Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response

A review

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Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3–12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80–1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.

Abbreviations used in this paper: HSD = honestly significant difference; LSD = least significant difference; VNS = vagus nerve stimulation.

Abstract

Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3–12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80–1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.

Approximately 30% of patients with epilepsy continue to seize despite tailored medical therapy.61 While resection of an epileptic focus can be curative in the carefully chosen patient, many individuals are poor surgical candidates because of multifocal seizure origin or eloquent cortex near epileptic foci.44 Moreover, resection has failed in some patients, and they continue to have seizures postoperatively.29,71 Left-sided VNS was approved by the US FDA in 1997 as an adjunctive treatment for epilepsy, and stimulators have now been implanted in more than 60,000 patients with pharmacologically resistant epilepsy.8,17,76 The neurobiological mechanisms of VNS in epilepsy remain poorly understood, although animal and human studies have suggested that VNS may desynchronize activity and decrease abnormal spiking patterns on electroencephalography.18,38,48 Early clinical trials suggested modest clinical benefit, showing that VNS decreased the frequency of recurrent partial seizures in adults.70,83,84 Subsequently, a small number of blinded, randomized controlled trials and a larger series of prospective and retrospective studies have evaluated the efficacy of VNS in epilepsy. However, confusion over the utility of VNS in epilepsy continues among practitioners because of the variability in benefit reported across clinical studies, and many questions remain. Importantly, although VNS was only approved in the US for patients 12 years and older with partial epilepsy, its benefit in children and in patients with generalized epilepsy syndromes remains unclear. Furthermore, it is not known whether specific etiologies of epilepsy can predict a better or worse outcome.

Here, we provide a meta-analysis of clinical studies examining the efficacy of VNS in reducing seizure frequency in epilepsy. Class I, II, and III evidence is identified, and overall outcomes reported across prospective and retrospective studies in the literature are measured. Seizure type and epilepsy etiology are also analyzed as possible predictors of postoperative outcome.

Methods

Article Selection and Data Extraction

A PubMed query was performed for all articles in the English literature published up to November 2010 using the following search terms alone and in combination: “seizure,” “epilepsy,” “vagus,” “vagal,” “nerve,” “stimulation,” “stimulator,” and “surgery.” Initially, 892 papers were returned. Prospective or retrospective clinical studies were identified in which seizure frequency after VNS surgery was compared with preoperative seizure frequency as a primary outcome. Articles either specified a precise change in seizure frequency after surgery or used the Engel28 or comparable classification scheme to stratify outcomes. A minimum of 3 months postoperative follow-up was required for inclusion. References from all selected papers were further examined for additional suitable studies and to identify possible patient duplication. Overall, 111 studies met our initial inclusion criteria before we applied the following exclusion criteria: 1) review only or registry survey (17 papers excluded to avoid duplication), 2) sample size < 5 patients (6 papers excluded), and 3) data fully redundant with those in another report (11 papers excluded). In total, 77 articles remained after applying all exclusion criteria, including 6 papers from 3 author groups with some data redundancy, which were collapsed into 3 studies (74 total studies). When possible, data were disaggregated according to the predominant seizure type (partial/focal, generalized, or mixed/other), patient age (< 18 or ≥ 18 years), and epilepsy etiology. Epilepsy etiologies included Lennox-Gastaut syndrome or other epileptic encephalopathies, tuberous sclerosis, tumor, posttrauma, postinfection, postischemia, or unknown/idiopathic. Genetic disorders, disorders of neuronal migration, and disorders of metabolism were combined into one category given the variability in reporting; for example, some studies classified disorders of neuronal migration or metabolism as simply “genetic.” Studies providing Class I (blinded, randomized controlled trials), Class II (nonblinded, randomized controlled trials), and Class III evidence (prospective observational studies) were noted.

Statistical Analysis

The overall change in seizure frequency from before VNS to the last follow-up was measured across all studies reporting this difference. Overall rates of Engel seizure outcome were calculated when possible. To evaluate the likelihood that VNS would produce a ≥ 50% decrease in seizure frequency as compared with baseline (our main dependent variable of interest), heterogeneity across the studies was evaluated using the Cochran Q statistic, and random-effects models were used to incorporate any heterogeneity present to generate a pooled proportion. Individual studies were weighted using the inverse variance method, and between-group hypothesis testing was performed on the calculated odds ratio of the pooled proportions. Forest plots were generated to express effect size across all studies, comparing the likelihood of a patient experiencing a ≥ 50% decrease in seizures versus a < 50% decrease in seizures. Separate analyses of change in seizure frequency were also performed for patients 1) with < 1 versus ≥ 1 year of follow-up, 2) < 18 versus ≥ 18 years of age at the time of surgery, 3) with partial/focal versus generalized versus mixed/other seizure type, and 4) across various epilepsy etiologies. Rates of decreased seizure frequency were compared using 1-way ANOVA followed by the Tukey HSD and Fisher LSD post hoc tests for analyses with > 2 groups or by using unpaired 2-tailed Student t-tests for analyses with 2 groups. Normality of data distributions were verified before applying parametric tests. The Friedman and Kendall W tests were used to test data heterogeneity between studies to ensure that a fixed-effects model was appropriate. The possible effect of publication bias was assessed using funnel plots, which did not demonstrate significant asymmetry (data not shown). Given the number of comparisons being made, the level of significance was set at 0.02 for all analyses. Statistical analysis was performed using SPSS version 17 (SPSS, Inc.).

