Vagus Nerve Stimulation in Pediatric Epilepsy: Weighing the Risks and Benefits

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The need for continuous VNS to achieve optimal effects also stresses the importance of careful matching of the patient with appropriate treatment.
The need for continuous VNS to achieve optimal effects also stresses the importance of careful matching of the patient with appropriate treatment.

Vagus nerve stimulation (VNS) was approved in 1997 by the United States Food and Drug Administration as an adjunct to antiepileptic drug (AED) therapy for reducing the frequency of seizures in children 12 years and older who have partial-onset seizures refractory to AEDs and who are not candidates for potentially curative surgical resection.1 The indication was expanded in 2017 to include patients 4 years of age and older.1

The American Academy of Neurology (AAN) evidence-based guidelines for the use of VNS for the treatment of epilepsy, published in 2013, endorsed the consideration of VNS for seizures in children.2 The 2013 guidelines were based on the available literature and addressed salient questions related to the benefits and risks of adjunct VNS in children, including the impact on seizure frequency, mood, and safety concerns or adverse effects that may differ from those seen in the adult population. The AAN recommendations acknowledged the limitations of the evidence base because of the small number of pediatric patients in the studies evaluated and recommended more studies in specific populations with epilepsy.2

Since the publication of the 2013 AAN guidelines, studies that have evaluated the use of VNS in children, including those as young as 6 months old, have generally concluded that it is well tolerated and is effective as an adjunct therapy to reduce seizure frequency and improve quality of life.3-5 More specifically, a recent study demonstrated the positive effects of VNS in reducing the incidence of status epilepticus and the frequency of generalized convulsions seizures significantly when assessed one year after implantation.6

Similarly, VNS has been shown to reduce heart rate variability in children with epileptic seizure by increasing the parasympathetic influences on the cardiovascular system substantially while diminishing the excessive sympathetic influences caused by epileptic seizures.7

The positive effect of VNS on reducing the stress level of parents caring for children with epilepsy has also been reported.3 Although these studies support the widely held view that VNS is an effective treatment for drug-resistant epilepsy, it is important to recognize that many of these studies are limited in scope and sample size and therefore do not allow generalization of the findings to the wider population of children with epilepsy.

For example, the improvement in heart rate variability with VNS was limited in its duration to the first 6 months, and in fact, the effect was diminished with prolonged epilepsy.7 In many of these studies, the small sample size, confounding influences of several factors that are not controlled in the study design, such as age, epilepsy duration, seizure frequency and AED, as well as a lack of a unified definition of seizure, may have an impact on the study results and call into question the efficacy and safety of VNS in the pediatric population.

Indeed based on limited evidence from a randomized control trial in children, Chambers and colleagues questioned the efficacy of VNS, concluding that they found little evidence to support the benefits of VNS in reducing seizure frequency, although they did report that after VNS implantation, children had significantly fewer hospitalizations and emergency department visits.8

In the setting of VNS, AED is the primary treatment of epilepsy, with dose adjustments for optimal effect. It has been reported that the efficacy of VNS for the permanent treatment of epilepsy is approximately 50% with monotherapy, increasing marginally with increasing number of AEDs, although with parallel increase in side effects.9 Such statistics have also raised questions regarding the efficacy of VNS, specifically whether the effects seen are simply a reflection of medications and dose adjustments. The latter is a valid speculation, given that the study by Arcand and colleagues found that although VNS improved seizure rate by 43%, 48%, 41%, and 50%, at 6, 12, 24, and 36 months follow-up, these improvements paralleled changes in medication type or dose of 57%, 33%, 59%, and 81%, respectively.10 Although the study was conducted in adult patients, it raises speculation of similar effects in children. In addition, given that there is a subset of children who are unresponsive or refractory to all the therapies and combined regimens,9 it is important to make the correct diagnosis and to monitor treatment effect to avoid unnecessary prolonged ineffective treatment. 

