Prospect of application of novel neuromodulation technology in children with drug-refractory epilepsy_Journal of Epilepsy

Authors：

HUANG Wenmin ¹ ,  CAO Dezhi ²

1. Shantou University, Shantou 515000, China;
2. Department of Neurology, Shenzhen Children's Hospital, Shenzhen 518000, China;

Corresponding author：

CAO Dezhi, Email: caodezhi888@aliyun.com

Keywords：

Refractory epilepsy in children; Transcranial electrical stimulation; Transcranial magnetic stimulation; transcutaneous auricular-Vagus nerve stimulation; Deep brain stimulation; Reactive neurostimulation

DOI：

10.7507/2096-0247.202411007

Video：

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In the treatment of drug-refractory epilepsy in children, surgical treatment has a good clinical effect. However, for children whose surgical site is difficult to determine and who cannot undergo resectional surgery, neuromodulation techniques are one of the treatments that can be considered. At present, new neuromodulation technologies in children mainly include transcutaneous vagus nerve stimulation (transcutaneous auricular vagus nerve stimulation, ta-VNS), deep brain stimulation (deep brain stimulation, DBS), reactive nerve stimulation (responsive neurostimulation, RNS), transcranial magnetic stimulation (transcranial magnetic stimulation, TMS), transcranial direct current stimulation (transcranial direct current stimulation, TDCS) and transcranial alternating current stimulation (transcranial alternating current stimulation, TACS). This article briefly discussed the clinical efficacy and safety of various currently available neuromodulation technologies, so as to provide a reference for the rational selection and application of neuromodulation technologies, and improve the clinical efficacy and quality of life of children with drug-refractory epilepsy.

Citation： HUANG Wenmin, CAO Dezhi. Prospect of application of novel neuromodulation technology in children with drug-refractory epilepsy. Journal of Epilepsy, 2025, 11(1): 50-56. doi: 10.7507/2096-0247.202411007 Copy