Results

Our literature analysis revealed 74 clinical studies including outcome data from 3321 distinct patients who underwent VNS surgery for medically refractory epilepsy.1–7,9–14,16,19–27,31–37,39–43,45–47,49–54,56–60,62–69,72–75,77–82,84–93 Among these were 15 articles producing Class I, II, or III clinical evidence, whereas the remainder were retrospective studies.

Class I, II, and III Evidence of VNS Efficacy

All identified studies reporting Class I, II, and III evidence of VNS efficacy in medically refractory epilepsy are summarized in Table 1. Three blinded, randomized controlled trials (Class I) have been published. In the first trial, Ben-Menachem and colleagues10 randomized 114 patients with partial epilepsy at multiple centers to undergo either a high-frequency (presumed therapeutic) or a low-frequency (presumed sham) stimulation paradigm. The authors reported that 3 months after surgery, high stimulation reduced seizure frequency by 25% as compared with 6% in the sham group. Moreover, 31% of patients receiving high stimulation had ≥ 50% reduction in seizures. Handforth et al.36 performed a similar multicenter trial involving 196 patients with partial epilepsy and documented a 28% reduction in seizures with high stimulation versus a 15% reduction with sham stimulation, with 23% of individuals in the therapeutic group attaining ≥ 50% reduction in seizures at 3 months after surgery. Finally, Amar and colleagues5 reported more dramatic results in a smaller VNS trial of 17 individuals, with 57% of treated patients attaining ≥ 50% decrease in seizures.

TABLE 1:

Summary of Class I, II, and III evidence of VNS efficacy in treating epilepsy*

StudyNo. of CasesSeizure TypeNotesFollow-UpNo. of CentersMedian or Mean % Seizure Reduction% Patients w/ >50% Reduction
Class I evidence
 Ben-Menachem et al., 1994114partialhigh vs low stim comparison3 mosmulti25 vs 631
 Handforth et al., 1998196partialhigh vs low stim comparison3 mosmulti28 vs 1523
 Amar et al., 199817partialhigh vs low stim comparison3 mossingle71 vs 657
Class II evidence
 Scherrmann et al., 200128mixed2 stim paradigmsNRsingle30 overall45
 DeGiorgio et al., 200561partial3 stim paradigms3 mosmulti26 overall29
Class III evidence
 Ben-Manachem et al., 199964mixed3–64 mossingleNR45
 Parker et al., 199915mixedchildren w/ encephalopathy1 yrsingle1727
 Labar et al., 199924gen3 mossingle4646
 DeGiorgio et al., 2000195mixed12 mosmulti4535
 Chavel et al., 200329partial1–2 yrssingle5354
 Vonck & colleagues, 1999 & 2004118mixed>6 mosmulti5550
 Majoie & colleagues, 2001 & 200519mixedchildren w/ encephalopathy2 yrssingle20.621
 Huf et al., 200540NRadults w/ low IQ2 yrssingle2628
 Kang et al., 200616mixedchildren>1 yrmulti5050
 Ardesch et al., 200719partial>2 yrssingle25§33§

* gen = generalized; multi = multiple; NR = not reported; stim = stimulation.

† Refers to “high” stimulation group only.

‡ At 1 year.

§ At 2 years.

We identified 2 nonblinded, randomized controlled trials (Class II evidence) by Scherrmann et al.77 and DeGiorgio et al.,24 who studied the response of 28 and 61 patients, respectively, to various VNS stimulation paradigms. Across all paradigms, a mean seizure reduction rate between 26% and 30% was reported, with 29% to 45% of patients experiencing ≥ 50% decrease in seizures (Table 1). Finally, we identified 10 prospective observational clinical studies (Class III evidence) examining 16–195 patients each, with follow-ups ranging from 3 to 64 months. Most investigators examined patients suffering from partial or mixed seizure types, revealing seizure reduction rates of 17%–55%, with 21%–50% of patients experiencing ≥ 50% decrease in seizures. One study of 24 patients with generalized epilepsy reported a mean 46% decrease in seizure frequency.52 Thus, several high-quality studies have suggested that VNS is efficacious in reducing seizure frequency by a modest but clinically significant amount in patients with various seizure types.

Meta-Analysis of VNS Efficacy in the Published Literature

We next analyzed the effect of VNS on seizure frequency across all 3321 patients in the 74 reports.1–7,9–14,16,19–27,31–37,39–43,45–47,49–54,56–60,62–69,72–75,77–82,84–93 Weighted data included prospective data from 955 patients (Table 1) and retrospective data from 2366 patients. As a main effect, we determined whether patients did or did not attain ≥ 50% reduction in seizures at the last follow-up. Main effects for individual studies are displayed in Fig. 1. Overall, VNS did predict ≥ 50% reduction in seizure frequency with an OR of 1.83 (95% CI 1.80–1.86; p < 0.001).

Fig. 1.
Fig. 1.

Forest plots depicting effect size in each study. Effect size for each study is represented as the OR of attaining ≥ 50% reduction in seizure frequency as compared with the preoperative baseline. Error bars represent the 95% CI, while the size of each point estimates proportional study weight. Dashed lines indicate an OR = 1, and diamonds represent the mean effect size (OR 1.83, 95% CI 1.80–1.86).

