Vagus Nerve Stimulation for Intractable Seizures in Children

Vagus Nerve Stimulation for Intractable Seizures in Children

Vagus Nerve Stimulation for Intractable Seizures in Children Russell P. Saneto, DO, PhD*, Marcio A. Sotero de Menezes, MD*, Jeffrey G. Ojemann, MD†, B...

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Vagus Nerve Stimulation for Intractable Seizures in Children Russell P. Saneto, DO, PhD*, Marcio A. Sotero de Menezes, MD*, Jeffrey G. Ojemann, MD†, Brian D. Bournival, MS†, Patricia J. Murphy, ARNP*, William B. Cook, ANRP†, Anthony M. Avellino, MD†, and Richard G. Ellenbogen, MD† Forty-three children less than 12 years of age having intractable seizures were treated with vagus nerve stimulation. Five children were monitored for <12 months, 16 children for 12 to 17 months, and 22 children for >18 months with overall median seizure reduction of 55%. Thirty-seven percent had at least 90% reduction. Vagus nerve stimulation was effective in children with generalized, mixed, and partial medically refractory seizures. © 2006 by Elsevier Inc. All rights reserved. Saneto RP, Sotero de Menezes MA, Ojemann JG, Bournival BD, Murphy PJ, Cook WB, Avellino AM, Ellenbogen RG. Vagus nerve stimulation for intractable seizures in children. Pediatr Neurol 2006;35:323-326.

Introduction Vagus nerve stimulation is an alternative treatment for patients with medically intractable and inoperable seizures. The efficacy of seizure control has been studied in children 12 years of age and older; however, only small numbers of younger children have been investigated. Larger studies of children have been multicenter [1] or company database [2] series, with most single center studies ranging from single to 28 patients [3-7]. Many of these studies have not separated the younger (⬍12 years) from older children (ⱖ12 years) in their analysis. Although numbers are small, children less than 12 years of age exhibit a 40-50% seizure reduction, which improves over 6-18 months of stimulation [1-3,5,6]. This report presents our single-institution experience with 43 children less than 12 years of age, who underwent vagus nerve stimulation.

From the *Division of Pediatric Neurology, Children’s Hospital and Regional Medical Center/University of Washington, Seattle, Washington; and †Department of Neurosurgery, Children’s Hospital and Regional Medical Center/University of Washington, Seattle, Washington.

© 2006 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2006.06.005 ● 0887-8994/06/$—see front matter

Methods Charts of 63 children implanted with the Neurocyberonics pacemaker (Cyberonics Inc., Webster, TX at ⬍12 years of age were reviewed. Children were considered for vagus nerve stimulator implantation based on lack of anatomic or functional seizure focus using magnetic resonance imaging and long-term electroencephalographic monitoring, and resistance to antiepileptic drugs. Parents were advised that implantation was not Food and Drug Administration approved for this age group. Twenty patients were not part of our epilepsy clinic or were only recently implanted and therefore had no follow-up. Pre- and postimplantation seizure frequency, antiepileptic drugs, and seizure type (generalized, partial, or mixed) were recorded. Our Institutional Review Board approved this study. Baseline frequency was determined by documented clinical history provided just before implantation and at the most recent clinic visit, closest to the 6, 12, or ⱖ18-month return visit after implantation. The device was implanted as previously described [8]. After implantation, the device and lead integrity test were performed intraoperatively. The device was activated approximately 2 weeks after surgery. Subsequent device alterations were determined by clinical response, tolerability, and timing outpatient visits to suit the convenience of the patient. Generally, device ramping up occurred every 2 weeks. Review of charts did not reveal that increasing duty cycle or output significantly changed outcome. The median duty cycle was 30 seconds on and 3 minutes off time, and median output was 1.75 milliAmperes.

Results Forty-three children with a mean age of 8 years (range 2.6-11.9 years, 24 males) at device implantation were included in this study. Seizure onset began at 23.6 months (range 1-89 months). Median age at implantation was 7.4 years (range 2.2 to 11.9 years). All children had persistent seizures and had been exposed to an average of 5.6 ⫾ 2.6 antiepileptic medications (range 2-13). Fourteen of the 43 children had been on the ketogenic diet, with 4 patients on the diet at vagus nerve stimulator implantation. At the time

Communications should be addressed to: Dr. Saneto; Children’s Hospital and Regional Medical Center; Division of Pediatric Neurology, B-5552; 4800 Sand Point Way; Seattle, WA 98105. E-mail: [email protected] Received February 9, 2006; accepted June 5, 2006.