In an interview with Neurology Advisor, Yoshimi Sogawa, MD, associate professor of pediatrics, University of Pittsburgh, and director for clinical research, Comprehensive Epilepsy Center at the Children's Hospital of Pittsburgh, said “The rule is that if you fail 2 appropriately chosen AEDs by efficacy, you have intractable epilepsy. Further AED trial will yield only 4% to 10% choice of seizure freedom. If you are not a resective surgical candidate, then VNS is an option.” Among children who are responsive, Dr Sogawa said, “VNS is every 5 minutes stimulation (default), so it is a continuous treatment. Titration (programming) takes 3 months to get the initial goal, then is individualized based on the response. We typically assess the outcome at 6 months and 12 months.”

The need for continuous VNS to achieve optimal effects also highlights the importance of careful matching of the patient with appropriate treatment to minimize the risk for inappropriate treatment-related adverse effects. Indeed, the safety of VNS was one of the questions explored by the AAN Guideline Development Subcommittee for the 2013 guideline recommendations.2 The guidelines presented several case reports of VNS treatment-related complications, including symptomatic tachycardia, fever of unknown origin, discomfort at the implantation site, superficial and deep infection at the surgical site requiring antibiotic treatment and/or explantation, hoarseness, cough, dysphagia, neck pain, involuntary arm movement, inappropriate laughter, drooling, torticollis, and urinary retention.2,11

Despite the risks associated with these invasive procedures, long-term adverse events appear to be limited and can be managed.8 The risk in children may also be associated with their involvement in physical activity, such as sports. In fact, Dr Sogawa commented that the side effects from VNS are not specific to children, adding that “patients who cannot take care of surgical wound (hygiene) will be [at] higher risk for infection, but this is the same for adults.”

Although recent studies have improved knowledge of the efficacy and safety of VNS for the treatment of epilepsy in children, several questions remain that can only be answered with well-controlled clinical studies. The 2013 AAN guidelines included specific recommendations for further studies, including techniques to reduce infection risk at the VNS site in children and more research on the interaction between AED treatment and VNS stimulation, including studies that control medication management and explore the influences of age, epilepsy duration, and seizure frequency.

Until further studies are available, evidence-based guidelines provide a useful approach to the use of VNS as an adjunct treatment for epilepsy in children.

References

  1. US Food and Drug Administration. PMA P970003/S207: FDA Summary of Safety and Effectiveness Data. https://www.accessdata.fda.gov/cdrh_docs/pdf/p970003s207b.pdf. June 23, 2017. Accessed July 16, 2018.
  2. Morris GL 3rd, 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. Epilepsy Curr. 2013;13(6):297-303.
  3. Fan HC, Hsu TR, Chang KP, Chen SJ, Tsai JD; VNS TCNS. Vagus nerve stimulation for 6- to 12-year-old children with refractory epilepsy: impact on seizure frequency and parenting stress index. Epilepsy Behav. 2018;83:119-123.
  4. Orosz I, McCormick D, Zamponi N, et al. Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children. Epilepsia. 2014;55(10):1576-1584.
  5. Elliott RE, Rodgers SD, Bassani L, et al. Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases. J Neurosurg Pediatr. 2011;7(5):491-500.
  6. Gedela S, Sitwat B, Welch WP, Krafty RT, Sogawa Y. The effect of vagus nerve stimulator in controlling status epilepticus in children. Seizure. 2018;55:66-69.
  7. Hirfanoglu T, Serdaroglu A, Cetin I, et al. Effects of vagus nerve stimulation on heart rate variability in children with epilepsy. Epilepsy Behav. 2018;81:33-40.
  8. Chambers A, Bowen JM. Electrical stimulation for drug-resistant epilepsy: an evidence-based analysis. Ont Health Technol Assess Ser. 2013;13(18):1-37.
  9. Ekmekçi H, Kaptan H. Vagus nerve stimulation. Open Access Maced J Med Sci. 2017;5(3):391-394.
  10. Arcand J, Waterhouse K, Hernandez-Ronquillo L, Vitali A, Tellez-Zenteno JF. Efficacy of vagal nerve stimulation for drug-resistant epilepsy: is it the stimulation or medication? Can J Neurol Sci. 2017;44(5):532-537.
  11. Rossignol E, Lortie A, Thomas T, et al. Vagus nerve stimulation in pediatric epileptic syndromes. Seizure. 2009;18(1):34-37.
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