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Vagus nerve stimulation: Longitudinal follow-up of patients treated for 5 years
Seizure 18 (2009) 269–274
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Vagus nerve stimulation: Longitudinal follow-up of patients treated for 5 years Robert Kuba a,*, Milan Bra´zdil a, Miroslav Kalina b, Toma´sˇ Procha´zka b, Jirˇı´ Hovorka c, Toma´sˇ Nezˇa´dal c, ˇ ova´ e, Vladimı´r Koma´rek e, Petr Marusicˇ f, Hana Osˇlejsˇkova´ a, Jan Hadacˇ d, Kla´ra Brozˇova´ d, Veˇra Sebron Jana Za´rubova´ d, Ivan Rektor a a
Brno Epilepsy Center; First Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Pekarˇska´ 53, Czech Republic Epilepsy Center Na Homolce Hospital, Prague, Czech Republic Neurology, Epileptology and Neuropsychiatry Department, Na Frantisˇku Hospital, Prague 1, First Medical School, Charles University, Prague, Czech Republic d Centre for Epileptology and Epileptosurgery, Thomayer’s Teaching Hospital, Prague, Czech Republic e Department of Pediatric Neurology, Charles University, Second Faculty of Medicine, Motol Hospital, Czech Republic f Neurology Department, Charles University, Second Faculty of Medicine, Motol Hospital, Czech Republic b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 May 2008 Received in revised form 29 October 2008 Accepted 31 October 2008
We performed a retrospective, multicenter, open-label study to evaluate the efficacy of vagus nerve stimulation (VNS) in all patients in the Czech Republic who have received this treatment for at least 5 years (n = 90). The mean last follow-up was 6.6 1.1 years (79 13 months). The median number of seizures among all patients decreased from 41.2 seizures/month in the prestimulation period to 14.9 seizures/month at 5 years follow-up visit. The mean percentage of seizure reduction was 55.9%. The responder rate in these patients is in concordance with the decrease of overall seizure frequency. At 1 year after beginning the stimulation, 44.4% of patients were responders; this percentage increased to 58.7% after 2 years. At the 5 years last follow-up 64.4% of patients were responders, 15.5% experienced 90% seizure reduction, and 5.5% were seizure-free. A separate analysis of patients younger than 16 years of age showed lower efficacy rates of VNS in comparison to the whole group. Complications and chronic adverse effects occurred in 13.3% of patients. VNS is an effective and safe method to refractory epilepsy in common clinical practice. ß 2008 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Vagus nerve stimulation Efficacy Long-term outcome Complications
1. Introduction Vagus nerve stimulation (VNS) is an adjunctive treatment in patients with refractory focal and generalized epilepsies. VNS belongs to the group of so-called palliative surgical procedures used to treat refractory epilepsy. VNS is not an alternative of resective surgery and is indicated only in patients in whom the resection is not possible. Since the first human implantation of VNS device in 1988, reported by Penry,1 more that 55 000 patients have received VNS therapy worldwide. The efficacy of VNS in treating epilepsy has been demonstrated in numerous studies. The first two major studies were titled E03
* Corresponding author. Tel.: +420 5 43 18 26 26; fax: +420 5 43 18 26 24. E-mail addresses: [email protected] (R. Kuba), [email protected] (M. Brzdil), [email protected] (M. Kalina), [email protected] (T. Prochzka), [email protected] (J. Hovorka), [email protected] (T. Nedal), [email protected] (J. Hadacˇ), [email protected] ˇ ov), (K. Brozˇov), [email protected] (V. Sebron [email protected] (V. Komrek), [email protected] (P. Marusicˇ), [email protected] (H. Olejkov), [email protected] (J. Zrubov), [email protected] (I. Rektor).
and E05, which were multicenter, double-blind, and randomized trials. In both studies high frequency stimulation (30 Hz) and low frequency stimulation (1 Hz) were compared. Patients receiving low frequency stimulation constituted the control group. Both these studies were short-term, each lasting 3 months. Respectively, 114 and 199 patients were randomized and implanted. In both studies, mean seizure reduction was significantly higher in the high frequency stimulation group than in the low frequency stimulation group (24.5% and 6.1% in E03 and 28% and 15% in E05). Similarly, the number of responders (patients with 50% seizure reduction) was significantly higher in the high stimulation group in both studies.2,4 Although these types of studies are fundamentally necessary for the establishment of indication of the treatment, they have numerous limitations. The effect of VNS as a long-term treatment of epilepsy was definitively demonstrated by evaluating the results of all patients from 5 open prospective long-term clinical trials. The aggregate responder rate of these studies (n = 440) was 43% at 3 years.5 In addition to its demonstrated efficacy in focal epilepsies, other studies have shown that VNS has positive effects on various types of generalized seizures and epilepsies, including idiopathic generalized epilepsy and Lennox–Gastaut syndrome.6–9 Among
1059-1311/$ – see front matter ß 2008 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2008.10.012
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others, Murphy has published a study confirming the effect of VNS in the long-term treatment of children with refractory focal and generalized seizures.10 From the practical point of view, we need data from open-label studies performed under natural clinical conditions. Several multicenter and open-label studies have already been published. All of them demonstrated positive long-term effects of VNS in patients with various types of epilepsy. Some of these studies included patients pooled from centers in different countries.11–13 In this study, we pooled the retrospective data for all patients implanted with VNS in the Czech Republic with a follow-up of 5 years. 2. Methods
patients’ seizure diaries at the preoperative visit; follow-up visits 1, 2, and 5 years after the onset of stimulation. The mean monthly seizure frequency at baseline and each follow-up visit was the mean seizure frequency of the previous 3 months. We recorded the seizure reduction at each follow-up visit for all patients and the responder rate for each follow-up visit. According to the effect of VNS, patients were assigned to one of four outcome groups: Seizure-free, 90% seizure reduction, 50% seizure reduction, Seizure reduction <50%, no change, or worsening of the seizure frequency.
This study was retrospective, multicenter, and open-label. It was designed as a retrospective audit of efficacy and tolerability of VNS during long-term stimulation. The data were collected from the documentation of physicians in Czech epilepsy centers. We obtained data, which reflect common clinical practice in managing VNS treatment in epilepy patients. All patients were implanted between August 1997 and April 2002. The data were collected in May and June 2007.
The patients in groups 1, 2 and 3 were considered responders, and the patients in group 4 were considered to be nonresponders. Secondary outcomes of this study were the following parameters: effect of magnetic stimulation administered by the patient or caregiver in aborting seizures and complications and clinically significant adverse effects.
2.1. Patient population
We performed a statistical analysis of the change in seizure frequency at predefined visits. Wilcoxon signed ranks test was performed to evaluate the differences between individual visits. SPSS 13.0 was used to perform the statistical analysis. P < 0.01 was considered to be statistically significant.
