Transcutaneous auricular vagus nerve stimulation for pediatric epilepsy: study protocol for a randomized controlled trial

Wei He, Xiao-Yu Wang, Li Zhou, Zhi-Mei Li, Xiang-Hong Jing, Zhong-Li Lv, Yu-Feng Zhao, Hong Shi, Ling Hu, Yang-Shuai Su, Bing Zhu, Wei He, Xiao-Yu Wang, Li Zhou, Zhi-Mei Li, Xiang-Hong Jing, Zhong-Li Lv, Yu-Feng Zhao, Hong Shi, Ling Hu, Yang-Shuai Su, Bing Zhu

Abstract

Background: Recently, clinical observations reported the potential benefit of vagus nerve stimulation (VNS) for pediatric epilepsy. Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a newer non-invasive VNS, making it more accessible for treating pediatric epilepsy, yet there is limited clinical evidence for its effectiveness.

Methods/design: A three-center, randomized, parallel, controlled trial will be carried out to evaluate whether ta-VNS improves pediatric epilepsy. Pediatric patients aged 2 to 14 years with epilepsy will be recruited and randomly assigned to transcutaneous auricular vagus nerve stimulation (ta-VNS) group, transcutaneous auricular non-vagus nerve stimulation (tan-VNS) group, and control group with a 1:1: sqrt(2) allocation, as per a computer generated randomization schedule stratified by study center using permuted blocks of random sizes. We will use Zelen's design, in which randomization occurs before informed consent. Patients in the stimulation groups will receive tan-VNS or ta-VNS three times a day for 6 months. Patients in the control group will not be provided with any stimulation during the 6 months. The guardians of the patients are required to keep a detailed diary to record the data. Outcome assessment including seizure frequency, electroencephalogram (EEG), heart rate variability (HRV) analysis, quality of life (QOL) and adverse events will be made at baseline and 2, 4 and 6 months after ta-VNS initiation. The seizure frequency and adverse events will be followed up at 1 year and 1.5 years after ta-VNS initiation.

Discussion: Results of this trial will help clarify whether ta-VNS treatment is beneficial for pediatric patients, and will make clear whether the anticonvulsive effect of ta-VNS is correlated with the improvement of sympathovagal imbalance.

Clinical trials identifier: NCT02004340 . Registration date: 13 November 2013.

Figures

Fig. 1
Fig. 1
Trial flow chart

References

    1. Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol. 2002;1:477–82. doi: 10.1016/S1474-4422(02)00220-X.
    1. Healy S, Lang J, Te WNJ, Gibbon F, Leach P. Vagal nerve stimulation in children under 12 years old with medically intractable epilepsy. Childs Nerv Syst. 2013;29:2095–9. doi: 10.1007/s00381-013-2143-3.
    1. Murphy JV. Left vagal nerve stimulation in children with medically refractory epilepsy. The Pediatric VNS Study Group. J Pediatr. 1999;134:563–6. doi: 10.1016/S0022-3476(99)70241-6.
    1. Ben-Menachem E, Revesz D, Simon BJ, Silberstein S. Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Eur J Neurol. 2015
    1. Rong P, Liu A, Zhang J, Wang Y, Yang A, Li L, et al. An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation. Chin Med J (Engl) 2014;127:300–4.
    1. Rong P, Liu A, Zhang J, Wang Y, He W, Yang A . Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial. Clin Sci (Lond) 2014, Epub ahead of print.
    1. He W, Jing X, Wang X, Rong P, Li L, Shi H, et al. Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial. Epilepsy Behav. 2013;28:343–6. doi: 10.1016/j.yebeh.2013.02.001.
    1. Meghana A, Sathyaprabha TN, Sinha S, Satishchandra P. Cardiac autonomic dysfunction in drug naive hot water epilepsy. Seizure. 2012;21:706–10. doi: 10.1016/j.seizure.2012.07.014.
    1. Jeppesen J, Beniczky S, Johansen P, Sidenius P, Fuglsang-Frederiksen A. Detection of epileptic seizures with a modified heart rate variability algorithm based on Lorenz plot. Seizure. 2015;24:1–7. doi: 10.1016/j.seizure.2014.11.004.
    1. Raju KN, Choudhary N, Gulati S, Kabra M, Jaryal AK, Deepak KK, et al. Comparison of heart rate variability among children with well controlled versus refractory epilepsy: a cross-sectional study. Epilepsy Res. 2012;101:88–91. doi: 10.1016/j.eplepsyres.2012.03.005.
    1. Lotufo PA, Valiengo L, Bensenor IM, Brunoni AR. A systematic review and meta-analysis of heart rate variability in epilepsy and antiepileptic drugs. Epilepsia. 2012;53:272–82. doi: 10.1111/j.1528-1167.2011.03361.x.
    1. Elliott RE, Morsi A, Tanweer O, Grobelny B, Geller E, Carlson C, et al. Efficacy of vagus nerve stimulation over time: review of 65 consecutive patients with treatment-resistant epilepsy treated with VNS > 10 years. Epilepsy Behav. 2011;20:478–83. doi: 10.1016/j.yebeh.2010.12.042.
    1. Achenbach TM, Edelbrock CS. Manual for the Child Behavior Checklist and Revised Child Behavior profile. Burlington, VT: Department of Child and Adolescent Psychiatry, University of Vermont; 1983.
    1. Lundgren J, Amark P, Blennow G, Stromblad LG, Wallstedt L. Vagus nerve stimulation in 16 children with refractory epilepsy. Epilepsia. 1998;39:809–13. doi: 10.1111/j.1528-1157.1998.tb01173.x.
    1. Schomer AC, Nearing BD, Schachter SC, Verrier RL. Vagus nerve stimulation reduces cardiac electrical instability assessed by quantitative T-wave alternans analysis in patients with drug-resistant focal epilepsy. Epilepsia. 2014;55:1996–2002. doi: 10.1111/epi.12855.
    1. Chen M, Yu L, Liu Q, Wang Z, Wang S, Jiang H, et al. Low level tragus nerve stimulation is a non-invasive approach for anti-atrial fibrillation via preventing the loss of connexins. Int J Cardiol. 2015;179:144–5. doi: 10.1016/j.ijcard.2014.10.114.
    1. Li S, Zhai X, Rong P, McCabe MF, Zhao J, Ben H, et al. Transcutaneous auricular vagus nerve stimulation triggers melatonin secretion and is antidepressive in Zucker diabetic fatty rats. PLoS One. 2014;9:e111100. doi: 10.1371/journal.pone.0111100.
    1. Kreuzer PM, Landgrebe M, Resch M, Husser O, Schecklmann M, Geisreiter F, et al. Feasibility, safety and efficacy of transcutaneous vagus nerve stimulation in chronic tinnitus: an open pilot study. Brain Stimul. 2014;7:740–7. doi: 10.1016/j.brs.2014.05.003.
    1. Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014;7:871–7. doi: 10.1016/j.brs.2014.07.031.
    1. Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology. 2002;59:S3–14. doi: 10.1212/WNL.59.6_suppl_4.S3.
    1. He W, Jing XH, Zhu B, Zhu XL, Li L, Bai WZ, et al. The auriculo-vagal afferent pathway and its role in seizure suppression in rats. BMC Neurosci. 2013;14:85. doi: 10.1186/1471-2202-14-85.
    1. Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul. 2014

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren