Epilepsy & Behavior 150 (2024) 109562 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh Favorable combinations of antiseizure medication with vagus nerve stimulation to improve health-related quality of life in patients with epilepsy Victoria Sauer a,b, Martin Glaser c, Erik Ellwardt d, Assel Saryyeva e, Joachim K. Krauss e, Florian Ringel c, Sergiu Groppa f, Yaroslav Winter a,b,* a Mainz Comprehensive Epilepsy and Sleep Medicine Center, Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany b Department of Neurology, Philipps-University Marburg, Germany c Department of Neurosurgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany d Department of Neurology, Helios-HSK Wiesbaden, Wiesbaden, Germany e Department of Neurosurgery, Hannover Medical School, MHH, Hannover, Germany f Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany A R T I C L E I N F O A B S T R A C T Keywords: Background: Vagus nerve stimulation (VNS) is a non-pharmacological treatment of refractory epilepsy, which also Epilepsy has an antidepressive effect. The favorable combinations of VNS with specific mechanisms of action of antisei- Vagus nerve stimulation zure medication (ASM) on mood and health-related quality of life (HrQol) have not yet been studied. The Antiseizure medication objective was to identify favourable combinations of specific ASMs with VNS for the HrQoL and depression in Quality of life Depression refractory epilepsy. Methods: We performed an observational study including patients with refractory epilepsy and an implanted VNS (N = 151). In the first 24 months after VNS implantation, all patients were on stable ASM therapy. We used the standardized questionnaires QOLIE10, EQVAS and EQ5D to evaluate HrQoL as well as the Beck Depression Inventory (BDI). Multiple regression analysis was performed to evaluate the synergistic combinations of ASM with VNS for HrQoL. Results: At the year-two follow-up (N = 151, age 45.2 ± 17.0 years), significant improvement (p < 0.05) in BDI scores was found for combination of VNS with SV2A modulators (58.4 %) or AMPA antagonists (44.4 %). A significant increase of HrQoL by at least 30 % (p < 0.05) was measured for a combination of VNS with SV2A modulators (brivaracetam, levetiracetam) or slow sodium channel inhibitors (eslicarbazepine, lacosamide). Conclusion: The results of our study suggests a favorable effect of the combination of SV2A modulators or slow sodium channel inhibitors with VNS on the HrQoL in comparison to other ASMs. Besides the possible synergistic effects on the seizure frequency, the amelioration of behavioral side effects of SV2A modulators by VNS is an important factor of HrQoL-improvement in these combinations. 1. Introduction stimulation (VNS) is an established, effective procedure for the treat- ment of refractory epilepsy in addition to antiseizure medication (ASM) The prevalence of refractory epilepsy is within the range of 27–35 % when resective surgery is not possible or is rejected by the patient [2]. and therefore requires increased medical attention [1]. Vagus nerve Other options of neurostimulation include deep brain stimulation and Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ASM, antiseizure medication; BDI, Beck Depression Inventory; CI, confidence in- terval; EASEE, Epicranial Application of Stimulation Electrodes for Epilepsy; EEG, electroencephalography; EQVAS, EuroQol Visual analogue scale; EQ5D, EuroQol- 5-Dimensions Questionnaire; HrQoL, Health-related Quality of Life; MAINZ-EPIREG, Mainz Epilepsy Registry; QOLIE10, Quality of Life in Epilepsy-10; SD, standard deviation; SV2A, synaptic vesicle glycoprotein 2A; VNS, vagus nerve stimulation. * Corresponding author. E-mail address: yaroslav.winter@unimedizin-mainz.de (Y. Winter). https://doi.org/10.1016/j.yebeh.2023.109562 Received 26 September 2023; Received in revised form 12 November 2023; Accepted 22 November 2023 Available online 9 December 2023 1525-5050/© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). V. Sauer et al. E p i l e p s y & B e h a v i o r 150 (2024) 109562 responsive stimulation [3]. In addition, a new type of neurostimulation, obtained from all participating patients prior to the start of the study. direct cortical stimulation with the EASEE® device (Epicranial Appli- The study conforms with World Medical Association Declaration of cation of Stimulation Electrodes for Epilepsy), was recently approved in Helsinki. Europe [4]. The response rate (at least 50 % reduction in seizure fre- quency) of implantable VNS varies from 45 to 65 % and increases in the 2.2. Evaluation of HrQoL and depression long term [5–7]. The antidepressive effect of VNS is widely known as well as the in- We used standardized questionnaires including the Quality of Life in fluence of different antiseizure medications (ASM) on mood and the Epilepsy-10 (QOLIE10), the EuroQol Visual analogue scale (EQVAS) and health-related quality of life (HrQoL) in epilepsy [3]. However, the ef- the EuroQol-5-Dimensions Questionnaire (EQ5D) to evaluate HrQoL. fect of the combination of VNS with different mechanisms of action of The results of the individual questionnaires were analyzed for each ASM on mood and HrQoL in epilepsy have not been studied before. ASMs and for substance groups (fast sodium channel inhibitors: lamo- Identifying the favorable combination of VNS with some specific trigine, carbamazepine, oxcarbazepine; valproate; slow sodium channel mechanisms of actions of ASMs in patients with refractory epilepsy inhibitors: eslicarbazepine, lacosamide; AMPA-antagonists: per- could be an opportunity to improve the course of the disease and to ampanel; GABAergic drugs: clobazam, pregabaline, topiramate, improve the patients’ HrQoL [8]. A recent study evaluated HrQoL in phenobarbital, valproate; calcium channel inhibitors: ethosuximid; epilepsy patients without VNS and found that ASM side effects and topiramate, zonisamide; carbonic anhydrase inhibitors: topiramate, depression are the main HrQoL determinants in this population [9]. The zonisamide). The questionnaire EQ5D is a validated tool to assess the HrQoL in patients with polytherapy was by 20 % lower than in mono- subjective HrQoL of patients with epilepsy [11]. It reports the health therapy. The use of VNS helps to avoid the drug burden. Taking into status of the patients via 5 dimensions (mobility, self-care, usual activ- consideration this data, the search for favorable combinations of VNS ities, pain/discomfort and anxiety/depression) with 3 levels for each and pharmacotherapy in order to reduce side effects and improve the item (1 = no problems, 2 = moderate problems, 3 = severe problems) as mood would be the next logical step. well as via a visual analogue scale (EQVAS) with values from 0 (“worst The aim of this study was to identify synergistic effects of specific conceivable health status”) to 100 (“best conceivable health status”). We ASMs in combination with VNS on HrQoL and depression in patients also used a validated disease-specific questionnaire, the QOLIE-10, to with epilepsy and to identify clinical variables improving HrQoL. assess HrQoL in epilepsy, applied in its extended version QOLIE-10-P (version 2.0) and consisting of parts A-C with a total of 12 questions 2. Methods [12]. Part A asks about emotions and medication/disease-related limi- tations in daily life within the last four weeks; Part B refers to the 2.1. Study design and