Original Article
Predictors of Response to Vagus Nerve Stimulation in Childhood-Onset Medically Refractory Epilepsy
Journal of Child Neurology 2014, Vol. 29(12) 1652-1659 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813510970 jcn.sagepub.com
Ravindra Arya, MD, DM1, Hansel M. Greiner, MD1, Amanda Lewis, BS1, Paul S. Horn, PhD1,2, Francesco T. Mangano, DO3, Cornelia Gonsalves, RN, CNP1, and Katherine D. Holland, MD, PhD1
Abstract This study explored predictors of response to vagus nerve stimulation in childhood-onset epilepsy. This retrospective chart review included all patients with new vagus nerve stimulator insertion between January 1, 2006, and December 31, 2011. Primary outcome was change in seizure frequency classified on the International League Against Epilepsy scale. Overall, 67.4% (95% confidence limits 53.3%-81.6%) of the patients had outcome of class 4 or better, and 4 patients (9.3%, 95% confidence interval 0.5%-18.1%) achieved complete seizure freedom (mean follow-up 3.5 y). Absence of magnetic resonance imaging (MRI) lesion (odds ratio 6.068, 95% confidence interval 1.214-30.329, P ¼ .028) and duration of epilepsy before implantation (odds ratio 1.291, 95% confidence interval 1.015-1.642, P ¼ .038) were found to be statistically significant predictors of good outcome and provided a sufficient fit to the data (area under the receiver operating characteristic curve .80, Hosmer-Lemeshow goodness of fit P ¼ .92). This study provides preliminary evidence that nonlesional patients are significantly more likely to have better outcome with vagus nerve stimulation. Keywords vagus nerve stimulation, response, predictors, medically refractory epilepsy Received April 02, 2013. Received revised August 27, 2013; October 02, 2013. Accepted for publication October 09, 2013.
Vagus nerve stimulation is an approved treatment modality for selected patients above 12 years of age with medically refractory partial epilepsy.1,2 Vagus nerve stimulation also has open-label efficacy data in other patients with various epilepsy syndromes.1 However, there is paucity of literature regarding predictors of vagus nerve stimulation efficacy, particularly in children. A meta-analysis of 74 studies analyzed age, seizure type, and etiology as independent predictors of response to vagus nerve stimulation in medically refractory epilepsy.3 The mean reduction in seizure frequency was significantly better in children 4, Respectively. Variable Age (y, mean + SD) Female (n, %) Age at seizure onset (y, mean + SD) Age at VNS implantation (y, mean + SD) Duration of epilepsy before receiving VNS (y, mean + SD) Seizure frequency (per day, median, IQR) GDD/ID (n, %) Follow-up (mo, mean + SD) Lesion present (n, %)
ILAE outcome 4 (n ¼ 30)
ILAE outcome >4 (n ¼ 13)
P valuea
14.1 + 5.4 20 (46%) 3.5 + 4.3 10.9 + 5.3 6.9 + 4.9
15.33 + 5.66 13 (43.33%) 3.25 + 3.96 11.77 + 5.54 7.93 + 5.56
11.38 + 3.84 7 (53.85%) 4.05 + 4.98 8.80 + 4.14 4.74 + 2.18
t ¼ 2.29, df ¼ 41, P ¼ .0274 Fisher exact P ¼ .7402 t ¼ 0.5455, df ¼ 37, P ¼ .5887 t ¼ 1.73, df ¼ 41, P ¼ .0905 t ¼ 1.983, df ¼ 37, P ¼ .0546
3.0, 9.1 31 (74%) 32.1 + 21.2 17 (39.53%)
4, 12.75 21 (72.41%) 36.57 + 22.49 9 (30%)
1, 4.4 10 (76.92%) 21.85 + 13.41 8 (61.54%)
Wilcoxon 2-sample P ¼ .2188 Fisher exact P ¼ .9998 t ¼ 2.188, df ¼ 41, P ¼ .0344 Fisher exact P ¼ .0441
Total (n ¼ 43)
Abbreviations: GDD, global developmental delay; ID, intellectual disability; ILAE, International League Against Epilepsy; IQR, interquartile range; SD, standard deviation. a Bold values indicate significance.
Appropriate summary statistics (mean, standard deviation, median, and interquartile range) were estimated for different variables.
Statistical Analysis A multivariate logistic regression analysis was done to model the probability of good outcome. For this purpose, a good outcome was defined as an International League Against Epilepsy outcome of 4 or better. This choice was made to capture 50% responder rate, which is one of the standard outcome measures for patients with medically refractory epilepsy.3,6 The cut-off for backward elimination in the variable selection for multivariate model was P .05. Odds ratios with 95% confidence limits were calculated for statistically significant variables, and the area under the receiver operating characteristic curve was derived for the model containing these variables. The adequacy of model was tested by using the Hosmer-Lemeshow goodnessof-fit test. SAS statistical software version 9.3 (SAS Institute Inc, Cary, NC) was used for statistical analyses.