While not all studies specified precise values for seizure frequency, data for 1789 patients were available to calculate the frequency after treatment as compared with the pretreatment baseline. Across these 1789 patients, seizures were reduced by 44.6% ± 0.5% (mean ± SEM) at the last follow-up, with follow-ups ranging from 3 months to 5 years (mean approximately 10 months). To determine whether treatment duration contributes to seizure reduction, we compared changes in seizure frequency in patients seen 3–12 months after surgery versus those with > 1 year of follow-up. Seizure reduction was 36.2% ± 0.5% in 1178 patients seen ≤ 1 year after surgery and 51.0% ± 0.5% for 1247 patients seen > 1 year postoperatively (patient duplication due to serial follow-up). This difference was statistically significant, suggesting a delayed benefit to sustained VNS therapy (p < 0.001, 2-tailed t-test).

While precise seizure frequency data were not reported in all studies, the Engel outcome could be determined for 2634 of 3321 patients who underwent VNS, as summarized in Table 2. Overall, 1333 patients (50.6%) attained ≥ 50% reduction in seizure frequency (Engel Class I–III) at the last follow-up, whereas 1301 (49.4%) had < 50% reduction in seizure frequency (Engel Class IV). Moreover, 321 patients (12.2%) benefited from ≥ 90% decrease (Engel Class II), with 4.6% attaining seizure freedom (Engel Class I). For 1513 patients across all studies, we determined whether there was any measurable decrease in seizure frequency post-VNS, or whether seizures remained unchanged or increased in frequency after therapy. Among these patients, decreased seizures were reported in 1128 (74.6%), whereas 385 individuals (25.4%) experienced no measurable benefit from treatment. These results suggest that approximately one-half of patients treated with VNS may receive marked benefit (≥ 50% reduction in seizure frequency), but about one-quarter of individuals experience no clinical benefit, and complete seizure freedom is very rarely (< 5%) attained.

TABLE 2:

Seizure outcomes reported by Engel class

ParameterEngel Class, % Seizure DecreaseTotal*
I, 100%II, >90%III, 50%–90%IV, <50%
no. of patients (%)121 (4.6)200 (7.6)1012 (38.4)1301 (49.4)2634

* Only individuals for whom Engel classification could be determined are tallied.

Predictors of Response to VNS Therapy

We next analyzed whether age or seizure type predicted response to VNS in epilepsy, given the device's initial approval for adults and adolescents with partial or focal epilepsy only. Of the 3321 patients, an age < 18 versus ≥ 18 years could be disaggregated in 1489 individuals. Among this subset, adults experienced 49.5% ± 4.2% fewer seizures compared with the preoperative baseline level, whereas seizures decreased by 55.3% ± 4.1% in children. This represents a small but statistically significant trend toward a greater benefit in pediatric patients (p < 0.001, 2-tailed t-test). Interestingly, children younger than 6 years old (104 patients) attained a more dramatic decrease in seizure frequency, that is, 62.0% ± 4.1% at the last follow-up, further suggesting that young patients may benefit from therapy.

Seizure type could be disaggregated as partial/focal, generalized, or mixed/other in a subset of 787 patients (Fig. 2). Interestingly, patients with generalized epilepsy experienced significantly greater benefit from VNS (57.5% ± 1.9% decrease in seizures) at the last follow-up than did those with partial seizures (42.5% ± 0.9% reduction). Individuals with mixed or other seizure types had a 53.7% ± 1.9% decrease in seizure frequency. The data suggest that patients with generalized epilepsy may receive important benefit from VNS therapy despite its initial approval for focal epilepsy only.

Fig. 2.
Fig. 2.

Bar graph depicting the decrease in seizure frequency after VNS by seizure type. The mean decrease in seizure frequency after VNS was greater in patients with generalized epilepsy than in those with partial epilepsy or other/mixed seizure types (p < 0.001, 1-way ANOVA). *p < 0.001, Tukey HSD and Fisher LSD post hoc tests, comparing patients with generalized (gen.) versus partial epilepsy. Number of patients = 507 (partial), 111 (generalized), and 169 (mixed).

Finally, we determined whether epilepsy etiology might predict the response to VNS by looking at a subset of 517 patients in which etiology could be disaggregated (Fig. 3). Compared with 141 patients with an unknown or idiopathic epilepsy etiology and whose seizures decreased by 51.1% ± 3.8% after VNS, individuals with posttraumatic epilepsy (78.6% ± 8.7% seizure reduction) or tuberous sclerosis (68.1% ± 4.6% reduction) achieved a significantly better outcome at the last follow-up. Other etiologies did not predict a significantly different response as compared with idiopathic epilepsy. Notably, a subset of 93 patients with Lennox-Gastaut syndrome or other epileptic encephalopathies had a reduction similar to that in patients with idiopathic epilepsy (47.8% ± 1.9%).

Fig. 3.
Fig. 3.

Bar graph demonstrating the decrease in seizure frequency after VNS by epilepsy etiology. The mean decrease in seizure frequency after VNS varied between 47.8% ± 1.9% and 78.6% ± 8.7%, depending on the etiology attributed to a patient's epilepsy syndrome (p < 0.001, 1-way ANOVA). *Significantly greater decrease in seizure freedom versus patients with unknown epilepsy etiology (p < 0.02, Tukey HSD and Fisher LSD post hoc tests). Number of patients = 93 (Lennox-Gastaut syndrome [LGS]), 58 (unknown/idiopathic), 27 (tuberous sclerosis [scl.]), 16 (infection), 13 (disorders of neuronal migration [migr.] or genetics [genet.] or metabolism), 11 (trauma), 5 (ischemia), and 4 (tumor).