1.	Fiest KM, Sauro KM, Wiebe S, et al. The prevalence and incidence of epilepsy: a systematic review and meta-analysis. Neurology, 2016, 87(16): 164-171.
2.	Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia, 2010, 51(6): 1069-1077.
3.	Harijan P, Seal AK, Prasad M, et al. Fifteen-minute consultation: when medicines don't work-the child with poorly controlled seizures. Arch Dis Child Educ Pract Ed, 2019, 104: 135-140.
4.	Kellermann TS, Wagner JL, Smith G, et al. Surgical management of pediatric epilepsy: decision-making and outcomes. Pediatr Neurol, 2016, 64: 21-31.
5.	Wirrell EC. Predicting pharmacoresistance in pediatric epilepsy. Epilepsia, 2013, 54(1): 19-22.
6.	Boggio PS, Rigonatti SP, Ribeiro RB, et al. A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. Int J Neuropsychopharmacol, 2008, 11: 239-252.
7.	Chadaide Z, Arlt S, Antal A, et al. Transcranial direct current stimulation reveals inhibitory deficiency in migraine. Cephalalgia, 2007, 27: 833-839.
8.	Hummel F, Celnik P, Giraux P, et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain, 2005, 128: 490-499.
9.	Fregni F, Boggio PS, Lima MC, et al. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain, 2006, 122: 197-209.
10.	Hameed MQ, Dhamne SC, Gersner R, et al. Transcranial magnetic and direct current stimulation in children. Current Neurology and Neuroscience Reports, 2017, 17(2): 11.
11.	Nitsche M, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol, 2000, 527(Pt 3): 633-639.
12.	Regner GG, Pereira P, Leffa DT, et al. Preclinical to clinical translation of studies of transcranial direct-current stimulation in the treatment of epilepsy: a systematic review. Front Mol Neurosci, 2018, 12: 189.
13.	Fregni F, Thome-Souza S, Nitsche M, et al. A controlled clinical trial of cathodal DC polarization in patients with refractory epilepsy. Epilepsia, 2006, 47(2): 335-342.
14.	Ashrafzadeh F, Akhondian J, Hashemi N, et al. Therapeutical impacts of transcranial direct current stimulation on drug-resistant epilepsy in pediatric patients: a double-blind parallel-group randomized clinical trial. Epilepsy Res, 2023, 190: 107074.
15.	Palm U, Segmiller FM, Epple AN, et al. Transcranial direct current stimulation in children and adolescents: a comprehensive review. J Neural Transm (Vienna), 2016, 123(10): 1219-1234.
16.	Zewdie E, Ciechanski P, Kuo HC, et al. Safety and tolerability of transcranial magnetic and direct current stimulation in children: Prospective single center evidence from 3. 5 million stimulations. Brain Stimul, 2020, 13(3): 565-575.
17.	Grossman P, Woods AJ, Knotkova H, et al. Safety of transcranial direct current stimulation: evidence based update 2016. Brain Stimul, 2016, 9(5): 641-661.
18.	Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol, 2003, 2(3): 145-156.
19.	Pereira LS, Müller VT, da Mota Gomes M, et al. Safety of repetitive transcranial magnetic stimulation in patients with epilepsy: a systematic review. Epilepsy Behav, 2016, 57: 167-176.
20.	Malone LA, Sun LR. Transcranial magnetic stimulation for the treatment of pediatric neurological disorders. Curr Treat Options Neurol, 2019, 21(11): 58.
21.	Lefaucheur, Jean-Pascal. , Aleman, André. , et al Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018). Clinical Neurophysiology, 2020, 131(2): 474-528.
22.	Fregni F, Thome-Souza S, Bermpohl F, et al. Antiepileptic effects of repetitive transcranial magnetic stimulation in patients with cortical malformations: an EEG and clinical study. Stereotact Funct Neurosurg, 2005, 83(2-3): 57-62.
23.	Menkes DL, Gruenthal M. Slow-frequency repetitive transcranial magnetic stimulation in a patient with focal cortical dysplasia. Epilepsia, 2000, 41(2): 240-242.
24.	Cantello R, Rossi S, Varrasi C, et al. Slow repetitive, TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial. Epilepsia, 2007, 48(2): 366-374.
25.	Seynaeve L, Devroye A, Dupont P, et al Randomized crossover sham-controlled clinical trial of targeted low-frequency transcranial magnetic stimulation comparing a figure‐8 and a round coil to treat refractory neocortical epilepsy. Epilepsia, 2016, 57(1): 141-150.
26.	Narayana S, Gibbs SK, Fulton SP, et al. Clinical utility of transcranial magnetic stimulation (TMS) in the presurgical evaluation of motor, speech, and language functions in young children with refractory epilepsy or brain tumor: preliminary evidence. Front Neurol, 2021, 12: 650830.