Results A total of 43 patients (23 males, 20 females) were identified who received vagus nerve stimulator during the study period, ranging in age from 5 to 31 years (mean 14.14, standard deviation 5.45) at the time of data extraction. The age at seizure onset varied from 3 days to 17 years (3.52 + 4.28), whereas the age at vagus nerve stimulator implantation ranged from 2.4 to 26 years (10.87 + 5.29). Seizure frequency, as reported by caregivers, was captured from last available chart before implantation. It varied extensively from 1 seizure/mo up to hundreds of daily seizures (median daily seizure frequency 3, interquartile range 9.1), with 16/41 patients (39%) having a history of status epilepticus. Thirtyone (73.8%) of 42 patients had global developmental delay or intellectual disability (Table 1). Preoperative electroencephalographic (EEG) data were available for all except 2 patients. Twenty-five patients (61%) showed bilateral multiple foci of interictal and ictal abnormalities with or without secondary generalization, 12 showed primary generalized pattern, and 4 patients had a single
Table 2. Lesions Found on Preoperative MRI. MRI findings
n
Congenital infection Bilateral parietal cortical dysplasia and cerebral calcification Developmental malformation Right hemimegalencephaly and left diffuse cortical dysplasia Perinatal brain injury Right hemispheric encephalomalacia and gliosis, with volume loss in left hippocampus, amygdala, and insula Microcephaly with extensive cerebral volume loss and gliosis with moderate cerebellar volume loss Bilateral asymmetric encephalomalacia Bilateral frontoparietal encephalomalacia Periventricular leukomalacia (2) Multiple bilateral areas of loss of gray–white junction, volume loss, and signal abnormality in supratentorial white matter with increased T2 signal in thalami Mesial temporal sclerosis All left sided, with one also showing right-sided volume loss Tuberous sclerosis complex Vascular Cavernous angiomas Uncharacterized Subtle signal changes in left frontal lobe suggestive of abnormal myelination or dysplasia
1 1 7
3 3 1 1
Abbreviation: MRI, magnetic resonance imaging.
consistent focus of epileptiform discharges. Preoperative MRI was done in all patients and showed a lesion in 17 (39.5%, Table 2). Etiology could be established in an additional 16 patients. This group included 9 patients with clinical and EEG features consistent with idiopathic generalized epilepsy, 4 patients with pathogenic mutations of the SCN1A gene, and 1 patient each with glucose transporter 1 deficiency, Rett syndrome, and history of herpes encephalitis in infancy. Detailed neuroimaging data including SPECT, PET, and magnetoencephalography with source localization were available for 19 patients. There was hemispheric concordance among these modalities in only 3 patients, with lobar concordance in none.
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Figure 2. Reduction in seizure frequency classified by the ILAE outcome scale. Twenty-nine (67.4%) patients had at least 50% reduction in seizure burden (ILAE class 4). The predictor variables included gender, presence of global developmental delay or intellectual disability, epilepsy type (generalized, partial, or unclear), and presence of an MRI lesion (categorical) and age of onset, duration of epilepsy prior to vagus nerve stimulator implant, and daily seizure frequency (continuous; Table 1). Overall, 67.4% (95% confidence interval 53.3%-81.6%) of the patients had an outcome of class 4 or better, and 4 patients (9.3%, 95% confidence interval 0.5%-18.1%) achieved complete seizure freedom (mean follow-up 3.5 y). In the final multivariate model, absence of an MRI lesion (odds ratio 6.068, 95% confidence interval 1.214-30.329, P ¼ .028) and duration of epilepsy before vagus nerve stimulator implant (odds ratio 1.291, 95% confidence interval 1.015-1.642, P ¼ .038) were found to be statistically significant predictors of good outcome (area under the receiver operating characteristic curve ¼ 0.80, HosmerLemeshow goodness of fit P ¼ .92). The 50% responder rate was 80.8% (95% confidence interval 65.3%-96.2%) in patients without an MRI lesion compared to 52.9% (95% confidence
interval 28.5%-77.4%) in the lesional group. Univariate comparison of lesional versus nonlesional groups is presented in Table 4. Although there was no statistically significant interaction between these 2 factors, the effect of duration of epilepsy on good outcome was further explored in the 2 lesional groups separately. For patients having an MRI lesion, preimplant duration of epilepsy 7.3 years predicted a bad outcome (sensitivity 0.875, specificity 0.75, classification accuracy 0.812, Fisher exact test P value ¼ .04), whereas for nonlesional patients, a duration 3.3 years was found to predict bad outcome but the result was not statistically significant (sensitivity 0.4, specificity 0.89, classification accuracy 0.783, Fisher exact test P value ¼ .19). The correlation between duration of epilepsy before vagus nerve stimulator implant and seizure frequency was found to be weak (Pearson correlation coefficient 0.1388). There were no short-term perioperative adverse events recorded. Seven patients (16.3%) had device-related complications. Four patients had lead fracture, 3 of which required removal of the stimulator; however, 1 patient’s device continued to be used. Two patients had very high lead impedance without obvious fracture on radiograph and required revision, whereas 1 had local infection necessitating removal.
Discussion This study found absence of an MRI lesion and longer preimplant duration of epilepsy to predict International League Against Epilepsy class 4 or better outcome with vagus nerve stimulation. The odds of having a good outcome in patients without MRI lesion are 6 times that of those with one. Overall, 21/26 (80.8%) of nonlesional patients had a good outcome, as compared to 9/17 (52.9%) of patients with an MRI lesion. This observation somewhat agrees with Elliott et al,4 who found presence of neuronal migration disorder to predict a poor outcome with vagus nerve stimulation. However, no significant difference was found between patients with a lesion (n ¼ 199, weighted mean ¼ 57.1%) versus those without (n ¼ 224, mean ¼ 57%) on reanalysis of their data.4 In contrast, Ghaemi et al4 found presence of cortical dysgenesis to predict successful response to vagus nerve stimulation (class I outcome). However, on reanalysis of data, there was no significant difference in the seizure-free proportions of nonlesional (6.8%, n ¼ 73) and lesional (7.0%, n ¼ 71) patients.5 The considerable variability in the reported proportion of patients with desired outcome in the nonlesional group is most likely due to differences in the definition of successful outcome, the time point for its assessment, and methods of data analysis. More importantly, the etiologic makeup of lesional group likely influences the distribution of outcomes across the studies. At our center, children with focal MRI lesions consistent with cortical dysplasia typically go on to have resective surgery, unless the lesion overlaps with eloquent cortex. Thus, our lesional population with vagus nerve stimulation comprised patients with multiple lesions and multifocal sites of seizure onset: 8/17 (47%) had evidence of perinatal brain injury or congenital infection with bilateral hemispheric dysfunction. It can be postulated that this group with bilateral multifocal pathology is less responsive to
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Female
Female Female
Male
31
17 14
19
18.3
12.3 10.1
25.9
Age at VNS implant (y)
5
3 5
6
AEDs failed
No
Yes Yes
Yes
Intellectual disability
2/week
20-30/d 1-2/mo
3/d
Seizure frequency
Unknown
Tuberous Sclerosis complex Unknown Perinatal injury
Etiology
Normal Bilateral frontoparietal encephalomalacia Normal
Consistent
MRI
PET: normal; SPECT: doubtful right temporal
Not done Not done
Not done
Functional imaging
15
58 35
60
Follow-up (mo)
Abbreviations: AED, antiepileptic drug; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography; VNS, vagus nerve stimulator.