Discussion

To our knowledge, this study represents the first meta-analysis of VNS efficacy in epilepsy. An understanding of this adjunctive surgical therapy for refractory epilepsy is important given both the significant proportion of epileptics who have exhausted medical therapy options and the devastating effects that ongoing seizures can have on quality of life.15,30,55,61 We identified 74 clinical studies of VNS in epilepsy including 3321 patients. These studies consisted of 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 studies reporting prospective data (Class III evidence); and numerous retrospective studies. Among prospective studies (Class I–III evidence), seizure reduction rates were 17%–55% after 3–64 months of VNS therapy, with 21% to 50% of patients experiencing ≥ 50% decrease in seizure frequency. Across all studies, VNS reduced seizure frequency by approximately 45%, although the rate of seizure reduction increased from 36% at the 3- to 12-month follow-up to 51% after > 1 year of therapy.

Importantly, a more modest seizure reduction was found in the initial 2 large blinded, randomized controlled trials10,36 (25%–28% seizure decrease), compared with noncontrolled observational studies (approximately 50% seizure decrease). One possible reason for this finding is that follow-up was limited to 3 months in the controlled studies, potentially leading to a failure to capture a delayed benefit from therapy. Nevertheless, the possibility of author bias in noncontrolled observational series must be considered. A randomized controlled study examining the long-term effects of VNS in epilepsy would be helpful to further clarify this issue.

In examining outcomes using the Engel classification system, we found that approximately 50% of patients did attain a clinically significant reduction in seizure frequency ≥ 50%, with about 12% experiencing ≥ 90% decrease in seizures. Overall, VNS predicted ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80–1.86). Nevertheless, it is important to recognize that not all patients with medically refractory epilepsy improve after VNS. Consider, for example, that we found that approximately one-quarter of the patients in the published literature received no measurable clinical benefit from therapy. Moreover, attaining complete seizure freedom is very rare with VNS, having been reported in < 5% of patients. Thus, the possibility that a particular individual might receive little or no benefit from VNS must be clearly stated and emphasized during treatment discussions with patients.

We also stratified outcomes by patient age and seizure type and observed interesting results. Although VNS was approved in the US in 1997 only for adults and adolescents with partial or focal epilepsy,8,17,76 we found that children experienced a slightly better outcome than adults (55% vs 50% reduction in seizures, respectively), with patients younger than 6 years old achieving a 62% decrease in seizure frequency. Furthermore, patients with generalized epilepsy received increased benefit compared with those with partial seizures (58% vs 43% reduction in seizures). Caution must be used in interpreting these results, as less than one-half of all patients from source studies could be definitively classified as adult versus pediatric and because the predominant seizure type was specified in less than one-quarter of individuals. Therefore, while the data are insufficient to determine if VNS truly conveys increased benefit in children and in patients with generalized epilepsy, available data do suggest that both of these patient groups may receive benefit from VNS therapy despite their initial exclusion during device approval.

Finally, outcomes were stratified by epilepsy etiology. The greatest benefit from VNS was seen in patients with posttraumatic epilepsy (79% reduction in seizures) and with tuberous sclerosis (68% decrease in seizures). Individuals with an unknown or idiopathic epilepsy etiology experienced 51% fewer seizures after VNS, and patients suffering from Lennox-Gastaut syndrome or other epileptic encephalopathies had a 48% decrease in seizures. This result suggests that posttraumatic epilepsy or tuberous sclerosis may predict an improved response to VNS compared with idiopathic epilepsy or epileptic encephalopathy. Nonetheless, caution should be used in interpreting these results, as only 517 of 3321 patients from the literature could be disaggregated by epilepsy etiology.

Although adverse effects related to VNS therapy were not systematically studied here, they do represent important considerations in making treatment decisions. Commonly reported adverse effects of VNS are summarized in Table 3, as reported in 3 large prospective studies. Hoarseness or a change in voice was the most common, reported by 37%–62% of patients. Cough, paresthesia, pain, dyspnea, and headache were also reported. Infection occurred in 4%–6% of implants, often necessitating device explantation.25,36 Moreover, asystole has been reported in 5 cases of VNS (< 0.1%), although it remains unclear if stimulation directly caused these serious occurrences.8

TABLE 3:

Incidence of adverse effects of VNS for epilepsy

ParameterBen-Menachem et al., 1994Handforth et al., 1998DeGiorgio et al., 2000
no. of patients114196195
follow-up (mos)3312
adverse effect (% cases)
 hoarseness376255
 cough72115
 paresthesia62515
 pain61715
 dyspnea61613
 headache22016
 infectionNR46

Conclusions

Through a meta-analysis of VNS outcomes in treating medically refractory epilepsy, we found that VNS is effective in reducing seizure frequency by ≥ 50% in approximately 50% of patients, with a delayed benefit more than 1 year after surgery. Evidence for the efficacy of VNS comes from a small number of randomized controlled trials as well as from numerous other prospective and retrospective clinical studies. Vagus nerve stimulation should be considered in patients in whom medical therapy has failed but who remain poor candidates for resection or who continue to experience seizures after resection. Despite its initial approval in the US only for adults and adolescents with partial epilepsy, children and patients with generalized epilepsy have also benefited significantly from VNS. It is important to recognize, however, that complete seizure freedom is rarely achieved with VNS and that one-quarter of patients do not receive any benefit from therapy.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: all authors. Acquisition of data: Englot. Analysis and interpretation of data: Englot. Drafting the article: Englot. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Englot. Statistical analysis: Englot. Study supervision: Auguste.

