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Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: A pilot trial
Epilepsy & Behavior 28 (2013) 343–346
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: A pilot trial Wei He a, Xianghong Jing a, Xiaoyu Wang a, Peijing Rong a, Liang Li a, Hong Shi a, Hongyan Shang a, Yuping Wang b, Jianguo Zhang c, Bing Zhu a,⁎ a b c
Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, China Xuanwu Hospital, Capital Medical University, China Tiantan Hospital, Capital Medical University, China
a r t i c l e
i n f o
Article history: Received 30 September 2012 Revised 1 February 2013 Accepted 2 February 2013 Available online 29 June 2013 Keywords: Pediatric epilepsy Transcutaneous auricular vagus nerve stimulation Auricular branch of the vagus nerve
a b s t r a c t Objective: We investigated the safety and efficacy of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of pediatric epilepsy. Methods: Fourteen pediatric patients with intractable epilepsy were treated by ta-VNS of the bilateral auricular concha using an ear vagus nerve stimulator. The baseline seizure frequency was compared with that after 8 weeks, from week 9 to 16 and from week 17 to the end of week 24, according to the seizure diaries of the patients. Results: One patient dropped out after 8 weeks of treatment due to lack of efficacy, while the remaining 13 patients completed the 24-week study without any change in medication regimen. The mean reduction in seizure frequency relative to baseline was 31.83% after week 8, 54.13% from week 9 to 16 and 54.21% from week 17 to the end of week 24. The responder rate was 28.57% after 8 weeks, 53.85% from week 9 to 16 and 53.85% from week 17 to the end of week 24. No severe adverse events were reported during treatment. Conclusion: Transcutaneous auricular VNS may be a complementary treatment option for reducing seizure frequency in pediatric patients with intractable epilepsy and should be further studied. © 2013 Elsevier Inc. All rights reserved.
1. Introduction An estimated 10.5 million children worldwide under 15 years of age have active epilepsy. Population-based studies on childhood-onset epilepsy indicate annual incidence rates of 61–124 per 100 000 in developing countries and 41–50 per 100 000 in developed countries [1]. In 1997, vagus nerve stimulation (VNS) was approved as an adjunct therapy for treatment of refractory seizures in patients older than 12 years. Short-term and long-term studies have shown that VNS is an effective method for seizure frequency reduction in adults [2–4], but few studies have assessed the efficacy of VNS against pediatric epilepsy. Results from small observational studies suggest that VNS may be more effective in children than in adults and that the therapeutic benefits are achieved more rapidly [5,6]. Indeed, VNS in pediatric patients is associated with fewer epilepsy-related events and improved quality of life, as well as cost savings and reduced use of medical resources [7]. The auricular branch of the vagus nerve (ABVN) innervates the auricular concha and so provides non-invasive access to the vagus nerve (VN). Several studies have suggested stimulation of the ABVN for the
⁎ Corresponding author at: Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China. Fax: +86 10 64032682. E-mail address: [email protected] (B. Zhu). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.02.001
treatment of epilepsy [8–10]. In animal experiments, we observed equivalent antiseizure effects of transcutaneous auricular vagus nerve stimulation (ta-VNS) and direct cervical VNS [11]. A preliminary trial reported an overall reduction of seizure frequency in five of seven patients after 9 months of ta-VNS and verified the long-term safety of ta-VNS [12]. In this preliminary study, we examined the efficacy and clinical outcome of ta-VNS in patients no more than 12 years old with medically refractory epilepsy. 2. Methods 2.1. Patients Patients were enrolled in Xuanwu Hospital, Tiantan Hospital, and Beijing Children's Hospital, all institutions affiliated with Capital Medical University. The patients were defined as having medically refractory seizures based on the failure of two or more antiepileptic drugs (AEDs). Patients were included based on the following inclusion criteria: a) diagnosed with epilepsy, b) 12 years old or younger, c) following a constant drug regimen (number and dose) for at least eight weeks prior to ta-VNS, and d) willing and able to document seizure frequency until the completion of the study or having guardians willing and able to document seizure frequency until the completion of the study. Patients
