Electrical stimulation and gene-based neuromodulation for control of medically-refractory epilepsy

  • A. V. Alexopoulos
  • V. Gonugunta
  • J. Yang
  • Nicholas M. Boulis
Part of the Acta Neurochirurgica Supplements book series (NEUROCHIRURGICA, volume 97/2)


The failure of available antiepileptic medications to adequately control seizures in a substantial number of patients underscores the need to develop novel epilepsy therapies. Recent advancements in technology and the success of neuromodulation in treating a variety of neurological disorders have spurred interest in exploring promising therapeutic alternatives, such as electrical stimulation and gene-based synaptic control. A variety of different stimulation approaches to seizure control targeting structures in the central or peripheral nervous system have been investigated. Most studies have been based on uncontrolled observations and empirical stimulation protocols. Today the vagus nerve stimulator is the only FDA approved adjunctive treatment for epilepsy that utilizes electrical stimulation. Other potential strategies including direct stimulation of the epileptogenic cortex and deep brain stimulation of various targets are currently under investigation. Chronically implanted devices for electrical stimulation have a variety of limitations. First, they are susceptible to malfunction and infection. Second, most systems require battery replacement. Finally, electrical stimulation is incapable of manipulating neuronal function in a transmitter specific fashion. Gene delivery to epileptogenic targets or targets implicated in regulating seizure threshold has been investigated as an alternative means of neuromodulation in animal models. In summary, positive preliminary results and the lack of alternative treatment options provide the impetus for further exploration of electrical stimulation and gene-based therapies in pharmacoresistant epilepsy. Various specific targets and approaches to modulating their activity have been investigated in human studies.


Neuromodulation gene therapy epilepsy seizures electrical stimulation review 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Akamatsu N, Fueta Y, Endo Y, Matsunaga K, Uozumi T, Tsuji S (2001) Decreased susceptibility to pentylenetetrazol-induced seizures after low-frequency transcranial magnetic stimulation in rats. Neurosci Lett 310: 153–156PubMedCrossRefGoogle Scholar
  2. 2.
    Annegers JF, Coan SP, Hauser WA, Leestma J, Duffell W, Tarver B (1998) Epilepsy, vagal nerve stimulation by the NCP system, mortality, and sudden, unexpected, unexplained death. Epilepsia 39: 206–212PubMedCrossRefGoogle Scholar
  3. 3.
    Bailey P, Bremer F (1938) A sensory cortical representation of the vagus nerve. J Neurophysiol 1: 405–412Google Scholar
  4. 4.
    Barker AT, Jalinous R, Freeston IL (1985) Non-invasive magnetic stimulation of human motor cortex. Lancet 1: 1106–1107PubMedCrossRefGoogle Scholar
  5. 5.
    Benabid AL, Minotti L, Koudsie A, de Saint MA, Hirsch E (2002) Antiepileptic effect of high-frequency stimulation of the subthalamic nucleus (corpus luysi) in a case of medically intractable epilepsy caused by focal dysplasia: a 30-month follow-up: technical case report. Neurosurgery 50: 1385–1391PubMedCrossRefGoogle Scholar
  6. 6.
    Berns KI, Hauswirth WW (1979) Adeno-associated viruses. Adv Virus Res 25: 407–449PubMedCrossRefGoogle Scholar
  7. 7.
    Bridgers SL (1991) The safety of transcranial magnetic stimulation reconsidered: evidence regarding cognitive and other cerebral effects. Electroencephalogr Clin Neurophysiol Suppl 43: 170–179Google Scholar
  8. 8.
    Chabardes S, Kahane P, Minotti L, Koudsie A, Hirsch E, Benabid AL (2002) Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus. Epileptic Disord 4Suppl 3: S83–S93PubMedGoogle Scholar
  9. 9.
    Chkhenkeli SA, Chkhenkeli IS (1997) Effects of therapeutic stimulation of nucleus caudatus on epileptic electrical activity of brain in patients with intractable epilepsy. Stereotact Funct Neurosurg 69: 221–224PubMedCrossRefGoogle Scholar
  10. 10.
    Cooper IS, Amin I, Gilman S (1973) The effect of chronic cerebellar stimulation upon epilepsy in man. Trans Am Neurol Assoc 98: 192–196PubMedGoogle Scholar
  11. 11.
    DeGiorgio CM, Shewmon DA, Whitehurst T (2003) Trigeminal nerve stimulation for epilepsy. Neurology 61: 421–422PubMedGoogle Scholar
  12. 12.