27.	Garvey MA, Gilbert DL. Transcranial magnetic stimulation in children. Eur J Paediatr Neurol, 2004, 8: 7-19.
28.	Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol, 1998, 108(1): 1-16.
29.	Wassermann EM, Blaxton TA, Hoffman EA, et al. Repetitive transcranial magnetic stimulation of the dominant hemisphere can disrupt visual naming in temporal lobe epilepsy patients. Neuropsychologia, 1999, 37(5): 537-544.
30.	Koudijs SM, Leijten FS, Ramsey NF , et al. Lateralization of motor innervation in children with intractable focal epilepsy--a TMS and fMRI study. Epilepsy Res, 2010, 90(1-2): 140-150.
31.	Takano B, Drzezga A, Peller M, et al. Short-term modulation of regional excitability and blood flow in human motor cortex following rapid-rate transcranial magnetic stimulation. Neuroimage, 2004, 23(3): 849-859.
32.	San-Juan D, Sarmiento CI, Hernandez-Ruiz A, et al. Transcranial alternating current stimulation: a potential risk for genetic generalized epilepsy patients (study case). Front Neurol, 2016, 7: 213.
33.	San-Juan D, Espinoza-López DA, Vázquez-Gregorio R, et al. A pilot randomized controlled clinical trial of transcranial alternating current stimulation in patients with multifocal pharmaco-resistant epilepsy. Epilepsy Behav, 2022, 130: 108676.
34.	Yang AC, Zhang JG, Rong PJ, et al. A new choice for the treatment of epilepsy: electrical auricula-vagus-stimulation. Med Hypotheses, 2011, 77: 244-245.
35.	He W, Rong PJ, Li L, Ben H, et al. Auricular Acupuncture may suppress epileptic seizures via activating the parasympathetic nervous system: a hypothesis based on innovative methods. Evid Based Complement Alternat Med, 2012, 615476.
36.	Wu K, Wang Z, Zhang Y, et al. Transcutaneous vagus nerve stimulation for the treatment of drug-resistant epilepsy: a meta-analysis and systematic review. ANZ J Surg, 2020, 90(4): 467-471.
37.	Liu H, Huang F, Li X, et al. An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation. Chin Med J, 2014, 127: 300-304.
38.	He W, Jing X, Wang X, et al. Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial. Epilepsy Behavior, 2013, 28: 343-346.
39.	Rong P, Liu A, Zhang J, et al. Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial. Clin Sci, 2014, 127(2): 300-304.
40.	Rong P, Liu A, Zhang J, et al. An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation. Chin Med J, 2014, 127(4): 300-304.
41.	Mertens A, Raedt R, Gadeyne S, et al. Recent advances in devices for vagus nerve stimulation. Expert Rev Med Devices, 2018, 15(8): 527-539.
42.	Redgrave J, Day D, Leung H, et al. Safety and tolerability of transcutaneous vagus nerve stimulation in humans: a systematic review. Brain Stimul, 2018, 11(6): 1225-1238.
43.	Schiefer TK, Matsumoto JY, Lee KH. Moving forward: advances in the treatment of movement disorders with deep brain stimulation. Front Integr Neurosci, 2011, 5: 69.
44.	牛朝诗, 张世鑫. 2019年脑深部刺激术治疗相关进展. 中华医学信息导报, 2020, 35(5): 14.
45.	Valentín A, Selway RP, Amarouche M, et al. Intracranial stimulation for children with epilepsy. Eur J Paediatr Neurol, 2017, 21(1): 223-231.
46.	Li MCH, Cook MJ. Deep brain stimulation for drug-resistant epilepsy. Epilepsia, 2018, 59(2): 273-290.
47.	Herrera ML, Suller-Marti A, Parrent A, et al. Stimulation of the anterior nucleus of the thalamus for epilepsy: a canadian experience. Can J Neurol Sci, 2021, 48(4): 469-478.
48.	Singh RK, Eschbach K, Samanta D, et al. Responsive neurostimulation in drug-resistant pediatric epilepsy: findings from the epilepsy surgery subgroup of the pediatric epilepsy research consortium. Pediatr Neurol, 2023, 143: 106-112.
49.	Nagahara Y, Zervos TM, Murata KK, et al. Real-world preliminary experience with responsive neurostimulation in pediatric epilepsy: a multicenter retrospective observational study. Neurosurgery, 2021, 89(6): 997-1004.
50.	Hartnett SM, Greiner HM, Arya R, et al. Responsive neurostimulation device therapy in pediatric patients with complex medically refractory epilepsy. J Neurosurg Pediatr, 2022, 30(5): 499-506.
51.	Curtis K, Hect JL, Harford E, et al. Responsive neurostimulation for pediatric patients with drug-resistant epilepsy: a case series and review of the literature. Neurosurg Focus, 2022, 53(4): E10.
52.	Bercu MM, Friedman D, Silverberg A, et al. Responsive neurostimulation for refractory epilepsy in the pediatric population: a single-center experience. Epilepsy Behav, 2020, 112: 107389.

