Vagus nerve stimulation as an add-on therapy in patients with epilepsy: A prospective, multicenter, real-world study in China

Vagus nerve stimulation as an add-on therapy in patients with epilepsy: A prospective, multicenter, real-world study in China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Vagus nerve stimulation as an add-on therapy in patients with epilepsy: A prospective, multicenter, real-world study in China Chenyang Zhao, Enhui Zhang, Hesheng Zhang, Raowei Yan, Zhijun Le, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8136450/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Vagus nerve stimulation (VNS) has been proven as an effective and safe adjunct therapy for epilepsy, but real-world evidence is limited. This study aimed to evaluate outcomes of VNS and its cumulative effect through a prospective, multicenter, real-world survey in China, with dynamic follow-up. Methods A total of 83 sites in China participated and 124 epilepsy patients enrolled. Visits were scheduled at 1, 3, 6, 9, and 12 months after VNS. Primary outcomes included seizure response rate (≥ 50% frequency reduction) and seizure-free rate. Secondary outcomes assessed changes in the 31-item Quality of Life in Epilepsy Inventory (QOILE-31) score, overall anti-seizure medication (ASM) burden, and adverse events. Results The responder rates were 35.4%, 41.6%, 62.2%, 64.2%, and 76.6% at 1, 3, 6, 9, and 12 months after VNS, respectively. Seizure-free rates were 2.4%, 2.7%, 9.2%, 8.6%, and 10.9% at 1, 3, 6, 9, and 12 months, respectively. No significant differences were observed in overall ASM load between baseline and any follow-up visit. Significant improvements were noted in QOLIE-31 from baseline to each follow-up visit, with mean (± SD) score improvements as follows: 1 month (2.93 ± 8.65), 3 months (4.27 ± 9.84), 6 months (4.69 ± 11.5), 9 months (6.68 ± 12.5), and 12 months (9.32 ± 13.8). A significant trend toward improved seizure outcomes and change in quality of life was observed with longer treatment durations. Adverse events occurred in 34 patients (26.6%). Conclusions VNS is an effective and safe adjunctive treatment for epilepsy, reducing seizure frequency and significantly improving quality of life, with a cumulative effect over time. outcome neurostimulation follow-up VNS Figures Figure 1 Figure 2 Figure 3 1. Introduction Epilepsy is a common neurological disorder, affecting an estimated 70 million people globally[ 1 ]. Approximately one-third of people with epilepsy who are treated with two appropriately chosen, administered, and well-tolerated anti-seizure medications (ASMs), either as monotherapy or in combination, still struggle to control their seizures[ 2 ]. For such patients, early pre-surgical evaluation is recommended. However, resection or disconnection of the seizure-onset zone is only feasible for certain patients. When surgery is not applicable, neuromodulation therapy is recommended[ 3 ]. Vagus nerve stimulation (VNS) is a neuromodulation therapy that stimulates the left cervical vagus nerve, sending afferent signals to the nucleus tractus solitarius, which then activates the locus coeruleus and other brain regions[ 4 ]. Several long-term open-label studies have reported the efficacy and safety of VNS for epilepsy patients[ 5 , 6 ]. It was approved by the Food and Drug Administration in 1997 as an adjunctive therapy for patients with pharmacoresistant epilepsy. In China, VNS was gradually introduced into clinical practice starting in 2008, although it remained underutilized initially[ 7 ]. The domestic VNS product in China completed its clinical trial registration in 2014 and began being used in clinical settings in 2016. Following the registration and application of domestic VNS, the number of VNS treatments saw rapid growth from 2015 to 2018. Currently, over 140 hospitals in China offer VNS therapy, and nearly 5,000 epilepsy patients have received this treatment[ 8 ]. Xu et al. reported that 52 adult patients underwent VNS implantation for the treatment of refractory epilepsy between May 2016 and May 2017 at five Epilepsy Centers, with a 66.0% responder rate at the 1-year follow-up[ 9 ]. Shan et al. retrospectively evaluated the clinical outcome of 45 consecutive patients with drug-resistant epilepsy undergoing VNS implantation in a single center between November 2016 and August 2021 and reported a 48.9% responder rate[ 10 ]. However, there is still a lack of large-scale cohort studies with nationwide coverage involving more than 100 patients in China regarding the application of VNS. And it remains unclear whether longer follow-up periods are associated with a significantly greater trend toward seizure freedom or an increased responder rate[ 3 ]. Here, we present the one-year outcomes from this nationwide real-world study of epilepsy patients receiving add-on VNS therapy to: (1) evaluate the clinical outcomes of VNS treatment in epilepsy patients, including changes in seizure burden, quality of life, and overall ASM burden; (2) assess the safety of VNS application; and (3) determine, through dynamic follow-up, whether the effects of VNS on seizure control and quality of life accumulate over time. 2. Methods 2.1 Participants This is a multicenter, prospective, real-world study of the application of VNS for adult patients with epilepsy in China. A total of 83 sites in China participated in this study, and patients included in this study underwent VNS device implantation surgery between January 2022 and December 2024. This study was approved by the ethics committee of West China Hospital (2022 − 1847), and informed consent was obtained from all patients. Eligible participants were patients diagnosed with epilepsy according to the 2017 International League Against Epilepsy (ILAE) criteria[ 11 ]. Exclusion criteria included: (1) age 75 years, (2) failure to complete at least one month of follow-up after implantation. 2.2 Study design Presurgical evaluation, implantation of the VNS device (PINS, Beijing, China), adjustment of ASMs, and setting of VNS parameters were all carried out by each respective hospital, following a standardized procedure[ 8 , 12 ]. Patients who met the eligibility criteria underwent a 12-week prospective baseline period to collect baseline data, including seizure frequency, the 31-item Quality of Life in Epilepsy Inventory (QOLIE-31), and other demographic and clinical information (Table 1 ). Following VNS implantation, study visits were scheduled at 1, 3, 6, 9, and 12 months to gather follow-up data. All data collection was carried out using standardized Case Report Forms (CRFs). ASM burden was defined as the total dosage rate relative to the standard dose for all ASMs used, as follows[ 13 ]: Overall ASM burden = ∑ (Dosage / Standard dosage) The standard dose was referenced from the World Health Organization (WHO) website ( https://atcddd.fhi.no/atc_ddd_index/ ). 