300

Chin Med J 2014;127 (2)

Original article
An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation
Rong Peijing, Liu Aihua, Zhang Jianguo, Wang Yuping, Yang Anchao, Li Liang, Ben Hui, Li Liping, Liu Rupeng, He Wei, Liu Huanguang, Huang Feng, Li Xia, Wu Peng and Zhu Bing
Background Previous studies demonstrated that vagus nerve stimulation (VNS) is an effective therapy for drugresistant epilepsy. Acupuncture is also used to treat epilepsy. This study was designed to examine the safety and effectiveness of transcutaneous auricular vagus nerve stimulation (ta-VNS) for patients with drug-resistantepilepsy. Methods A total of 50 volunteer patients with drug-resistantepilepsy were selected for a random clinical trial to observe the therapeutic effect of ta-VNS. The seizure frequency, quality of life, and severity were assessed in weeks 8, 16, and 24 of the treatment according to the percentage of seizure frequency reduction. Results In the pilot study, 47 of the 50 epilepsy patients completed the 24-week treatment; three dropped off. After 8-week treatment, six of the 47 patients (12%) were seizure free and 12 (24%) had a reduction in seizure frequency. In week 16 of the continuous treatment, six of the 47 patients (12%) were seizure free; 17 (34%) had a reduction in seizure frequency. After 24 weeks treatment, eight patients (16%) were seizure free; 19 (38%) had reduced seizure frequency. Conclusion Similar to the therapeutic effect of VNS, ta-VNS can suppress epileptic seizures and is a safe, effective, economical, and widely applicable treatment option for drug-resistantepilepsy. (ChiCTR-TRC-10001023) Chin Med J 2014;127 (2): 300-304

rug-resistant epilepsy is a seizure that resists drug treatment. When the course of disease is more than 2 years and, though with standardized treatment of three or more than three kinds of antiepileptic drugs (AEDs), the frequency of seizures is still more than four times per month, we call it drug-induced drug-resistantepilepsy. Epilepsy is a chronic neurological disorder that may affect people of all ages all over the world.1 In China, the prevalence rate of epilepsy is estimated to be 0.7% with about 9 million people. 2 About 20%30% of the patients have drug-resistantepilepsy and the current AEDs have various side effects.3 The development of a new effective therapy for refractory seizures is of considerable importance. It should be emphasized that during the test, the type and dose of the original AEDs were kept unchanged in both the control group and the treatment group. Vagus nerve stimulation (VNS) is an established effective therapy for epilepsy and was first presented by Corning, an American neurobiologist in the nineteenth century.4 In 1997, as an adjunctive therapy for refractory partialonset seizures in adults and adolescents aged more than 12 years, VNS was approved by the US Food and Drug Administration (FDA).5 During the process of VNS, the left cervical vagus nerve is stimulated by an implanted electrode, which may cause safety and practicability issues.6 It is believed that the nucleus tractus solitarius (NTS) plays an important role in the VNS therapy for epilepsy.7 Anatomy studies have shown that the ear is the only place on the surface of the human body where there is afferent vagus nerve distribution.8,9 Our previous studies found that there is a direct projection from the auricular branch

of the vagus nerve to the NTS. Thus, direct stimulation of the afferent nerve fibers on the ear could produce an effect similar to classic VNS in reducing seizure frequency without the burden of surgical intervention.10 In this research, we examined the anti-seizure effects of transcutaneous auricular-VNS (ta-VNS) on patients with refractory seizures and tried to provide a safe and practicable therapy for epilepsy. METHODS Recruitment of patients This study was approved by the Institutional Ethics Committee of the China Academy of Chinese Medical Sciences before starting. All clinical investigation procedures were conducted according to the principles
DOI: 10.3760/cma.j.issn.0366-6999.20131511 Function Laboratory, Institute of Acu-Mox, China Academy of Chinese Medical Sciences, Beijing 100700, China (Rong PJ, Li L, Ben H, Liu RP, He W, Huang F, Li X, Wu P and Zhu B) Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China (Liu AH, Wang YP and Li LP) Institute of Neurosurgery, Tiantan Hospital, Beijing 100050, China (Zhang JG, Yang AC and Liu HG) Correspondence to: Dr. Zhu Bing, Function Laboratory, Institute of Acu-Mox, China Academy of Chinese Medical Sciences, Beijing 100700, China (Tel: 86-10-64014411 ext. 2915. Email: zhubing@ mail.cintcm.ac.cn) Dr. Rong Peijing, Dr. Liu Aihua, and Dr. Zhang Jianguo contributed equally to this work. This scientific study was funded by the General Program of National Natural Science Foundation of China (No. 30973798), the Special Program of Chinese Medicine of the National Basic Research Program of China (973 Program, No. 2012CB518503), National Twelfth Five-year Science and Technology Support Program (No. 2012BAF14B10), and the Capital Medical Development Foundation of China (TCM-SF-2009-II-15).

