L,  et al.  Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation.  Neurology. 1999;53(9):2073-2081. doi:10.1212/WNL.53.9.2073PubMedGoogle Scholar
21.
Skarpaas  TL, Morrell  MJ.  Intracranial stimulation therapy for epilepsy.  Neurotherapeutics. 2009;6(2):238-243. doi:10.1016/j.nurt.2009.01.022PubMedGoogle Scholar
22.
Morrell  MJ, Halpern  C.  Responsive direct brain stimulation for epilepsy.  Neurosurg Clin N Am. 2016;27(1):111-121. doi:10.1016/j.nec.2015.08.012PubMedGoogle Scholar
23.
Thomas  GP, Jobst  BC.  Critical review of the responsive neurostimulator system for epilepsy.  Med Devices (Auckl). 2015;8:405-411.PubMedGoogle Scholar
24.
Berg  AT, Berkovic  SF, Brodie  MJ,  et al.  Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009.  Epilepsia. 2010;51(4):676-685. doi:10.1111/j.1528-1167.2010.02522.xPubMedGoogle Scholar
25.
Fisher  RS, Cross  JH, French  JA,  et al.  Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commission for classification and terminology.  Epilepsia. 2017;58(4):522-530. doi:10.1111/epi.13670PubMedGoogle Scholar
26.
Sisterson  ND, Wosny  TA, Kokkinos  V, Constantino  A, Richardson  RM.  Closed-loop brain stimulation for drug-resistant epilepsy: towards an evidence-based approach to personalized medicine.  Neurotherapeutics. 2019;16(1):119-127. doi:10.1007/s13311-018-00682-4PubMedGoogle Scholar
27.
Nowell  M, Rodionov  R, Zombori  G,  et al.  Utility of 3D multimodality imaging in the implantation of intracranial electrodes in epilepsy.  Epilepsia. 2015;56(3):403-413. doi:10.1111/epi.12924PubMedGoogle Scholar
28.
Fisher  RS, Nune  G, Roberts  SE, Cramer  JA.  The Personal Impact of Epilepsy Scale (PIES).  Epilepsy Behav. 2015;42:140-146. doi:10.1016/j.yebeh.2014.09.060PubMedGoogle Scholar
29.
Engel  J  Jr, Van Ness  PC, Rasmussen  TB, Ojemann  LM. Outcome with respect to epileptic seizures. In: Engel  J  Jr, ed.  Surgical Treatment of the Epilepsies. New York, NY: Raven Press; 1993:609-621.
30.
Jefferys  JGR.  Influence of electric fields on the excitability of granule cells in guinea-pig hippocampal slices.  J Physiol. 1981;319:143-152. doi:10.1113/jphysiol.1981.sp013897PubMedGoogle Scholar
31.
Durand  D.  Electrical stimulation can inhibit synchronized neuronal activity.  Brain Res. 1986;382(1):139-144. doi:10.1016/0006-8993(86)90121-6PubMedGoogle Scholar
32.
Osorio  I, Frei  MG, Sunderam  S,  et al.  Automated seizure abatement in humans using electrical stimulation.  Ann Neurol. 2005;57(2):258-268. doi:10.1002/ana.20377PubMedGoogle Scholar
33.
Bragin  A, Wilson  CL, Engel  J  Jr.  Chronic epileptogenesis requires development of a network of pathologically interconnected neuron clusters: a hypothesis.  Epilepsia. 2000;41(suppl 6):S144-S152. doi:10.1111/j.1528-1157.2000.tb01573.xPubMedGoogle Scholar
34.
Schevon  CA, Ng  SK, Cappell  J,  et al.  Microphysiology of epileptiform activity in human neocortex.  J Clin Neurophysiol. 2008;25(6):321-330. doi:10.1097/WNP.0b013e31818e8010PubMedGoogle Scholar
35.
Khambhati  AN, Davis  KA, Oommen  BS,  et al.  Dynamic network drivers of seizure generation, propagation and termination in human neocortical epilepsy.  PLoS Comput Biol. 2015;11(12):e1004608. doi:10.1371/journal.pcbi.1004608PubMedGoogle Scholar
36.
Zangaladze  A, Nei  M, Liporace  JD, Sperling  MR.  Characteristics and clinical significance of subclinical seizures.  Epilepsia. 2008;49(12):2016-2021. doi:10.1111/j.1528-1167.2008.01672.xPubMedGoogle Scholar
37.
Singh  S, Sandy  S, Wiebe  S.  Ictal onset on intracranial EEG: do we know it when we see it? state of the evidence.  Epilepsia. 2015;56(10):1629-1638. doi:10.1111/epi.13120PubMedGoogle Scholar
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