2.3 Endpoints The primary endpoint was the change in seizure frequency from baseline, expressed as the percentage change from baseline frequency. This included seizure-free, a ≥ 75% but < 100% reduction (75% reduction), a ≥ 50% but < 75% reduction (50% reduction), a ≥ 25% but < 50% reduction (25% reduction), a ≥ 0% but < 25% reduction (no change), and an increase in frequency. Patients were considered responders if they had a reduction of ≥ 50% in seizure frequency compared to baseline; conversely, they were classified as non-responders. Secondary endpoints included the change in score of QOLIE-31, overall ASM burden, and adverse events. 2.4 Statistical analysis All statistical analyses were performed using SPSS 26.0 software, with P -values < 0.05 considered statistically significant. Continuous variables were presented as mean ± standard deviation or median (IQR), depending on the data distribution. Categorical variables were described using absolute frequencies and percentages. The Wilcoxon signed-rank test or Student’s paired t-test was used for continuous variables, depending on their distribution. The Chi-Square Test or Fisher’s exact test was used for the comparison of categorical variables. Correlation analyses were conducted between changes in QOLIE-31 scores and clinical characteristics prior to VNS implantation, including sex, age at implantation, age at seizure onset, epilepsy duration, seizure frequency, number of ASMs, overall ASM load, etiology, seizure types, and comorbidities, as well as whether the patient was a responder at the last visit. These analyses were performed using Pearson correlation, Spearman correlation, or Kendall’s tau-b correlation analysis. 3. Results 3.1 Demographic and baseline clinical features A total of 124 patients (77 males and 47 females) with a mean age of 28.3 ± 11.2 years were enrolled in this study. The mean age at seizure onset was 14.5 ± 11.3 years, the mean duration of epilepsy was 14.8 ± 10.2 years, and the mean seizure frequency was 13.4 ± 39.6 seizures per month. Details are presented in Table 1 . Table 1 Patient characteristics Variables Number (%) or mean ± SD Sex Male Female 77 (62.1%) 47 (37.9%) Age at VNS implantation (years) Mean ± SD 28.311.2 Age at seizure onset (years) Mean ± SD 14.5 ± 11.3 Epilepsy duration prior to VNS (years) Mean ± SD 14.8 ± 10.2 Seizure frequency prior to VNS, no./m 13.4 ± 39.6 ASMs no. prior to VNS 0 1 2 3 4 5 6 3 (2.4%) 28 (22.6%) 45 (36.3%) 27 (21.8%) 13 (10.5%) 6 (4.8%) 2 (1.6%) Overall ASMs load prior to VNS Mean ± SD 1.57 ± 1.02 Etiology Structural Genetic Infectious Metabolic Immune Unknown 81 (65.3%) 6 (4.8%) 13 (10.5%) 6 (4.8%) 2 (1.6%) 16 (12.9%) Seizure types Focal onset FBTCS yes / no Generalized onset Focal and generalized onset Unknown 69 (55.6%) 51 (73.9%) / 18 (26.1%) 47 (37.9%) 1 (0.8%) 7 (5.6%) Comorbidities No comorbidities Anxiety Depression Migraine Mental retardation Language development delay Cerebrovascular diseases Cognitive impairment Developmental encephalopathy Others 56 (45.2%) 23 (18.5%) 13 (10.5%) 1 (0.8%) 22 (17.7%) 12 (9.7%) 1 (0.8%) 34 (27.4%) 5 (3.9%) 5 (3.9%) SD, standard deviation; VNS, vagus nerve stimulation; no./m, number per month; ASMs, antiseizure medications; FBTCS, focal to bilateral tonic-clonic seizure. 3.2 Seizure outcomes after VNS A ≥ 50% seizure reduction was achieved in 35.4%, 41.6%, 62.2%, 64.2%, and 76.6% of patients at 1, 3, 6, 9, and 12 months after VNS, respectively, with the proportion of responders increasing over time ( P < 0.05, Table 2 , Table S2, Fig. 1 ). For seizure-free patients, there were 3 (2.4%), 3 (2.7%), 9 (9.2%), 7 (8.6%), and 7 (10.9%) at 1, 3, 6, 9, and 12 months after VNS, respectively, showing a significant trend toward increased seizure freedom with longer follow-up periods ( P < 0.05, Table S1 -2). No significant differences in overall ASM load were observed between baseline and each follow-up visit (Table S1 ). Table 2 Responder rate for each follow-up compared to baseline Responder (%) Non-responder (%) χ 2 P Baseline 0 (0.0) 124 (100.0) - - 1 month 44 (35.4) 80 (64.5) 53.5 < 0.001 3 months 47 (41.6) 66 (58.4) 64.3 < 0.001 6 months 61 (62.2) 37 (37.8) 106.4 < 0.001 9 months 52 (64.2) 29 (35.8) 106.7 < 0.001 12 months 49 (76.6) 15 (23.4) 128.4 < 0.001 3.3 QOLIE-31 outcomes after VNS Significant improvements were observed in QOLIE-31 scores between baseline and each follow-up visit, with increasing benefits over time ( P < 0.05, Table S2). The mean (± SD) score improvements were as follows: 1 month (2.93 ± 8.65), 3 months (4.27 ± 9.84), 6 months (4.69 ± 11.5), 9 months (6.68 ± 12.5), and 12 months (9.32 ± 13.8). Details are shown in Fig. 2 and Table S1 . 3.4 Safety At least one adverse event was reported in 34 patients (26.6%) throughout the entire follow-up period. Among these, the most commonly reported adverse events were voice changes or hoarseness and cough, accounting for 76.5% and 32.4% of all adverse events, respectively (Table 3 ). Table 3 Adverse events after VNS. Adverse events Number (%) No Yes Voice change or hoarseness Cough Nausea Headache Infection Hematoma Pain 94 (73.4%) 34 (26.6%) 26 (20.3%) 11 (8.6%) 2 (1.6%) 1 (0.8%) 2 (1.6%) 2 (1.6%) 1 (0.8%) VNS, vagus nerve stimulation. 3.5 Correlation analysis There were no significant correlations between sex, age at VNS implantation, age at seizure onset, epilepsy duration prior to VNS, seizure frequency before VNS, overall ASM load prior to VNS, etiology, seizure types, comorbidities, and the change in QOLIE-31 scores at 1, 3, 6, 9, and 12 months following VNS implementation ( P > 0.05). However, the number of ASMs prior to VNS showed a positive correlation with the change in QOLIE-31 scores at 3 months after implantation ( r = 0.243, P = 0.010, Table S2, Fig. 3 ). In addition, whether the patient was a responder at the last visit positively correlated with change of QOLIE-31 scores at 3 ( r = 0.167, P = 0.031), 6 ( r = 0.168, P = 0.044), 9 ( r = 0.200, P = 0.030), and 12 ( r = 0.242, P = 0.019) months following VNS implementation (Table S2). 