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were excluded a) if they had already received VNS therapy or b) if their epilepsy was accompanied by a progressive central nervous system disease or severe heart, liver, kidney, or blood diseases. The patients were required to maintain the same drug regimen throughout the study. The study was approved by the Ethics Committee of the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences. Written informed consent was obtained from the patients and their guardians. 2.2. Study design Each guardian was given a diary and a home ta-VNS device. The subjects and their guardians were carefully instructed on the use of the ta-VNS device. The diary was used to record the frequency of seizures, usage of the ta-VNS instrument, and any adverse events associated with ta-VNS. The seizure frequency of each subject was assessed at baseline and after 8 weeks, from week 9 to 16 and from week 17 to the end of week 24. Correlations between seizure frequency reduction after 24 weeks of ta-VNS and age, gender, seizure type, seizure duration, and initial seizure frequency at baseline were also investigated. 2.3. Transcutaneous auricular VNS Transcutaneous stimulation was performed on bilateral auricular conchae using an ear vagus nerve stimulator (TENS-200, Suzhou, China) attached by two pairs of electrode clips (Fig. 1). The electrode clips are made of conductive rubber and are 5 mm in diameter. For ta-VNS, one electrode was clipped on the concha cavity and the other on the concha cymba. The stimulation frequency of the ta-VNS was 20 Hz, and the intensity was increased gradually from 0.4 mA to 1.0 mA according to patient tolerance. Transcutaneous stimulation was performed three times a day, 30 min per session. Professional
technicians trained the patients and their caregivers on the proper use of the stimulator. 2.4. Outcome assessment The primary treatment outcome measure was the change in seizure frequency from baseline to that after 8 weeks, from week 9 to 16 and from week 17 to the end of week 24 of ta-VNS treatment as recorded in the patient's seizure diary. Seizure outcomes were expressed by a modified Engel scale [13]. According to the effect of ta-VNS, patients were assigned to one of four outcome groups: I — seizure-free, II — frequency reduction ≥90% but b 100%, III — reduction ≥50% but b 90%, and IV — reduction ≥0 but b50%. Patients exhibiting a seizure frequency reduction of ≥50% (outcome groups I–III) were considered responders, and group IV patients were considered nonresponders. 2.5. Data analyses The raw data from the seizure diaries and medical records were entered into Microsoft Excel (Office 2010). All statistical calculations were performed using SPSS v.14.0 (SPSS, Inc., Chicago, IL). The seizure frequency was counted over 8-week epochs. The mean numbers of seizures after 8 weeks, from week 9 to week 16 and from week 17 to the end of week 24, were compared with baseline frequency by paired sample t-tests. Categorical data were compared by chi-square tests. The correlations between seizure frequency reduction class (groups I–IV) after 24 weeks of ta-VNS and the clinical parameters of age, gender, seizure type, seizure duration, and seizure frequency at baseline were evaluated by Pearson's correlation test. A P-valueb 0.05 was considered statistically significant. 3. Results 3.1. Patient characteristics Fourteen patients with epilepsy (11 males and 3 females) of mean age 7.64 years (range: 1–12 years) were enrolled in this study to evaluate the therapeutic efficacy of ta-VNS (Table 1). Three patients were 2 to 4 years old (21.43%), four were 5 to 8 years old (35.71%), and seven were 9 to 12 years old (42.86%). Three patients had complex partial seizures with secondary generalization (21.43%), four had generalized seizures (28.57%), one had simple partial and generalized seizures (7.14%), one had simple partial seizures (7.14%), and five had complex partial seizures (35.71%). The median seizure frequency at baseline was 25.25 events per week (range: 0.75–75). 3.2. Seizure frequency reduction by ta-VNS
Fig. 1. The ta-VNS device, the stimulator clips, and the stimulation positions at the concha cavity and the concha cymba.