    Fanselow EE, Reid AP, Nicolelis MA (2000) Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation. J Neurosci 20: 8160–8168PubMedGoogle Scholar
  13. 13.
    Fisher RS, Uematsu S, Krauss GL, Cysyk BJ, McPherson R, Lesser RP, Gordon B, Schwerdt P, Rise M (1992) Placebo-controlled pilot study of centromedian thalamic stimulation in treatment of intractable seizures. Epilepsia 33: 841–851PubMedCrossRefGoogle Scholar
  14. 14.
    Gale K, Iadarola MJ (1980) Seizure protection and increased nerve-terminal GABA: delayed effects of GABA transaminase inhibition. Science 208: 288–291PubMedCrossRefGoogle Scholar
  15. 15.
    Haberman RP, Samulski RJ, McCown TJ (2003) Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. Nat Med 9: 1076–1080PubMedCrossRefGoogle Scholar
  16. 16.
    Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, Henry TR, Collins SD, Vaughn BV, Gilmartin RC, Labar DR, Morris GL III, Salinsky MC, Osorio I, Ristanovic RK, Labiner DM, Jones JC, Murphy JV, Ney GC, Wheless JW (1998) Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 51: 48–55PubMedCrossRefGoogle Scholar
  17. 17.
    Hauser WA, Annegers JF, Kurland LT (1993) Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 34: 453–468PubMedCrossRefGoogle Scholar
  18. 18.
    Hauser WA, Annegers JF, Kurland LT (1991) Prevalence of epilepsy in Rochester, Minnesota: 1940–1980. Epilepsia 32: 429–445PubMedCrossRefGoogle Scholar
  19. 19.
    Hodaie M, Wennberg RA, Dostrovsky JO, Lozano AM (2002) Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 43: 603–608PubMedCrossRefGoogle Scholar
  20. 20.
    Johns DC, Marx R, Mains RE, O’Rourke B, Marban E (1999) Inducible genetic suppression of neuronal excitability. J Neurosci 19: 1691–1697PubMedGoogle Scholar
  21. 21.
    Kwan P, Brodie MJ (2000) Early identification of refractory epilepsy. N Engl J Med 342: 314–319PubMedCrossRefGoogle Scholar
  22. 22.
    Kwan P, Brodie MJ (2001) Effectiveness of first antiepileptic drug. Epilepsia 42: 1255–1260PubMedCrossRefGoogle Scholar
  23. 23.
    Lesser RP, Kim SH, Beyderman L, Miglioretti DL, Webber WR, Bare M, Cysyk B, Krauss G, Gordon B (1999) Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation. Neurology 53: 2073–2081PubMedGoogle Scholar
  24. 24.
    Lin EJ, Richichi C, Young D, Baer K, Vezzani A, During MJ (2003) Recombinant AAV-mediated expression of galanin in rat hippocampus suppresses seizure development. Eur J Neurosci 18: 2087–2092PubMedCrossRefGoogle Scholar
  25. 25.
    Loddenkemper T, Lüders HO (2004) Mechanisms and efficacy of deep brain stimulation in epilepsy. In: Rosenow F, Lüders HO (eds) Presurgical assessment of the epilepsy with clinical neurophysiology and functional imaging, vol. 3. Elsevier, Amsterdam, pp 539–570Google Scholar
  26. 26.
    Maksimow K (1976) Interruption of grand mal epileptic seizures by the trigeminal nerve stimulation. Neurol Neurochir Pol 10: 205–208PubMedGoogle Scholar
  27. 27.
    Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, Williamson PD, Treiman DM, McNamara JO, McCutchen CB (1985) Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 313: 145–151PubMedCrossRefGoogle Scholar
  28. 28.
    Mazarati A, Wasterlain CG (2002) Anticonvulsant effects of four neuropeptides in the rat hippocampus during self-sustaining status epilepticus. Neurosci Lett 331: 123–127PubMedCrossRefGoogle Scholar
  29. 29.
    McKhann GM (2004) Novel surgical treatments for epilepsy. Curr Neurol Neurosci Rep 4: 335–339PubMedCrossRefGoogle Scholar
  30. 30.
    McNamara JO (1999) Emerging insights into the genesis of epilepsy. Nature 399: A15–A22PubMedCrossRefGoogle Scholar
  31. 31.
    Menkes DL, Gruenthal M (2000) Slow-frequency repetitive transcranial magnetic stimulation in a patient with focal cortical dysplasia. Epilepsia 41: 240–242PubMedCrossRefGoogle Scholar
  32. 32.