4. Discussion This study, the first nationwide, multicenter, real-world study of VNS patients in China, evaluated the efficacy and safety of VNS therapy for epilepsy patients through a dynamic one-year follow-up. We reported a mean responder rate of 56.0% and a mean seizure-free rate of 6.8% following VNS therapy. Our results were comparable to those of other studies. A recent systematic review, which included 11 studies, reported a mean responder rate of 56.94%, ranging from 48.90% to 83.00%[ 14 ]. A multicenter study from Japan reported mean seizure freedom rates of 6.4%, and mean responder rates of 52.9%, respectively [ 13 ]. Another multicenter study from Belgium reported a seizure freedom rate of 9% and a responder rate of 59%, with a mean follow-up of 44 months[ 15 ]. A recent meta-analysis found that the proportion of individuals experiencing seizure freedom at the last follow-up was 3.3% (based on data pooled from 10 case series), and the proportion of responders was 42.7% (based on data pooled from 19 case series)[ 3 ]. Our data revealed a significant cumulative effect of VNS therapy, with the responder rate and seizure-free rate reaching their highest values at the final follow-up, at 76.6% and 10.9%, respectively. Previous studies[ 5 , 10 , 13 , 16 , 17 ] have also demonstrated that VNS leads to a gradual improvement in seizure reduction over time. However, a meta-analysis study, which pooled data from 4 randomized controlled trials and 19 case series to investigate the application of VNS, proposed that there was a non-significant trend toward greater seizure freedom or proportion of responders with longer follow-up periods[ 3 ]. In our study, we directly compared the proportion of seizure freedom and responders during dynamic follow-up and showed a significant cumulative effect of VNS. Our study reported a substantial improvement in quality of life following VNS therapy, with a mean improvement of 5.58 in QOLIE-31 scores. Consistent with our findings, several studies have demonstrated the impact of VNS on the quality of life of epilepsy patients. The PuLsE study showed a significant difference between the VNS plus best medical practice (BMP) group and the BMP-only group, with patients in the VNS + BMP group experiencing a greater improvement in quality of life[ 5 ]. Klinkenberg et al. reported a significant mean increase of 6.56 in the QOLIE-89 score after 6 months of VNS treatment[ 18 ]. Additionally, two prospective cohort studies from Japan[ 13 ] and Korea[ 19 ] also confirmed the role of VNS in improving the quality of life of epilepsy patients. Similar to the seizure outcomes, the improvement in quality of life gradually increased over time, reaching its peak at the end of the follow-up period, consistent with previous studies[ 5 ]. However, it is important to note that as the follow-up duration increased, the dropout rate also rose, which may introduce a potential selection bias. The study found a positive correlation between the number of ASMs used prior to VNS and the improvement in quality of life following VNS therapy. In other words, the greater the number of ASMs taken before VNS, the more significant the improvement in quality of life after VNS treatment. Previous studies confirmed that adverse events related to ASMs are a key factor influencing the quality of life in epilepsy patients[ 20 , 21 ]. Also, the responder of VNS has a more significant improvement in QOLIE-31 scores. No severe or life-threatening adverse events were reported in our study, nor were there any events that led to the removal of the VNS device. The overall incidence of adverse events was 26.6%, with the most commonly reported events being voice changes or hoarseness (20.3%) and cough (8.6%). Compared to other reports, our results are generally consistent and may even show a slight improvement. Shan et al. reported that among 45 VNS patients, the overall incidence of adverse events was 57.8%, with the most common being hoarseness (22.2%), surgical site discomfort (11.1%), and coughing (8.9%)[ 10 ]. The overall incidence of adverse events in other studies was 45.8% (3) and 71.4%, respectively[ 22 ]. A meta-analysis revealed that the most common complications of VNS were hoarseness (37.2%), followed by cough (14.2%) and throat pain (9.6%)[ 3 ]. Our study has several limitations. Firstly, the dosing of ASMs and the adjustment of parameters during VNS therapy for each patient were not standardized and were left to the discretion of their respective physicians. However, as a real-world study, this approach reflects typical clinical practice, where treatment decisions are individualized based on each patient's specific needs and circumstances. Secondly, there was a loss to follow-up at every visit, which may introduce bias into the results. Lastly, our study had a maximum follow-up period of 12 months. Future research will involve extended follow-up to assess the long-term effects of VNS on seizure outcomes and quality of life, as well as its cumulative effects. 5. Conclusion This prospective, multicenter, real-world study with continuous follow-up affirmed that VNS is an effective adjunctive treatment and safe for epilepsy patients in a highly heterogeneous cohort. Patients who are not suitable for conventional resective surgery can benefit from VNS, which not only reduces seizure frequency but also significantly improves quality of life, with evidence showing a cumulative effect of this efficacy over time. Abbreviations ASMs anti-seizure medications VNS vagus nerve stimulation QOLIE-31 31-item Quality of Life in Epilepsy Inventory CRFs Case Report Forms WHO World Health Organization SD standard deviation FBTCS focal to bilateral tonic-clonic seizure BMP best medical practice Declarations Ethics approval and consent to participate This study was approved by the ethics committee of Sichuan University (2022-1847). Patients provided written consent for their anonymized medical data to be analyzed and published for research purposes. Consent for publication Not applicable. Availability of data and materials All data are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Fundings This study was supported by the National Key Research and Development Program (grant number 2021YFC2401204), the Science and Technology Department of Sichuan Province (grant number 2023YFQ0109), the National Key R&D Program of China (grant number 2022YFC2503805), and Health Commission of Sichuan Province Medical Science and Technology Program (grant number 2023-109 and 24LCYJPT08) Authors' contributions DZ and XW conceived and designed the study. CZ, EZ, HZ, RY, ZL, and YC collected and analyzed the data. CZ, WL, WX, XW, and DZ contributed to the interpretation of the results. CZ wrote the manuscript. All authors approved the final version of the manuscript. Acknowledgements We thank all the patients included in our cohort. References Beghi E. 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Epilepsia. 2011;52(12):2181–91. 10.1111/j.1528-1167.2011.03325.x . Tohanean N, Pharmacy CN, Pinzaru C, Mirea L, Perju-Dumbrava L. Impact of vagal nerve stimulation on quality of life in drug-resistant epilepsy. Romanian J Neurology/ Revista Romana de Neurologie. 