Chinese Medical Journal 2014;127 (2)

301

expressed in Declaration of Helsinki. Patients signed the patient consent form when they joined the study. All patients and data were from three hospitals: the Department of Neurology of the Xuanwu Hospital, the Institute of Neurosurgery of the Tiantan Hospital, and the Acupuncture Hospital of the China Academy of Chinese Medical Sciences, Beijing. The doctors were familiar with ta-VNS treatment principles. Recruitment date was from December 2008 to December 2009. The average age of the 50 epilepsy patients (30 males and 20 females) was (25.213.1) years. Patients were volunteers and were selected randomly in all visits. Before and after the treatment of ta-VNS, all the patients completed the Liverpool Seizure Severity Scale (LESS) and Quality of Life in epilepsy inventory (QOLIE-31). 11 The seizure frequency was recorded according to the patients seizures per month. Among the 50 patients, there were 42 cases (84%) of complex partial seizures (seven cases with secondary generalized seizures) and eight cases (18%) of generalized seizures. The average duration of epilepsy in these patients was 12.07 years (Table 1). Inclusion criteria for epilepsy patients The inclusion criteria are as follows: (1) frequent and disabling seizures with falls, injuries, and significant impairment of the quality of life, intractable to treatment with multiple AEDs for at least 1 year; (2) bilateral and/ or non-localized findings with precluded consideration for surgical treatment after screening with scalp videoelectroencephalograph (EEG); (3) aged between 12 and 65 years; and (4) with a valid record of the patients daily frequency of seizures. Physical examinations including ECG, MRI, and videoEEG monitoring were prescribed in each hospitals outpatient department to evaluate whether the patient met the inclusion criteria. Exclusion criteria for epilepsy patients Epilepsy patients with tumors, progressive encephalopathy, progressive neurodegenerative disorders, and other serious pulmonary heart diseases and patients treated concomitantly with corticosteroids and other drugs that are antidepressant or antianxiety disorder medications were excluded.
Table 1. General characteristics of the 50 epilepsy patients recruited (n=50)
Characteristics Gender (male/female, n) Age (years) Duration of epilepsy (years) Seizures frequency* (times/month) QOLIE-31 scores LESS scores
*

Procedures Pilot descriptive multicenter study A pilot study of epilepsy treatment was performed in the three hospitals. Data were collected from 50 patients with medically intractable epilepsy who were treated by ta-VNS, 30 min/session, twice a day for 24 weeks (Figure 1). Choice of endpoints All endpoints were measured at weeks 0 and 12. Data safety monitoring Independent members of the data safety monitoring board met every 4 weeks and as needed. Participants who showed persistent worsening symptoms during the course of the clinical trial were withdrawn from the study and referred to appropriate treatment immediately. All adverse events were reported to the Human Research Committee promptly in accordance with the guidelines. Treatments Transcutaneous Electrical Nerve Stimulator (TENS, Suzhou Medical Appliance Co. Ltd., Suzhou, China) was used in this study. The electrode clamp was designed to have two carbon-impregnated silicone electrode tips which were connected to the TENS by metal wires for electrical stimulations (ta-VNS, Figure 2). One of the electrode tips was used as the common terminal end, and the other tip was placed on the skin surface of the triangular fossa of the auricle.12 The initial diagnosis of patients was performed by experienced doctors who had received 120-hour training on the proper administration of the treatment and the use of TENS as well as the standard operation procedures. The stimulation of ta-VNS was 1 mA, 2030 Hz frequency, and 1 ms pulse duration. The patients received consultations every 4 weeks during the treatment. Patients and their family members were also given a basic training on the use of the equipment. Patients were asked to complete a standard questionnaire

Values 30/20 25.213.1 12.08.1 85.214.4 107.0 44.5

Partial seizures accounted for 95%, generalized seizures accounted for 5%.