    Mirski MA, Fisher RS (1994) Electrical stimulation of the mammillary nuclei increases seizure threshold to pentylenetetrazol in rats. Epilepsia 35: 1309–1316PubMedCrossRefGoogle Scholar
  33. 33.
    Motamedi GK, Lesser RP, Miglioretti DL, Mizuno-Matsumoto Y, Gordon B, Webber WR, Jackson DC, Sepkuty JP, Crone NE (2002) Optimizing parameters for terminating cortical afterdischarges with pulse stimulation. Epilepsia 43: 836–846PubMedCrossRefGoogle Scholar
  34. 34.
    Nair DR, Matsumoto R, Lüders HO, Burgess R, Bingaman W (2004) Direct cortical electrical stimulation in the treatment of epilepsy. In: Lüders HO (ed) Deep brain stimulation and epilepsy. Martin Dunitz, London, pp 275–284Google Scholar
  35. 35.
    Neme S, Montgomery EB Jr, Rezai A, Wilson K, Lüders HO (2004) Subthalamic nucleus stimulation in patients with intractable epilepsy: the Cleveland experience. In: Lüders HO (ed) Deep brain stimulation and epilepsy. Martin Dunitz, London, pp 349–355Google Scholar
  36. 36.
    Nilsen KE, Cock HR (2004) Focal treatment for refractory epilepsy: hope for the future? Brain Res Brain Res Rev 44: 141–153PubMedCrossRefGoogle Scholar
  37. 37.
    Osorio I, Frei MG, Sunderam S, Giftakis J, Bhavaraju NC, Schaffner SF, Wilkinson SB (2005) Automated seizure abatement in humans using electrical stimulation. Ann Neurol 57: 258–268PubMedCrossRefGoogle Scholar
  38. 38.
    Pascual-Leone A, Houser CM, Reese K, Shotland LI, Grafman J, Sato S, Valls-Sole J, Brasil-Neto JP, Wassermann EM, Cohen LG (1993) Safety of rapid-rate transcranial magnetic stimulation in normal volunteers. Electroencephalogr Clin Neurophysiol 89: 120–130PubMedCrossRefGoogle Scholar
  39. 39.
    Richichi C, Lin EJ, Stefanin D, Colella D, Ravizza T, Grignaschi G, Veglianese P, Sperk G, During MJ, Vezzani A (2004) Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J Neurosci 24: 3051–3059PubMedCrossRefGoogle Scholar
  40. 40.
    Rutecki P (1990) Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation. Epilepsia 31Suppl 2: S1–S6PubMedCrossRefGoogle Scholar
  41. 41.
    Salinsky MC, Uthman BM, Ristanovic RK, Wernicke JF, Tarver WB (1996) Vagus nerve stimulation for the treatment of medically intractable seizures. Results of a 1-year open-extension trial. Vagus Nerve Stimulation Study Group. Arch Neurol 53: 1176–1180PubMedGoogle Scholar
  42. 42.
    Schroeder BC, Kubisch C, Stein V, Jentsch TJ (1998) Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 396: 687–690PubMedCrossRefGoogle Scholar
  43. 43.
    Schulze-Bonhage A, Scheufler K, Zentner J, Elger CE (1999) Safety of single and repetitive focal transcranial magnetic stimuli as assessed by intracranial EEG recordings in patients with partial epilepsy. J Neurol 246: 914–919PubMedCrossRefGoogle Scholar
  44. 44.
    Sudhof TC (1995) The synaptic vesicle cycle: a cascade of proteinprotein interactions. Nature 375: 645–653PubMedCrossRefGoogle Scholar
  45. 45.
    Tergau F, Naumann U, Paulus W, Steinhoff BJ (1999) Lowfrequency repetitive transcranial magnetic stimulation improves intractable epilepsy. Lancet 353: 2209PubMedCrossRefGoogle Scholar
  46. 46.
    Theodore WH, Hunter K, Chen R, Vega-Bermudez F, Boroojerdi B, Reeves-Tyer P, Werhahn K, Kelley KR, Cohen L (2002) Transcranial magnetic stimulation for the treatment of seizures: a controlled study. Neurology 59: 560–562PubMedGoogle Scholar
  47. 47.
    Upton AR, Amin I, Garnett S, Springman M, Nahmias C, Cooper IS (1987) Evoked metabolic responses in the limbic-striate system produced by stimulation of anterior thalamic nucleus in man. Pacing Clin Electrophysiol 10: 217–225PubMedCrossRefGoogle Scholar
  48. 48.
    Van Buren JM, Wood JH, Oakley J, Hambrecht F (1978) Preliminary evaluation of cerebellar stimulation by double-blind stimulation and biological criteria in the treatment of epilepsy. J Neurosurg 48: 407–416PubMedGoogle Scholar
  49. 49.