2018(3). Additional Declarations No competing interests reported. Supplementary Files Supplementarytables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8136450","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":549973847,"identity":"24a424ab-364f-4ad0-bb12-ed8e3d96ecb1","order_by":0,"name":"Chenyang Zhao","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Chenyang","middleName":"","lastName":"Zhao","suffix":""},{"id":549973848,"identity":"38126063-4c20-4761-b9e9-9c3b696c7317","order_by":1,"name":"Enhui Zhang","email":"","orcid":"","institution":"West China Hospital of Sichuan 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University","correspondingAuthor":false,"prefix":"","firstName":"Weixi","middleName":"","lastName":"Xiong","suffix":""},{"id":549973855,"identity":"86f333ef-814b-4ef1-afed-519adbdb6648","order_by":8,"name":"Xintong Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYBACefbm4x8/VNTI8ROtxbDnWBqzxJljxpINROu54WPGwNvGnLjhALE6GGewpT2QOMOWuPl48gaGHxXbCGthl24+blBQIWO87cyzAsaeM7eJsGXOsQQJoC2y227kGDAzthGhhQGoUgLoF8bNM0jQYgbSorhBglgtwEBONgYFsgTQLweJ8gswKg8+BEdle/LGBz8qiHEYAiQYHCBJPVgLqTpGwSgYBaNghAAAsg1BcIj9O3sAAAAASUVORK5CYII=","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":true,"prefix":"","firstName":"Xintong","middleName":"","lastName":"Wu","suffix":""},{"id":549973856,"identity":"11393d5b-b826-4cc4-a196-72edf04e71e5","order_by":9,"name":"Dong Zhou","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Dong","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2025-11-17 14:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8136450/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8136450/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97113350,"identity":"a491677f-cb57-462f-9939-6d8e10e63619","added_by":"auto","created_at":"2025-12-01 06:54:19","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":457444,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-8136450/v1/9c7ab867f967a02a8942b35b.docx"},{"id":97113349,"identity":"0f57892d-7cf7-4524-8f82-7486b7a1713e","added_by":"auto","created_at":"2025-12-01 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06:54:19","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":19957,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8136450/v1/b5940610c44e2722772980cd.png"},{"id":97113352,"identity":"edd81bc2-c458-4e0a-82f6-ecc1ab7ef799","added_by":"auto","created_at":"2025-12-01 06:54:19","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":79804,"visible":true,"origin":"","legend":"","description":"","filename":"d8c5511232594b4bbe7b41ee8e2936f01structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8136450/v1/26823d61a4617989b7cf546e.xml"},{"id":97113348,"identity":"9413b960-6d9b-46fc-a875-9812a7770dbd","added_by":"auto","created_at":"2025-12-01 06:54:19","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":88754,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8136450/v1/08414a676dc10369e36457ea.html"},{"id":97141265,"identity":"d87c7a0a-3b80-49f3-8f0c-0c7bc7bfca1a","added_by":"auto","created_at":"2025-12-01 10:06:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":285349,"visible":true,"origin":"","legend":"\u003cp\u003eThe proportion of patients with different seizure changes according to duration of VNS therapy. VNS, vagus nerve stimulation.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8136450/v1/f05f82d9ca304a00a8295305.png"},{"id":97113356,"identity":"def3de2f-5630-48f8-b4d8-6b8ad83590d1","added_by":"auto","created_at":"2025-12-01 06:54:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":168688,"visible":true,"origin":"","legend":"\u003cp\u003eChange in QOLIE-31 overall score from baseline to 1, 3, 6, 9, and 12 months after VNS. QOLIE-31, 31-item Quality of Life in Epilepsy Inventory; VNS, vagus nerve stimulation. *** \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8136450/v1/2e96b702dca1c9a2aaae18fa.png"},{"id":97113354,"identity":"76f36a15-7533-4af1-8e04-9a9a1e092f62","added_by":"auto","created_at":"2025-12-01 06:54:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":19957,"visible":true,"origin":"","legend":"\u003cp\u003ePositive correlation between the number of ASMs prior to VNS and change in QOLIE-31 scores at 3 months post-implantation. The scatter plot illustrates the positive correlation between the number of ASMs no. prior to VNS and the change in QOLIE-31 scores at 3 months after implantation (\u003cem\u003ers\u003c/em\u003e = 0.243, \u003cem\u003eP\u003c/em\u003e = 0.010). VNS, vagus nerve stimulation; ASMs, anti-seizure medications; QOLIE-31, 31-item Quality of Life in Epilepsy Inventory.\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8136450/v1/f8f85308f503143bb74bf83d.png"},{"id":97145146,"identity":"f724470b-19bc-4414-97c7-b9afd91c6861","added_by":"auto","created_at":"2025-12-01 10:13:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1345150,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8136450/v1/00f44222-7f86-481d-9805-b32dff336be6.pdf"},{"id":97113358,"identity":"a99e3244-16e5-4613-92c3-14969585ddb8","added_by":"auto","created_at":"2025-12-01 06:54:20","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":29122,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8136450/v1/647742ee19cf2f4250281ca3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Vagus nerve stimulation as an add-on therapy in patients with epilepsy: A prospective, multicenter, real-world study in China","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eEpilepsy is a common neurological disorder, affecting an estimated 70\u0026nbsp;million people globally[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Approximately one-third of people with epilepsy who are treated with two appropriately chosen, administered, and well-tolerated anti-seizure medications (ASMs), either as monotherapy or in combination, still struggle to control their seizures[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For such patients, early pre-surgical evaluation is recommended. However, resection or disconnection of the seizure-onset zone is only feasible for certain patients. When surgery is not applicable, neuromodulation therapy is recommended[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eVagus nerve stimulation (VNS) is a neuromodulation therapy that stimulates the left cervical vagus nerve, sending afferent signals to the nucleus tractus solitarius, which then activates the locus coeruleus and other brain regions[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Several long-term open-label studies have reported the efficacy and safety of VNS for epilepsy patients[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. It was approved by the Food and Drug Administration in 1997 as an adjunctive therapy for patients with pharmacoresistant epilepsy. In China, VNS was gradually introduced into clinical practice starting in 2008, although it remained underutilized initially[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The domestic VNS product in China completed its clinical trial registration in 2014 and began being used in clinical settings in 2016. Following the registration and application of domestic VNS, the number of VNS treatments saw rapid growth from 2015 to 2018. Currently, over 140 hospitals in China offer VNS therapy, and nearly 5,000 epilepsy patients have received this treatment[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Xu et al. reported that 52 adult patients underwent VNS implantation for the treatment of refractory epilepsy between May 2016 and May 2017 at five Epilepsy Centers, with a 66.0% responder rate at the 1-year