One patient discontinued treatment due to lack of treatment effect after 8 weeks. The remaining 13 patients completed the entire 24-week study with no changes in medication. After 8 weeks of ta-VNS, one patient was seizure-free (class I), two patients experienced seizure frequency reductions of no less than 90% (class II), one patient experienced a seizure frequency reduction of ≥50% but b 90% (class III), while the remaining 9 patients experienced reductions of b 50% (class IV, classified as nonresponders). Four patients were seizure-free by the end of week 16, one patient experienced a seizure frequency reduction of more than 90%, two patients experienced seizure frequency reductions of less than 90% but more than 50%, and six patients experienced seizure frequency reductions of less than 50%. By the end of the 24-week ta-VNS study, four patients were seizure-free, one patient achieved a reduction of more than 90%, two patients achieved a reduction of less than 90% but more than 50%, and six patients achieved a reduction of less than 50% (Fig. 2). The mean number of seizures during the baseline prior to ta-VNS was 26.04±8.37 per week, falling to 16.38±6.48 per week during the first 8 weeks, to 8.89±3.77 per week during the second 8-week
W. He et al. / Epilepsy & Behavior 28 (2013) 343–346
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Table 1 Demographic and clinical characteristics of the study patients at baseline. No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Gender
M M F F M F M M M M M M M M
Age
12 11 11 4 9 11 9 8 7 7 6 3 2 7
Seizure duration
Seizure type
11 1 6 4 0.5 0.3 0.6 4 2 1 3 1 1 2
Complex partial Complex partial Complex partial Simple partial and generalized Complex partial with secondary generalized Complex partial with secondary generalized Simple partial Complex partial Generalized Complex partial with secondary generalized Generalized Generalized Complex partial Generalized
period (week 9 to week 16), and to 8.88±3.77 per week over the last 8-week period (week 17 to week 24). In comparison to baseline, the seizure frequency decreased significantly from week 9 to 16 and from week 17 to 24 (both Pb 0.05; Fig. 3). Overall, the mean reductions in seizure frequency during the three 8-week epochs were 31.83%±10.77% after 8 weeks, 54.13%±12.37% from weeks 9–16 and 54.21±12.39% from weeks 17–24. The responder rate was 28.57% (4/14) after 8 weeks,
Seizure frequency (per week)
Classification of seizure reduction Weeks 1–8
Weeks 9–16
Weeks 17–24
75 0.75 5 1.25 27.5 4 75 22.5 37.5 75 1.5 12.5 15 1
IV I IV IV IV II IV III IV II IV IV IV IV
I III IV IV IV I III II IV I I IV
I III IV IV IV I III II IV I I IV
IV
IV
53.85% (7/13) from weeks 9–16 and 53.85% (7/13) from weeks 17–24 (Fig. 4). 3.3. Correlation between treatment efficacy group (classes I–IV) after 24 weeks of ta-VNS and baseline clinical data We found no correlation between treatment response class (I–IV) and age at the start of the study (r=−0.324, P=0.280), gender (r=0.043, P=0.889), seizure duration (r=−0.218, P=0.474), seizure type (r= 0.182, P=0.553), or baseline seizure frequency (r=−0.346, P=0.248). 3.4. Side effects Only two patients reported mild ulceration of the skin at the stimulation area after initiation of ta-VNS, while no severe side effects were reported by the remaining patients. 4. Discussion
Fig. 2. The number of patients responsive to ta-VNS (classification groups I–III) increased over the treatment duration. Bar graph plots the fraction of patients in each response group after 8, 16, and 24 weeks of ta-VNS. Note that class IV (purple bars) is the nonresponsive group (≤50% reduction) (n = 13).
Fig. 3. Transcutaneous auricular vagus nerve stimulation (ta-VNS) reduced seizure frequency over treatment time. The mean seizure frequency at pre ta-VNS baseline after 8 weeks, from week 9 to week 16 and from week 17 to the end of week 24 during ta-VNS. * P b 0.05 compared with baseline (n = 13).
In the 1880s, neurologist James Leonard Corning first proposed that transcutaneous vagal nerve stimulation may disrupt seizures by decreasing cerebral blood flow. The idea was based on the then widely held theory that cerebral hyperemia caused seizures [14]. One hundred years later, Penry and Dean implanted the first direct nerve stimulator in a human [15]. Vagus nerve stimulation is now considered an effective method to manage patients with medically intractable epilepsy, reducing seizure relapse and generally improving patient quality of life [4]. Vagus nerve stimulation was approved by the U.S. Food and Drug Administration in 1997 for the treatment of intractable epilepsy in adults and adolescents but is not approved for children younger than 12 years [16]. However, VNS reduced seizure frequency by 40%–50% in children younger than 12 years [6,17–19] with few adverse events,
Fig. 4. The responder rate after 8, 16, and 24 weeks of ta-VNS (n = 13).