The following epilepsy centers participated in this study: Epilepsy Center Brno; Epilepsy Center Na Homolce HospitalPrague; Neurology, Epileptology and Neuropsychiatry Department, Na Frantisˇku Hospital, Prague; Centre for epileptology and epileptosurgery, Thomayer’s Teaching Hospital, Prague; Neurology Department, Charles University, Second Faculty of Medicine, Motol Hospital Department of Pediatric Neurology, Charles University, Second Faculty of Medicine, Motol Hospital. All patients suffered from refractory epilepsy and all were not candidates for resection surgery at the time of implantation of VNS. We performed an efficacy analysis of the whole cohort and a subanalysis of patients younger than 16 years. The data collected for this study were based on seizure diaries and patient’s files collected in each individual department. These data included basal demographic data, type of epilepsy, type of seizure, seizure frequency, change of AED treatment in the time of stimulation, stimulation parameters and adverse events. We did not established any specific inclusion criteria. All patients implanted between August 1997 and April 2002 were included. 2.2. Vagus nerve stimulation The implantation procedure was performed in all centers in the standardized manner and under general anesthesia (two incisions procedure). VNS Therapy Systems 100 and 101 were used in all patients. During all implantation procedures, the impedance was tested by the use of a standardized lead test of the VNS pulse stimulator. Reimplantation of the pulse generator was performed under the local anesthesia. VNS Therapy System 102R was used in all ‘‘reimplanted’’ patients. 2.3. Outcome evaluation The primary objective of this retrospective study was to evaluate the efficacy of VNS in reducing various types of epileptic seizures after 1, 2 and 5 years of stimulation. Only patients who received stimulation for 5 years and longer were included in the analysis. The monthly seizure frequency was counted from
2.4. Statistics
3. Results 3.1. Patient population Ninety patients (50 men, 40 women) were included in the study with a mean follow up of 6.6 1.1 years. At the time of initial evaluation, the age ranged from 13 to 64 years with a mean of 36.3 years. Epilepsy surgery had been attempted with unsatisfactory results in 23 patients. The age of the onset of epilepsy ranged from 1 month to 45 years with a mean 10.2 years, and the duration of epilepsy at the time of evaluation ranged from 11 to 56 years with a mean of 26.3 years. Fifteen patients were younger than 16 years at the time of VNS implantation. This subgroup of 15 children consisted of 9 males and 6 females, aged from 7 to 16 years with a mean of 11.7 years in the time of implantation. Three of the children had received a diagnosis of Lennox–Gastaut syndrome. The preoperative investigation identified the symptomatic etiology in 54 patients, but the etiology was cryptogenic in the remaining 36 patients. None of the patients had idiopathic focal or generalized epilepsy. We were also able to determine the probable localization of the seizure onset zone during the preoperative investigation (via magnetic resonance imaging [MRI] and videoelectroencephalogram [EEG] monitoring). Thirty patients had temporal lobe epilepsy, 26 patients (28.9%) had frontal lobe epilepsy, 26 patients (28.9%) had multifocal seizure onset, and 6 patients (6.7%) had another localization of seizure onset (4 patients had generalized epilepsy, 1 patient had parietal lobe epilepsy, 1 patient had operculo-insular epilepsy). We were not able to identify the precise localization of seizure onset in two patients (2.2%). Forty-three patients (47.8%) experienced both partial seizures and generalized tonic–clonic seizures. In 20 patients (22.2%), we analyzed the effect of VNS on partial seizures only. Four patients (4.4%) experienced generalized tonic–clonic seizures only, 5
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patients (5.5%) experienced other types of generalized seizures, 6 patients (6.6%) experienced both generalized tonic–clonic and other types of generalized seizures. The remaining three patients (3.3%) experienced partial, generalized tonic–clonic, and other types of generalized seizures. In the group with other types of generalized seizures, one patient experienced absence seizures, one patient experienced tonic seizures, one patient experienced myoclonic seizures, and one patient experienced atonic seizures. In addition, six patients experienced a combination of more than one of these seizure types, and four patients experienced seizures that were unclassified. In 6 out of 90 patients, the seizures occurred in clusters and could not be counted. These patients were included only in the analysis of responders and nonresponders. 3.2. Percentage seizure reduction All 90 patients were evaluated at the preoperative visit. We evaluated 88 patients after 1 year of VNS treatment, 87 patients at 2 years and 85 patients at 5 years follow-up visit. A total of five patients discontinued VNS treatment before 5 years follow-up visit. The individual reasons for discontinuation were: death after complicated status epilepticus, explantation of VNS device because of lack of efficacy at pulse generator end of service, early explantation because of local inflammatory complication, resective reoperation, and switching off the VNS pulse generator because of worsening seizures. The seizure reductions between the preoperative visit and all follow-up visits were statistically significant for patients in all seizure type groups. The seizure frequency ranges and means for all seizure types and seizure type groups separately and the results of statistical analyses are displayed in Table 1. Fig. 1 shows the longitudinal decline compared to baseline (i.e., at the preoperative visit) of seizure frequency in all seizure types. 3.3. Responder rates After 1 year of VNS treatment, none of the patients were seizure-free, 3 patients (3.3%) experienced 90% seizure reduction, and 37 patients (41.1%) experienced 50% seizure reduction. In
Fig. 1. Longitudinal decline in seizure reduction in all seizure types together and individual seizure types in comparison to the baseline (i.e., the seizure frequency at preoperative visit).
total, 40 patients (44.4%) were responders, 48 patients (53.3%) were nonresponders and 2 patients (2.3%) discontinued VNS. The follow-up visit after 2 years was characterized by an increase in responders to VNS. Three patients (3.3%) were seizurefree, 2 patients (2.2%) experienced 90% seizure reduction, and 48 patients (53.2%) experienced 50% seizure reduction. In total, 53 patients (58.9%) were responders, 34 patients (37.8%) were nonresponders, and 3 patients (3.3%) discontinued VNS. A further increase in responders to VNS occurred after 5 years. Five patients (5.5%) were seizure-free, 9 patients (10%) experienced 90% seizure reduction, and 44 patients (48.9%) experienced 50% seizure reduction. In total, 58 (64.4%) patients were responders, 27 patients (30.1%) were nonresponders, and 5 patients (5.5%) discontinued VNS. A summary of responder rates to VNS at predefined follow-up visits is displayed in Fig. 2.