    Velasco F, Carrillo-Ruiz JD, Brito F, Velasco M, Velasco AL, Marquez I, Davis R (2005) Double-blind, randomized controlled pilot study of bilateral cerebellar stimulation for treatment of intractable motor seizures. Epilepsia 46: 1071–1081PubMedCrossRefGoogle Scholar
  50. 50.
    Velasco F, Velasco M, Jimenez F, Velasco AL, Brito F, Rise M, Carrillo-Ruiz JD (2000a) Predictors in the treatment of difficult-to-control seizures by electrical stimulation of the centromedian thalamic nucleus. Neurosurgery 47: 295–304PubMedCrossRefGoogle Scholar
  51. 51.
    Velasco F, Velasco M, Ogarrio C, Fanghanel G (1987) Electrical stimulation of the centromedian thalamic nucleus in the treatment of convulsive seizures: a preliminary report. Epilepsia 28: 421–430PubMedCrossRefGoogle Scholar
  52. 52.
    Velasco M, Velasco F, Velasco AL, Boleaga B, Jimenez F, Brito F, Marquez I (2000b) Subacute electrical stimulation of the hippocampus blocks intractable temporal lobe seizures and paroxysmal EEG activities. Epilepsia 41: 158–169PubMedCrossRefGoogle Scholar
  53. 53.
    Velasco M, Velasco F, Velasco AL, Brito F, Jimenez F, Marquez I, Rojas B (1997) Electrocortical and behavioral responses produced by acute electrical stimulation of the human centromedian thalamic nucleus. Electroencephalogr Clin Neurophysiol 102: 461–471PubMedCrossRefGoogle Scholar
  54. 54.
    Vezzani A (2004) Gene therapy in epilepsy. Epilepsy Curr 4: 87–90PubMedCrossRefGoogle Scholar
  55. 55.
    Vonck K, Boon P, Achten E, De RJ, Caemaert J (2002) Long-term amygdalohippocampal stimulation for refractory temporal lobe epilepsy. Ann Neurol 52: 556–565PubMedCrossRefGoogle Scholar
  56. 56.
    Vonck K, Van LK, Dedeurwaerdere S, Caemaert J, De RJ, Boon P (2001) The mechanism of action of vagus nerve stimulation for refractory epilepsy: the current status. J Clin Neurophysiol 18: 394–401PubMedCrossRefGoogle Scholar
  57. 57.
    Walker BR, Easton A, Gale K (1999) Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Epilepsia 40: 1051–1057PubMedCrossRefGoogle Scholar
  58. 58.
    Wassermann EM, Grafman J, Berry C, Hollnagel C, Wild K, Clark K, Hallett M (1996) Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr Clin Neurophysiol 101: 412–417PubMedGoogle Scholar
  59. 59.
    Weiss SR, Li XL, Rosen JB, Li H, Heynen T, Post RM (1995) Quenching: inhibition of development and expression of amygdala kindled seizures with low frequency stimulation. Neuroreport 6: 2171–2176PubMedCrossRefGoogle Scholar
  60. 60.
    Wright GD, McLellan DL, Brice JG (1984) A double-blind trial of chronic cerebellar stimulation in twelve patients with severe epilepsy. J Neurol Neurosurg Psychiatry 47: 769–774PubMedGoogle Scholar
  61. 61.
    Yang J, Teng Q, Garrity-Moses M, Federici T, Najm I, Chabardes S, Moffitt M, Boulis NM (2005) Gene therapy of epilepsy by adenovirus-mediated tetanus toxin light chain gene transfer. Mol Ther 11Suppl 1: S168 (Abstract)CrossRefGoogle Scholar
  62. 62.
    Zabara J (1992) Inhibition of experimental seizures in canines by repetitive vagal stimulation. Epilepsia 33: 1005–1012PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • A. V. Alexopoulos
    • 2
  • V. Gonugunta
    • 4
  • J. Yang
    • 3
  • Nicholas M. Boulis
    • 3
    • 4
  1. 1.Center for Neurological RestorationCleveland Clinic Foundation NB2-126ClevelandUSA
  2. 2.Department of Neurology, Section of Adult EpilepsyCleveland Clinic FoundationClevelandUSA
  3. 3.Center for Neurological Restoration, Lerner Research InstituteCleveland Clinic FoundationClevelandUSA
  4. 4.Department of NeurosurgeryCleveland Clinic FoundationClevelandUSA

Personalised recommendations