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even in young children [20]. In addition to reducing seizure frequency, VNS was associated with improvements in verbal ability and school performance [7]. Furthermore, VNS counteracted the known adverse effects of epilepsy on sleep and increased slow-wave sleep in children [21]. The precise neurocellular mechanisms by which VNS disrupts, inhibits, and prevents seizures are unclear. Afferent projections from the ABVN to the nucleus tractus solitarius (NTS) [22] rather than to the spinal trigeminal nucleus are thought to be critical for the antiseizure effect, but the downstream signaling pathways engaged by these inputs are still debated. In previous pediatric VNS studies, mean percent seizure reduction ranged from 23% to 39% at 3 months and from 31% to 38% at 6 months, with a highly variable responder rate from 12.5% to 48% at 6 months [19,23,24]. In the present ta-VNS study, the mean reduction in seizure frequency was greater than 50% during the last 8 weeks of the trial, higher than the ~30%–40% reported after this same treatment duration in previous studies. The responder rate increased gradually from 28.57% to 53.85% by the last 8-week treatment period, a response rate similar to that reported in previous pediatric VNS studies [6,24]. In the present study, all the responsive patients improved in the first 2 months of VNS activation, suggesting that there are highly VNSresponsive and VNS-unresponsive subpopulations. We found no correlation between therapeutic efficacy (as expressed by the 4 classes of seizure frequency reduction) and baseline seizure frequency, in accordance with a previous study [24], indicating that ta-VNS can benefit highly active seizure syndromes. Furthermore, neither age, gender, nor seizure syndrome predicted VNS response. Compared with conventional VNS treatment, ta-VNS has several distinct advantages. First, it is practicable to use ta-VNS on both sides of the external auricle, while direct right VNS is always avoided because the right VN carries efferent fibers to the sinoatrial node. Second, ta-VNS is less invasive and safer than VNS. During our study, no severe side effects were observed except for mild skin ulcerations at the site of stimulation in two patients. Third, ta-VNS can be used as a complementary method to reduce the AED burden and can be terminated if ineffective. This study is limited by the small sample size and lack of a control population. Based on the result of the present study, larger scale multicenter studies with randomized case and control groups are currently underway to confirm the efficacy of ta-VNS for pediatric patients with epilepsy. 5. Conclusion Our results indicate that ta-VNS is well tolerated and may reduce seizure frequency without the risk of significant side effects. It may be an adjunctive treatment option for reducing seizure frequency in pediatric patients with intractable epilepsy. Authors' contributions Z. B. designed the experiment; H. W., J. X. H., W. X. Y., R. P. J., L. L., S. H., and S. H. Y. performed the trials; H. W. and Z. B. analyzed the data; and all authors discussed the data and the analysis methods and contributed to the preparation of the manuscript.
Acknowledgments This work was supported by the National Basic Research Program (973 Program, No. 2011CB505201), National Natural Science Foundation of China (No. 81273829), and Beijing Natural Science Foundation (No. 7102120). References [1] Guerrini R. Epilepsy in children. Lancet 2006;367:499–524. [2] Ben-Menachem E, Manon-Espaillat R, Ristanovic R, 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;35:616–26. [3] Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 1998;51: 48–55. [4] Cersosimo RO, Bartuluchi M, Fortini S, Soraru A, Pomata H, Caraballo RH. Vagus nerve stimulation: effectiveness and tolerability in 64 paediatric patients with refractory epilepsies. Epileptic Disord 2011;13:382–8. [5] Zamponi N, Rychlicki F, Cardinali C, Luchetti A, Trignani R, Ducati A. Intermittent vagal nerve stimulation in paediatric patients: 1-year follow-up. Childs Nerv Syst 2002;18:61–6. [6] Buoni S, Mariottini A, Pieri S, et al. Vagus nerve stimulation for drug-resistant epilepsy in children and young adults. Brain Dev 2004;26:158–63. [7] Helmers SL, Duh MS, Guerin A, et al. Clinical outcomes, quality of life, and costs associated with implantation of vagus nerve stimulation therapy in pediatric patients with drug-resistant epilepsy. Eur J Paediatr Neurol 2012;16:449–58. [8] 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. [9] Yang AC, Zhang JG, Rong PJ, Liu HG, Chen N, Zhu B. A new choice for the treatment of epilepsy: electrical auricula-vagus-stimulation. Med Hypotheses 2011;77: 244–5. [10] Ventureyra EC. Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new concept. Childs Nerv Syst 2000;16:101–2. [11] He W, Zhu B, Rong PJ. A new concept of transcutaneous vagus nerve stimulation for epileptic seizure. Chicago: Neuroscience; 2009. p. 539.4. [12] Stefan H, Kreiselmeyer G, Kerling F, et al. Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial. Epilepsia 2012;53:e115–8. [13] Elliott RE, Morsi A, Tanweer O, 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. [14] Lanska DJ. J.L. Corning and vagal nerve stimulation for seizures in the 1880s. Neurology 2002;58:452–9. [15] Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Epilepsia 1990;31(Suppl. 2):S40–3. [16] Englot DJ, Chang EF, Auguste KI. Vagus nerve stimulation for epilepsy: a metaanalysis of efficacy and predictors of response. J Neurosurg 2011;115:1248–55. [17] Helmers SL, Wheless JW, Frost M, et al. Vagus nerve stimulation therapy in pediatric patients with refractory epilepsy: retrospective study. J Child Neurol 2001;16:843–8. [18] Wheless JW, Maggio V. Vagus nerve stimulation therapy in patients younger than 18 years. Neurology 2002;59:S21–5. [19] Murphy JV. Left vagal nerve stimulation in children with medically refractory epilepsy. The Pediatric VNS Study Group. J Pediatr 1999;134:563–6. [20] Coykendall DS, Gauderer MW, Blouin RR, Morales A. Vagus nerve stimulation for the management of seizures in children: an 8-year experience. J Pediatr Surg 2010;45:1479–83. [21] Hallbook T, Lundgren J, Kohler S, Blennow G, Stromblad LG, Rosen I. Beneficial effects on sleep of vagus nerve stimulation in children with therapy resistant epilepsy. Eur J Paediatr Neurol 2005;9:399–407. [22] Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology 2002;59: S3–S14. [23] Rychlicki F, Zamponi N, Trignani R, Ricciuti RA, Iacoangeli M, Scerrati M. Vagus nerve stimulation: clinical experience in drug-resistant pediatric epileptic patients. Seizure 2006;15:483–90. [24] Arhan E, Serdaroglu A, Kurt G, et al. The efficacy of vagal nerve stimulation in children with pharmacoresistant epilepsy: practical experience at a Turkish tertiary referral center. Eur J Paediatr Neurol 2010;14:334–9.
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: A pilot trial Wei He a, Xianghong Jing a, Xiaoyu Wang a, Peijing Rong a, Liang Li a, Hong Shi a, Hongyan Shang a, Yuping Wang b, Jianguo Zhang c, Bing Zhu a,⁎ a b c
Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, China Xuanwu Hospital, Capital Medical University, China Tiantan Hospital, Capital Medical University, China
a r t i c l e
i n f o
Article history: Received 30 September 2012 Revised 1 February 2013 Accepted 2 February 2013 Available online 29 June 2013 Keywords: Pediatric epilepsy Transcutaneous auricular vagus nerve stimulation Auricular branch of the vagus nerve
a b s t r a c t Objective: We investigated the safety and efficacy of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of pediatric epilepsy. Methods: Fourteen pediatric patients with intractable epilepsy were treated by ta-VNS of the bilateral auricular concha using an ear vagus nerve stimulator. The baseline seizure frequency was compared with that after 8 weeks, from week 9 to 16 and from week 17 to the end of week 24, according to the seizure diaries of the patients. Results: One patient dropped out after 8 weeks of treatment due to lack of efficacy, while the remaining 13 patients completed the 24-week study without any change in medication regimen. The mean reduction in seizure frequency relative to baseline was 31.83% after week 8, 54.13% from week 9 to 16 and 54.21% from week 17 to the end of week 24. The responder rate was 28.57% after 8 weeks, 53.85% from week 9 to 16 and 53.85% from week 17 to the end of week 24. No severe adverse events were reported during treatment. Conclusion: Transcutaneous auricular VNS may be a complementary treatment option for reducing seizure frequency in pediatric patients with intractable epilepsy and should be further studied. © 2013 Elsevier Inc. All rights reserved.