Table 1 Range and average seizure frequency of all seizures and individual seizure types at preoperative and all follow-up visits. The statistical analysis used Wilcoxon signed ranks test. Preoperative
1 year
2 years
5 years
All seizure types together Range Mean comparison to preoperative Z P
4–210 41.2 47.4 – –
1–176 20.7 26.4 7.102 <0.001
0–300 19.5 36.7 6.685 <0.001
0–138 14.9 25.2 6.989 <0.001
Partial seizures Range Mean comparison to preoperative Z P
3–210 34.2 37.8 – –
0–150 18.1 23.9 7.534 <0.001
0–300 18.3 38.1 7.384 <0.001
0–120 14.3 24.9 7.549 <0.001
Generalized tonic–clonic seizures Range Mean comparison to preoperative Z P
1–30 6.5 7.0 – –
0–20 3.5 4.2 5.104 <0.001
0–75 3.7 10.1 5.514 <0.001
0–17 1.9 3.3 5.857 <0.001
Other types of generalized seizures Range Mean comparison to preoperative Z P
3–200 52.1 63.4 – –
3–100 22.2 28.4 6.978 <0.001
3–60 18.2 16.8 7.231 <0.001
3–30 11.1 8.7 7.487 <0.001
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classified as responders, 10 patients as nonresponders, and 1 patient left the study. After 5 years of VNS, the number of responders increased to seven patients, the number of nonresponders decreased to seven patients, and one patient left the study. None of these experienced seizure freedom or 90% seizure reduction after 1, 2, or 5 years of VNS. A summary of responder rates to VNS at predefined follow-up visits in children is displayed in Fig. 3. 3.5. Adverse effects Adverse effects were evaluated in all 90 patients (Table 2). Intermittent hoarseness during active stimulation was not considered to be an adverse effect. Adverse effects were present in 12 patients (13.3%). 3.6. VNS and stimulation parameters
Fig. 2. Response rate to VNS, whole group (n = 90).
3.4. Group of children Fifteen patients, in this population were 16 years of age or younger at VNS implantation. In 6 out of 16 children the seizures occurred in clusters and could not be counted therefore we only analyzed the response rate in this group (Fig. 3). After 1 year of VNS, seven patients were classified as responders, seven patients were classified as nonresponders, and one patient left the study. The number of these patients who responded to VNS dropped after 2 years of stimulation. At this follow-up visit, 4 patients were
Chronic stimulation began within 4 weeks of surgery. In all patients, the baseline output current was 0.25 mA. The output current was increased for each patient according to clinical status and adverse events. The follow-up visits were conducted individually. Other parameters were set based on the standardized recommendation: frequency of 20 or 30 Hz, pulse width of 250 or 500 ms, and an on/off cycle of 30 s ON and 3 or 5 min OFF. The on/ off cycle was also changed based on the clinical condition in each patient. Reimplantation of the pulse generator had been performed in 44 out of 90 patients. The reason of reimplantation in all of these patients was the end of service of the VNS pulse generator. Explantation of the VNS system was performed in three patients because of lack of efficacy at the pulse generator’s end of service. Also, the explantation of one patient’s pulse generator was followed by delayed reimplantation because of a local inflammatory complication. Stimulation parameters were analyzed at the latest follow-up visit in 87 patients. The range of the output current was between 0.5 and 2.25 mA with a mean of 1.43 0.41 mA. The range of the duty cycle was from 10% to 35% (from 30 s ON/5 min OFF to 30 s ON/ 1.1 min OFF). The most frequent duty setting (n = 20) was 30 s ON/ 3 min OFF (duty cycle 16%). 3.7. Magnet stimulation During the interview at the last follow-up visit, 35 patients (38.9%) reported that self-managed activation of the generator with the VNS magnet at the time of seizure onset led to suppression or shortening of the seizure. 3.8. Changes in antiepileptic drug (AED) treatment Changes in AED treatment during long-term VNS stimulation were analyzed retrospectively at the last follow-up visit. Only two patients (2.2%) were not evaluated. No patient was completely
Table 2 Adverse effects of VNS in 12 patients.
Fig. 3. Response rate to VNS, patients 16 years of age and younger at time of implantation (n = 16).
Type of adverse effect
Number of patients
Local inflammation Interruption of the electrode due to the trauma Untolerated chronic hoarseness and/or cough Technical malfunction of the generator Nausea, cough, and chronic aches in the neck region Chronic vocal cord palsy
3 3 3 1 1 1
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withdrawn from AED treatment. In 9 patients (10%), at least 1 AED was withdrawn, and in 10 patients (11.1%) no change of AED treatment occurred. In 69 patients (76.7%), an increase of the current treatment or add-on therapy to the next AED occurred. 4. Discussion Several studies have analyzed the long-term efficacy of VNS. The range of mean follow-up was from 20 months to 7 years and the range of included patients from 20 to 138 patients.11,12,14–17 From this point of view, our study is one of the longest and most extensive open-label studies which have been published. Only Spanaki et al.16 has also restricted its patient population to those with follow-up of longer than 5 years. The primary outcome of this study was the efficacy of VNS. The median number of seizures in the whole group gradually decreased from 41.2 seizures/month in the prestimulation period to 14.9 seizures/month at the 5 years follow-up visit. Therefore, the mean seizure reduction at the 5 years follow-up visit was 55,9%. Other long-term open label studies provide similar response results. Morris and Mueller, who analyzed all patients enrolled in the VNS pivotal studies E01-E05, reported a mean seizure reduction of 43% after 3 years.5 Similar results were reported by other authors.15,17 Our study is comparable to a recent Belgian study, which reported a reduction of overall monthly seizure frequency of 51% at a mean follow-up of 44 months. The mean number of seizures in this study was reduced from 41 seizures/ month at preimplantation to 7 seizures/month at last follow-up.11 Probably the highest reduction in seizure count was reported by Spanaki et al.16 This study also included only patients with followup longer than 5 years. They reported an overall seizure reduction of 72% (n = 28).16 The overall seizure reduction reported in our study is consistent with previously published studies. The responder rate in our study is consistent with the decrease of overall seizure frequency. The response rate increased from 44.4% after 1 year of VNS to 64.4% after 5 years of stimulation. The range of responder rates at the last follow up visit in previously published open label studies varied from 44% to 59%.11,12,14–17 The percentage of patients experiencing 90% seizure reduction ranged from 3.3% after 1 year of VNS to 15.5% at the 5 years follow-up visit. Similarly, the number of patients who experienced seizure freedom ranged from 0% after 1 year of VNS to 5.5% at the 5 years follow-up. Seizure-free rates in other studies varied from 2% to 9%.11,12,14,15 Our study also included an analysis of the effectiveness of VNS to particular seizure types. Fig. 1 shows the gradual decrease of seizure frequency of all evaluated seizure types. We report decreases in the mean number of partial seizures from 34.2 to 14.3 seizures/month, generalized tonic–clonic seizures from 6.5 to 1.9 seizures/month, and other types of generalized seizures from 52.1 to 11.1 seizures. This consistent reduction of individual seizure types was parallel with the decrease in all seizures. In agreement with our study, almost all published data analyzing the long-tem outcome of VNS report improved outcomes over long periods of time.5,11,12,14,16 The analysis of patients younger than 16 years of age at VNS implantation demonstrated lower response rates in comparison to the whole group. Data about the efficacy of VNS in children are less extensive than in adults. Morris and Mueller published one of the largest studies on a preadolescent epileptic population suffering from partial and generalized tonic–clonic seizures. They reported an overall seizure reduction to 42% at the last follow-up in 46 patients.5 Similar data were published by Rychlicki et al. and by Alexopoulos et al.18,19 Blount et al. described the efficacy of VNS in children less than 5 years old.20 Several studies reported the