Figure 1. Flow diagram.

302

Chin Med J 2014;127 (2)

males, 19 females, 94%) who received ta-VNS treatment completed the 24-week treatment of the pilot study and 3 patients (6%) withdrew (dropped off): one case (2.1%) due to severe dizziness after the use of ta-VNS and two cases (4.1%) reported red rashes and swelling. Seizure frequency (times/month) Patients After the first 8 weeks of ta-VNS intervention, six of the 47 patients (12%) were seizure free; 12 (24%) had a 50%89% reduction in seizure frequency; 32 (64%) (including the three cases dropped off) did not show significant changes or had a <50% reduction of seizure frequency. After 16 weeks treatment, six of the 47 patients (12%) were seizure free; 17 (34%) had a 50%89% reduction in seizure frequency; 27 (54%, including the three cases dropped off) did not show significant changes or had a <50% reduction of seizure frequency. After 24 weeks treatment, eight of the 47 patients (16%) were seizure free; 19 (38%) had a 50%89% reduction in seizure frequency; 23 (46%, including the three cases dropped off) did not show significant changes and had a <50% reduction of seizure frequency. Seizure frequency The mean seizure frequency before the treatment (baseline) was 85.2 times/month. After 8, 16, and 24 weeks of taVNS the mean seizure frequency had decreased in varying degrees. They were 48.5 (comparison with before the treatment P <0.05), 28.9, and 31.7 (comparison with before the treatment P <0.01 for the latter two), respectively. The percentage change in seizure frequency Comparison of the ta-VNS to baseline verified that after 8 weeks treatment, the average percentage reduction in seizure frequency in patients was up to 34.3%. After 16 and 24 weeks treatment, the percentage was up to 46.6% and 51.3%, respectively. Quality of daily life of patients Compared with the baseline (207.0), the scores of QOLIE-31 of patients were significantly improved after 24 weeks treatment (211.4, P <0.001). Severity of seizures Compared with the baseline, the scores of LESS of patients were significantly improved after 24 weeks treatment (P=0.017). It is worth mentioning that though some patients showed no obvious reduction in seizure frequency, after 24 weeks of ta-VNS their scores of LESS and QOLIE-31 were improved significantly. Correlation At the beginning of the study, we found no correlation between treatment efficacy and age (r= 0.090, P=0.317), gender ( r =0.075, P =0.346), duration of epilepsy ( r =

Figure 2. Study design and stimulation locations. Black spots indicate the transcutaneous auricular vagus nerve stimulation (taVNS).

concerning their demographic characteristics, medical and behavioral history, seizure frequency, treatment condition, and occurrence conditions of epilepsy, side effects, and other information of themselves, their parents, or guardians. The case report forms were given to the patients by the related physicians before the treatment and in weeks 8, 16, and 24 of the treatment. Patients were asked to send the completed questionnaires back to the research office in sealed envelopes every 4 weeks. Follow-up questionnaires were distributed to these patients by the research office at the same time points. The primary outcome was assessed using the percentage of seizure frequency reduction. The seizure frequency 8 weeks before the treatment was documented and then compared with that after the treatment. During the ta-VNS intervention, these patients still received the same dosage of antiepilepsy drugs as before, but corticosteroids and other drugs that affected the central nervous system were discontinued due to potential counteracting effects on the ta-VNS therapy. Statistical analysis Statistical analysis was conducted by the Clinical Data Center of China Academy of Chinese Medical Sciences and by using SPSS 15.0 software (SPSS Inc., Chicago, IL, USA). Data were expressed as mean standard error (SE). Wilcoxon matched-pairs signed-ranks test was used to analyze pre- and post-treatment seizure frequencies. Oneway analysis of variance (ANOVA) was used to analyze the correlation between efficacy and age, gender, duration, or baseline seizure frequency. P <0.05 was considered significant. RESULTS Of the 50 epilepsy patients with refractory seizures 47 (28

Chinese Medical Journal 2014;127 (2)