follow-up[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Shan et al. retrospectively evaluated the clinical outcome of 45 consecutive patients with drug-resistant epilepsy undergoing VNS implantation in a single center between November 2016 and August 2021 and reported a 48.9% responder rate[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, there is still a lack of large-scale cohort studies with nationwide coverage involving more than 100 patients in China regarding the application of VNS. And it remains unclear whether longer follow-up periods are associated with a significantly greater trend toward seizure freedom or an increased responder rate[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHere, we present the one-year outcomes from this nationwide real-world study of epilepsy patients receiving add-on VNS therapy to: (1) evaluate the clinical outcomes of VNS treatment in epilepsy patients, including changes in seizure burden, quality of life, and overall ASM burden; (2) assess the safety of VNS application; and (3) determine, through dynamic follow-up, whether the effects of VNS on seizure control and quality of life accumulate over time.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Participants\u003c/h2\u003e\u003cp\u003eThis is a multicenter, prospective, real-world study of the application of VNS for adult patients with epilepsy in China. A total of 83 sites in China participated in this study, and patients included in this study underwent VNS device implantation surgery between January 2022 and December 2024. This study was approved by the ethics committee of West China Hospital (2022\u0026thinsp;\u0026minus;\u0026thinsp;1847), and informed consent was obtained from all patients. Eligible participants were patients diagnosed with epilepsy according to the 2017 International League Against Epilepsy (ILAE) criteria[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Exclusion criteria included: (1) age\u0026thinsp;\u0026lt;\u0026thinsp;18 years or \u0026gt;\u0026thinsp;75 years, (2) failure to complete at least one month of follow-up after implantation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Study design\u003c/h2\u003e\u003cp\u003ePresurgical evaluation, implantation of the VNS device (PINS, Beijing, China), adjustment of ASMs, and setting of VNS parameters were all carried out by each respective hospital, following a standardized procedure[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePatients who met the eligibility criteria underwent a 12-week prospective baseline period to collect baseline data, including seizure frequency, the 31-item Quality of Life in Epilepsy Inventory (QOLIE-31), and other demographic and clinical information (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Following VNS implantation, study visits were scheduled at 1, 3, 6, 9, and 12 months to gather follow-up data. All data collection was carried out using standardized Case Report Forms (CRFs). ASM burden was defined as the total dosage rate relative to the standard dose for all ASMs used, as follows[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]:\u003c/p\u003e\u003cp\u003eOverall ASM burden = \u0026sum; (Dosage / Standard dosage)\u003c/p\u003e\u003cp\u003eThe standard dose was referenced from the World Health Organization (WHO) website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://atcddd.fhi.no/atc_ddd_index/\u003c/span\u003e\u003cspan address=\"https://atcddd.fhi.no/atc_ddd_index/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Endpoints\u003c/h2\u003e\u003cp\u003eThe primary endpoint was the change in seizure frequency from baseline, expressed as the percentage change from baseline frequency. This included seizure-free, a\u0026thinsp;\u0026ge;\u0026thinsp;75% but \u0026lt;\u0026thinsp;100% reduction (75% reduction), a\u0026thinsp;\u0026ge;\u0026thinsp;50% but \u0026lt;\u0026thinsp;75% reduction (50% reduction), a\u0026thinsp;\u0026ge;\u0026thinsp;25% but \u0026lt;\u0026thinsp;50% reduction (25% reduction), a\u0026thinsp;\u0026ge;\u0026thinsp;0% but \u0026lt;\u0026thinsp;25% reduction (no change), and an increase in frequency. Patients were considered responders if they had a reduction of \u0026ge;\u0026thinsp;50% in seizure frequency compared to baseline; conversely, they were classified as non-responders. Secondary endpoints included the change in score of QOLIE-31, overall ASM burden, and adverse events.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed using SPSS 26.0 software, with \u003cem\u003eP\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant. Continuous variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (IQR), depending on the data distribution. Categorical variables were described using absolute frequencies and percentages. The Wilcoxon signed-rank test or Student\u0026rsquo;s paired t-test was used for continuous variables, depending on their distribution. The Chi-Square Test or Fisher\u0026rsquo;s exact test was used for the comparison of categorical variables. Correlation analyses were conducted between changes in QOLIE-31 scores and clinical characteristics prior to VNS implantation, including sex, age at implantation, age at seizure onset, epilepsy duration, seizure frequency, number of ASMs, overall ASM load, etiology, seizure types, and comorbidities, as well as whether the patient was a responder at the last visit. These analyses were performed using Pearson correlation, Spearman correlation, or Kendall\u0026rsquo;s tau-b correlation analysis.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Demographic and baseline clinical features\u003c/h2\u003e\u003cp\u003eA total of 124 patients (77 males and 47 females) with a mean age of 28.3\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2 years were enrolled in this study. The mean age at seizure onset was 14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3 years, the mean duration of epilepsy was 14.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2 years, and the mean seizure frequency was 13.4\u0026thinsp;\u0026plusmn;\u0026thinsp;39.6 seizures per month. Details are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber (%) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003cp\u003eMale\u003c/p\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77 (62.1%)\u003c/p\u003e\u003cp\u003e47 (37.9%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at VNS implantation (years)\u003c/p\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.311.2\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge at seizure onset (years)\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEpilepsy duration prior to VNS (years)\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSeizure frequency prior to VNS, no./m\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e13.4\u0026thinsp;\u0026plusmn;\u0026thinsp;39.