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efficacy of VNS in Lennox–Gastaut syndrome.8,9,21 De Herdt et al., similar to our study, analyzed a large patient population that included a small number of patients younger than 16 years of age. Our study included 15 of these patients (16.7%), and De Herdt’s study included 21 of these patients (15.3%). Like De Herdt et al., we found lower response rates in the pediatric population when compared to the whole group.11 One explanation may be that the pediatric population in our study had more severe epilepsy. Three of these patients had Lennox–Gastaut syndrome, and in six patients the seizures could not be expressed numerically because they experienced series and clusters of seizures. Similar conclusions were reached by De Herdt et al.11 Adverse effects occurred in 13.3% of patients in our study, including three patients in whom the stimulating electrode was interrupted due to a mechanical injury. Local complication occurred in three patients and was the reason for explantation in one patient. Intolerable hoarseness or cough were present only in three patients. This numbers confirm that VNS is a relatively safe procedure. Other studies provide similar rates.14,23 On-demand activation of the generator via a magnet may improve quality of life in some patients. It is difficult to measure the efficacy of such stimulation. Our interviews found that 38.9% patients reported that manual activation of VNS usually led to shortening or aborting seizures. Murphy et al. found that about 50% of their pediatric patients benefitted from on-demand activation of the generator.21 No patient was completely withdrawn from AED treatment and in most of the patients an increase of the current treatment or addon therapy to the next AED occurred. De Herdt et. al demonstrated that the mean number of AEDs remained unchanged after several years of stimulation.11 This data demonstrate that VNS should be considered as a palliative surgical procedure. Implantation and the onset of chronic stimulation do not replace AEDs. Other add-on therapies are needed in most patients. The stimulation parameters of our study paralleled those of controlled studies.2–4 We did not analyze the efficacy of rapid cycling. In general, rapid cycling has been studied in patients who have not responded to VNS, and in almost all cases rapid cycling did not lead to long-term efficacy.11,15,24 The mean output current in our cohort was 1.43 at the last follow-up visit. The value of this output current is lower than in some other studies, although the results are similar.11,14,22 The recent study by Bunch et al. concluded that output current is not the major determinant of acute response to VNS.25 Rigorous data showing the relationship between chronic response to and stimulation parameters of VNS are still missing. In summary, our study shows that VNS is an effective and safe method to refractory epilepsy in common clinical practice. Our multicenter, open-label study examines the practical, long-term management of VNS. Acknowledgments Tim Peoples, a medical writing consultant to Cyberonics, Inc, edited this manuscript before submission. References 1. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent stimulation in humans. Epilepsia 1990;31(Suppl. 2):S40–3. ˜ on-Espaillat R, Ristanovic R, Wilder BJ, Stefan H, et al. 2. Ben-Menachem E, Man Vagus nerve stimulation for treatment of partial seizures. 1. A controlled study of effect on seizures. Epilepsia 1994;35:616–26. 3. Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 1998;51:48–55.
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4. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. The Vagus Nerve Stimulation Study Group. Neurology 1995;45:224–30. 5. Morris GL, Mueller VM, the Vagus Nerve Stimulation Group E01–E05. Long– term treatment with vagus nerve stimulation in patients with refractory epilepsy. Neurology 1999;53:1731–5. 6. Holmes MD, Silbergeld DL, Drouhard D, Wilensky AJ, Ojemann LM. Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy. Seizure 2004;13:340–5. 7. Ng M, Devinsky O. Vagus nerve stimulation for refractory idiopathic generalised epilepsy. Seizure 2004;3:176–8. 8. Hosain S, Nikalov B, Harden C, Li M, Fraser R, Labar D. Vagus nerve stimulation treatment for Lennox–Gastaut syndrome. J Child Neurol 2000;15:509–12. 9. Karceski S. Vagus nerve stimulation and Lennox–Gastaut syndrome. A review of the literature and data from the VNS Patient Registry. CNS Spectr 2001;6:766– 70. 10. Murphy JV, the Pediatric VNS Study Group. Left vagal nerve stimulation in children with medically refractory epilepsy. J Pediatr 1999;134:563–6. 11. De Herdt V, Boon R, Ceulemans B, Hauman H, Lagae L, Legros B, et al. Vagus nerve stimulation for refractory epilepsy: a Belgian multicenter study. Eur J Paediatr Neurol 2007;11:261–9. 12. Vonck K, Thadani V, Gilbert K, Dedeurwerdere S, De Groote L, De Herdt V, et al. Vagus nerve stimulation for refractory epilepsy: a transatlantic experience. J Clin Neurophysiol 2004;21:283–9. 13. Sakas DE, Korfias S, Nicholson CL, Panourias IG, Georgakoulias N, Gatzonis S, et al. Vagus nerve stimulation for incractable epilepsy: outcome in two series combining 90 patients. Acta Neurochir Suppl 2007;97:287–91. 14. Ben-Menachem E, Hellstro¨m K, Waldton C, Augustinsson LE. Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years. Neurology 1999;52:1265–7.
15. Scherrmann J, Hoppe C, Kral T, Schramm J, Elger CE. Vagus nerve stimulation. Clinical experience in a large patient series. J Clin Neurophysiol 2001;18:408–14. 16. Spanaki MV, Allen LS, Mueller WM, Morris GL. Vagus nerve stimulation therapy: 5-year or greater outcome at a university-based epilepsy center. Seizure 2004;13:587–90. 17. Uthman BM, Reichl AM, Dean JC, Eisenschenk S, Gilmore R, Reid S, et al. Effectiveness of vagus verve stimulation in epilepsy patients. A 12-year observation. Neurology 2004;63:1124–6. 18. Alexopoulos AV, Kotagal P, Loddenkemper T, Hammel J, Bingaman WE. Longterm results with vagus nerve stimulation in children with pharmacoresistant epilepsy. Seizure 2006;15:491–503. 19. Rychlicki F, Zamponi N, Trignani R, Ricciuti RA, Iacoangeli M, Scerrati M. Vagus nerve stimulation: clinical experience in drug-resistant pediatric epileptic patients. Seizure 2006;15:483–90. 20. Blount JP, Tubbs RS, Kankirawatana P, Kiel S, Knowlton R, Grabb PA, et al. Vagus nerve stimulation in children less than 5 years old. Childs Nerv Syst 2006;22:1167–9. 21. Murphy JV, Torkelson R, Dowler I, Simon S, Hudson S. Vagal nerve stimulation in refractory epilepsy. Arch Pediatr Adolesc Med 2003;157:560–4. 22. Labar D. Vagus nerve stimulation for 1 year in 269 patients on unchanged antiepileptic drugs. Seizure 2004;13:392–8. 23. Landy HJ, Ramsay ER, Slater J, Casiano RR, Morgan R. Vagus nerve stimulation for complex partial seizures: surgical technique, safety, and efficacy. Neurosurgery 1993;78:26–31. 24. DeGiorgio CM, Schachter SC, Handforth A, Salinsky M, Thompson J, Uthman B, et al. Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures. Epilepsia 2000;41:1195–200. 25. Bunch S, DeGiorgio CM, Krahl S, Britton J, Green P, Lancman M, et al. Vagus nerve stimulation for epilepsy: is output current correlated with acute response? Acta Neurol Scand 2007;116:217–20.