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Figure 1. Median seizure reduction in children ⬍12 years of age treated with vagus nerve stimulation. Bar graph represents the median seizure reduction in children who were monitored for 6-11, 12-17, and ⱖ18 months. The overall median seizure reduction is represented by the dark gray bar.

of implantation, the average number of antiepileptic medications was 2.6 ⫾ 1.0 (range ⫽ 1-5). Twenty patients (46%) had generalized seizures, 8 (19%) had partial seizures, and 15 (35%) had mixed, both partial and generalized seizures. Only four of the patients with generalized seizures manifested a single seizure type, the others had multiple generalized seizure semiologies. The preimplantation median seizure frequency was 105 per month (range ⫽ 1-16,200). Overall, the 43 patients (mean ⫽ 18 months, range 7-40 months) monitored after implantation had a median seizure frequency reduction of 84% (range ⫽ 0-1146). The average number of seizure medications at follow-up was essentially unchanged from preimplantation, 2.4 ⫾ 0.9. Five patients were monitored ⬍12 months (9 to 11 months) with median seizure reduction of 33%. Sixteen patients had 12- to 17-month follow-up with a median seizure reduction of 55%. Twenty-two patients have been monitored for ⱖ18 months (18 to 40 months) with median seizure reduction of 42% (Fig 1). Thirteen patients had ⬍50% response and 8 patients had a mild increase in seizure frequency (19% increase). Patient seizure reduction at 6-11, 12-17, and ⱖ18 months was not universal, as only 22 patients had ⱖ50% seizure reduction (Fig 1). Of the responders, 20 patients (47%) had ⬎75% reduction and 16 patients (37%) had ⬎90%. There were 21 patients with ⬍50% seizure reduction, and they are considered nonresponders. Efficacy did not seem to depend on seizure type with ⱖ50% seizure reduction rates in patients with generalized, partial, and mixed seizures (Fig 2). There were four patients who became seizure-free. Two of these patients had generalized seizures with the others having mixed seizure types. No patient who had responded to vagus nerve stimulation had regression/reversion to increased seizures at follow-up visits. There were five patients with 6- to 11-month follow-up. Only one patient, who had generalized seizures, responded with ⬎90% seizure reduction.



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Figure 2. Reduction of seizure frequency in generalized, partial, and mixed seizures. Bar graph represents the percentage of patients having a ⱖ50% reduction of seizure frequency with vagus nerve stimulation having generalized, partial, or mixed seizures.

There were a total of 16 patients with 12- to 17-month follow-up. Eleven patients manifested ⱖ50% seizure reduction, with 8 patients having ⬎90% reduction, 1 patient ⬎75% reduction, and 2 patients with ⱖ50% reduction. One patient, who had mixed seizures, became seizure-free. Five of seven patients with generalized, two of three with partial, and two of three with mixed seizures responded with ⱖ50% seizure reduction. Twenty-two patients had ⱖ18 months follow-up. Ten patients had a ⱖ50% seizure reduction, 7 patients had ⬎90%, 2 patients had ⬎75%, and 1 patient had a ⱖ50% seizure reduction. Six of 10 patients with generalized, no patient with partial, and 4 of 7 patients with mixed seizures responded with ⱖ50% seizure reduction. Seizure response was also subdivided by the International League Against Epilepsy classification of epileptic seizures and syndromes [9]. There were only three patients who had a definable epilepsy syndrome; all had Lennox-Gastaut syndrome. Only one of these children responded with a ⬎50% seizure reduction. Response rate for epileptic seizures was subdivided as summarized in Table 1. Vagus nerve stimulator settings were increased as recommended by the manufacturer. The output settings ranged from 0.5 to 2.0 milliAmperes. The median output was 2.0 milliAmperes. All patients, except one, had the on time set at 30 seconds. The one exception Table 1. Epileptic seizure types and response rate using the International League Against Epilepsy classification [9]

Epileptic Seizure Type Focal Seizures With motor seizures With 2nd generalized seizures Generalized Tonic-clonic Myoclonic Atypical absence Tonic Spasm

Patients With >50% Seizure Reduction

5/9 11/25 4/5 4/7 3/3 2/3 1/5

was a patient with Lennox-Gastaut syndrome who had an on time of 7 seconds (off time was 30 seconds). Interestingly, this was the only Lennox-Gastaut syndrome patient who responded with a ⬎50% seizure reduction. However, this patient’s vagus nerve stimulator was replaced (because of battery failure) and his settings were changed to 30 seconds on and 3 minutes off without a change in seizure frequency. The range of the off time was between 1.1 to 10 minutes with a median of 3 minutes. The exception was the LennoxGastaut syndrome patient described above. There was not a significant difference in vagus nerve stimulator settings in those patients who responded compared with those who did not. We have performed 63 surgeries. There were four short-term complications (6%); two infections (3%) required explantation; one patient developed worsening of respiratory symptoms (1.5%), which later resolved; and one patient experienced device failure (1.5%) secondary to a loose connection. Our infection rate was similar to other reports of implantation in children ⬍12 years [10].