clinical evaluation assessment of quality of life in the last four weeks; in Part C, seven areas (energy, emotional state, daily activities, mental activity, effects of the We performed an observational study in patients with refractory medication, worries about seizures, overall quality of life) are ranked epilepsy who were implanted with VNS and remained on unchanged according to their subjective importance. A lower total score indicates a ASM during the first 24 months after the initiation of VNS. The im- better HrQol. plantation of the VNS-system was performed in the neurosurgical de- Depression was evaluated by the Beck Depression Inventory (BDI, partments of three German university medical centers (Hannover, Mainz version 2), which assesses the presence of depression within the last two and Mannheim). After implantation, all study participants were evalu- weeks via 21 statement groups such as “feelings of failure”, “concen- ated in the neurological department of the University Medical Center in tration difficulties”, “loss of energy”, “suicidal thoughts”, etc. It uses Mainz and participated in the Mainz Epilepsy Registry (MAINZ-EPIREG) values from 0 (the statement does not apply at all) to 3 (the statement [10]. The Registry is led by the Mainz Comprehensive Epilepsy and applies completely). Depression within the BDI is categorized as “mild” Sleep Medicine Center, which is part of the Department of Neurology of (scores < 20), “moderate” (scores of 20 to 28) or “severe” (scores >/= the University Medical Center of the Johannes-Gutenberg University, 29) [13]. Mainz, Germany. The patients were motivated not to change ASM dur- ing the first years after VNS implantation, even if the result of VNS 2.3. Statistics treatment did not correspond to their initial expectations. It is known that VNS therapy improves the seizure control even after years since the Statistical analysis was performed using IBM SPSS Statistics Version implantation and it was our argument to motivate the patients‘ patiency. 28.0 (IBM Corp., Armonk, NY, USA). Normal distributed data was In order to exclude the possibility of selection bias and to prove the proved by use of the Kolmogorov-Smirnov test and, additionally, by generalizability of the results, we compared clinical parameters of pa- application of a t-test or analysis of variance. For non-normally tients excluded from the participation due to changes of ASM (approx- distributed data, we applied the Kruskal-Wallis test (>two indepen- imately 30 %) with those who paticipated in the study. No significant dent groups) or the Mann-Whitney U test (two independent groups). The differences in demographics, number of ASM or the seizure frequency at data is presented by determining a mean value within a 95 % confidence baseline were detected. interval (CI) and by calculating the standard deviation (SD). Statistical Data collection was performed before the implantation of VNS significance was determined using a p-value of < 0.05. Independent (baseline) and at the follow-up after two years. The following data was factors influencing the HrQoL were evaluated by applying multivariate collected: demographics, epilepsy type, implanted VNS type, ASM, regression analysis. We applied the R2 method to estimate the variability seizure frequency, depression and HrQol. In order to collect the infor- accounted for by independent factors of HrQol. mation on ASM we used self-report questionnaires and compared this data with clinical documentation. Data concerning seizure freedom and 3. Results responder rate was collected using standardized diaries. Seizure freedom was defined as the absence of epileptic seizures for a period of The study included 151 adult patients with a mean age of 45.2 years at least six months before the end of the study period. The definition of ± 15.3 years. In this cohort, 55.0 % of patients were female. The ma- the responder rate refers to the monthly reduction of at least 50 % in jority of patients suffered from a structural epilepsy (69. 