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    Hornig GWMurphy JVSchallert GTilton C: Left vagus nerve stimulation in children with refractory epilepsy: an update. South Med J 90:4844881997

  • 41

    Hosain SNikalov BHarden CLi MFraser RLabar D: Vagus nerve stimulation treatment for Lennox-Gastaut syndrome. J Child Neurol 15:5095122000

  • 42

    Hsiang JNWong LKKay RPoon WS: Vagus nerve stimulation for seizure control: local experience. J Clin Neurosci 5:2942971998

  • 43

    Huf RLMamelak AKneedy-Cayem K: Vagus nerve stimulation therapy: 2-year prospective open-label study of 40 subjects with refractory epilepsy and low IQ who are living in long-term care facilities. Epilepsy Behav 6:4174232005

  • 44

    Jehi LESilveira DCBingaman WNajm I: Temporal lobe epilepsy surgery failures: predictors of seizure recurrence, yield of reevaluation, and outcome following reoperation. Clinical article. J Neurosurg 113:118611942010

  • 45

    Kabir SMRajaraman CRittey CZaki HSKemeny AAMcMullan J: Vagus nerve stimulation in children with intractable epilepsy: indications, complications and outcome. Childs Nerv Syst 25:109711002009

  • 46

    Kang HCHwang YSKim DSKim HD: Vagus nerve stimulation in pediatric intractable epilepsy: a Korean bicentric study. Acta Neurochir Suppl 99:93962006

  • 47

    Kawai KShimizu HMaehara TMurakami H: Outcome of long-term vagus nerve stimulation for intractable epilepsy. Neurol Med Chir (Tokyo) 42:4814902002

  • 48

    Koo B: EEG changes with vagus nerve stimulation. J Clin Neurophysiol 18:4344412001

  • 49

    Kostov KKostov HTaubøll E: Long-term vagus nerve stimulation in the treatment of Lennox-Gastaut syndrome. Epilepsy Behav 16:3213242009

  • 50

    Kuba RBrázdil MKalina MProcházka THovorka JNezádal T: Vagus nerve stimulation: longitudinal follow-up of patients treated for 5 years. Seizure 18:2692742009

  • 51

    Kuba RBrázdil MNovák ZChrastina JRektor I: Effect of vagal nerve stimulation on patients with bitemporal epilepsy. Eur J Neurol 10:91942003

  • 52

    Labar DMurphy JTecoma E: Vagus nerve stimulation for medication-resistant generalized epilepsy. E04 VNS Study Group. Neurology 52:151015121999

  • 53

    Labar DNikolov BTarver BFraser R: Vagus nerve stimulation for symptomatic generalized epilepsy: a pilot study. Epilepsia 39:2012051998

  • 54

    Landy HJRamsay RESlater JCasiano RRMorgan R: Vagus nerve stimulation for complex partial seizures: surgical technique, safety, and efficacy. J Neurosurg 78:26311993

  • 55

    Leach JP: When the antiepileptic drugs are not working. Pract Neurol 9:27322009

  • 56

    Lund CKostov HBlomskjøld BNakken KO: Efficacy and tolerability of long-term treatment with vagus nerve stimulation in adolescents and adults with refractory epilepsy and learning disabilities. Seizure 20:34372011

  • 57

    Lundgren JAmark PBlennow GStrömblad LGWallstedt L: Vagus nerve stimulation in 16 children with refractory epilepsy. Epilepsia 39:8098131998

  • 58

    Majoie HJBerfelo MWAldenkamp APEvers SMKessels AGRenier WO: Vagus nerve stimulation in children with therapy-resistant epilepsy diagnosed as Lennox-Gastaut syndrome: clinical results, neuropsychological effects, and cost-effectiveness. J Clin Neurophysiol 18:4194282001

  • 59

    Majoie HJBerfelo MWAldenkamp APRenier WOKessels AG: Vagus nerve stimulation in patients with catastrophic childhood epilepsy, a 2-year follow-up study. Seizure 14:10182005

  • 60

    Major PThiele EA: Vagus nerve stimulation for intractable epilepsy in tuberous sclerosis complex. Epilepsy Behav 13:3573602008

  • 61

    Mohanraj RBrodie MJ: Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 13:2772822006

  • 62

    Morrow JIBingham ECraig JJGray WJ: Vagal nerve stimulation in patients with refractory epilepsy. Effect on seizure frequency, severity and quality of life. Seizure 9:4424452000

  • 63

    Müller KFabó DEntz LKelemen AHalász PRásonyi G: Outcome of vagus nerve stimulation for epilepsy in Budapest. Epilepsia 51:Suppl 3981012010

  • 64

    Murphy JVTorkelson RDowler ISimon SHudson S: Vagal nerve stimulation in refractory epilepsy: the first 100 patients receiving vagal nerve stimulation at a pediatric epilepsy center. Arch Pediatr Adolesc Med 157:5605642003

  • 65

    Nei MO'Connor MLiporace JSperling MR: Refractory generalized seizures: response to corpus callosotomy and vagal nerve stimulation. Epilepsia 47:1151222006

  • 66

    Ng MDevinsky O: Vagus nerve stimulation for refractory idiopathic generalised epilepsy. Seizure 13:1761782004

  • 67

    Parain DPenniello MJBerquen PDelangre TBillard CMurphy JV: Vagal nerve stimulation in tuberous sclerosis complex patients. Pediatr Neurol 25:2132162001

  • 68

    Parker APPolkey CEBinnie CDMadigan CFerrie CDRobinson RO: Vagal nerve stimulation in epileptic encephalopathies. Pediatrics 103:7787821999