16 y
8y 2 weeks
3 mo
Age at Gender seizure onset
Age (y)
Table 3. Clinical Profile of Completely Seizure Free (International League Against Epilepsy Outcome Class I) Patients.
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Table 4. Demographic and Outcome Variables Compared in Lesional and Nonlesional Groups. Variable Age (y, mean + SD) Female (n, %) Age at seizure onset (y, mean + SD) Age at VNS implantation (y, mean + SD) Duration of epilepsy before receiving VNS (y, mean + SD) Seizure frequency (per day, median, IQR) History of status epilepticus (n, %) GDD/ID (n, %) Follow-up (mo, mean + SD) ILAE outcome 4 (n, %)
Lesional (n ¼ 17)
Nonlesional (n ¼ 26)
P valuea
13.5 + 6.3 7 (41%) 2.4 + 4.0 10.4 + 6.0 7.7 + 6.8 1.0, 3.0 6 (38%) 14 (88%) 32.1 + 19.4 8 (47.1%)
14.5 + 4.9 13 (50%) 4.3 + 4.3 11.2 + 4.9 5.3 + 3.4 5.0, 22.1 10 (40%) 17 (65%) 32.2 + 22.6 21 (80.8%)
.58 .76 .16 .62 .09 .05 1.00 .16 .99 .05
Abbreviations: GDD, global developmental delay; ID, intellectual disability; ILAE, International League Against Epilepsy; IQR, interquartile range; SD, standard deviation. a P values are based on Fisher exact test for categorical variables and Student’s t test for the other variables, except for seizure frequency, where the Wilcoxon rank-sum test was used.
vagus nerve stimulation. In support of this, though Ghaemi et al5 reported 10/144 patients to be seizure-free poststimulation, no patients with a history of neuroinfection or trauma became seizure free. However, in a larger sample, >50% reduction in seizure burden has been demonstrated in multifocal symptomatic epilepsies.4 Finally, although absence of a lesion was found to predict good outcome, the converse remains to be established. That is, an abnormal MRI does not necessarily preclude good outcome with vague nerve stimulation. In our study, 2 of the 4 seizurefree patients had abnormal MRI and approximately half of the lesional patients had outcomes of International League Against Epilepsy scale score 4 (Tables 3 and 4). Another significant predictor of outcome was found to be preimplant duration of epilepsy. For every 1-year increase in this duration, the odds of good outcome were observed to increase by 29%. As an interaction effect, a duration of 7.3 years was noted to be statistically associated with poor outcome (class >4) in patients with an MRI lesion. The data from vagus nerve stimulation outcomes registry also found longer duration of epilepsy to be significantly predictive of good outcome with vagus nerve stimulation.8 However, the median duration of epilepsy in their study was 22 years versus 5.3 years in the present study. The median reduction in seizure burden at 12 months was 64% for patients having a duration of epilepsy 22 years. This study also had considerable heterogeneity in terms of patient demographics and stimulation settings.8 Two other studies focusing on duration of epilepsy contradict these observations and found epilepsy duration of 6 years to be associated with decreased chance of seizure freedom with vagus nerve stimulation.9,10 Another study by Alexopoulos et al11 divided patients according to the age at device placement into those 12 years (n ¼ 21) and those between 12 and 18 years (n ¼ 25). The median duration of epilepsy in the 2 groups was 6.04 years (+2.7) versus 11.25 years (+3.4), respectively (Wilcoxon rank-sum P ¼ .05). Seizure outcome measured by reduction in seizure frequency was more favorable in the younger age group. However, the effect of duration of epilepsy on seizure outcome was not assessed independent of the nesting within the groups formed according to age of implantation.11 The possibility that patients receiving vagus nerve stimulator earlier can
represent those with high seizure burden was investigated. However, the correlation between preimplant duration of epilepsy and seizure frequency was too weak to substantiate this hypothesis. Although this finding is difficult to explain, it can be speculated that optimal patient selection for vagus nerve stimulation will include time to establish medical refractoriness and workup to exclude the possibility of resective surgery. Regarding vagus nerve stimulation efficacy, 4 patients (9.3%) achieved complete seizure freedom (class 1 outcome, mean follow-up 3.5 years) and 67.4% had at least 50% reduction in seizure days (class 4 outcome). These observations agree with other comparable retrospective reports including both children and adults. Ghaemi et al5 reported 6.9% of their patients (n ¼ 144) to be seizure free at 2 years postimplant and 61.8% to have 50% seizure reduction. Elliot et al also found 63.8% patients to have 50% improvement (n ¼ 400, follow-up 4.94 + 3.2 y).4 However, the randomized controlled trials that led to approval of the vagus nerve stimulator generated more conservative estimates for efficacy. The E03 study, in its high stimulation group (n ¼ 31) corresponding to device settings in this study, reported 30.9% reduction in mean seizure frequency and a 50% responder rate of 39% at 14 weeks.12 The E05 trial (n ¼ 95) found a mean reduction of 28% and a 50% responder rate of only 23.4% at 3 months in the group with stimulation settings comparable to the present study.13 It is known that seizure burden progressively reduces with continued use of vagus nerve stimulator.1 Longterm open-label follow-up data from these trials also found relatively less efficacy. In the E05 study (n ¼ 195) at 12 months, 34% of patients had a reduction in seizure burden of 50%.14 In the E01-E05 cohort (n ¼ 440), 50% seizure reduction was found in 37% patients at 1 year and 43% patients at 2 years, when it plateaued.15 These trials, however, only included patients >12 years of age with refractory partial-onset seizures. The E04 study, a prospective, open safety study, included 60 children aged 3-18 years with 27% of the patients having primary generalized seizures.16 The median reduction in seizure frequency was 34% at 12 months and 42% at 18 months. The recently published guideline update by the American Academy of Neurology that included data from 470 children from 13 studies found >50% seizure reduction in
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Journal of Child Neurology 29(12)
