, Volume 5, Issue 1, pp 68–74 | Cite as

Responsive cortical stimulation for the treatment of epilepsy

  • Felice T. Sun
  • Martha J. MorrellEmail author
  • Robert E. Wharen
Review Article


Epilepsy is a common chronic neurological disorder affecting ∼1–2% of the population. Despite the available treatment options (pharmacotherapy, surgery, and vagus nerve stimulation), a large percentage of patients continue to have seizures. With the success of deep brain stimulation for treatment of movement disorders, brain stimulation has received renewed attention as a potential treatment option for epilepsy. Responsive stimulation aims to suppress epileptiform activity by delivering stimulation directly in response to electrographic activity. Animal and human data support the concept that responsive stimulation can abort epileptiform activity, and this modality may be a safe and effective treatment option for epilepsy. Responsive stimulation has the advantage of specificity. In contrast to the typically systemic administration of pharmacotherapy, with the concomitant possibility of side effects, electrical stimulation can be targeted to the specific brain regions involved in the seizure. In addition, responsive stimulation provides temporal specificity. Treatment is provided as needed, potentially reducing the likelihood of functional disruption or habituation due to continuous treatment. Here we review current animal and human research in responsive brain stimulation for epilepsy and then discuss the NeuroPace RNS System, an investigational implantable responsive neurostimulator system that is being evaluated in a multicenter, randomized, double-blinded trial to assess the safety and efficacy of responsive stimulation for the treatment of medically refractory epilepsy.