  • 69

    Patwardhan RVStong BBebin EMMathisen JGrabb PA: Efficacy of vagal nerve stimulation in children with medically refractory epilepsy. Neurosurgery 47:135313582000

  • 70

    Penry JKDean JC: Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Epilepsia 31:Suppl 2S40S431990

  • 71

    Ramos EBenbadis SVale FL: Failure of temporal lobe resection for epilepsy in patients with mesial temporal sclerosis: results and treatment options. Clinical article. J Neurosurg 110:112711342009

  • 72

    Rossignol ELortie AThomas TBouthiller AScavarda DMercier C: Vagus nerve stimulation in pediatric epileptic syndromes. Seizure 18:34372009

  • 73

    Rychlicki FZamponi NTrignani RRicciuti RAIacoangeli MScerrati M: Vagus nerve stimulation: clinical experience in drug-resistant pediatric epileptic patients. Seizure 15:4834902006

  • 74

    Sakas DEKorfias SNicholson CLPanourias IGGeorgakoulias NGatzonis S: Vagus nerve stimulation for intractable epilepsy: outcome in two series combining 90 patients. Acta Neurochir Suppl 97:2872912007

  • 75

    Saneto RPSotero de Menezes MAOjemann JGBournival BDMurphy PJCook WB: Vagus nerve stimulation for intractable seizures in children. Pediatr Neurol 35:3233262006

  • 76

    Schachter SCSaper CB: Vagus nerve stimulation. Epilepsia 39:6776861998

  • 77

    Scherrmann JHoppe CKral TSchramm JElger CE: Vagus nerve stimulation: clinical experience in a large patient series. J Clin Neurophysiol 18:4084142001

  • 78

    Shahwan ABailey CMaxiner WHarvey AS: Vagus nerve stimulation for refractory epilepsy in children: more to VNS than seizure frequency reduction. Epilepsia 50:122012282009

  • 79

    Sherman EMConnolly MBSlick DJEyrl KLSteinbok PFarrell K: Quality of life and seizure outcome after vagus nerve stimulation in children with intractable epilepsy. J Child Neurol 23:9919982008

  • 80

    Siddiqui FHerial NAAli II: Cumulative effect of vagus nerve stimulators on intractable seizures observed over a period of 3 years. Epilepsy Behav 18:2993022010

  • 81

    Spanaki MVAllen LSMueller WMMorris GL III: Vagus nerve stimulation therapy: 5-year or greater outcome at a university-based epilepsy center. Seizure 13:5875902004

  • 82

    Tanganelli PFerrero SColotto PRegesta G: Vagus nerve stimulation for treatment of medically intractable seizures. Evaluation of long-term outcome. Clin Neurol Neurosurg 105:9132002

  • 83

    Uthman BMWilder BJHammond EJReid SA: Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures. Epilepsia 31:Suppl 2S44S501990

  • 84

    Uthman BMWilder BJPenry JKDean CRamsay REReid SA: Treatment of epilepsy by stimulation of the vagus nerve. Neurology 43:133813451993

  • 85

    Vonck KBoon PD'Havé MVandekerckhove TO'Connor SDe Reuck J: Long-term results of vagus nerve stimulation in refractory epilepsy. Seizure 8:3283341999

  • 86

    Vonck KThadani VGilbert KDedeurwaerdere SDe Groote LDe Herdt V: Vagus nerve stimulation for refractory epilepsy: a transatlantic experience. J Clin Neurophysiol 21:2832892004

  • 87

    Wakai SKotagal P: Vagus nerve stimulation for children and adolescents with intractable epilepsies. Pediatr Int 43:61652001

  • 88

    Wilfong AASchultz RJ: Vagus nerve stimulation for treatment of epilepsy in Rett syndrome. Dev Med Child Neurol 48:6836862006

  • 89

    You SJKang HCKim HDKo TSKim DSHwang YS: Vagus nerve stimulation in intractable childhood epilepsy: a Korean multicenter experience. J Korean Med Sci 22:4424452007

  • 90

    You SJKang HCKo TSKim HDYum MSHwang YS: Comparison of corpus callosotomy and vagus nerve stimulation in children with Lennox-Gastaut syndrome. Brain Dev 30:1951992008

  • 91

    Zamponi NPassamonti CCappanera SPetrelli C: Clinical course of young patients with Dravet syndrome after vagal nerve stimulation. Eur J Paediatr Neurol 15:8142011

  • 92

    Zamponi NPetrelli CPassamonti CMoavero RCuratolo P: Vagus nerve stimulation for refractory epilepsy in tuberous sclerosis. Pediatr Neurol 43:29342010

  • 93

    Zamponi NRychlicki FCorpaci LCesaroni ETrignani R: Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children. Neurosurg Rev 31:2912972008

Article Information

Address correspondence to: Dario J. Englot, M.D., Ph.D., Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Avenue, Box 0112, San Francisco, California 94143-0112. email: englotdj@neurosurg.ucsf.edu.

Please include this information when citing this paper: published online August 12, 2011; DOI: 10.3171/2011.7.JNS11977.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Forest plots depicting effect size in each study. Effect size for each study is represented as the OR of attaining ≥ 50% reduction in seizure frequency as compared with the preoperative baseline. Error bars represent the 95% CI, while the size of each point estimates proportional study weight. Dashed lines indicate an OR = 1, and diamonds represent the mean effect size (OR 1.83, 95% CI 1.80–1.86).