55% (95% confidence interval 50%-59%) patients with focal and generalized epilepsy.17 The 50% responder rate was found to increase by about 7% from 1 to 5 years postimplantation.17 We believe that these figures represent the best steady-state efficacy estimates available presently for vagus nerve stimulation. In the present study, 7 patients (16.3%) had device-related complications including broken lead (n ¼ 4), high lead impedance requiring revision (n ¼ 2), and local infection needing device removal (n ¼ 1). Although adverse effects produced by stimulation are commonly reported, there is limited information about device-related complications.1 A study on surgical complications of vagus nerve stimulator found hardware failure in 9.5% (10/105) patients.18 The major technical complication was lead fracture (7.6%), with some being visible on radiograph (macro-lesion) and others detected only by increased impedance (micro-lesion). Interestingly, the hardware failure was observed only in children (mean age 13.4 y). In this study, wound infections were seen in 4 patients (3.8%) who required device revision.18 In long-term retrospective reviews, lead or cable fractures have been documented in 1.5%-4% cases, and postoperative infections in up to 3%-6% patients, though rarely requiring removal of electrodes or generator.4,13,19 This study provides preliminary evidence that nonlesional patients are likely to have a better outcome with vagus nerve stimulation. Further, increased duration of epilepsy is probably associated with better outcome, though this finding is difficult to interpret clinically. This study has some inadvertent limitations because of retrospective design. First, concomitant changes in antiseizure medications represent an important confounder. Second, survival analysis methods are better suited for such data because the efficacy of vagus nerve stimulation is apparently duration dependent. However, because of retrospective design, not all data points were available for all patients. This increased the risk for the analyses to be biased toward patients with more follow-up data points, which are likely to be those with worse seizure outcomes. Despite modest sample size and these caveats, we believe it is important to report such data, so that subsequent regression meta-analysis can generate pooled association estimates for predictor variables. Such knowledge about predictors of vagus nerve stimulation outcome is likely to help optimize patient selection. Author Contributions Study concept was provided by KDH and HMG. RA and HMG planned the study. AL, RA, and HMG collected the data. FTM did the device placements and CG was involved in follow-up evaluations. PSH and RA analyzed the data. RA wrote the first draft of manuscript, which was critically reviewed by other authors. All authors approve of the final version.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors declared receipt of the following financial support for the research, authorship, and/or publication of this article: RA receives research support (20% effort) from NIH (NINDS 2U01 NS045911)
and American Epilepsy Society and Epilepsy Foundation of America Infrastructure award (pSERG); KDH receives research support from NIH (NINDS R01 NS062756 [principal investigator]).
Ethical Approval The study was approved by institutional review board (IRB) of Cincinnati Children’s Hospital Medical Center (IRB: 2008-1006).
References 1. Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol. 2002;1:477-482. 2. Schachter SC, Boon P. Vagus nerve stimulation. In: Engel JJ, Pedley TA, eds. Epilepsy: A Comprehensive Textbook, 2nd ed., Vol II. Philadelphia, PA: Lippincott, Williams & Wilkins; 2008:1395-1400. 3. Englot DJ, Chang EF, Auguste KI. Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. J Neurosurg. 2011;115:1248-1255. 4. Elliott RE, Morsi A, Kalhorn SP, et al. Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: longterm outcomes and predictors of response. Epilepsy Behav. 2011;20:57-63. 5. Ghaemi K, Elsharkawy AE, Schulz R, et al. Vagus nerve stimulation: outcome and predictors of seizure freedom in long-term follow-up. Seizure. 2010;19:264-268. 6. Wieser HG, Blume WT, Fish D, et al. Commission on Neurosurgery of the International League Against Epilepsy. ILAE Commission Report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia. 2001;42:282-286. 7. Milby AH, Halpern CH, Baltuch GH. Vagus nerve stimulation in the treatment of refractory epilepsy. Neurotherapeutics. 2009;6:228-237. 8. Labar D. Vagus nerve stimulation for 1 year in 269 patients on unchanged antiepileptic drugs. Seizure. 2004;13:392-398. 9. Helmers SL, Griesemer DA, Dean JC, et al. Observations on the use of vagus nerve stimulation earlier in the course of pharmacoresistant epilepsy: patients with seizures for six years or less. The Neurologist. 2003;9:160-164. 10. Renfroe JB, Wheless JW. Earlier use of adjunctive vagus nerve stimulation therapy for refractory epilepsy. Neurology. 2002; 59(6 suppl 4): S26-S30. 11. Alexopoulos AV, Kotagal P, Loddenkemper T, Hammel J, Bingaman WE. Long-term results with vagus nerve stimulation in children with pharmacoresistant epilepsy. Seizure. 2006;15:491-503. 12. Ben-Menachem E, Manon-Espaillat R, Ristanovic R, et al. Vagus nerve stimulation for treatment of partial seizures, 1: A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group. Epilepsia. 1994;35:616-626. 13. Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology. 1998;51:48-55. 14. DeGiorgio CM, Schachter SC, Handforth A, et al. Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures. Epilepsia. 2000;41:1195-1200. 15. Morris GL 3 rd, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus
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Nerve Stimulation Study Group E01-E05. Neurology. 1999;53(8): 1731-1735. 16. Murphy JV. Left vagal nerve stimulation in children with medically refractory epilepsy. The Pediatric VNS Study Group. J Pediatr. 1999;134:563-566. 17. Morris GL 3 rd, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development
Subcommittee of the American Academy of Neurology. Neurology. 2013. 18. Spuck S, Tronnier V, Orosz I, et al. Operative and technical complications of vagus nerve stimulator implantation. Neurosurgery. 2010;67(2 Suppl Operative):489-494. 19. Ben-Menachem E, Hellstrom K, Waldton C, Augustinsson LE. Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years. Neurology. 1999;52:1265-1267.