5 %), followed seizure frequency in comparison to the time before implantation. The by 29.1 % with an idiopathic generalized epilepsy and 1.3 % with an data were processed pseudonymously. unknown type of epilepsy. The AspireSR® stimulation system from This study was approved by the Ethics committee of the Rhineland- LivaNova, Inc. was implanted in 50.3 % of patients; SenTiva® in 37.1 %. Palatinate Chamber of Physicians and written informed consent was Older VNS devices such as Demipulse® and VNS Therapy® Pulse 102 2 V. Sauer et al. E p i l e p s y & B e h a v i o r 150 (2024) 109562 were used more rarely. Table 1 shows the demographic and clinical data. 0.05). From all ASMs analyzed in our study, brivaracetam, eslicarba- On average, patients took four ASMs in the period before implantation. zepine, lacosamide and levetiracetam showed significant improvement At the follow-up after two years, a reduction in seizure frequency of at of HrQol by at least 30 % (p < 0.05) at the follow-up after two years least 50 % was reported by 71 patients (47.0 %); seizure freedom was (Table 2). achieved by 11.9 % in total. No statistically significant differences in Table 3 summarizes the results of the regression analysis for the VNS parameters (output current, signal frequency, signal on-time and HrQol measures. Independent factors increasing HrQol were a lower signal off-time) were found between different ASM groups. severity depression measured by BDI and an improved effectiveness of At the two-year follow-up, the following improvements in mean treatment expressed by response rate. These clinical variables could scores of depression and HrQol measures were observed: 8.4 ± 17.1 on explain 48 % of QOLIE10-values, 54 % of EQ5D index scores and 51 % of BDI, 14.6 ± 17.8 on QOLIE10, 0.12 ± 0.17 on EQ5D index and 11.9 ± EQVAS values. 19.5 on EQVAS. Fig. 1 and Table 2 present the distribution of HrQol parameters and depression according to the substance groups and single 4. Discussion ASMs. The BDI scores at baseline were generally higher than at the follow-up after two years showing a trend for a better mood under VNS The role of different mechanisms of actions of ASMs in different types in the entire study population. For SV2A modulators and AMPA antag- of epilepsy and their influence on HrQol is becoming a matter of onists, the level of depression was more prominent at baseline but did increased interest in recent studies [14,15]. In refractory epilepsy, the not reach statistically significant values in comparison to other sub- effects of the combination of VNS with different ASMs and their influ- stance groups. At the follow-up after two years, depression was signifi- ence on the HrQol is of special importance. Few recent studies have cantly improved (p < 0.05) in these two substance groups (58.4 % in investigated the HrQol in epilepsy patients with VNS. The EQ5D, EQ- SV2A modulators and 44.4 % in AMPA antagonists) in comparison to VAS and QOLIE10 are the most common tools for measuring HrQol in baseline. The two years trends in the level of depression in other sub- epilepsy and were also used in our study. In a retrospective study with stance groups did not show statistically significant changes. According 70 epilepsy patients from Valencia, the influence of VNS treatment on to the single substances, the highest BDI scores at baseline were regis- HrQol was assessed by