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eASMs no. prior to VNS\u003c/b\u003e\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e2\u003c/p\u003e\u003cp\u003e3\u003c/p\u003e\u003cp\u003e4\u003c/p\u003e\u003cp\u003e5\u003c/p\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\u003cp\u003e3 (2.4%)\u003c/p\u003e\u003cp\u003e28 (22.6%)\u003c/p\u003e\u003cp\u003e45 (36.3%)\u003c/p\u003e\u003cp\u003e27 (21.8%)\u003c/p\u003e\u003cp\u003e13 (10.5%)\u003c/p\u003e\u003cp\u003e6 (4.8%)\u003c/p\u003e\u003cp\u003e2 (1.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOverall ASMs load prior to VNS\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.57\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEtiology\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStructural\u003c/p\u003e\u003cp\u003eGenetic\u003c/p\u003e\u003cp\u003eInfectious\u003c/p\u003e\u003cp\u003eMetabolic\u003c/p\u003e\u003cp\u003eImmune\u003c/p\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\u003cp\u003e81 (65.3%)\u003c/p\u003e\u003cp\u003e6 (4.8%)\u003c/p\u003e\u003cp\u003e13 (10.5%)\u003c/p\u003e\u003cp\u003e6 (4.8%)\u003c/p\u003e\u003cp\u003e2 (1.6%)\u003c/p\u003e\u003cp\u003e16 (12.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSeizure types\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFocal onset\u003c/p\u003e\u003cp\u003eFBTCS yes / no\u003c/p\u003e\u003cp\u003eGeneralized onset\u003c/p\u003e\u003cp\u003eFocal and generalized onset\u003c/p\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\u003cp\u003e69 (55.6%)\u003c/p\u003e\u003cp\u003e51 (73.9%) / 18 (26.1%)\u003c/p\u003e\u003cp\u003e47 (37.9%)\u003c/p\u003e\u003cp\u003e1 (0.8%)\u003c/p\u003e\u003cp\u003e7 (5.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eComorbidities\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNo comorbidities\u003c/p\u003e\u003cp\u003eAnxiety\u003c/p\u003e\u003cp\u003eDepression\u003c/p\u003e\u003cp\u003eMigraine\u003c/p\u003e\u003cp\u003eMental retardation\u003c/p\u003e\u003cp\u003eLanguage development delay\u003c/p\u003e\u003cp\u003eCerebrovascular diseases\u003c/p\u003e\u003cp\u003eCognitive impairment\u003c/p\u003e\u003cp\u003eDevelopmental encephalopathy\u003c/p\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\u003cp\u003e56 (45.2%)\u003c/p\u003e\u003cp\u003e23 (18.5%)\u003c/p\u003e\u003cp\u003e13 (10.5%)\u003c/p\u003e\u003cp\u003e1 (0.8%)\u003c/p\u003e\u003cp\u003e22 (17.7%)\u003c/p\u003e\u003cp\u003e12 (9.7%)\u003c/p\u003e\u003cp\u003e1 (0.8%)\u003c/p\u003e\u003cp\u003e34 (27.4%)\u003c/p\u003e\u003cp\u003e5 (3.9%)\u003c/p\u003e\u003cp\u003e5 (3.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSD, standard deviation; VNS, vagus nerve stimulation; no./m, number per month; ASMs, antiseizure medications; FBTCS, focal to bilateral tonic-clonic seizure.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Seizure outcomes after VNS\u003c/h2\u003e\u003cp\u003eA\u0026thinsp;\u0026ge;\u0026thinsp;50% seizure reduction was achieved in 35.4%, 41.6%, 62.2%, 64.2%, and 76.6% of patients at 1, 3, 6, 9, and 12 months after VNS, respectively, with the proportion of responders increasing over time (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table S2, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). For seizure-free patients, there were 3 (2.4%), 3 (2.7%), 9 (9.2%), 7 (8.6%), and 7 (10.9%) at 1, 3, 6, 9, and 12 months after VNS, respectively, showing a significant trend toward increased seizure freedom with longer follow-up periods (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e-2). No significant differences in overall ASM load were observed between baseline and each follow-up visit (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eResponder rate for each follow-up compared to baseline\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eResponder (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNon-responder (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eχ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBaseline\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e124 (100.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1 month\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e44 (35.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e80 (64.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e53.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3 months\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e47 (41.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e66 (58.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e64.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e6 months\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e61 (62.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e37 (37.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e106.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e9 months\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e52 (64.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e29 (35.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e106.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e12 months\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e49 (76.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15 (23.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e128.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.3 QOLIE-31 outcomes after VNS\u003c/h2\u003e\u003cp\u003eSignificant improvements were observed in QOLIE-31 scores between baseline and each follow-up visit, with increasing benefits over time (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table S2). The mean (\u0026plusmn;\u0026thinsp;SD) score improvements were as follows: 1 month (2.93\u0026thinsp;\u0026plusmn;\u0026thinsp;8.65), 3 months (4.27\u0026thinsp;\u0026plusmn;\u0026thinsp;9.84), 6 months (4.69\u0026thinsp;\u0026plusmn;\u0026thinsp;11.5), 9 months (6.68\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5), and 12 months (9.32\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8). Details are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Safety\u003c/h2\u003e\u003cp\u003eAt least one adverse event was reported in 34 patients (26.6%) throughout the entire follow-up period. Among these, the most commonly reported adverse events were voice changes or hoarseness and cough, accounting for 76.5% and 32.4% of all adverse events, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAdverse events after VNS.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdverse events\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003cp\u003eYes\u003c/p\u003e\u003cp\u003eVoice change or hoarseness\u003c/p\u003e\u003cp\u003eCough\u003c/p\u003e\u003cp\u003eNausea\u003c/p\u003e\u003cp\u003eHeadache\u003c/p\u003e\u003cp\u003eInfection\u003c/p\u003e\u003cp\u003eHematoma\u003c/p\u003e\u003cp\u003ePain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e94 (73.4%)\u003c/p\u003e\u003cp\u003e34 (26.6%)\u003c/p\u003e\u003cp\u003e26 (20.3%)\u003c/p\u003e\u003cp\u003e11 (8.6%)\u003c/p\u003e\u003cp\u003e2 (1.6%)\u003c/p\u003e\u003cp\u003e1 (0.8%)\u003c/p\u003e\u003cp\u003e2 (1.6%)\u003c/p\u003e\u003cp\u003e2 (1.6%)\u003c/p\u003e\u003cp\u003e1 (0.