Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02)

Published:January 20, 2016DOI:


      • We compared active transcutaneous vagus nerve stimulation (tVNS) with a sham stimulation paradigm for treatment of drug-resistant epilepsy in a double-blind, randomized clinical trial.
      • Superiority of active tVNS vs. control tVNS could not be proven, but seizure frequency was significantly reduced in patients who completed the full active tVNS treatment period of 20 weeks.
      • Treatment adherence was high.
      • tVNS is a well tolerated treatment procedure.



      Various brain stimulation techniques are in use to treat epilepsy. These methods usually require surgical implantation procedures. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique to stimulate the left auricular branch of the vagus nerve at the ear conch.


      We performed a randomized, double-blind controlled trial (cMPsE02) to assess efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy.


      Primary objective was to demonstrate superiority of add-on therapy with tVNS (stimulation frequency 25 Hz, n = 39) versus active control (1 Hz, n = 37) in reducing seizure frequency over 20 weeks. Secondary objectives comprised reduction in seizure frequency from baseline to end of treatment, subgroup analyses and safety evaluation.


      Treatment adherence was 84% in the 1 Hz group and 88% in the 25 Hz group, respectively. Stimulation intensity significantly differed between the 1 Hz group (1.02 ± 0.83 mA) and the 25 Hz group (0.50 ± 0.47 mA; p = 0.006). Mean seizure reduction per 28 days at end of treatment was –2.9% in the 1 Hz group and 23.4% in the 25 Hz group (p = 0.146). In contrast to controls, we found a significant reduction in seizure frequency in patients of the 25 Hz group who completed the full treatment period (20 weeks; n = 26, 34.2%, p = 0.034). Responder rates (25%, 50%) were similar in both groups. Subgroup analyses for seizure type and baseline seizure frequency revealed no significant differences. Adverse events were usually mild or moderate and comprised headache, ear pain, application site erythema, vertigo, fatigue, and nausea. Four serious adverse events were reported including one sudden unexplained death in epilepsy patients (SUDEP) in the 1 Hz group which was assessed as not treatment-related.


      tVNS had a high treatment adherence and was well tolerated. Superiority of 25 Hz tVNS over 1 Hz tVNS could not be proven in this relatively small study, which might be attributed to the higher stimulation intensity in the control group. Efficacy data revealed results that justify further trials with larger patient numbers and longer observation periods.


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        • Brodie M.J.
        • Shorvon S.D.
        • Canger R.
        • Halász P.
        • Johannessen S.
        • Thompson P.
        • et al.
        Commission on European Affairs: appropriate standards of epilepsy care across Europe. ILEA.
        Epilepsia. 1997; 38: 1245-1250
        • Kwan P.
        • Brodie M.J.
        Early identification of refractory epilepsy.
        N Engl J Med. 2000; 342: 314-319
        • Handforth A.
        • DeGiorgio C.M.
        • Schachter S.C.
        • Uthman B.M.
        • Naritoku D.K.
        • Tecoma E.S.
        • et al.
        Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.
        Neurology. 1998; 51: 48-55
      1. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. The Vagus Nerve Stimulation Study Group.
        Neurology. 1995; 45: 224-230
        • Boon P.
        • Raedt R.
        • de Herdt V.
        • Wyckhuys T.
        • Vonck K.
        Electrical stimulation for the treatment of epilepsy.
        Neurother. 2009; 6: 218-227
        • Ellrich J.
        Transcutaneous vagus nerve stimulation.
        Eur Neurol Rev. 2011; 6: 254-256
        • Peuker E.T.
        • Filler T.J.
        The nerve supply of the human auricle.
        Clin Anat. 2002; 15: 35-37
        • 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: 343-346
        • Stefan H.
        • Kreiselmeyer G.
        • Kerling F.
        • Kurzbuch K.
        • Rauch C.
        • Heers M.
        • et al.
        Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial.
        Epilepsia. 2012; 53: e115-18
        • Baker G.A.
        • Smith D.F.
        • Dewey M.
        • Morrow J.
        • Crawford P.M.
        • Chadwick D.W.
        The development of a seizure severity scale as an outcome measure in epilepsy.
        Epilepsy Res. 1991; 8: 245-251
        • Cramer J.A.
        • Perrine K.
        • Devinsky O.
        • Bryant-Comstock L.
        • Meador K.
        • Hermann B.
        Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory.
        Epilepsia. 1998; 39: 81-88
        • Montgomery S.A.
        • Asberg M.
        A new depression scale designed to be sensitive to change.
        Br J Psychiatry. 1979; 134: 382-389
        • He W.
        • Zhu B.
        • Rong P.
        A new concept of transcutaneous vagus nerve stimulation for epileptic seizure.
        Abstr - Soc Neurosci. 2009; 4
        • Kreuzer P.M.
        • 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: 740-747
        • Kreuzer P.M.
        • Landgrebe M.
        • Husser O.
        • Resch M.
        • Schecklmann M.
        • Geisreiter F.
        • et al.
        Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study.
        Front Psychiatry. 2012; 3: 70
        • Shorvon S.
        • Tomson T.
        Sudden unexpected death in epilepsy.
        Lancet. 2011; 378: 2028-2038
        • Hoppe C.
        • Poepel A.
        • Elger C.E.
        Epilepsy: accuracy of patient seizure counts.
        Arch Neurol. 2007; 64: 1595-1599