means of QOLIE10: in the first year after VNS- tered for levetiracetam and perampanel. The improvement of depression implantation, approximately 93 % of patients reported an increase in after two years of VNS treatment was best in patients with brivaracetam, HrQol. The mean improvement in QOLIE10 scores was 8.5 ± 7.2 [16]. A levetiracetam or perampanel (54.2–63.2 %, p > 0.05). similar trend was detected in our study with a mean change in QOLIE10 A general trend to HrQol-improvement on VNS-treatment was scores of 14.6 ± 17.8 during the two-year follow-up. The response rate observed in the entire study population. However, the magnitude of (≥50 % reduction in seizure frequency) was higher in the Spanish study HrQol-improvement was different depending on the combination of (57.2 % vs 47.0 % in our patients), probably because further adjust- VNS with different ASMs. The combination of VNS with an ASM acting ments of ASMs were undertaken during the first year after VNS im- via slow sodium channel inhibition showed a significant increase in plantation. In our study, ASMs were kept unchanged during the first two HrQol after two years as measured by QOLIE10 (48.7 %, p < 0.05), by years after implantation. According to various studies and meta-ana- EQ5D index score (33.9 %, p < 0.05) and by EQVAS (30.0 %, p < 0.05). lyses, the response rate of implantable VNS varies from 45 % to 65 % and Similarly, the combination of VNS with SV2A modulators led to signif- increases in the long term [5,17]. The effect on the seizure frequency in icant HrQol-improvement on QOLIE10 (by 48.6 %, p < 0.05), in the our study was within this range. EQ5D index score (by 31.1 %, p < 0.05) and on EQVAS (by 32.1 %, p < The influence of the combination of VNS with different types of ASMs on the HrQol in epilepsy has not been investigated until now. Therefore, our results concerning this specific question cannot be compared with Table 1 other studies. The multiple regression analysis revealed that the most Demographic and clinical data of patients with epilepsy and VNS. important factors influencing HrQol in the context of combination of All Idiopathic Focal Unknown VNS with different ASMs are the response rate (effectiveness) and the patients generalised epilepsy epilepsy reduction of depression. These factors are already known as predictors epilepsy type n ¼ 151 n ¼ 44 n ¼ 105 n ¼ 2 of HrQol in epilepsy. For example, Chen et al. listed four negative pre- dictive factors (depression, seizure frequency of at least once in three Age [years] mean SD 45,2 34,7 11,8 49,8 36,5 0,7 months, anxiety and adverse events of ASM) and three positive pre-± ± ± ± ± 15,3 17,1 dictors (higher household income, male gender and social support) [18]. Gender [n] (%) Depression is a frequent comorbidity in epilepsy [19,20]. Due to the female 83 (55,0) 26 (59,1) 56 (53,3) 1 (50,0) neuroanatomical structures and neurotransmitters involved, a bidirec- male 68 (45,0) 18 (40,9) 49 (46,7) 1 (50,0) tional relationship between the two disorders is suspected [21]. Since VNS type [n] (%) SenTiva® 56 (37,1) 17 (38,6) 38 (36,2) 1 (50,0) VNS is also approved for the treatment of depression, the advantage of AspireSR® 76 (50,3) 22 (50,0) 53 (50,5) 1 (50,0) VNS in epilepsy is the possibility not only to influence the seizures but Demipulse® 6 (4,0) 3 (6,8) 3 (2,9) 0 (0) also to treat the concomitant depression. VNS Therapy® 13 (8,6) 2 (4,5) 11 (10,5) 0 (0) We found that two groups of ASMs with distinctive mechanisms of Pulse 102 Previous ASM [n] action show statistically significant improvement of HrQol in epilepsy mean ± SD 4,4 ± 2,9 4,2 ± 2,8 4,5 ± 3,0 2,0 ± 1,4 when combined with VNS: SV2A modulators and slow inhibitors of so- Response