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eVNS, vagus nerve stimulation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Correlation analysis\u003c/h2\u003e\u003cp\u003eThere were no significant correlations between sex, age at VNS implantation, age at seizure onset, epilepsy duration prior to VNS, seizure frequency before VNS, overall ASM load prior to VNS, etiology, seizure types, comorbidities, and the change in QOLIE-31 scores at 1, 3, 6, 9, and 12 months following VNS implementation (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, the number of ASMs prior to VNS showed a positive correlation with the change in QOLIE-31 scores at 3 months after implantation (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.243, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010, Table S2, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In addition, whether the patient was a responder at the last visit positively correlated with change of QOLIE-31 scores at 3 (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.167, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031), 6 (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.168, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044), 9 (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.200, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030), and 12 (\u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.242, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019) months following VNS implementation (Table S2).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study, the first nationwide, multicenter, real-world study of VNS patients in China, evaluated the efficacy and safety of VNS therapy for epilepsy patients through a dynamic one-year follow-up. We reported a mean responder rate of 56.0% and a mean seizure-free rate of 6.8% following VNS therapy. Our results were comparable to those of other studies. A recent systematic review, which included 11 studies, reported a mean responder rate of 56.94%, ranging from 48.90% to 83.00%[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A multicenter study from Japan reported mean seizure freedom rates of 6.4%, and mean responder rates of 52.9%, respectively [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Another multicenter study from Belgium reported a seizure freedom rate of 9% and a responder rate of 59%, with a mean follow-up of 44 months[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A recent meta-analysis found that the proportion of individuals experiencing seizure freedom at the last follow-up was 3.3% (based on data pooled from 10 case series), and the proportion of responders was 42.7% (based on data pooled from 19 case series)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Our data revealed a significant cumulative effect of VNS therapy, with the responder rate and seizure-free rate reaching their highest values at the final follow-up, at 76.6% and 10.9%, respectively. Previous studies[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] have also demonstrated that VNS leads to a gradual improvement in seizure reduction over time. However, a meta-analysis study, which pooled data from 4 randomized controlled trials and 19 case series to investigate the application of VNS, proposed that there was a non-significant trend toward greater seizure freedom or proportion of responders with longer follow-up periods[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In our study, we directly compared the proportion of seizure freedom and responders during dynamic follow-up and showed a significant cumulative effect of VNS.\u003c/p\u003e\u003cp\u003eOur study reported a substantial improvement in quality of life following VNS therapy, with a mean improvement of 5.58 in QOLIE-31 scores. Consistent with our findings, several studies have demonstrated the impact of VNS on the quality of life of epilepsy patients. The PuLsE study showed a significant difference between the VNS plus best medical practice (BMP) group and the BMP-only group, with patients in the VNS\u0026thinsp;+\u0026thinsp;BMP group experiencing a greater improvement in quality of life[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Klinkenberg et al. reported a significant mean increase of 6.56 in the QOLIE-89 score after 6 months of VNS treatment[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Additionally, two prospective cohort studies from Japan[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and Korea[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] also confirmed the role of VNS in improving the quality of life of epilepsy patients. Similar to the seizure outcomes, the improvement in quality of life gradually increased over time, reaching its peak at the end of the follow-up period, consistent with previous studies[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, it is important to note that as the follow-up duration increased, the dropout rate also rose, which may introduce a potential selection bias. The study found a positive correlation between the number of ASMs used prior to VNS and the improvement in quality of life following VNS therapy. In other words, the greater the number of ASMs taken before VNS, the more significant the improvement in quality of life after VNS treatment. Previous studies confirmed that adverse events related to ASMs are a key factor influencing the quality of life in epilepsy patients[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Also, the responder of VNS has a more significant improvement in QOLIE-31 scores.\u003c/p\u003e\u003cp\u003eNo severe or life-threatening adverse events were reported in our study, nor were there any events that led to the removal of the VNS device. The overall incidence of adverse events was 26.6%, with the most commonly reported events being voice changes or hoarseness (20.3%) and cough (8.6%). Compared to other reports, our results are generally consistent and may even show a slight improvement. Shan et al. reported that among 45 VNS patients, the overall incidence of adverse events was 57.8%, with the most common being hoarseness (22.2%), surgical site discomfort (11.1%), and coughing (8.9%)[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The overall incidence of adverse events in other studies was 45.8% (3) and 71.4%, respectively[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A meta-analysis revealed that the most common complications of VNS were hoarseness (37.2%), followed by cough (14.2%) and throat pain (9.6%)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur study has several limitations. Firstly, the dosing of ASMs and the adjustment of parameters during VNS therapy for each patient were not standardized and were left to the discretion of their respective physicians. However, as a real-world study, this approach reflects typical clinical practice, where treatment decisions are individualized based on each patient's specific needs and circumstances. Secondly, there was a loss to follow-up at every visit, which may introduce bias into the results. Lastly, our study had a maximum follow-up period of 12 months. Future research will involve extended follow-up to assess the long-term effects of VNS on seizure outcomes and quality of life, as well as its cumulative effects.