303

0.229, P=0.112), or baseline seizure frequency (r=0.042, P=0.415). Adverse effects According to the patients seizure diary reports, we found that one (2.1%) patient quit our study due to severe dizziness after the use of ta-VNS; two cases reported red rashes and swelling (4.1%) that lasted only about 1030 minutes; and fewer patients could not keep this treatment for more than an hour. No severe side effects were found by the remaining patients. DISCUSSION Since 1994, VNS has been used for drug-resistantepilepsy around the world. Over 50 000 epilepsy patients have received VNS treatment. Thus, VNS becomes a valuable option for drug-resistantepilepsy. In fact, up to 50% of the enrolled patients had no seizure reduction, and in about 40%50% of the patients seizure frequency reduced by around 50%.13-17 In this study, our outcomes with a high follow-up rate showed that seizure frequency was reduced by 63% compared to the baseline, about 29% lower than that of the VNS therapy in McHugh et als study.18 Auricular-concha stimulation is a safe therapy for epilepsy. Since VNS is an expensive surgery, not all epilepsy patients can afford VNS implantation. A previous study demonstrated that VNS therapy also had some side effects.19 In addition, since the battery life of the implant device is around 10 years,20 patients have to replace the device after 10 years. If an electrode for stimulating the auricular vagus nerve was implanted and the stimulation was performed more than twice a day, the effects would be better. Therefore, auricular-concha stimulation is an effective approach for drug-resistantepilepsy, especially for simple and juvenile epilepsy. Comparison of the ta-VNS to baseline verified that after 8, 16, and 24 weeks of treatment, the effects of ta-VNS in reducing seizure frequency and lengthening interval of seizures were obviously better than the baseline. The mean reduction in seizure frequency was up to 34.3%, 46.6%, and 51.3%, respectively. It was consistent with a recent pilot study which showed that of the 10 patients with pharmacoresistant epilepsy, five had a reduction of seizure frequency after 9 months.21 The stimulation parameters and protocol that the authors employed in this study for ta-VNS were different from a previous study by Stefan et al.21 Atthesametime, we found that (1) 2.1% patients quited our study due to palpitation and severe dizziness after the use of ta-VNS; (2) 4.2% cases reported red rashes and swelling that lasted only about 1030 minutes, much less than the adverse effect in VNS therapy. Common adverse effects following VNS included voice alteration (53% 54%), headache (23%), neck pain (13%17%), dyspnoea (16%17%) and cough (5%13%).22,23 VNS has been used as a predictor of seizure events.24,25 VNS

was approved as an effective way to deal with medicationresistant depression by the FDA although its mechanism still remains unclear. Physiological and anatomic studies suggested that parasympathetic efferent activities underlie these anti-seizure effects.8 Some investigators proposed that VNS might decrease seizure frequency through reducing thalamic activities. F-18 fluorodeoxyglucose positron emission tomography observation showed a decreased metabolism within the thalamus in a 31-year-old epilepsy man.26 Previous studies provided evidences that antiepileptic stimulation of the left vagus nerve activated several forebrain structures including the posterior cortical amygdaloid nucleus, cingulate and retrosplenial cortex, and ventromedial and arcuate hypothalamic nuclei and caused a specific nuclear fos expression concomitantly in these regions. A specific immunolabeling detected in vagus nerve nuclei in the brainstem implied that several brain structures activated by VNS were important for genesis or regulation of seizures. These structures might mediate the antiepileptic effect of VNS.27 Patients who received ta-VNS therapy not only showed a decrease in seizure frequency and duration, but also reported an improvement in quality of life, such as alertness, better verbal skills, memory, schooling and working, speaking, mood, and postictal period clusters. A recent study applied ta-VNS to the treatment of refractory depression and achieved good results.28 According to our multicenter studies, after 8 weeks, epileptic patients who received ta-VNS intervention had a more significant reduction in seizure frequency, seizure duration, time of consciousness recovery, and abolition of daytime seizures than the baseline, suggesting the therapeutic method was location specific. In summary, our study of ta-VNS for refractory epileptic seizures indicates that ta-VNS is a safe, effective, simple, and economical therapeutic method with mild side effects, and it may have great potential in the treatment of epilepsy. Auricular-vagal reflex might be one of the mechanisms underlying the efficacy of auricular-concha stimulation in the treatment of epileptic seizures.
REFERENCES 1. Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005; 46: 470-472. 2. Wang WZ, Wu JZ, Wang DS, Dai XY, Yang B, Wang TP, et al. The prevalence and treatment gap in epilepsy in China: an ILAE/IBE/WHO study. Neurology 2003; 60: 1544-1545. 3. Van Ness PC. Therapy for the epilepsies. Arch Neurol 2002; 59: 732-735. 4. Lanska DJ. Corning and vagal nerve stimulation for seizures in