Key Words

Epilepsy responsive stimulation neurostimulation device closed-loop 


  1. 1.
    Begley CE, Famulari M, Annegers JF, et al. The cost of epilepsy in the United States: An estimate from population-based clinical and survey data. Epilepsia 2000;41:342–351.CrossRefPubMedGoogle Scholar
  2. 2.
    Brodic MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996;334:168–175.CrossRefGoogle Scholar
  3. 3.
    Morrell MJ. Antiepileptic medications for the treatment of epilepsy. Semin Neurol 2002;22:247–258.CrossRefPubMedGoogle Scholar
  4. 4.
    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 [Erratum in: Neurology 2003;60:1396]. Neurology 2003;60:538–547.PubMedGoogle Scholar
  5. 5.
    Fisher RS, Handforth A. Reassessment: vagus nerve stimulation for epilepsy: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1999;53:666–669.PubMedGoogle Scholar
  6. 6.
    Penfield W, Jasper H. Electrocorticography. In: Epilepsy and the functional anatomy of the human brain. Boston: Little, Brown, 1954:692–738.Google Scholar
  7. 7.
    Oommen J, Morrell M, Fisher RS. Experimental electrical stimulation therapy for epilepsy. Curr Treat Options Neurol 2005;7:261–271.CrossRefPubMedGoogle Scholar
  8. 8.
    Morrell M. Brain stimulation for epilepsy: can scheduled or responsive neurostimulation stop seizures? Curr Opin Neurol 2006;19:164–168.CrossRefPubMedGoogle Scholar
  9. 9.
    Li Y, Mogul DJ. Electrical control of epileptic seizures. J Clin Neurophysiol 2007;24:197–204.CrossRefPubMedGoogle Scholar
  10. 10.
    Cooper IS, Amin I, Riklan M, Waltz JM, Poon TP. Chronic cerebellar stimulation in epilepsy: clinical and anatomical studies. Arch Neurol 1976;33:559–570.PubMedGoogle Scholar
  11. 11.
    Cooper IS, Upton AR. Therapeutic implications of modulation of metabolism and functional activity of cerebral cortex by chronic stimulation of cerebellum and thalamus. Biol Psychiatry 1985;20:811–813.CrossRefPubMedGoogle Scholar
  12. 12.
    Chkhenkeli SA, Chkhenkeli IS. Effects of therapeutic stimulation of nucleus caudatus on epileptic electrical activity of brain in patients with intractable epilepsy. Stereotact Funct Neurosurg 1997;69:221–224.CrossRefPubMedGoogle Scholar
  13. 13.
    Elisevich K, Jenrow K, Schuh L, Smith B. Long-term electrical stimulation-induced inhibition of partial epilepsy: case report. J Neurosurg 2006;105:894–897.CrossRefPubMedGoogle Scholar
  14. 14.
    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;41:158–169.CrossRefPubMedGoogle Scholar
  15. 15.
    Vonck K, Boon P, Goossens L, et al. Neurostimulation for refractory epilepsy. Acta Neurol Belg 2003;103:213–217.PubMedGoogle Scholar
  16. 16.
    Halpern CH, Samadani U, Litt B, Jaggi JL, Baituch GH. Deep brain stimulation for epilepsy. Neurotherapeutics 2008;5:000–000 (this issue).CrossRefGoogle Scholar
  17. 17.
    Psatta DM. Control of chronic experimental focal epilepsy by feedback caudatum stimulations. Epilepsia 1983;24: 444–454.CrossRefPubMedGoogle Scholar
  18. 18.
    Nakagawa M, Durand D. Suppression of spontaneous epileptiform activity with applied currents. Brain Res 1991;567:241–247.CrossRefPubMedGoogle Scholar
  19. 19.
    Kayyali H, Durand D. Effects of applied currents on epileptiform bursts in vitro. Exp Neurol 1991;113: 249–254.CrossRefPubMedGoogle Scholar
  20. 20.
    Warren RJ, Durand DM. Effects of applied currents on spontaneous epileptiform activity induced by low calcium in the rat hippocampus. Brain Res 1998;806:186–195.CrossRefPubMedGoogle Scholar
  21. 21.
    Lesser RP, Kim SH, Beyderman L, et al. Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation. Neurology 1999;53:2073–2081.PubMedGoogle Scholar
  22. 22.
    Motamedi GK, Lesser RP, Miglioretti DL, et al. Optimizing parameters for terminating cortical afterdischarges with pulse stimulation [Erratum in: Epilepsia;43:1441]. Epilepsia 2002;43:836–846.CrossRefPubMedGoogle Scholar
  23. 23.
    Peters TE, Bhavaraju NC, Frei MG, Osorio I. Network system for automated seizure detection and contingent delivery of therapy. J Clin Neurophysiol 2001;18:545–549.CrossRefPubMedGoogle Scholar
  24. 24.
    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;45:1560–1567.CrossRefPubMedGoogle Scholar
  25. 25.
    Osorio I, Frei MG, Wilkinson SB. Real-time automated detection and quantitative analysis of seizures and short-term prediction of clinical onset. Epilepsia 1998;39:615–627.CrossRefPubMedGoogle Scholar