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis prospective, multicenter, real-world study with continuous follow-up affirmed that VNS is an effective adjunctive treatment and safe for epilepsy patients in a highly heterogeneous cohort. Patients who are not suitable for conventional resective surgery can benefit from VNS, which not only reduces seizure frequency but also significantly improves quality of life, with evidence showing a cumulative effect of this efficacy over time.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eASMs\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eanti-seizure medications\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eVNS\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003evagus nerve stimulation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eQOLIE-31\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e31-item Quality of Life in Epilepsy Inventory\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCRFs\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCase Report Forms\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eWHO\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWorld Health Organization\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eSD\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003estandard deviation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eFBTCS\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003efocal to bilateral tonic-clonic seizure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eBMP\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebest medical practice\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethics committee of Sichuan University (2022-1847). Patients provided written consent for their anonymized medical data to be analyzed and published for research purposes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFundings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Key Research and Development Program (grant number 2021YFC2401204), the Science and Technology Department of Sichuan Province (grant number 2023YFQ0109), the National Key R\u0026amp;D Program of China (grant number 2022YFC2503805), and Health Commission of Sichuan Province Medical Science and Technology Program (grant number 2023-109 and 24LCYJPT08)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDZ and XW conceived and designed the study. CZ, EZ, HZ, RY, ZL, and YC collected and analyzed the data. CZ, WL, WX, XW, and DZ contributed to the interpretation of the results. CZ wrote the manuscript. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the patients included in our cohort.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBeghi E. The Epidemiology of Epilepsy. Neuroepidemiology. 2020;54(2):185\u0026ndash;91. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000503831\u003c/span\u003e\u003cspan address=\"10.1159/000503831\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. 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Determinants of health-related quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments. Epilepsia. 2011;52(12):2181\u0026ndash;91. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1528-1167.2011.03325.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1528-1167.2011.03325.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTohanean N, Pharmacy CN, Pinzaru C, Mirea L, Perju-Dumbrava L. Impact of vagal nerve stimulation on quality of life in drug-resistant epilepsy. Romanian J Neurology/ Revista Romana de Neurologie. 2018(3).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"outcome, neurostimulation, follow-up, VNS","lastPublishedDoi":"10.21203/rs.3.rs-8136450/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8136450/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eVagus nerve stimulation (VNS) has been proven as an effective and safe adjunct therapy for epilepsy, but real-world evidence is limited. This study aimed to evaluate outcomes of VNS and its cumulative effect through a prospective, multicenter, real-world survey in China, with dynamic follow-up.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA total of 83 sites in China participated and 124 epilepsy patients enrolled. Visits were scheduled at 1, 3, 6, 9, and 12 months after VNS. Primary outcomes included seizure response rate (\u0026ge;\u0026thinsp;50% frequency reduction) and seizure-free rate. Secondary outcomes assessed changes in the 31-item Quality of Life in Epilepsy Inventory (QOILE-31) score, overall anti-seizure medication (ASM) burden, and adverse events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe responder rates were 35.4%, 41.6%, 62.2%, 64.2%, and 76.6% at 1, 3, 6, 9, and 12 months after VNS, respectively. Seizure-free rates were 2.4%, 2.7%, 9.2%, 8.6%, and 10.9% at 1, 3, 6, 9, and 12 months, respectively. No significant differences were observed in overall ASM load between baseline and any follow-up visit. Significant improvements were noted in QOLIE-31 from baseline to each follow-up visit, with mean (\u0026plusmn;\u0026thinsp;SD) score improvements as follows: 1 month (2.93\u0026thinsp;\u0026plusmn;\u0026thinsp;8.65), 3 months (4.27\u0026thinsp;\u0026plusmn;\u0026thinsp;9.84), 6 months (4.69\u0026thinsp;\u0026plusmn;\u0026thinsp;11.5), 9 months (6.68\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5), and 12 months (9.32\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8). A significant trend toward improved seizure outcomes and change in quality of life was observed with longer treatment durations. Adverse events occurred in 34 patients (26.6%).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eVNS is an effective and safe adjunctive treatment for epilepsy, reducing seizure frequency and significantly improving quality of life, with a cumulative effect over time.\u003c/p\u003e","manuscriptTitle":"Vagus nerve stimulation as an add-on therapy in patients with epilepsy: A prospective, multicenter, real-world study in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 06:54:05","doi":"10.21203/rs.3.rs-8136450/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2ef9f168-21fc-4c3e-a031-32e35ca3ee62","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-20T02:23:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 06:54:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8136450","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8136450","identity":"rs-8136450","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}