  • View in gallery

    Bar graph depicting the decrease in seizure frequency after VNS by seizure type. The mean decrease in seizure frequency after VNS was greater in patients with generalized epilepsy than in those with partial epilepsy or other/mixed seizure types (p < 0.001, 1-way ANOVA). *p < 0.001, Tukey HSD and Fisher LSD post hoc tests, comparing patients with generalized (gen.) versus partial epilepsy. Number of patients = 507 (partial), 111 (generalized), and 169 (mixed).

  • View in gallery

    Bar graph demonstrating the decrease in seizure frequency after VNS by epilepsy etiology. The mean decrease in seizure frequency after VNS varied between 47.8% ± 1.9% and 78.6% ± 8.7%, depending on the etiology attributed to a patient's epilepsy syndrome (p < 0.001, 1-way ANOVA). *Significantly greater decrease in seizure freedom versus patients with unknown epilepsy etiology (p < 0.02, Tukey HSD and Fisher LSD post hoc tests). Number of patients = 93 (Lennox-Gastaut syndrome [LGS]), 58 (unknown/idiopathic), 27 (tuberous sclerosis [scl.]), 16 (infection), 13 (disorders of neuronal migration [migr.] or genetics [genet.] or metabolism), 11 (trauma), 5 (ischemia), and 4 (tumor).

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Holmes MDSilbergeld DLDrouhard DWilensky AJOjemann LM: Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy syndromes. Seizure 13:3403452004

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Hornig GWMurphy JVSchallert GTilton C: Left vagus nerve stimulation in children with refractory epilepsy: an update. South Med J 90:4844881997

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Hosain SNikalov BHarden CLi MFraser RLabar D: Vagus nerve stimulation treatment for Lennox-Gastaut syndrome. J Child Neurol 15:5095122000

42

Hsiang JNWong LKKay RPoon WS: Vagus nerve stimulation for seizure control: local experience. J Clin Neurosci 5:2942971998

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Huf RLMamelak AKneedy-Cayem K: Vagus nerve stimulation therapy: 2-year prospective open-label study of 40 subjects with refractory epilepsy and low IQ who are living in long-term care facilities. Epilepsy Behav 6:4174232005

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Jehi LESilveira DCBingaman WNajm I: Temporal lobe epilepsy surgery failures: predictors of seizure recurrence, yield of reevaluation, and outcome following reoperation. Clinical article. J Neurosurg 113:118611942010

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Kabir SMRajaraman CRittey CZaki HSKemeny AAMcMullan J: Vagus nerve stimulation in children with intractable epilepsy: indications, complications and outcome. Childs Nerv Syst 25:109711002009

46

Kang HCHwang YSKim DSKim HD: Vagus nerve stimulation in pediatric intractable epilepsy: a Korean bicentric study. Acta Neurochir Suppl 99:93962006

47

Kawai KShimizu HMaehara TMurakami H: Outcome of long-term vagus nerve stimulation for intractable epilepsy. Neurol Med Chir (Tokyo) 42:4814902002

48

Koo B: EEG changes with vagus nerve stimulation. J Clin Neurophysiol 18:4344412001

49

Kostov KKostov HTaubøll E: Long-term vagus nerve stimulation in the treatment of Lennox-Gastaut syndrome. Epilepsy Behav 16:3213242009

50

Kuba RBrázdil MKalina MProcházka THovorka JNezádal T: Vagus nerve stimulation: longitudinal follow-up of patients treated for 5 years. Seizure 18:2692742009

51

Kuba RBrázdil MNovák ZChrastina JRektor I: Effect of vagal nerve stimulation on patients with bitemporal epilepsy. Eur J Neurol 10:91942003

52

Labar DMurphy JTecoma E: Vagus nerve stimulation for medication-resistant generalized epilepsy. E04 VNS Study Group. Neurology 52:151015121999

53

Labar DNikolov BTarver BFraser R: Vagus nerve stimulation for symptomatic generalized epilepsy: a pilot study. Epilepsia 39:2012051998

54

Landy HJRamsay RESlater JCasiano RRMorgan R: Vagus nerve stimulation for complex partial seizures: surgical technique, safety, and efficacy. J Neurosurg 78:26311993

55

Leach JP: When the antiepileptic drugs are not working. Pract Neurol 9:27322009

56

Lund CKostov HBlomskjøld BNakken KO: Efficacy and tolerability of long-term treatment with vagus nerve stimulation in adolescents and adults with refractory epilepsy and learning disabilities. Seizure 20:34372011

57

Lundgren JAmark PBlennow GStrömblad LGWallstedt L: Vagus nerve stimulation in 16 children with refractory epilepsy. Epilepsia 39:8098131998

58

Majoie HJBerfelo MWAldenkamp APEvers SMKessels AGRenier WO: Vagus nerve stimulation in children with therapy-resistant epilepsy diagnosed as Lennox-Gastaut syndrome: clinical results, neuropsychological effects, and cost-effectiveness. J Clin Neurophysiol 18:4194282001

59

Majoie HJBerfelo MWAldenkamp APRenier WOKessels AG: Vagus nerve stimulation in patients with catastrophic childhood epilepsy, a 2-year follow-up study. Seizure 14:10182005

60

Major PThiele EA: Vagus nerve stimulation for intractable epilepsy in tuberous sclerosis complex. Epilepsy Behav 13:3573602008

61

Mohanraj RBrodie MJ: Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 13:2772822006