rate1 71 (47,0) 23 (52,3) 47 (44,8) 1 (50,0) dium channels. According to our previous data, the combination of VNS after year 2 [n] and ASMs with these mechanisms of action has a synergistic effect on (%) 2 seizure frequency. As a possible pathophysiological explanation, the Seizure freedom 18 (11,9) 6 (13,6) 11 (10,5) 1 (50,0) after year 2 [n] mutual potentiation in desynchronization of electroencephalographic (%) (EEG) rhythms, which is known for VNS [22] and SV2A modulators Abbreviations: ASM, antiseizure medication; SD, standard deviation; VNS, vagus [23–25] was discussed. As outlined above, the improvement of depres- nerve stimulation. sion is an important factor influencing HrQol. The level of depression 1 Response rate was defined as a reduction in seizure frequency of ≥ 50 % was higher at baseline in our patients treated with SV2A modulators. compared to baseline. The initiation of additional VNS therapy in these patients helped to 2 Seizure freedom was defined as the absence of epileptic seizures for a period significantly improve depression. Therefore, the combination of VNS of at least six months before the end of the observation period. with SV2A modulators could be favorable not only because of 3 V. Sauer et al. E p i l e p s y & B e h a v i o r 150 (2024) 109562 Fig. 1. Health-related quality of life data prior to VNS-implantation and at two-year follow-up, divided according to substance groups * Statistically significant difference at p < 0.05 in comparison to baseline (presented in red color). The values of the EQ5D index score were multiplied by factor 100 in order to optimize the graphical presentation. Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ASM, antiseizure medication; BDI, Beck Depression Inventory (Version 2); EQVAS, EuroQol visual analogue scale; EQ5D, EuroQol-5-Dimensions Questionnaire; GABA, gamma-aminobutyric acid; QOLIE10, Quality of Life in Epilepsy-10; SD, standard deviation; SV2A, synaptic vesicle glycoprotein 2A; VNS, vagus nerve stimulation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Table 2 Health-related quality of life data prior to VNS-implantation and at two-year follow-up, divided according to adjunctive ASMs. BDI BDI QOLIE10 QOLIE10 EQVAS EQVAS EQ5D EQ5D baseline year two baseline year two baseline year two index score index score baseline year two mean ± SD mean ± SD mean ± SD mean ± SD mean ± SD mean ± SD mean ± SD mean ± SD Adjunctive ASM Valproate 21.0 ± 11.6 15.4 ± 9.9 43.7 ± 8.8 36.3 ± 13.4 59.5 ± 9.1 66.3 ± 17.8 0.61 ± 0.09 0.68 ± 0.18 Lamotrigine 19.8 ± 12.4 17.5 ± 11.1 43.7 ± 8.3 35.4 ± 14.1 61.7 ± 10.6 68.4 ± 17.5 0.63 ± 0.10 0.69 ± 0.17 Lacosamide 22.5 ± 11.6 12.0 ± 8.3 47.0 ± 4.8 24.1 ± 15.2* 60.5 ± 8.6 78.5 ± 15.4* 0.59 ± 0.08 0.78 ± 0.15* Levetiracetam 27.7 ± 11.2 10.2 ± 7.9* 46.7 ± 6.0 25.3 ± 15.1* 61.0 ± 10.1 78.3 ± 14.7* 0.60 ± 0.09 0.78 ± 0.14* Brivaracetam 22.7 ± 10.2 10.4 ± 8.1* 46.6 ± 5.2 22.8 ± 12.5* 60.9 ± 9.1 82.4 ± 12.1* 0.62 ± 0.09 0.82 ± 0.12* Carbamazepine 20.8 ± 10.2 15.6 ± 7.4 46.4 ± 6.5 38.2 ± 15.0 61.8 ± 9.5 68.2 ± 13.7 0.59 ± 0.08 0.67 ± 0.13 Eslicarbazepine 19.9 ± 10.1 14.0 ± 11.1 47.5 ± 4.6 22.1 ± 12.5* 59.8 ± 9.7 83.3 ± 11.9* 0.58 ± 0.07 0.84 ± 0.12* Topiramate 22.8 ± 12.1 15.5 ± 10.0 44.9 ± 8.5 35.4 ± 14.2 59.5 ± 9.5 68.9 ± 14.2 0.60 ± 0.08 0.68 ± 0.13 Zonisamide 20.4 ± 13.5 19.3 ± 11.3 44.2 ± 8.2 33.8 ± 16.2 61.5 ± 10.9 67.9 ± 18.8 0.60 ± 0.09 0.69 ± 0.19 Perampanel 27.7 ± 10.6 14.0 ± 9.3* 45.2 ± 7.3 34.6 ± 15.0 59.0 ± 9.6 69.4 ± 16.9 0.61 ± 0.08 0.69 ± 0.16 Pregabalin 24.3 ± 11.0 19.5 ± 9.6 44.9 ± 5.5 35.3 ± 14.5 60.9 ± 9.2 69.5 ± 13.7 0.63 ± 0.05 0.69 ± 0.15 Oxcarbazepine 20.0 ± 14.3 16.9 ± 8.6 44.8 ± 10.0 38.7 ± 16.6 63.5 ± 7.1 60.0 ± 19.6 0.60 ± 0.11 0.59 ± 