Vagus Nerve Stimulation Therapy in Pediatric Epilepsy: Current Understanding and Future Directions

The first use of vagus nerve stimulation (VNS) in humans started in 1988.1Beekwilder J.P. Beems T. Overview of the clinical applications of vagus nerve stimulation.J Clin Neurophysiol. 2010; 27: 130-138Crossref PubMed Scopus (136) Google Scholar Over the past 20 years, many publications have established its therapeutic role in patients with difficult-to-treat epilepsy.1Beekwilder J.P. Beems T. Overview of the clinical applications of vagus nerve stimulation.J Clin Neurophysiol. 2010; 27: 130-138Crossref PubMed Scopus (136) Google Scholar Accordingly, VNS was approved as a treatment for medically refractory epilepsy in Europe in 1994, and in the United States and Canada in 1997 for patients aged 12 years and older. The evidence supporting VNS use for epilepsy was classified as Class I in 1999 by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.2Fisher R.S. Handforth A. Reassessment: vagus nerve stimulation for epilepsy: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.Neurology. 1999; 53: 666-669Crossref PubMed Google Scholar Initially, VNS therapy was applied in adults. However, many studies have also shown its effectiveness in adolescent and young children. A multicenter, retrospective study of VNS in 125 pediatric patients aged 3 to 18 years with refractory epilepsy showed the overall seizure reduction after 3 and 6 months was 36% and 45%, respectively.3Helmers S.L. Wheless J.W. Frost M. et al.Vagus nerve stimulation therapy in pediatric patients with refractory epilepsy: retrospective study.J Child Neurol. 2001; 16: 843-848Crossref PubMed Scopus (176) Google Scholar Common adverse events included voice change and coughing during stimulation. Rare adverse events were drooling and increasing hyperactivity. Another study comparing the results of children younger than and older than 12 years disclosed no difference in the seizure reduction in these two groups, despite of longer history of refractory epilepsy in the latter.4Murphy J.V. Torkelson R. Dowler I. Simon S. Hudson S. Vagal nerve stimulation in refractory epilepsy: the first 100 patients receiving vagal nerve stimulation at a pediatric epilepsy center.Arch Pediatr Adolesc Med. 2003; 157: 560-564Crossref PubMed Scopus (103) Google Scholar Even in younger children, one study for six children less than 3 years of age showed >60% seizure reduction in four of them.5Zamponi N. Rychlicki F. Corpaci L. Cesaroni E. Trignani R. Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children.Neurosurg Rev. 2008; 31: 291-297Crossref PubMed Scopus (63) Google Scholar The study of VNS therapy on cognition, quality of life, behavior, and mood in 15 children with therapy resistant epilepsy demonstrated significant impact of improvement of quality of life, behavior, and mood after use of VNS.6Hallbook T. Lundgren J. Stjernqvist K. Blennow G. Stromblad L.G. Rosen I. Vagus nerve stimulation in 15 children with therapy resistant epilepsy: its impact on cognition, quality of life, behaviour and mood.Seizure. 2005; 14: 504-513Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar The antiepileptic effects for VNS are multifactorial, though the exact mechanism remains unclear.1Beekwilder J.P. Beems T. Overview of the clinical applications of vagus nerve stimulation.J Clin Neurophysiol. 2010; 27: 130-138Crossref PubMed Scopus (136) Google Scholar From the current understanding, effective VNS therapy probably involves the following processes: (a) an increase of synaptic activity in the thalamus and thalamocortical projection, which might result in a decreased synchrony of synaptic activities between cortical neurons, (b) decreased synaptic activity in the limbic system, (c) intermittent increase of synaptic activities in central autonomic system, and (d) increased release of norepinephrine and serotonin over cortical regions, which are mostly innervated, directly or indirectly, by the spread of vagus nerve fibers. In this issue of Pediatrics and Neonatology, Chen and colleagues7Chen C.Y. Lee H.T. Chen C.C. et al.Short-term results of vagus nerve stimulation in pediatric patients with refractory epilepsy. The Taiwan Child Neurology Society VNS Study Group.Pediatr Neonatol. 2012; 53: 184-187Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar report the preliminary study of short-term results of VNS in pediatric patients with refractory epilepsy from a multicenter cooperative survey. Actually, this report is a part product of the nationwide cooperative study of Taiwan Child Neurology Society under a project called the “Clinical Study on the Catastrophic Pediatric Refractory Epilepsy Patients with Vagus Nerve Stimulation in Relation to Seizure Reduction, Intelligence Quotient, Memory, Alertness, Verbal and Speech Ability” during 2009 to 2011. Another project called “Long-term Outcome of Vagus Nerve Stimulation in Seizure Reduction, Intelligence Quotient, Memory, Alertness, Verbal and Speech Improvement on the Catastrophic Pediatric Refractory Epilepsy Patients” is currently underway. In this report, the authors describe the results of VNS therapy for refractory epilepsy in a sample of four adolescents and four children with a follow-up duration ranging from 9 to 33 months. Five of the eight patients responded to VNS, and four of them experienced a ≥ 90% seizure reduction. No significant adverse effects were noted in all patients during the observation period. This report suggests that VNS is well tolerated in pediatric patients and can be a favorable and safe therapy for children with intractable seizures. Some limitations exist in this study. First, the case number is rather small. Compared to the fact that a total of more than 60 cases so far have been collected till the end of 2011, the preliminary data shown here might not the true picture of VNS effect for Taiwanese children. Second, the study participants are limited in seizure diagnosis. It does not cover the major epilepsies and epileptic syndromes of all difficult seizures in children. Nevertheless, this study may highlight an optimistic therapeutic direction for those suffering from difficult-to-treat seizures and also warrant further larger scale, multicenter cooperative studies in Taiwan.

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