62

Morrow JIBingham ECraig JJGray WJ: Vagal nerve stimulation in patients with refractory epilepsy. Effect on seizure frequency, severity and quality of life. Seizure 9:4424452000

63

Müller KFabó DEntz LKelemen AHalász PRásonyi G: Outcome of vagus nerve stimulation for epilepsy in Budapest. Epilepsia 51:Suppl 3981012010

64

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65

Nei MO'Connor MLiporace JSperling MR: Refractory generalized seizures: response to corpus callosotomy and vagal nerve stimulation. Epilepsia 47:1151222006

66

Ng MDevinsky O: Vagus nerve stimulation for refractory idiopathic generalised epilepsy. Seizure 13:1761782004

67

Parain DPenniello MJBerquen PDelangre TBillard CMurphy JV: Vagal nerve stimulation in tuberous sclerosis complex patients. Pediatr Neurol 25:2132162001

68

Parker APPolkey CEBinnie CDMadigan CFerrie CDRobinson RO: Vagal nerve stimulation in epileptic encephalopathies. Pediatrics 103:7787821999

69

Patwardhan RVStong BBebin EMMathisen JGrabb PA: Efficacy of vagal nerve stimulation in children with medically refractory epilepsy. Neurosurgery 47:135313582000

70

Penry JKDean JC: Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Epilepsia 31:Suppl 2S40S431990

71

Ramos EBenbadis SVale FL: Failure of temporal lobe resection for epilepsy in patients with mesial temporal sclerosis: results and treatment options. Clinical article. J Neurosurg 110:112711342009

72

Rossignol ELortie AThomas TBouthiller AScavarda DMercier C: Vagus nerve stimulation in pediatric epileptic syndromes. Seizure 18:34372009

73

Rychlicki FZamponi NTrignani RRicciuti RAIacoangeli MScerrati M: Vagus nerve stimulation: clinical experience in drug-resistant pediatric epileptic patients. Seizure 15:4834902006

74

Sakas DEKorfias SNicholson CLPanourias IGGeorgakoulias NGatzonis S: Vagus nerve stimulation for intractable epilepsy: outcome in two series combining 90 patients. Acta Neurochir Suppl 97:2872912007

75

Saneto RPSotero de Menezes MAOjemann JGBournival BDMurphy PJCook WB: Vagus nerve stimulation for intractable seizures in children. Pediatr Neurol 35:3233262006

76

Schachter SCSaper CB: Vagus nerve stimulation. Epilepsia 39:6776861998

77

Scherrmann JHoppe CKral TSchramm JElger CE: Vagus nerve stimulation: clinical experience in a large patient series. J Clin Neurophysiol 18:4084142001

78

Shahwan ABailey CMaxiner WHarvey AS: Vagus nerve stimulation for refractory epilepsy in children: more to VNS than seizure frequency reduction. Epilepsia 50:122012282009

79

Sherman EMConnolly MBSlick DJEyrl KLSteinbok PFarrell K: Quality of life and seizure outcome after vagus nerve stimulation in children with intractable epilepsy. J Child Neurol 23:9919982008

80

Siddiqui FHerial NAAli II: Cumulative effect of vagus nerve stimulators on intractable seizures observed over a period of 3 years. Epilepsy Behav 18:2993022010

81

Spanaki MVAllen LSMueller WMMorris GL III: Vagus nerve stimulation therapy: 5-year or greater outcome at a university-based epilepsy center. Seizure 13:5875902004

82

Tanganelli PFerrero SColotto PRegesta G: Vagus nerve stimulation for treatment of medically intractable seizures. Evaluation of long-term outcome. Clin Neurol Neurosurg 105:9132002

83

Uthman BMWilder BJHammond EJReid SA: Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures. Epilepsia 31:Suppl 2S44S501990

84

Uthman BMWilder BJPenry JKDean CRamsay REReid SA: Treatment of epilepsy by stimulation of the vagus nerve. Neurology 43:133813451993

85

Vonck KBoon PD'Havé MVandekerckhove TO'Connor SDe Reuck J: Long-term results of vagus nerve stimulation in refractory epilepsy. Seizure 8:3283341999

86

Vonck KThadani VGilbert KDedeurwaerdere SDe Groote LDe Herdt V: Vagus nerve stimulation for refractory epilepsy: a transatlantic experience. J Clin Neurophysiol 21:2832892004

87

Wakai SKotagal P: Vagus nerve stimulation for children and adolescents with intractable epilepsies. Pediatr Int 43:61652001

88

Wilfong AASchultz RJ: Vagus nerve stimulation for treatment of epilepsy in Rett syndrome. Dev Med Child Neurol 48:6836862006

89

You SJKang HCKim HDKo TSKim DSHwang YS: Vagus nerve stimulation in intractable childhood epilepsy: a Korean multicenter experience. J Korean Med Sci 22:4424452007

90

You SJKang HCKo TSKim HDYum MSHwang YS: Comparison of corpus callosotomy and vagus nerve stimulation in children with Lennox-Gastaut syndrome. Brain Dev 30:1951992008

91

Zamponi NPassamonti CCappanera SPetrelli C: Clinical course of young patients with Dravet syndrome after vagal nerve stimulation. Eur J Paediatr Neurol 15:8142011

92

Zamponi NPetrelli CPassamonti CMoavero RCuratolo P: Vagus nerve stimulation for refractory epilepsy in tuberous sclerosis. Pediatr Neurol 43:29342010

93

Zamponi NRychlicki FCorpaci LCesaroni ETrignani R: Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children. Neurosurg Rev 31:2912972008

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