Discussion Data on the use of vagus nerve stimulation in young children ⬍12 years of age have been reported, but typically in small numbers grouped together with older children. The largest studies are multicenter series [1] or database [2] accounts, with few series of children ⬍12 years of age in single-center reports [3-7]. As a group, in children ⬍12 years approximately 40-60% of patients have a 40-60% reduction in seizure frequency. The seizure response rate in our series was promising, with 51% exhibiting a reduction in seizure rate of ⱖ50%. Given that these are patients with severe, intractable seizures, averaging over 100 seizures per month, such response rates are promising. Of particular interest, the number of patients with ⬎90% reduction was 37% in our series and appears to be the same in the small number of cases of children ⬍12 years across other pediatric series. Vagus nerve stimulation was approved for partial onset seizures in patients ⱖ12 years of age. There are no randomized controlled studies investigating vagus nerve stimulation efficacy with generalized seizures. Open-labeled uncontrolled studies suggest that vagus nerve stimulation may be efficacious for generalized seizures in older adolescents and adults [11]. The data presented in the present study suggest that vagus nerve stimulation is efficacious in children ⬍12 years who have generalized, partial, and mixed seizure types. This finding indicates that a broad range of seizure types may be responsive to vagus nerve stimulation therapy across age ranges. Patients who had longer duration of epilepsy have been associated with worse outcome after epilepsy surgery for

partial seizures [12,13]. It is currently unknown whether vagus nerve stimulation in patients with a shorter duration of seizures would increase the responsiveness to vagus nerve stimulation. Our retrospective study did not address this question, as most of our patients began having seizures at approximately 2 years of age and the device was not implanted until approximately 7.4 years of age. Another question is whether changes in device settings and duty cycle (on and off times) would alter efficacy of vagus nerve stimulation in our study group. This retrospective study was not a dose-response study and therefore could not answer this question. However, in adults it has been concluded that device changes were not the primary determinant of increased efficacy at 12 months of follow-up with device settings at 30 seconds on and 5 minutes off [14]. This latter study suggested that although device changes were not primarily responsible for improvement over the course of 1 year, a prospective study of device settings and their impact on efficacy was indicated. To our knowledge, data concerning dose-response responsiveness with vagus nerve stimulation have not been published. Prospective studies on both of these issues should be undertaken. As reported herein, postimplant seizures were reduced by ⬎50% in 51% of children. However, medication burden was not relieved. It is unknown whether this response rate impacts quality of life or is truly costeffective, as these issues are not addressed by this retrospective study. However, in children with medically intractable seizures and a variety of seizure types, vagus nerve stimulation offers an effective option with response rates that compare quite favorably to that in older children and adults to those patients who respond to vagus nerve stimulation.

References [1] Helmers SL, Wheless JW, Frost M, et al. Vagus nerve stimulation therapy in pediatric patients with refractory epilepsy: Retrospective study. J Child Neurol 2001;16:843-8. [2] Wheless JW, Maggio. V. Vagus nerve stimulation therapy in patients younger than 18 years. Neurology 2002;59(Suppl. 4):S21-5. [3] Murphy JV. Pediatric VNS study group. Left vagal nerve stimulation in children with medically refractory epilepsy. J Pediatr 1999;134:563-6. [4] Patwardhan RV, Stong B, Bebin EM, Mathisen J, Grabb PA. Efficacy of vagal nerve stimulation in children with medically refractory epilepsy. Neurosurg 2000;47:1353-8. [5] Buoni S, Mariottini A, Pieri S, et al. Vagus stimulation for drug-resistant epilepsy in children and young adults. Brain Devel 2004;26:158-63. [6] Parker APJ, Polkey CE, Binnie CD, Madigan C, Ferrie CD, Robinson RO. Vagal nerve stimulation in epileptic encephalopathies. Pediatrics 1999;103:778-82. [7] Nagarajan L. Walsh P, Gregory P, Lee M. VNS therapy in clinical practice in children with refractory epilepsy. Acta Neurol Scand 2002;105:13-7. [8] Shauchter S, Saper CB. Vagus nerve stimulation. Epilepsia 1998;39:677-86. [9] Engel J Jr. A proposed diagnostic scheme for people with

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epileptic seizures and with epilepsy: Report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001;42:796-803. [10] Smyth MD, Tubbs RS, Bebin EM, Grabb PA, Blount JP. Complications of chronic vagus nerve stimulation for epilepsy in children. J Neurosurg 2003;99:500-3. [11] Ng M, Devinsky O. Vagus nerve stimulation for refractory idiopathic generalized epilepsy. Seizure 2004;13:176-8. [12] Janszky J, Janszky I, Schulz R, Hoppe M, Pannck HW, Ebner



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A. Temporal lobe epilepsy with hippocampal sclerosis: Predictors for long term surgical outcome. Brain 2005;128:395-404. [13] Siegel AM, Cascino GC, Meyer FB, et al. Resective reoperation for failed epilepsy surgery: Seizure outcome in 64 patients. Neurology 2004;63:2298-302. [14] DeGiorgio CM, Thompson J, Lewis P, et al. Vagus nerve stimulation: Analysis of device parameters in 154 patients during the long-term XES study. Epilepsia 2001;42:1017-20.