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Seizure journal homepage: www.elsevier.com/locate/yseiz
Vagus nerve stimulation: Longitudinal follow-up of patients treated for 5 years Robert Kuba a,*, Milan Bra´zdil a, Miroslav Kalina b, Toma´sˇ Procha´zka b, Jirˇı´ Hovorka c, Toma´sˇ Nezˇa´dal c, ˇ ova´ e, Vladimı´r Koma´rek e, Petr Marusicˇ f, Hana Osˇlejsˇkova´ a, Jan Hadacˇ d, Kla´ra Brozˇova´ d, Veˇra Sebron Jana Za´rubova´ d, Ivan Rektor a a
Brno Epilepsy Center; First Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Pekarˇska´ 53, Czech Republic Epilepsy Center Na Homolce Hospital, Prague, Czech Republic Neurology, Epileptology and Neuropsychiatry Department, Na Frantisˇku Hospital, Prague 1, First Medical School, Charles University, Prague, Czech Republic d Centre for Epileptology and Epileptosurgery, Thomayer’s Teaching Hospital, Prague, Czech Republic e Department of Pediatric Neurology, Charles University, Second Faculty of Medicine, Motol Hospital, Czech Republic f Neurology Department, Charles University, Second Faculty of Medicine, Motol Hospital, Czech Republic b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 May 2008 Received in revised form 29 October 2008 Accepted 31 October 2008
We performed a retrospective, multicenter, open-label study to evaluate the efficacy of vagus nerve stimulation (VNS) in all patients in the Czech Republic who have received this treatment for at least 5 years (n = 90). The mean last follow-up was 6.6 1.1 years (79 13 months). The median number of seizures among all patients decreased from 41.2 seizures/month in the prestimulation period to 14.9 seizures/month at 5 years follow-up visit. The mean percentage of seizure reduction was 55.9%. The responder rate in these patients is in concordance with the decrease of overall seizure frequency. At 1 year after beginning the stimulation, 44.4% of patients were responders; this percentage increased to 58.7% after 2 years. At the 5 years last follow-up 64.4% of patients were responders, 15.5% experienced 90% seizure reduction, and 5.5% were seizure-free. A separate analysis of patients younger than 16 years of age showed lower efficacy rates of VNS in comparison to the whole group. Complications and chronic adverse effects occurred in 13.3% of patients. VNS is an effective and safe method to refractory epilepsy in common clinical practice. ß 2008 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Vagus nerve stimulation Efficacy Long-term outcome Complications
1. Introduction Vagus nerve stimulation (VNS) is an adjunctive treatment in patients with refractory focal and generalized epilepsies. VNS belongs to the group of so-called palliative surgical procedures used to treat refractory epilepsy. VNS is not an alternative of resective surgery and is indicated only in patients in whom the resection is not possible. Since the first human implantation of VNS device in 1988, reported by Penry,1 more that 55 000 patients have received VNS therapy worldwide. The efficacy of VNS in treating epilepsy has been demonstrated in numerous studies. The first two major studies were titled E03
* Corresponding author. Tel.: +420 5 43 18 26 26; fax: +420 5 43 18 26 24. E-mail addresses: [email protected] (R. Kuba), [email protected] (M. Brzdil), [email protected] (M. Kalina), [email protected] (T. Prochzka), [email protected] (J. Hovorka), [email protected] (T. Nedal), [email protected] (J. Hadacˇ), [email protected] ˇ ov), (K. Brozˇov), [email protected] (V. Sebron [email protected] (V. Komrek), [email protected] (P. Marusicˇ), [email protected] (H. Olejkov), [email protected] (J. Zrubov), [email protected] (I. Rektor).
and E05, which were multicenter, double-blind, and randomized trials. In both studies high frequency stimulation (30 Hz) and low frequency stimulation (1 Hz) were compared. Patients receiving low frequency stimulation constituted the control group. Both these studies were short-term, each lasting 3 months. Respectively, 114 and 199 patients were randomized and implanted. In both studies, mean seizure reduction was significantly higher in the high frequency stimulation group than in the low frequency stimulation group (24.5% and 6.1% in E03 and 28% and 15% in E05). Similarly, the number of responders (patients with 50% seizure reduction) was significantly higher in the high stimulation group in both studies.2,4 Although these types of studies are fundamentally necessary for the establishment of indication of the treatment, they have numerous limitations. The effect of VNS as a long-term treatment of epilepsy was definitively demonstrated by evaluating the results of all patients from 5 open prospective long-term clinical trials. The aggregate responder rate of these studies (n = 440) was 43% at 3 years.5 In addition to its demonstrated efficacy in focal epilepsies, other studies have shown that VNS has positive effects on various types of generalized seizures and epilepsies, including idiopathic generalized epilepsy and Lennox–Gastaut syndrome.6–9 Among
1059-1311/$ – see front matter ß 2008 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2008.10.012
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others, Murphy has published a study confirming the effect of VNS in the long-term treatment of children with refractory focal and generalized seizures.10 From the practical point of view, we need data from open-label studies performed under natural clinical conditions. Several multicenter and open-label studies have already been published. All of them demonstrated positive long-term effects of VNS in patients with various types of epilepsy. Some of these studies included patients pooled from centers in different countries.11–13 In this study, we pooled the retrospective data for all patients implanted with VNS in the Czech Republic with a follow-up of 5 years. 2. Methods
patients’ seizure diaries at the preoperative visit; follow-up visits 1, 2, and 5 years after the onset of stimulation. The mean monthly seizure frequency at baseline and each follow-up visit was the mean seizure frequency of the previous 3 months. We recorded the seizure reduction at each follow-up visit for all patients and the responder rate for each follow-up visit. According to the effect of VNS, patients were assigned to one of four outcome groups: Seizure-free, 90% seizure reduction, 50% seizure reduction, Seizure reduction <50%, no change, or worsening of the seizure frequency.
This study was retrospective, multicenter, and open-label. It was designed as a retrospective audit of efficacy and tolerability of VNS during long-term stimulation. The data were collected from the documentation of physicians in Czech epilepsy centers. We obtained data, which reflect common clinical practice in managing VNS treatment in epilepy patients. All patients were implanted between August 1997 and April 2002. The data were collected in May and June 2007.
The patients in groups 1, 2 and 3 were considered responders, and the patients in group 4 were considered to be nonresponders. Secondary outcomes of this study were the following parameters: effect of magnetic stimulation administered by the patient or caregiver in aborting seizures and complications and clinically significant adverse effects.
2.1. Patient population
We performed a statistical analysis of the change in seizure frequency at predefined visits. Wilcoxon signed ranks test was performed to evaluate the differences between individual visits. SPSS 13.0 was used to perform the statistical analysis. P < 0.01 was considered to be statistically significant.