  26. 26.
    Gotman J. Automatic seizure detection: improvements and evaluation. Electroencephalogr Clin Neurophysiol 1990;76: 317–324.CrossRefPubMedGoogle Scholar
  27. 27.
    Osorio I, Frei MG, Giftakis J, et al. Performance reassessment of a real-time seizure-detection algorithm on long ECoG series. Epilepsia 2002;43:1522–1535.CrossRefPubMedGoogle Scholar
  28. 28.
    Osorio I, Frei MG, Sunderam S, et al. Automated seizure abatement in humans using electrical stimulation. Ann Neurol 2005;57:258–268.CrossRefPubMedGoogle Scholar
  29. 29.
    Bertram E. The relevance of kindling for human epilepsy. Epilepsia 2007;48 Suppl 2:65–74.CrossRefPubMedGoogle Scholar
  30. 30.
    Gotman J. Automatic recognition of epileptic seizures in the EEG. Electroencephalogr Clin Neurophysiol 1982;54: 530–540.CrossRefPubMedGoogle Scholar
  31. 31.
    D’Alessandro M, Esteller R, Vachtsevanos G, Hinson A, Echauz J, Litt B. Epileptic seizure prediction using hybrid feature selection over multiple intracranial EEG electrode contacts: a report of four patients [Erratum in: IEEE Trans Biomed Eng;50:1041]. IEEE Trans Biomed Eng 2003;50:603–615.CrossRefPubMedGoogle Scholar
  32. 32.
    Esteller R, Echauz J, Tcheng T, Litt B, Pless B. Line length: an efficient feature for seizure onset detection. Engineering in Medicine and Biology, 2001, EMBS ’01. Proc Annu Int Conf IEEE 23rd 2001;2: 1707–1710.Google Scholar
  33. 33.
    Echauz J, Padovani DA, Esteller R, Litt B, Vachtsevanos G. Median-based filtering methods for EEG seizure detection. Proc Joint BMES/IEEE-EMBS Conf 1st, Atlanta, GA, 1999;1:439.Google Scholar
  34. 34.
    Litt B, Esteller R, Echauz J, et al. Epileptic seizures may begin hours in advance of clinical onset: a report of five patients. Neuron 2001;30:51–64.CrossRefPubMedGoogle Scholar
  35. 35.
    Litt B, Esteller R, D’Alessandro M, et al. Evolution of accumulated energy predicts seizures in mesial temporal lobe epilepsy. Proc Joint BMES/IEEE-EMBS Conf 1st, Atlanta, GA, 1999;1:440.Google Scholar
  36. 36.
    Lesser RP, Lüders H, Klem G, et al. Extraoperative cortical functional localization in patients with epilepsy. J Clin Neurophysiol 1987;4:27–53.CrossRefPubMedGoogle Scholar
  37. 37.
    Risinger MW, Gumnit RJ. Intracranial electrophysiologic studies. Neuroimaging Clin N Am 1995;5: 559–573.PubMedGoogle Scholar
  38. 38.
    Haberler C, Alesch F, Mazal PR, et al. No tissue damage by chronic deep brain stimulation in Parkinson’s disease. Ann Neurol 2000;48:372–376.CrossRefPubMedGoogle Scholar
  39. 39.
    Nguyen JP, Lefaucheur JP, Decq P, et al. Chronic motor cortex stimulation in the treatment of central and neuropathic pain: correlations between clinical, electrophysiological and anatomical data. Pain 1999;82:245–251.CrossRefPubMedGoogle Scholar
  40. 40.
    Ebel H, Rust D, Tronnier V, Boker D, Kunze S. Chronic precentral stimulation in trigeminal neuropathic pain. Acta Neurochir (Wien) 1996;138:1300–1306.CrossRefGoogle Scholar
  41. 41.
    Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama S. Chronic motor cortex stimulation in patients with thalamic pain. J Neurosurg 1993;78:393–401.CrossRefPubMedGoogle Scholar
  42. 42.
    Bartlett JR, Doty RW Sr, Lee BB, Negrão N, Overman WH Jr. Deleterious effects of prolonged electrical excitation of striate cortex in macaques. Brain Behav Evol 1977;14:46–66.CrossRefPubMedGoogle Scholar
  43. 43.
    Dauth G, Defendini R, Gilman S, Tennyson V, Kremzner L. Long-term surface stimulation of the cerebellum in the monkey: I. Light microscopic, electrophysiologic, and clinical observations. Surg Neurol 1977;7: 377–384.PubMedGoogle Scholar
  44. 44.
    Gordon B, Lesser RP, Rance NE, et al. Parameters for direct cortical electrical stimulation in the human: histopathologic confirmation. Electroencephalogr Clin Neurophysiol 1990;75:371–377.CrossRefPubMedGoogle Scholar
  45. 45.
    Lesser R, Gordon B, Uematsu S. Electrical stimulation and language. J Clin Neurophysiol 1994;11:191–204.CrossRefPubMedGoogle Scholar

Copyright information

© Springer New York 2008

Authors and Affiliations

  • Felice T. Sun
    • 1
  • Martha J. Morrell
    • 1
    Email author
  • Robert E. Wharen
    • 2
  1. 1.NeuroPace, Inc.Mountain View
  2. 2.Department of NeurosurgeryMayo Clinic College of MedicineJacksonville

Personalised recommendations