0.20 Clobazam 21.4 ± 11.1 16.9 ± 9.1 42.7 ± 8.2 36.1 ± 14.3 64.0 ± 8.9 67.1 ± 18.9 0.65 ± 0.09 0.67 ± 0.19 Ethosuximide 23.8 ± 12.5 19.2 ± 8.6 44.6 ± 10.4 43.0 ± 14.3 65.6 ± 11.6 61.7 ± 15.2 0.62 ± 0.10 0.63 ± 0.17 Phenobarbital 24.7 ± 15.1 16.1 ± 7.4 45.4 ± 6.1 36.9 ± 11.4 63.2 ± 10.1 68.6 ± 10.5 0.63 ± 0.05 0.69 ± 0.12 Abbreviations: ASM, antiseizure medication; BDI, Beck Depression Inventory (Version 2); EQVAS, EuroQol visual analogue scale; EQ5D, EuroQol-5-Dimensions Questionnaire; QOLIE10, Quality of Life in Epilepsy-10; SD, standard deviation; VNS, vagus nerve stimulation. * Statistically significant difference at p < 0.05 in comparison to baseline. synergistic effects on the effectiveness but also in order to ameliorate the BDI and EQ5D index score are due to high variability and due to the behavioral side effects of SV2A modulators. It is important to remark small numbers (<100) of patients in the subgroup analyzes. Some sub- that VNS therapy also significantly reduced the level of depression in groups of ASMs were quite small, such as in case of oxcarbazepine, combination with perampanel. However, the synergistic effect of this pregabalin, ethosuximide and phenobarbital. These ASMs should be combination on the seizure frequency was not shown in our previous addressed in larger populations. It is also important to stress that a analysis and, therefore, no significant influence on HrQol was number of ASMs were not present in our analysis (phenytoin, gaba- registered. pentin, cannabidiol, fenfluramine and cenobamate). Consequently, no Our study has several limitations. First, we did not collect data from evidence of their combination with VNS could be provided. long-term follow-ups beyond two years. The evidence of our observa- tional study is inferior to randomized controlled studies. However, no 5. Conclusion randomized controlled studies have been performed to investigate the effects of VNS in combination with different ASMs. The large ranges of The results of our study suggest a favorable effect of the combination 4 V. Sauer et al. E p i l e p s y & B e h a v i o r 150 (2024) 109562 Table 3 Multiple regression analysis of health-related life quality two years after the VNS-implantation. EQVAS EQ5D index score QOLIE10 B 95 % CI p-value B 95 % CI p-value B 95 % CI p-value Age − 0.01 − 0.11; 0.80 0.78 0.00 − 0.00; 0.00 0.63 − 0.03 − 0.13; 0.08 0.59 Female gender 1.12 − 1.85; 4.10 0.46 − 0.01 − 0.04; 0.02 0.58 − 0.64 − 3.92; 2.63 0.70 Epilepsy type1 2.27 − 1.01; 5.55 0.17 0.03 − 0.01; 0.06 0.12 − 1.44 − 5.06; 2.17 0.43 VNS type2 0.40 − 1.44; 2.25 0.67 0.01 − 0.01; 0.03 0.34 0.17 − 1.87; 2.20 0.87 Previous ASM − 0.07 − 0.64; 0.05 0.81 − 0.00 − 0.01; 0.00 0.50 0.28 − 0.35; 0.91 0.39 Response rate3 10.16 6.30; 14.02 0.00 0.11 0.07; 0.15 0.00 − 9.91 − 14.17; − 5.65 0.00 BDI − 1.20 − 1.36; − 1.03 0.00 − 0.1 − 0.01; − 0.01 0.00 0.91 0.73; 1.10 0.00 Constant 70.62 1.09; 87.13 0.00 0.81 0.71; 0.90 0.00 25.01 14.72; 35.30 0.00 Adjusted R2 0.48 0.54 0.48 ^Abbreviations: ASM, antiseizure medication; B, regression coefficient; BDI, Beck Depression Inventory (Version 2); CI, confidence interval; EQVAS, EuroQol visual analogue scale; EQ5D, EuroQol-5-Dimensions Questionnaire; QOLIE10, Quality of Life in Epilepsy-10; VNS, vagus nerve stimulation. 1 Idiopathic generalized epilepsy in comparison to focal epilepsy. 2 VNS devices with autostimulation in comparison to VNS devices without autostimulation 3 Response rate was defined as a reduction in seizure frequency of ≥ 50 % compared to baseline. of SV2A modulators or slow inhibitors of sodium channels with VNS on outcomes in 2 prospective multicenter single-arm trials. 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