1. Introduction An estimated 10.5 million children worldwide under 15 years of age have active epilepsy. Population-based studies on childhood-onset epilepsy indicate annual incidence rates of 61–124 per 100 000 in developing countries and 41–50 per 100 000 in developed countries [1]. In 1997, vagus nerve stimulation (VNS) was approved as an adjunct therapy for treatment of refractory seizures in patients older than 12 years. Short-term and long-term studies have shown that VNS is an effective method for seizure frequency reduction in adults [2–4], but few studies have assessed the efficacy of VNS against pediatric epilepsy. Results from small observational studies suggest that VNS may be more effective in children than in adults and that the therapeutic benefits are achieved more rapidly [5,6]. Indeed, VNS in pediatric patients is associated with fewer epilepsy-related events and improved quality of life, as well as cost savings and reduced use of medical resources [7]. The auricular branch of the vagus nerve (ABVN) innervates the auricular concha and so provides non-invasive access to the vagus nerve (VN). Several studies have suggested stimulation of the ABVN for the
⁎ Corresponding author at: Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China. Fax: +86 10 64032682. E-mail address: [email protected] (B. Zhu). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.02.001
treatment of epilepsy [8–10]. In animal experiments, we observed equivalent antiseizure effects of transcutaneous auricular vagus nerve stimulation (ta-VNS) and direct cervical VNS [11]. A preliminary trial reported an overall reduction of seizure frequency in five of seven patients after 9 months of ta-VNS and verified the long-term safety of ta-VNS [12]. In this preliminary study, we examined the efficacy and clinical outcome of ta-VNS in patients no more than 12 years old with medically refractory epilepsy. 2. Methods 2.1. Patients Patients were enrolled in Xuanwu Hospital, Tiantan Hospital, and Beijing Children's Hospital, all institutions affiliated with Capital Medical University. The patients were defined as having medically refractory seizures based on the failure of two or more antiepileptic drugs (AEDs). Patients were included based on the following inclusion criteria: a) diagnosed with epilepsy, b) 12 years old or younger, c) following a constant drug regimen (number and dose) for at least eight weeks prior to ta-VNS, and d) willing and able to document seizure frequency until the completion of the study or having guardians willing and able to document seizure frequency until the completion of the study. Patients
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were excluded a) if they had already received VNS therapy or b) if their epilepsy was accompanied by a progressive central nervous system disease or severe heart, liver, kidney, or blood diseases. The patients were required to maintain the same drug regimen throughout the study. The study was approved by the Ethics Committee of the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences. Written informed consent was obtained from the patients and their guardians. 2.2. Study design Each guardian was given a diary and a home ta-VNS device. The subjects and their guardians were carefully instructed on the use of the ta-VNS device. The diary was used to record the frequency of seizures, usage of the ta-VNS instrument, and any adverse events associated with ta-VNS. The seizure frequency of each subject was assessed at baseline and after 8 weeks, from week 9 to 16 and from week 17 to the end of week 24. Correlations between seizure frequency reduction after 24 weeks of ta-VNS and age, gender, seizure type, seizure duration, and initial seizure frequency at baseline were also investigated. 2.3. Transcutaneous auricular VNS Transcutaneous stimulation was performed on bilateral auricular conchae using an ear vagus nerve stimulator (TENS-200, Suzhou, China) attached by two pairs of electrode clips (Fig. 1). The electrode clips are made of conductive rubber and are 5 mm in diameter. For ta-VNS, one electrode was clipped on the concha cavity and the other on the concha cymba. The stimulation frequency of the ta-VNS was 20 Hz, and the intensity was increased gradually from 0.4 mA to 1.0 mA according to patient tolerance. Transcutaneous stimulation was performed three times a day, 30 min per session. Professional
technicians trained the patients and their caregivers on the proper use of the stimulator. 2.4. Outcome assessment The primary treatment outcome measure was the change in seizure frequency from baseline to that after 8 weeks, from week 9 to 16 and from week 17 to the end of week 24 of ta-VNS treatment as recorded in the patient's seizure diary. Seizure outcomes were expressed by a modified Engel scale [13]. According to the effect of ta-VNS, patients were assigned to one of four outcome groups: I — seizure-free, II — frequency reduction ≥90% but b 100%, III — reduction ≥50% but b 90%, and IV — reduction ≥0 but b50%. Patients exhibiting a seizure frequency reduction of ≥50% (outcome groups I–III) were considered responders, and group IV patients were considered nonresponders. 2.5. Data analyses The raw data from the seizure diaries and medical records were entered into Microsoft Excel (Office 2010). All statistical calculations were performed using SPSS v.14.0 (SPSS, Inc., Chicago, IL). The seizure frequency was counted over 8-week epochs. The mean numbers of seizures after 8 weeks, from week 9 to week 16 and from week 17 to the end of week 24, were compared with baseline frequency by paired sample t-tests. Categorical data were compared by chi-square tests. The correlations between seizure frequency reduction class (groups I–IV) after 24 weeks of ta-VNS and the clinical parameters of age, gender, seizure type, seizure duration, and seizure frequency at baseline were evaluated by Pearson's correlation test. A P-valueb 0.05 was considered statistically significant. 3. Results 3.1. Patient characteristics Fourteen patients with epilepsy (11 males and 3 females) of mean age 7.64 years (range: 1–12 years) were enrolled in this study to evaluate the therapeutic efficacy of ta-VNS (Table 1). Three patients were 2 to 4 years old (21.43%), four were 5 to 8 years old (35.71%), and seven were 9 to 12 years old (42.86%). Three patients had complex partial seizures with secondary generalization (21.43%), four had generalized seizures (28.57%), one had simple partial and generalized seizures (7.14%), one had simple partial seizures (7.14%), and five had complex partial seizures (35.71%). The median seizure frequency at baseline was 25.25 events per week (range: 0.75–75). 3.2. Seizure frequency reduction by ta-VNS
Fig. 1. The ta-VNS device, the stimulator clips, and the stimulation positions at the concha cavity and the concha cymba.