The following epilepsy centers participated in this study: Epilepsy Center Brno; Epilepsy Center Na Homolce HospitalPrague; Neurology, Epileptology and Neuropsychiatry Department, Na Frantisˇku Hospital, Prague; Centre for epileptology and epileptosurgery, Thomayer’s Teaching Hospital, Prague; Neurology Department, Charles University, Second Faculty of Medicine, Motol Hospital Department of Pediatric Neurology, Charles University, Second Faculty of Medicine, Motol Hospital. All patients suffered from refractory epilepsy and all were not candidates for resection surgery at the time of implantation of VNS. We performed an efficacy analysis of the whole cohort and a subanalysis of patients younger than 16 years. The data collected for this study were based on seizure diaries and patient’s files collected in each individual department. These data included basal demographic data, type of epilepsy, type of seizure, seizure frequency, change of AED treatment in the time of stimulation, stimulation parameters and adverse events. We did not established any specific inclusion criteria. All patients implanted between August 1997 and April 2002 were included. 2.2. Vagus nerve stimulation The implantation procedure was performed in all centers in the standardized manner and under general anesthesia (two incisions procedure). VNS Therapy Systems 100 and 101 were used in all patients. During all implantation procedures, the impedance was tested by the use of a standardized lead test of the VNS pulse stimulator. Reimplantation of the pulse generator was performed under the local anesthesia. VNS Therapy System 102R was used in all ‘‘reimplanted’’ patients. 2.3. Outcome evaluation The primary objective of this retrospective study was to evaluate the efficacy of VNS in reducing various types of epileptic seizures after 1, 2 and 5 years of stimulation. Only patients who received stimulation for 5 years and longer were included in the analysis. The monthly seizure frequency was counted from
2.4. Statistics
3. Results 3.1. Patient population Ninety patients (50 men, 40 women) were included in the study with a mean follow up of 6.6 1.1 years. At the time of initial evaluation, the age ranged from 13 to 64 years with a mean of 36.3 years. Epilepsy surgery had been attempted with unsatisfactory results in 23 patients. The age of the onset of epilepsy ranged from 1 month to 45 years with a mean 10.2 years, and the duration of epilepsy at the time of evaluation ranged from 11 to 56 years with a mean of 26.3 years. Fifteen patients were younger than 16 years at the time of VNS implantation. This subgroup of 15 children consisted of 9 males and 6 females, aged from 7 to 16 years with a mean of 11.7 years in the time of implantation. Three of the children had received a diagnosis of Lennox–Gastaut syndrome. The preoperative investigation identified the symptomatic etiology in 54 patients, but the etiology was cryptogenic in the remaining 36 patients. None of the patients had idiopathic focal or generalized epilepsy. We were also able to determine the probable localization of the seizure onset zone during the preoperative investigation (via magnetic resonance imaging [MRI] and videoelectroencephalogram [EEG] monitoring). Thirty patients had temporal lobe epilepsy, 26 patients (28.9%) had frontal lobe epilepsy, 26 patients (28.9%) had multifocal seizure onset, and 6 patients (6.7%) had another localization of seizure onset (4 patients had generalized epilepsy, 1 patient had parietal lobe epilepsy, 1 patient had operculo-insular epilepsy). We were not able to identify the precise localization of seizure onset in two patients (2.2%). Forty-three patients (47.8%) experienced both partial seizures and generalized tonic–clonic seizures. In 20 patients (22.2%), we analyzed the effect of VNS on partial seizures only. Four patients (4.4%) experienced generalized tonic–clonic seizures only, 5
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patients (5.5%) experienced other types of generalized seizures, 6 patients (6.6%) experienced both generalized tonic–clonic and other types of generalized seizures. The remaining three patients (3.3%) experienced partial, generalized tonic–clonic, and other types of generalized seizures. In the group with other types of generalized seizures, one patient experienced absence seizures, one patient experienced tonic seizures, one patient experienced myoclonic seizures, and one patient experienced atonic seizures. In addition, six patients experienced a combination of more than one of these seizure types, and four patients experienced seizures that were unclassified. In 6 out of 90 patients, the seizures occurred in clusters and could not be counted. These patients were included only in the analysis of responders and nonresponders. 3.2. Percentage seizure reduction All 90 patients were evaluated at the preoperative visit. We evaluated 88 patients after 1 year of VNS treatment, 87 patients at 2 years and 85 patients at 5 years follow-up visit. A total of five patients discontinued VNS treatment before 5 years follow-up visit. The individual reasons for discontinuation were: death after complicated status epilepticus, explantation of VNS device because of lack of efficacy at pulse generator end of service, early explantation because of local inflammatory complication, resective reoperation, and switching off the VNS pulse generator because of worsening seizures. The seizure reductions between the preoperative visit and all follow-up visits were statistically significant for patients in all seizure type groups. The seizure frequency ranges and means for all seizure types and seizure type groups separately and the results of statistical analyses are displayed in Table 1. Fig. 1 shows the longitudinal decline compared to baseline (i.e., at the preoperative visit) of seizure frequency in all seizure types. 3.3. Responder rates After 1 year of VNS treatment, none of the patients were seizure-free, 3 patients (3.3%) experienced 90% seizure reduction, and 37 patients (41.1%) experienced 50% seizure reduction. In
Fig. 1. Longitudinal decline in seizure reduction in all seizure types together and individual seizure types in comparison to the baseline (i.e., the seizure frequency at preoperative visit).
total, 40 patients (44.4%) were responders, 48 patients (53.3%) were nonresponders and 2 patients (2.3%) discontinued VNS. The follow-up visit after 2 years was characterized by an increase in responders to VNS. Three patients (3.3%) were seizurefree, 2 patients (2.2%) experienced 90% seizure reduction, and 48 patients (53.2%) experienced 50% seizure reduction. In total, 53 patients (58.9%) were responders, 34 patients (37.8%) were nonresponders, and 3 patients (3.3%) discontinued VNS. A further increase in responders to VNS occurred after 5 years. Five patients (5.5%) were seizure-free, 9 patients (10%) experienced 90% seizure reduction, and 44 patients (48.9%) experienced 50% seizure reduction. In total, 58 (64.4%) patients were responders, 27 patients (30.1%) were nonresponders, and 5 patients (5.5%) discontinued VNS. A summary of responder rates to VNS at predefined follow-up visits is displayed in Fig. 2.