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Predictors of Response to Vagus Nerve Stimulation in Childhood-Onset Medically Refractory Epilepsy
Journal of Child Neurology 2014, Vol. 29(12) 1652-1659 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813510970 jcn.sagepub.com
Ravindra Arya, MD, DM1, Hansel M. Greiner, MD1, Amanda Lewis, BS1, Paul S. Horn, PhD1,2, Francesco T. Mangano, DO3, Cornelia Gonsalves, RN, CNP1, and Katherine D. Holland, MD, PhD1
Abstract This study explored predictors of response to vagus nerve stimulation in childhood-onset epilepsy. This retrospective chart review included all patients with new vagus nerve stimulator insertion between January 1, 2006, and December 31, 2011. Primary outcome was change in seizure frequency classified on the International League Against Epilepsy scale. Overall, 67.4% (95% confidence limits 53.3%-81.6%) of the patients had outcome of class 4 or better, and 4 patients (9.3%, 95% confidence interval 0.5%-18.1%) achieved complete seizure freedom (mean follow-up 3.5 y). Absence of magnetic resonance imaging (MRI) lesion (odds ratio 6.068, 95% confidence interval 1.214-30.329, P ¼ .028) and duration of epilepsy before implantation (odds ratio 1.291, 95% confidence interval 1.015-1.642, P ¼ .038) were found to be statistically significant predictors of good outcome and provided a sufficient fit to the data (area under the receiver operating characteristic curve .80, Hosmer-Lemeshow goodness of fit P ¼ .92). This study provides preliminary evidence that nonlesional patients are significantly more likely to have better outcome with vagus nerve stimulation. Keywords vagus nerve stimulation, response, predictors, medically refractory epilepsy Received April 02, 2013. Received revised August 27, 2013; October 02, 2013. Accepted for publication October 09, 2013.
Vagus nerve stimulation is an approved treatment modality for selected patients above 12 years of age with medically refractory partial epilepsy.1,2 Vagus nerve stimulation also has open-label efficacy data in other patients with various epilepsy syndromes.1 However, there is paucity of literature regarding predictors of vagus nerve stimulation efficacy, particularly in children. A meta-analysis of 74 studies analyzed age, seizure type, and etiology as independent predictors of response to vagus nerve stimulation in medically refractory epilepsy.3 The mean reduction in seizure frequency was significantly better in children 4, Respectively. Variable Age (y, mean + SD) Female (n, %) Age at seizure onset (y, mean + SD) Age at VNS implantation (y, mean + SD) Duration of epilepsy before receiving VNS (y, mean + SD) Seizure frequency (per day, median, IQR) GDD/ID (n, %) Follow-up (mo, mean + SD) Lesion present (n, %)
ILAE outcome 4 (n ¼ 30)
ILAE outcome >4 (n ¼ 13)
P valuea
14.1 + 5.4 20 (46%) 3.5 + 4.3 10.9 + 5.3 6.9 + 4.9
15.33 + 5.66 13 (43.33%) 3.25 + 3.96 11.77 + 5.54 7.93 + 5.56
11.38 + 3.84 7 (53.85%) 4.05 + 4.98 8.80 + 4.14 4.74 + 2.18
t ¼ 2.29, df ¼ 41, P ¼ .0274 Fisher exact P ¼ .7402 t ¼ 0.5455, df ¼ 37, P ¼ .5887 t ¼ 1.73, df ¼ 41, P ¼ .0905 t ¼ 1.983, df ¼ 37, P ¼ .0546
3.0, 9.1 31 (74%) 32.1 + 21.2 17 (39.53%)
4, 12.75 21 (72.41%) 36.57 + 22.49 9 (30%)
1, 4.4 10 (76.92%) 21.85 + 13.41 8 (61.54%)
Wilcoxon 2-sample P ¼ .2188 Fisher exact P ¼ .9998 t ¼ 2.188, df ¼ 41, P ¼ .0344 Fisher exact P ¼ .0441
Total (n ¼ 43)
Abbreviations: GDD, global developmental delay; ID, intellectual disability; ILAE, International League Against Epilepsy; IQR, interquartile range; SD, standard deviation. a Bold values indicate significance.
Appropriate summary statistics (mean, standard deviation, median, and interquartile range) were estimated for different variables.
Statistical Analysis A multivariate logistic regression analysis was done to model the probability of good outcome. For this purpose, a good outcome was defined as an International League Against Epilepsy outcome of 4 or better. This choice was made to capture 50% responder rate, which is one of the standard outcome measures for patients with medically refractory epilepsy.3,6 The cut-off for backward elimination in the variable selection for multivariate model was P .05. Odds ratios with 95% confidence limits were calculated for statistically significant variables, and the area under the receiver operating characteristic curve was derived for the model containing these variables. The adequacy of model was tested by using the Hosmer-Lemeshow goodnessof-fit test. SAS statistical software version 9.3 (SAS Institute Inc, Cary, NC) was used for statistical analyses.
Results A total of 43 patients (23 males, 20 females) were identified who received vagus nerve stimulator during the study period, ranging in age from 5 to 31 years (mean 14.14, standard deviation 5.45) at the time of data extraction. The age at seizure onset varied from 3 days to 17 years (3.52 + 4.28), whereas the age at vagus nerve stimulator implantation ranged from 2.4 to 26 years (10.87 + 5.29). Seizure frequency, as reported by caregivers, was captured from last available chart before implantation. It varied extensively from 1 seizure/mo up to hundreds of daily seizures (median daily seizure frequency 3, interquartile range 9.1), with 16/41 patients (39%) having a history of status epilepticus. Thirtyone (73.8%) of 42 patients had global developmental delay or intellectual disability (Table 1). Preoperative electroencephalographic (EEG) data were available for all except 2 patients. Twenty-five patients (61%) showed bilateral multiple foci of interictal and ictal abnormalities with or without secondary generalization, 12 showed primary generalized pattern, and 4 patients had a single
Table 2. Lesions Found on Preoperative MRI. MRI findings
n
Congenital infection Bilateral parietal cortical dysplasia and cerebral calcification Developmental malformation Right hemimegalencephaly and left diffuse cortical dysplasia Perinatal brain injury Right hemispheric encephalomalacia and gliosis, with volume loss in left hippocampus, amygdala, and insula Microcephaly with extensive cerebral volume loss and gliosis with moderate cerebellar volume loss Bilateral asymmetric encephalomalacia Bilateral frontoparietal encephalomalacia Periventricular leukomalacia (2) Multiple bilateral areas of loss of gray–white junction, volume loss, and signal abnormality in supratentorial white matter with increased T2 signal in thalami Mesial temporal sclerosis All left sided, with one also showing right-sided volume loss Tuberous sclerosis complex Vascular Cavernous angiomas Uncharacterized Subtle signal changes in left frontal lobe suggestive of abnormal myelination or dysplasia
1 1 7
3 3 1 1
Abbreviation: MRI, magnetic resonance imaging.
consistent focus of epileptiform discharges. Preoperative MRI was done in all patients and showed a lesion in 17 (39.5%, Table 2). Etiology could be established in an additional 16 patients. This group included 9 patients with clinical and EEG features consistent with idiopathic generalized epilepsy, 4 patients with pathogenic mutations of the SCN1A gene, and 1 patient each with glucose transporter 1 deficiency, Rett syndrome, and history of herpes encephalitis in infancy. Detailed neuroimaging data including SPECT, PET, and magnetoencephalography with source localization were available for 19 patients. There was hemispheric concordance among these modalities in only 3 patients, with lobar concordance in none.
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Figure 2. Reduction in seizure frequency classified by the ILAE outcome scale. Twenty-nine (67.4%) patients had at least 50% reduction in seizure burden (ILAE class 4). The predictor variables included gender, presence of global developmental delay or intellectual disability, epilepsy type (generalized, partial, or unclear), and presence of an MRI lesion (categorical) and age of onset, duration of epilepsy prior to vagus nerve stimulator implant, and daily seizure frequency (continuous; Table 1). Overall, 67.4% (95% confidence interval 53.3%-81.6%) of the patients had an outcome of class 4 or better, and 4 patients (9.3%, 95% confidence interval 0.5%-18.1%) achieved complete seizure freedom (mean follow-up 3.5 y). In the final multivariate model, absence of an MRI lesion (odds ratio 6.068, 95% confidence interval 1.214-30.329, P ¼ .028) and duration of epilepsy before vagus nerve stimulator implant (odds ratio 1.291, 95% confidence interval 1.015-1.642, P ¼ .038) were found to be statistically significant predictors of good outcome (area under the receiver operating characteristic curve ¼ 0.80, HosmerLemeshow goodness of fit P ¼ .92). The 50% responder rate was 80.8% (95% confidence interval 65.3%-96.2%) in patients without an MRI lesion compared to 52.9% (95% confidence
interval 28.5%-77.4%) in the lesional group. Univariate comparison of lesional versus nonlesional groups is presented in Table 4. Although there was no statistically significant interaction between these 2 factors, the effect of duration of epilepsy on good outcome was further explored in the 2 lesional groups separately. For patients having an MRI lesion, preimplant duration of epilepsy 7.3 years predicted a bad outcome (sensitivity 0.875, specificity 0.75, classification accuracy 0.812, Fisher exact test P value ¼ .04), whereas for nonlesional patients, a duration 3.3 years was found to predict bad outcome but the result was not statistically significant (sensitivity 0.4, specificity 0.89, classification accuracy 0.783, Fisher exact test P value ¼ .19). The correlation between duration of epilepsy before vagus nerve stimulator implant and seizure frequency was found to be weak (Pearson correlation coefficient 0.1388). There were no short-term perioperative adverse events recorded. Seven patients (16.3%) had device-related complications. Four patients had lead fracture, 3 of which required removal of the stimulator; however, 1 patient’s device continued to be used. Two patients had very high lead impedance without obvious fracture on radiograph and required revision, whereas 1 had local infection necessitating removal.