One patient discontinued treatment due to lack of treatment effect after 8 weeks. The remaining 13 patients completed the entire 24-week study with no changes in medication. After 8 weeks of ta-VNS, one patient was seizure-free (class I), two patients experienced seizure frequency reductions of no less than 90% (class II), one patient experienced a seizure frequency reduction of ≥50% but b 90% (class III), while the remaining 9 patients experienced reductions of b 50% (class IV, classified as nonresponders). Four patients were seizure-free by the end of week 16, one patient experienced a seizure frequency reduction of more than 90%, two patients experienced seizure frequency reductions of less than 90% but more than 50%, and six patients experienced seizure frequency reductions of less than 50%. By the end of the 24-week ta-VNS study, four patients were seizure-free, one patient achieved a reduction of more than 90%, two patients achieved a reduction of less than 90% but more than 50%, and six patients achieved a reduction of less than 50% (Fig. 2). The mean number of seizures during the baseline prior to ta-VNS was 26.04±8.37 per week, falling to 16.38±6.48 per week during the first 8 weeks, to 8.89±3.77 per week during the second 8-week
W. He et al. / Epilepsy & Behavior 28 (2013) 343–346
345
Table 1 Demographic and clinical characteristics of the study patients at baseline. No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Gender
M M F F M F M M M M M M M M
Age
12 11 11 4 9 11 9 8 7 7 6 3 2 7
Seizure duration
Seizure type
11 1 6 4 0.5 0.3 0.6 4 2 1 3 1 1 2
Complex partial Complex partial Complex partial Simple partial and generalized Complex partial with secondary generalized Complex partial with secondary generalized Simple partial Complex partial Generalized Complex partial with secondary generalized Generalized Generalized Complex partial Generalized
period (week 9 to week 16), and to 8.88±3.77 per week over the last 8-week period (week 17 to week 24). In comparison to baseline, the seizure frequency decreased significantly from week 9 to 16 and from week 17 to 24 (both Pb 0.05; Fig. 3). Overall, the mean reductions in seizure frequency during the three 8-week epochs were 31.83%±10.77% after 8 weeks, 54.13%±12.37% from weeks 9–16 and 54.21±12.39% from weeks 17–24. The responder rate was 28.57% (4/14) after 8 weeks,
Seizure frequency (per week)
Classification of seizure reduction Weeks 1–8
Weeks 9–16
Weeks 17–24
75 0.75 5 1.25 27.5 4 75 22.5 37.5 75 1.5 12.5 15 1
IV I IV IV IV II IV III IV II IV IV IV IV
I III IV IV IV I III II IV I I IV
I III IV IV IV I III II IV I I IV
IV
IV
53.85% (7/13) from weeks 9–16 and 53.85% (7/13) from weeks 17–24 (Fig. 4). 3.3. Correlation between treatment efficacy group (classes I–IV) after 24 weeks of ta-VNS and baseline clinical data We found no correlation between treatment response class (I–IV) and age at the start of the study (r=−0.324, P=0.280), gender (r=0.043, P=0.889), seizure duration (r=−0.218, P=0.474), seizure type (r= 0.182, P=0.553), or baseline seizure frequency (r=−0.346, P=0.248). 3.4. Side effects Only two patients reported mild ulceration of the skin at the stimulation area after initiation of ta-VNS, while no severe side effects were reported by the remaining patients. 4. Discussion
Fig. 2. The number of patients responsive to ta-VNS (classification groups I–III) increased over the treatment duration. Bar graph plots the fraction of patients in each response group after 8, 16, and 24 weeks of ta-VNS. Note that class IV (purple bars) is the nonresponsive group (≤50% reduction) (n = 13).