Table 1 Range and average seizure frequency of all seizures and individual seizure types at preoperative and all follow-up visits. The statistical analysis used Wilcoxon signed ranks test. Preoperative
1 year
2 years
5 years
All seizure types together Range Mean comparison to preoperative Z P
4–210 41.2 47.4 – –
1–176 20.7 26.4 7.102 <0.001
0–300 19.5 36.7 6.685 <0.001
0–138 14.9 25.2 6.989 <0.001
Partial seizures Range Mean comparison to preoperative Z P
3–210 34.2 37.8 – –
0–150 18.1 23.9 7.534 <0.001
0–300 18.3 38.1 7.384 <0.001
0–120 14.3 24.9 7.549 <0.001
Generalized tonic–clonic seizures Range Mean comparison to preoperative Z P
1–30 6.5 7.0 – –
0–20 3.5 4.2 5.104 <0.001
0–75 3.7 10.1 5.514 <0.001
0–17 1.9 3.3 5.857 <0.001
Other types of generalized seizures Range Mean comparison to preoperative Z P
3–200 52.1 63.4 – –
3–100 22.2 28.4 6.978 <0.001
3–60 18.2 16.8 7.231 <0.001
3–30 11.1 8.7 7.487 <0.001
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classified as responders, 10 patients as nonresponders, and 1 patient left the study. After 5 years of VNS, the number of responders increased to seven patients, the number of nonresponders decreased to seven patients, and one patient left the study. None of these experienced seizure freedom or 90% seizure reduction after 1, 2, or 5 years of VNS. A summary of responder rates to VNS at predefined follow-up visits in children is displayed in Fig. 3. 3.5. Adverse effects Adverse effects were evaluated in all 90 patients (Table 2). Intermittent hoarseness during active stimulation was not considered to be an adverse effect. Adverse effects were present in 12 patients (13.3%). 3.6. VNS and stimulation parameters
Fig. 2. Response rate to VNS, whole group (n = 90).
3.4. Group of children Fifteen patients, in this population were 16 years of age or younger at VNS implantation. In 6 out of 16 children the seizures occurred in clusters and could not be counted therefore we only analyzed the response rate in this group (Fig. 3). After 1 year of VNS, seven patients were classified as responders, seven patients were classified as nonresponders, and one patient left the study. The number of these patients who responded to VNS dropped after 2 years of stimulation. At this follow-up visit, 4 patients were
Chronic stimulation began within 4 weeks of surgery. In all patients, the baseline output current was 0.25 mA. The output current was increased for each patient according to clinical status and adverse events. The follow-up visits were conducted individually. Other parameters were set based on the standardized recommendation: frequency of 20 or 30 Hz, pulse width of 250 or 500 ms, and an on/off cycle of 30 s ON and 3 or 5 min OFF. The on/ off cycle was also changed based on the clinical condition in each patient. Reimplantation of the pulse generator had been performed in 44 out of 90 patients. The reason of reimplantation in all of these patients was the end of service of the VNS pulse generator. Explantation of the VNS system was performed in three patients because of lack of efficacy at the pulse generator’s end of service. Also, the explantation of one patient’s pulse generator was followed by delayed reimplantation because of a local inflammatory complication. Stimulation parameters were analyzed at the latest follow-up visit in 87 patients. The range of the output current was between 0.5 and 2.25 mA with a mean of 1.43 0.41 mA. The range of the duty cycle was from 10% to 35% (from 30 s ON/5 min OFF to 30 s ON/ 1.1 min OFF). The most frequent duty setting (n = 20) was 30 s ON/ 3 min OFF (duty cycle 16%). 3.7. Magnet stimulation During the interview at the last follow-up visit, 35 patients (38.9%) reported that self-managed activation of the generator with the VNS magnet at the time of seizure onset led to suppression or shortening of the seizure. 3.8. Changes in antiepileptic drug (AED) treatment Changes in AED treatment during long-term VNS stimulation were analyzed retrospectively at the last follow-up visit. Only two patients (2.2%) were not evaluated. No patient was completely
Table 2 Adverse effects of VNS in 12 patients.
Fig. 3. Response rate to VNS, patients 16 years of age and younger at time of implantation (n = 16).
Type of adverse effect
Number of patients
Local inflammation Interruption of the electrode due to the trauma Untolerated chronic hoarseness and/or cough Technical malfunction of the generator Nausea, cough, and chronic aches in the neck region Chronic vocal cord palsy
3 3 3 1 1 1
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withdrawn from AED treatment. In 9 patients (10%), at least 1 AED was withdrawn, and in 10 patients (11.1%) no change of AED treatment occurred. In 69 patients (76.7%), an increase of the current treatment or add-on therapy to the next AED occurred. 4. Discussion Several studies have analyzed the long-term efficacy of VNS. The range of mean follow-up was from 20 months to 7 years and the range of included patients from 20 to 138 patients.11,12,14–17 From this point of view, our study is one of the longest and most extensive open-label studies which have been published. Only Spanaki et al.16 has also restricted its patient population to those with follow-up of longer than 5 years. The primary outcome of this study was the efficacy of VNS. The median number of seizures in the whole group gradually decreased from 41.2 seizures/month in the prestimulation period to 14.9 seizures/month at the 5 years follow-up visit. Therefore, the mean seizure reduction at the 5 years follow-up visit was 55,9%. Other long-term open label studies provide similar response results. Morris and Mueller, who analyzed all patients enrolled in the VNS pivotal studies E01-E05, reported a mean seizure reduction of 43% after 3 years.5 Similar results were reported by other authors.15,17 Our study is comparable to a recent Belgian study, which reported a reduction of overall monthly seizure frequency of 51% at a mean follow-up of 44 months. The mean number of seizures in this study was reduced from 41 seizures/ month at preimplantation to 7 seizures/month at last follow-up.11 Probably the highest reduction in seizure count was reported by Spanaki et al.16 This study also included only patients with followup longer than 5 years. They reported an overall seizure reduction of 72% (n = 28).16 The overall seizure reduction reported in our study is consistent with previously published studies. The responder rate in our study is consistent with the decrease of overall seizure frequency. The response rate increased from 44.4% after 1 year of VNS to 64.4% after 5 years of stimulation. The range of responder rates at the last follow up visit in previously published open label studies varied from 44% to 59%.11,12,14–17 The percentage of patients experiencing 90% seizure reduction ranged from 3.3% after 1 year of VNS to 15.5% at the 5 years follow-up visit. Similarly, the number of patients who experienced seizure freedom ranged from 0% after 1 year of VNS to 5.5% at the 5 years follow-up. Seizure-free rates in other studies varied from 2% to 9%.11,12,14,15 Our study also included an analysis of the effectiveness of VNS to particular seizure types. Fig. 1 shows the gradual decrease of seizure frequency of all evaluated seizure types. We report decreases in the mean number of partial seizures from 34.2 to 14.3 seizures/month, generalized tonic–clonic seizures from 6.5 to 1.9 seizures/month, and other types of generalized seizures from 52.1 to 11.1 seizures. This consistent reduction of individual seizure types was parallel with the decrease in all seizures. In agreement with our study, almost all published data analyzing the long-tem outcome of VNS report improved outcomes over long periods of time.5,11,12,14,16 The analysis of patients younger than 16 years of age at VNS implantation demonstrated lower response rates in comparison to the whole group. Data about the efficacy of VNS in children are less extensive than in adults. Morris and Mueller published one of the largest studies on a preadolescent epileptic population suffering from partial and generalized tonic–clonic seizures. They reported an overall seizure reduction to 42% at the last follow-up in 46 patients.5 Similar data were published by Rychlicki et al. and by Alexopoulos et al.18,19 Blount et al. described the efficacy of VNS in children less than 5 years old.20 Several studies reported the