Discussion This study found absence of an MRI lesion and longer preimplant duration of epilepsy to predict International League Against Epilepsy class 4 or better outcome with vagus nerve stimulation. The odds of having a good outcome in patients without MRI lesion are 6 times that of those with one. Overall, 21/26 (80.8%) of nonlesional patients had a good outcome, as compared to 9/17 (52.9%) of patients with an MRI lesion. This observation somewhat agrees with Elliott et al,4 who found presence of neuronal migration disorder to predict a poor outcome with vagus nerve stimulation. However, no significant difference was found between patients with a lesion (n ¼ 199, weighted mean ¼ 57.1%) versus those without (n ¼ 224, mean ¼ 57%) on reanalysis of their data.4 In contrast, Ghaemi et al4 found presence of cortical dysgenesis to predict successful response to vagus nerve stimulation (class I outcome). However, on reanalysis of data, there was no significant difference in the seizure-free proportions of nonlesional (6.8%, n ¼ 73) and lesional (7.0%, n ¼ 71) patients.5 The considerable variability in the reported proportion of patients with desired outcome in the nonlesional group is most likely due to differences in the definition of successful outcome, the time point for its assessment, and methods of data analysis. More importantly, the etiologic makeup of lesional group likely influences the distribution of outcomes across the studies. At our center, children with focal MRI lesions consistent with cortical dysplasia typically go on to have resective surgery, unless the lesion overlaps with eloquent cortex. Thus, our lesional population with vagus nerve stimulation comprised patients with multiple lesions and multifocal sites of seizure onset: 8/17 (47%) had evidence of perinatal brain injury or congenital infection with bilateral hemispheric dysfunction. It can be postulated that this group with bilateral multifocal pathology is less responsive to
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Female
Female Female
Male
31
17 14
19
18.3
12.3 10.1
25.9
Age at VNS implant (y)
5
3 5
6
AEDs failed
No
Yes Yes
Yes
Intellectual disability
2/week
20-30/d 1-2/mo
3/d
Seizure frequency
Unknown
Tuberous Sclerosis complex Unknown Perinatal injury
Etiology
Normal Bilateral frontoparietal encephalomalacia Normal
Consistent
MRI
PET: normal; SPECT: doubtful right temporal
Not done Not done
Not done
Functional imaging
15
58 35
60
Follow-up (mo)
Abbreviations: AED, antiepileptic drug; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography; VNS, vagus nerve stimulator.
16 y
8y 2 weeks
3 mo
Age at Gender seizure onset
Age (y)
Table 3. Clinical Profile of Completely Seizure Free (International League Against Epilepsy Outcome Class I) Patients.
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Table 4. Demographic and Outcome Variables Compared in Lesional and Nonlesional Groups. Variable Age (y, mean + SD) Female (n, %) Age at seizure onset (y, mean + SD) Age at VNS implantation (y, mean + SD) Duration of epilepsy before receiving VNS (y, mean + SD) Seizure frequency (per day, median, IQR) History of status epilepticus (n, %) GDD/ID (n, %) Follow-up (mo, mean + SD) ILAE outcome 4 (n, %)
Lesional (n ¼ 17)
Nonlesional (n ¼ 26)
P valuea
13.5 + 6.3 7 (41%) 2.4 + 4.0 10.4 + 6.0 7.7 + 6.8 1.0, 3.0 6 (38%) 14 (88%) 32.1 + 19.4 8 (47.1%)
14.5 + 4.9 13 (50%) 4.3 + 4.3 11.2 + 4.9 5.3 + 3.4 5.0, 22.1 10 (40%) 17 (65%) 32.2 + 22.6 21 (80.8%)
.58 .76 .16 .62 .09 .05 1.00 .16 .99 .05
Abbreviations: GDD, global developmental delay; ID, intellectual disability; ILAE, International League Against Epilepsy; IQR, interquartile range; SD, standard deviation. a P values are based on Fisher exact test for categorical variables and Student’s t test for the other variables, except for seizure frequency, where the Wilcoxon rank-sum test was used.