Fig. 3. Transcutaneous auricular vagus nerve stimulation (ta-VNS) reduced seizure frequency over treatment time. The mean seizure frequency at pre ta-VNS baseline after 8 weeks, from week 9 to week 16 and from week 17 to the end of week 24 during ta-VNS. * P b 0.05 compared with baseline (n = 13).
In the 1880s, neurologist James Leonard Corning first proposed that transcutaneous vagal nerve stimulation may disrupt seizures by decreasing cerebral blood flow. The idea was based on the then widely held theory that cerebral hyperemia caused seizures [14]. One hundred years later, Penry and Dean implanted the first direct nerve stimulator in a human [15]. Vagus nerve stimulation is now considered an effective method to manage patients with medically intractable epilepsy, reducing seizure relapse and generally improving patient quality of life [4]. Vagus nerve stimulation was approved by the U.S. Food and Drug Administration in 1997 for the treatment of intractable epilepsy in adults and adolescents but is not approved for children younger than 12 years [16]. However, VNS reduced seizure frequency by 40%–50% in children younger than 12 years [6,17–19] with few adverse events,
Fig. 4. The responder rate after 8, 16, and 24 weeks of ta-VNS (n = 13).
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even in young children [20]. In addition to reducing seizure frequency, VNS was associated with improvements in verbal ability and school performance [7]. Furthermore, VNS counteracted the known adverse effects of epilepsy on sleep and increased slow-wave sleep in children [21]. The precise neurocellular mechanisms by which VNS disrupts, inhibits, and prevents seizures are unclear. Afferent projections from the ABVN to the nucleus tractus solitarius (NTS) [22] rather than to the spinal trigeminal nucleus are thought to be critical for the antiseizure effect, but the downstream signaling pathways engaged by these inputs are still debated. In previous pediatric VNS studies, mean percent seizure reduction ranged from 23% to 39% at 3 months and from 31% to 38% at 6 months, with a highly variable responder rate from 12.5% to 48% at 6 months [19,23,24]. In the present ta-VNS study, the mean reduction in seizure frequency was greater than 50% during the last 8 weeks of the trial, higher than the ~30%–40% reported after this same treatment duration in previous studies. The responder rate increased gradually from 28.57% to 53.85% by the last 8-week treatment period, a response rate similar to that reported in previous pediatric VNS studies [6,24]. In the present study, all the responsive patients improved in the first 2 months of VNS activation, suggesting that there are highly VNSresponsive and VNS-unresponsive subpopulations. We found no correlation between therapeutic efficacy (as expressed by the 4 classes of seizure frequency reduction) and baseline seizure frequency, in accordance with a previous study [24], indicating that ta-VNS can benefit highly active seizure syndromes. Furthermore, neither age, gender, nor seizure syndrome predicted VNS response. Compared with conventional VNS treatment, ta-VNS has several distinct advantages. First, it is practicable to use ta-VNS on both sides of the external auricle, while direct right VNS is always avoided because the right VN carries efferent fibers to the sinoatrial node. Second, ta-VNS is less invasive and safer than VNS. During our study, no severe side effects were observed except for mild skin ulcerations at the site of stimulation in two patients. Third, ta-VNS can be used as a complementary method to reduce the AED burden and can be terminated if ineffective. This study is limited by the small sample size and lack of a control population. Based on the result of the present study, larger scale multicenter studies with randomized case and control groups are currently underway to confirm the efficacy of ta-VNS for pediatric patients with epilepsy. 5. Conclusion Our results indicate that ta-VNS is well tolerated and may reduce seizure frequency without the risk of significant side effects. It may be an adjunctive treatment option for reducing seizure frequency in pediatric patients with intractable epilepsy. Authors' contributions Z. B. designed the experiment; H. W., J. X. H., W. X. Y., R. P. J., L. L., S. H., and S. H. Y. performed the trials; H. W. and Z. B. analyzed the data; and all authors discussed the data and the analysis methods and contributed to the preparation of the manuscript.
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