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efficacy of VNS in Lennox–Gastaut syndrome.8,9,21 De Herdt et al., similar to our study, analyzed a large patient population that included a small number of patients younger than 16 years of age. Our study included 15 of these patients (16.7%), and De Herdt’s study included 21 of these patients (15.3%). Like De Herdt et al., we found lower response rates in the pediatric population when compared to the whole group.11 One explanation may be that the pediatric population in our study had more severe epilepsy. Three of these patients had Lennox–Gastaut syndrome, and in six patients the seizures could not be expressed numerically because they experienced series and clusters of seizures. Similar conclusions were reached by De Herdt et al.11 Adverse effects occurred in 13.3% of patients in our study, including three patients in whom the stimulating electrode was interrupted due to a mechanical injury. Local complication occurred in three patients and was the reason for explantation in one patient. Intolerable hoarseness or cough were present only in three patients. This numbers confirm that VNS is a relatively safe procedure. Other studies provide similar rates.14,23 On-demand activation of the generator via a magnet may improve quality of life in some patients. It is difficult to measure the efficacy of such stimulation. Our interviews found that 38.9% patients reported that manual activation of VNS usually led to shortening or aborting seizures. Murphy et al. found that about 50% of their pediatric patients benefitted from on-demand activation of the generator.21 No patient was completely withdrawn from AED treatment and in most of the patients an increase of the current treatment or addon therapy to the next AED occurred. De Herdt et. al demonstrated that the mean number of AEDs remained unchanged after several years of stimulation.11 This data demonstrate that VNS should be considered as a palliative surgical procedure. Implantation and the onset of chronic stimulation do not replace AEDs. Other add-on therapies are needed in most patients. The stimulation parameters of our study paralleled those of controlled studies.2–4 We did not analyze the efficacy of rapid cycling. In general, rapid cycling has been studied in patients who have not responded to VNS, and in almost all cases rapid cycling did not lead to long-term efficacy.11,15,24 The mean output current in our cohort was 1.43 at the last follow-up visit. The value of this output current is lower than in some other studies, although the results are similar.11,14,22 The recent study by Bunch et al. concluded that output current is not the major determinant of acute response to VNS.25 Rigorous data showing the relationship between chronic response to and stimulation parameters of VNS are still missing. In summary, our study shows that VNS is an effective and safe method to refractory epilepsy in common clinical practice. Our multicenter, open-label study examines the practical, long-term management of VNS. Acknowledgments Tim Peoples, a medical writing consultant to Cyberonics, Inc, edited this manuscript before submission. References 1. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent stimulation in humans. Epilepsia 1990;31(Suppl. 2):S40–3. ˜ on-Espaillat R, Ristanovic R, Wilder BJ, Stefan H, et al. 2. Ben-Menachem E, Man Vagus nerve stimulation for treatment of partial seizures. 1. A controlled study of effect on seizures. Epilepsia 1994;35:616–26. 3. Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 1998;51:48–55.
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4. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. The Vagus Nerve Stimulation Study Group. Neurology 1995;45:224–30. 5. Morris GL, Mueller VM, the Vagus Nerve Stimulation Group E01–E05. Long– term treatment with vagus nerve stimulation in patients with refractory epilepsy. Neurology 1999;53:1731–5. 6. Holmes MD, Silbergeld DL, Drouhard D, Wilensky AJ, Ojemann LM. Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy. Seizure 2004;13:340–5. 7. Ng M, Devinsky O. Vagus nerve stimulation for refractory idiopathic generalised epilepsy. Seizure 2004;3:176–8. 8. Hosain S, Nikalov B, Harden C, Li M, Fraser R, Labar D. Vagus nerve stimulation treatment for Lennox–Gastaut syndrome. J Child Neurol 2000;15:509–12. 9. Karceski S. Vagus nerve stimulation and Lennox–Gastaut syndrome. A review of the literature and data from the VNS Patient Registry. CNS Spectr 2001;6:766– 70. 10. Murphy JV, the Pediatric VNS Study Group. Left vagal nerve stimulation in children with medically refractory epilepsy. J Pediatr 1999;134:563–6. 11. De Herdt V, Boon R, Ceulemans B, Hauman H, Lagae L, Legros B, et al. Vagus nerve stimulation for refractory epilepsy: a Belgian multicenter study. Eur J Paediatr Neurol 2007;11:261–9. 12. Vonck K, Thadani V, Gilbert K, Dedeurwerdere S, De Groote L, De Herdt V, et al. Vagus nerve stimulation for refractory epilepsy: a transatlantic experience. J Clin Neurophysiol 2004;21:283–9. 13. Sakas DE, Korfias S, Nicholson CL, Panourias IG, Georgakoulias N, Gatzonis S, et al. Vagus nerve stimulation for incractable epilepsy: outcome in two series combining 90 patients. Acta Neurochir Suppl 2007;97:287–91. 14. Ben-Menachem E, Hellstro¨m K, Waldton C, Augustinsson LE. Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years. Neurology 1999;52:1265–7.
15. Scherrmann J, Hoppe C, Kral T, Schramm J, Elger CE. Vagus nerve stimulation. Clinical experience in a large patient series. J Clin Neurophysiol 2001;18:408–14. 16. Spanaki MV, Allen LS, Mueller WM, Morris GL. Vagus nerve stimulation therapy: 5-year or greater outcome at a university-based epilepsy center. Seizure 2004;13:587–90. 17. Uthman BM, Reichl AM, Dean JC, Eisenschenk S, Gilmore R, Reid S, et al. Effectiveness of vagus verve stimulation in epilepsy patients. A 12-year observation. Neurology 2004;63:1124–6. 18. Alexopoulos AV, Kotagal P, Loddenkemper T, Hammel J, Bingaman WE. Longterm results with vagus nerve stimulation in children with pharmacoresistant epilepsy. Seizure 2006;15:491–503. 19. Rychlicki F, Zamponi N, Trignani R, Ricciuti RA, Iacoangeli M, Scerrati M. Vagus nerve stimulation: clinical experience in drug-resistant pediatric epileptic patients. Seizure 2006;15:483–90. 20. Blount JP, Tubbs RS, Kankirawatana P, Kiel S, Knowlton R, Grabb PA, et al. Vagus nerve stimulation in children less than 5 years old. Childs Nerv Syst 2006;22:1167–9. 21. Murphy JV, Torkelson R, Dowler I, Simon S, Hudson S. Vagal nerve stimulation in refractory epilepsy. Arch Pediatr Adolesc Med 2003;157:560–4. 22. Labar D. Vagus nerve stimulation for 1 year in 269 patients on unchanged antiepileptic drugs. Seizure 2004;13:392–8. 23. Landy HJ, Ramsay ER, Slater J, Casiano RR, Morgan R. Vagus nerve stimulation for complex partial seizures: surgical technique, safety, and efficacy. Neurosurgery 1993;78:26–31. 24. DeGiorgio CM, Schachter SC, Handforth A, Salinsky M, Thompson J, Uthman B, et al. Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures. Epilepsia 2000;41:1195–200. 25. Bunch S, DeGiorgio CM, Krahl S, Britton J, Green P, Lancman M, et al. Vagus nerve stimulation for epilepsy: is output current correlated with acute response? Acta Neurol Scand 2007;116:217–20.