vagus nerve stimulation. In support of this, though Ghaemi et al5 reported 10/144 patients to be seizure-free poststimulation, no patients with a history of neuroinfection or trauma became seizure free. However, in a larger sample, >50% reduction in seizure burden has been demonstrated in multifocal symptomatic epilepsies.4 Finally, although absence of a lesion was found to predict good outcome, the converse remains to be established. That is, an abnormal MRI does not necessarily preclude good outcome with vague nerve stimulation. In our study, 2 of the 4 seizurefree patients had abnormal MRI and approximately half of the lesional patients had outcomes of International League Against Epilepsy scale score 4 (Tables 3 and 4). Another significant predictor of outcome was found to be preimplant duration of epilepsy. For every 1-year increase in this duration, the odds of good outcome were observed to increase by 29%. As an interaction effect, a duration of 7.3 years was noted to be statistically associated with poor outcome (class >4) in patients with an MRI lesion. The data from vagus nerve stimulation outcomes registry also found longer duration of epilepsy to be significantly predictive of good outcome with vagus nerve stimulation.8 However, the median duration of epilepsy in their study was 22 years versus 5.3 years in the present study. The median reduction in seizure burden at 12 months was 64% for patients having a duration of epilepsy 22 years. This study also had considerable heterogeneity in terms of patient demographics and stimulation settings.8 Two other studies focusing on duration of epilepsy contradict these observations and found epilepsy duration of 6 years to be associated with decreased chance of seizure freedom with vagus nerve stimulation.9,10 Another study by Alexopoulos et al11 divided patients according to the age at device placement into those 12 years (n ¼ 21) and those between 12 and 18 years (n ¼ 25). The median duration of epilepsy in the 2 groups was 6.04 years (+2.7) versus 11.25 years (+3.4), respectively (Wilcoxon rank-sum P ¼ .05). Seizure outcome measured by reduction in seizure frequency was more favorable in the younger age group. However, the effect of duration of epilepsy on seizure outcome was not assessed independent of the nesting within the groups formed according to age of implantation.11 The possibility that patients receiving vagus nerve stimulator earlier can
represent those with high seizure burden was investigated. However, the correlation between preimplant duration of epilepsy and seizure frequency was too weak to substantiate this hypothesis. Although this finding is difficult to explain, it can be speculated that optimal patient selection for vagus nerve stimulation will include time to establish medical refractoriness and workup to exclude the possibility of resective surgery. Regarding vagus nerve stimulation efficacy, 4 patients (9.3%) achieved complete seizure freedom (class 1 outcome, mean follow-up 3.5 years) and 67.4% had at least 50% reduction in seizure days (class 4 outcome). These observations agree with other comparable retrospective reports including both children and adults. Ghaemi et al5 reported 6.9% of their patients (n ¼ 144) to be seizure free at 2 years postimplant and 61.8% to have 50% seizure reduction. Elliot et al also found 63.8% patients to have 50% improvement (n ¼ 400, follow-up 4.94 + 3.2 y).4 However, the randomized controlled trials that led to approval of the vagus nerve stimulator generated more conservative estimates for efficacy. The E03 study, in its high stimulation group (n ¼ 31) corresponding to device settings in this study, reported 30.9% reduction in mean seizure frequency and a 50% responder rate of 39% at 14 weeks.12 The E05 trial (n ¼ 95) found a mean reduction of 28% and a 50% responder rate of only 23.4% at 3 months in the group with stimulation settings comparable to the present study.13 It is known that seizure burden progressively reduces with continued use of vagus nerve stimulator.1 Longterm open-label follow-up data from these trials also found relatively less efficacy. In the E05 study (n ¼ 195) at 12 months, 34% of patients had a reduction in seizure burden of 50%.14 In the E01-E05 cohort (n ¼ 440), 50% seizure reduction was found in 37% patients at 1 year and 43% patients at 2 years, when it plateaued.15 These trials, however, only included patients >12 years of age with refractory partial-onset seizures. The E04 study, a prospective, open safety study, included 60 children aged 3-18 years with 27% of the patients having primary generalized seizures.16 The median reduction in seizure frequency was 34% at 12 months and 42% at 18 months. The recently published guideline update by the American Academy of Neurology that included data from 470 children from 13 studies found >50% seizure reduction in
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Journal of Child Neurology 29(12)
55% (95% confidence interval 50%-59%) patients with focal and generalized epilepsy.17 The 50% responder rate was found to increase by about 7% from 1 to 5 years postimplantation.17 We believe that these figures represent the best steady-state efficacy estimates available presently for vagus nerve stimulation. In the present study, 7 patients (16.3%) had device-related complications including broken lead (n ¼ 4), high lead impedance requiring revision (n ¼ 2), and local infection needing device removal (n ¼ 1). Although adverse effects produced by stimulation are commonly reported, there is limited information about device-related complications.1 A study on surgical complications of vagus nerve stimulator found hardware failure in 9.5% (10/105) patients.18 The major technical complication was lead fracture (7.6%), with some being visible on radiograph (macro-lesion) and others detected only by increased impedance (micro-lesion). Interestingly, the hardware failure was observed only in children (mean age 13.4 y). In this study, wound infections were seen in 4 patients (3.8%) who required device revision.18 In long-term retrospective reviews, lead or cable fractures have been documented in 1.5%-4% cases, and postoperative infections in up to 3%-6% patients, though rarely requiring removal of electrodes or generator.4,13,19 This study provides preliminary evidence that nonlesional patients are likely to have a better outcome with vagus nerve stimulation. Further, increased duration of epilepsy is probably associated with better outcome, though this finding is difficult to interpret clinically. This study has some inadvertent limitations because of retrospective design. First, concomitant changes in antiseizure medications represent an important confounder. Second, survival analysis methods are better suited for such data because the efficacy of vagus nerve stimulation is apparently duration dependent. However, because of retrospective design, not all data points were available for all patients. This increased the risk for the analyses to be biased toward patients with more follow-up data points, which are likely to be those with worse seizure outcomes. Despite modest sample size and these caveats, we believe it is important to report such data, so that subsequent regression meta-analysis can generate pooled association estimates for predictor variables. Such knowledge about predictors of vagus nerve stimulation outcome is likely to help optimize patient selection. Author Contributions Study concept was provided by KDH and HMG. RA and HMG planned the study. AL, RA, and HMG collected the data. FTM did the device placements and CG was involved in follow-up evaluations. PSH and RA analyzed the data. RA wrote the first draft of manuscript, which was critically reviewed by other authors. All authors approve of the final version.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors declared receipt of the following financial support for the research, authorship, and/or publication of this article: RA receives research support (20% effort) from NIH (NINDS 2U01 NS045911)
and American Epilepsy Society and Epilepsy Foundation of America Infrastructure award (pSERG); KDH receives research support from NIH (NINDS R01 NS062756 [principal investigator]).
Ethical Approval The study was approved by institutional review board (IRB) of Cincinnati Children’s Hospital Medical Center (IRB: 2008-1006).
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Nerve Stimulation Study Group E01-E05. Neurology. 1999;53(8): 1731-1735. 16. Murphy JV. Left vagal nerve stimulation in children with medically refractory epilepsy. The Pediatric VNS Study Group. J Pediatr. 1999;134:563-566. 17. Morris GL 3 rd, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development
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