304 the 1880s. Neurology 2002; 58: 452-459. 5. Helmers SL, Duh MS, Gurin A, Sarda SP, Samuelson TM, Bunker MT, et al. Clinical and economic impact of vagus nerve stimulation therapy in patients with drug-resistant epilepsy. Epilepsy Behav 2011; 22: 370-375. 6. Cohen-Gadol AA, Britton JW, Wetjen NM, Marsh WR, Meyer FB, Raffel C. Neurostimulation therapy for epilepsy: current modalities and future directions. Mayo Clin Proc 2003; 78: 238248. 7. Magdaleno-Madrigal VM, Martnez-Vargas D, Valds-Cruz A, Almazn-Alvarado S, Fernndez-Mas R. Preemptive effect of nucleus of the solitary tract stimulation on amygdaloid kindling in freely moving cats. Epilepsia 2010; 51: 438-444. 8. Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology 2002; 59: S3-S14. 9. Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat 2002; 15: 35-37. 10. He W, Rong PJ, Li L, Ben H, Zhu B, Litscher G. Auricular acupuncture may suppress epileptic seizures via activating the parasympathetic nervous system: a hypothesis based on innovative methods. Evid Based Complement Alternat Med 2012; 2012: 615476. 11. Cramer JA, 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. 12. Rong PJ, Fang JL, Wang LP, Meng H, Liu J, Ma YG, et al. Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trails. BMC Complement Altern Med 2012; 12: 255. 13. Ben-Menachem E, Maon-Espaillat R, Ristanovic R, Wilder BJ, Stefan H, Mirza W, et al. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group. Epilepsia 1994; 35: 616-626. 14. Morris GL 3rd, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology 1999; 58: 1731-1735. 15. Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 1998; 51: 48-55. 16. Wheeler M, De Herdt V, Vonck K, Gilbert K, Manem S, Mackenzie T, et al. Efficacy of vagus nerve stimulation for

Chin Med J 2014;127 (2) refractory epilepsy among patient subgroups: a re-analysis using the Engel classification. Seizure 2011; 20: 331-335. Elliott RE, Morsi A, Kalhorn SP, Marcus J, Sellin J, Kang M, et al. Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomes and predictors of response. Epilepsy Behav 2011; 20: 57-63. McHugh JC, Singh HW, Phillips J, Murphy K, Doherty CP, Delanty N. Outcome measurement after vagal nerve stimulation therapy: proposal of a new classification. Epilepsia 2007; 48: 375-378. Guberman A. Vagus nerve stimulation in the treatment of epilepsy. CMAJ 2004; 171: 1165-1166. Valencia I, Holder DL, Helmers SL, Madsen JR, Riviello JJ Jr. Vagus nerve stimulation in pediatric epilepsy: a review. Pediatr Neurol 2001; 25: 368-376. 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-e118. Christmas DMB, Curran S, Matthews K, Eljamel MS. Neurosurgery for mental disorder, vagus nerve stimulation and deep brain stimulation. Psychiatry 2009; 8: 139-143. Eljamel MS. Ablative neurosurgery for mental disorders: is there still a role in the 21st century? A personal perspective. Neurosurg Focus 2008; 25: E4. Shahwan A, Bailey C, Maxiner W, Harvey AS. Vagus nerve stimulation for refractory epilepsy in children: more to VNS than seizure frequency reduction. Epilepsia 2009; 50: 1220-1228. Tanganelli P, Ferrero S, Colotto P, Regesta G. Vagus nerve stimulation for treatment of medically intractable seizures. Evaluation of long-term outcome. Clin Neurol Neurosurg 2002; 105: 9-13. Petrucci M, Hoh C, Alksne JF. Thalamic hypometabolism in a patient undergoing vagal nerve stimulation seen on F-18 FDG PET imaging. Clin Nucl Med 2003; 28: 784-785. Naritoku DK, Terry WJ, Helfert RH. Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res 1995; 22: 53-62. Hein E, Nowak M, Kiess O, Biermann T, Bayerlein K, Kornhuber J, et al. Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. J Neural Transm 2013; 120: 821-827.

17.

18.

19. 20.

21.

22.

23.

24.

25.

26.

27.

28.

(Received June 9, 2013) Edited by Ji Yuanyuan