1. Fiest KM, Sauro KM, Wiebe S, et al. The prevalence and incidence of epilepsy: a systematic review and meta-analysis. Neurology, 2016, 87(16): 164-171.
2. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia, 2010, 51(6): 1069-1077.
3. Harijan P, Seal AK, Prasad M, et al. Fifteen-minute consultation: when medicines don't work-the child with poorly controlled seizures. Arch Dis Child Educ Pract Ed, 2019, 104: 135-140.
4. Kellermann TS, Wagner JL, Smith G, et al. Surgical management of pediatric epilepsy: decision-making and outcomes. Pediatr Neurol, 2016, 64: 21-31.
5. Wirrell EC. Predicting pharmacoresistance in pediatric epilepsy. Epilepsia, 2013, 54(1): 19-22.
6. Boggio PS, Rigonatti SP, Ribeiro RB, et al. A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. Int J Neuropsychopharmacol, 2008, 11: 239-252.
7. Chadaide Z, Arlt S, Antal A, et al. Transcranial direct current stimulation reveals inhibitory deficiency in migraine. Cephalalgia, 2007, 27: 833-839.
8. Hummel F, Celnik P, Giraux P, et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain, 2005, 128: 490-499.
9. Fregni F, Boggio PS, Lima MC, et al. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain, 2006, 122: 197-209.
10. Hameed MQ, Dhamne SC, Gersner R, et al. Transcranial magnetic and direct current stimulation in children. Current Neurology and Neuroscience Reports, 2017, 17(2): 11.
11. Nitsche M, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol, 2000, 527(Pt 3): 633-639.
12. Regner GG, Pereira P, Leffa DT, et al. Preclinical to clinical translation of studies of transcranial direct-current stimulation in the treatment of epilepsy: a systematic review. Front Mol Neurosci, 2018, 12: 189.
13. Fregni F, Thome-Souza S, Nitsche M, et al. A controlled clinical trial of cathodal DC polarization in patients with refractory epilepsy. Epilepsia, 2006, 47(2): 335-342.
14. Ashrafzadeh F, Akhondian J, Hashemi N, et al. Therapeutical impacts of transcranial direct current stimulation on drug-resistant epilepsy in pediatric patients: a double-blind parallel-group randomized clinical trial. Epilepsy Res, 2023, 190: 107074.
15. Palm U, Segmiller FM, Epple AN, et al. Transcranial direct current stimulation in children and adolescents: a comprehensive review. J Neural Transm (Vienna), 2016, 123(10): 1219-1234.
16. Zewdie E, Ciechanski P, Kuo HC, et al. Safety and tolerability of transcranial magnetic and direct current stimulation in children: Prospective single center evidence from 3. 5 million stimulations. Brain Stimul, 2020, 13(3): 565-575.
17. Grossman P, Woods AJ, Knotkova H, et al. Safety of transcranial direct current stimulation: evidence based update 2016. Brain Stimul, 2016, 9(5): 641-661.
18. Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol, 2003, 2(3): 145-156.
19. Pereira LS, Müller VT, da Mota Gomes M, et al. Safety of repetitive transcranial magnetic stimulation in patients with epilepsy: a systematic review. Epilepsy Behav, 2016, 57: 167-176.
20. Malone LA, Sun LR. Transcranial magnetic stimulation for the treatment of pediatric neurological disorders. Curr Treat Options Neurol, 2019, 21(11): 58.
21. Lefaucheur, Jean-Pascal. , Aleman, André. , et al Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018). Clinical Neurophysiology, 2020, 131(2): 474-528.
22. Fregni F, Thome-Souza S, Bermpohl F, et al. Antiepileptic effects of repetitive transcranial magnetic stimulation in patients with cortical malformations: an EEG and clinical study. Stereotact Funct Neurosurg, 2005, 83(2-3): 57-62.
23. Menkes DL, Gruenthal M. Slow-frequency repetitive transcranial magnetic stimulation in a patient with focal cortical dysplasia. Epilepsia, 2000, 41(2): 240-242.
24. Cantello R, Rossi S, Varrasi C, et al. Slow repetitive, TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial. Epilepsia, 2007, 48(2): 366-374.
25. Seynaeve L, Devroye A, Dupont P, et al Randomized crossover sham-controlled clinical trial of targeted low-frequency transcranial magnetic stimulation comparing a figure‐8 and a round coil to treat refractory neocortical epilepsy. Epilepsia, 2016, 57(1): 141-150.
26. Narayana S, Gibbs SK, Fulton SP, et al. Clinical utility of transcranial magnetic stimulation (TMS) in the presurgical evaluation of motor, speech, and language functions in young children with refractory epilepsy or brain tumor: preliminary evidence. Front Neurol, 2021, 12: 650830.
27. Garvey MA, Gilbert DL. Transcranial magnetic stimulation in children. Eur J Paediatr Neurol, 2004, 8: 7-19.
28. Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol, 1998, 108(1): 1-16.
29. Wassermann EM, Blaxton TA, Hoffman EA, et al. Repetitive transcranial magnetic stimulation of the dominant hemisphere can disrupt visual naming in temporal lobe epilepsy patients. Neuropsychologia, 1999, 37(5): 537-544.
30. Koudijs SM, Leijten FS, Ramsey NF , et al. Lateralization of motor innervation in children with intractable focal epilepsy--a TMS and fMRI study. Epilepsy Res, 2010, 90(1-2): 140-150.
31. Takano B, Drzezga A, Peller M, et al. Short-term modulation of regional excitability and blood flow in human motor cortex following rapid-rate transcranial magnetic stimulation. Neuroimage, 2004, 23(3): 849-859.
32. San-Juan D, Sarmiento CI, Hernandez-Ruiz A, et al. Transcranial alternating current stimulation: a potential risk for genetic generalized epilepsy patients (study case). Front Neurol, 2016, 7: 213.
33. San-Juan D, Espinoza-López DA, Vázquez-Gregorio R, et al. A pilot randomized controlled clinical trial of transcranial alternating current stimulation in patients with multifocal pharmaco-resistant epilepsy. Epilepsy Behav, 2022, 130: 108676.
34. Yang AC, Zhang JG, Rong PJ, et al. A new choice for the treatment of epilepsy: electrical auricula-vagus-stimulation. Med Hypotheses, 2011, 77: 244-245.
35. He W, Rong PJ, Li L, Ben H, et al. Auricular Acupuncture may suppress epileptic seizures via activating the parasympathetic nervous system: a hypothesis based on innovative methods. Evid Based Complement Alternat Med, 2012, 615476.
36. Wu K, Wang Z, Zhang Y, et al. Transcutaneous vagus nerve stimulation for the treatment of drug-resistant epilepsy: a meta-analysis and systematic review. ANZ J Surg, 2020, 90(4): 467-471.
37. Liu H, Huang F, Li X, et al. An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation. Chin Med J, 2014, 127: 300-304.
38. He W, Jing X, Wang X, et al. Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial. Epilepsy Behavior, 2013, 28: 343-346.
39. Rong P, Liu A, Zhang J, et al. Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial. Clin Sci, 2014, 127(2): 300-304.
40. Rong P, Liu A, Zhang J, et al. An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation. Chin Med J, 2014, 127(4): 300-304.
41. Mertens A, Raedt R, Gadeyne S, et al. Recent advances in devices for vagus nerve stimulation. Expert Rev Med Devices, 2018, 15(8): 527-539.
42. Redgrave J, Day D, Leung H, et al. Safety and tolerability of transcutaneous vagus nerve stimulation in humans: a systematic review. Brain Stimul, 2018, 11(6): 1225-1238.
43. Schiefer TK, Matsumoto JY, Lee KH. Moving forward: advances in the treatment of movement disorders with deep brain stimulation. Front Integr Neurosci, 2011, 5: 69.
44. 牛朝诗, 张世鑫. 2019年脑深部刺激术治疗相关进展. 中华医学信息导报, 2020, 35(5): 14.
45. Valentín A, Selway RP, Amarouche M, et al. Intracranial stimulation for children with epilepsy. Eur J Paediatr Neurol, 2017, 21(1): 223-231.
46. Li MCH, Cook MJ. Deep brain stimulation for drug-resistant epilepsy. Epilepsia, 2018, 59(2): 273-290.
47. Herrera ML, Suller-Marti A, Parrent A, et al. Stimulation of the anterior nucleus of the thalamus for epilepsy: a canadian experience. Can J Neurol Sci, 2021, 48(4): 469-478.
48. Singh RK, Eschbach K, Samanta D, et al. Responsive neurostimulation in drug-resistant pediatric epilepsy: findings from the epilepsy surgery subgroup of the pediatric epilepsy research consortium. Pediatr Neurol, 2023, 143: 106-112.
49. Nagahara Y, Zervos TM, Murata KK, et al. Real-world preliminary experience with responsive neurostimulation in pediatric epilepsy: a multicenter retrospective observational study. Neurosurgery, 2021, 89(6): 997-1004.
50. Hartnett SM, Greiner HM, Arya R, et al. Responsive neurostimulation device therapy in pediatric patients with complex medically refractory epilepsy. J Neurosurg Pediatr, 2022, 30(5): 499-506.
51. Curtis K, Hect JL, Harford E, et al. Responsive neurostimulation for pediatric patients with drug-resistant epilepsy: a case series and review of the literature. Neurosurg Focus, 2022, 53(4): E10.
52. Bercu MM, Friedman D, Silverberg A, et al. Responsive neurostimulation for refractory epilepsy in the pediatric population: a single-center experience. Epilepsy Behav, 2020, 112: 107389.

Journal of Epilepsy

Prospect of application of novel neuromodulation technology in children with drug-refractory epilepsy

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