title: The effects of vagus nerve stimulation on tryptophan metabolites in children with intractable epilepsy.
abstract: BACKGROUND
  The mechanism of action of vagus nerve stimulation (VNS) in intractable epilepsy is not entirely clarified. It is believed that VNS causes alterations in cytokines, which can lead to rebalancing the release of neurotoxic and neuroprotective tryptophan metabolites. We aimed to evaluate VNS effects on tryptophan metabolites and on epileptic seizures and investigated whether the antiepileptic effectiveness correlated with changes in tryptophan metabolism.
  
  
  METHODS
  Forty-one children with intractable epilepsy were included in a randomized, active-controlled, double-blind study. After a baseline period of 12 weeks, all children underwent implantation of a vagus nerve stimulator and entered a blinded active-controlled phase of 20 weeks. Half of the children received high-output (therapeutic) stimulation (n=21), while the other half received low-output (active control) stimulation (n=20). Subsequently, all children received high-output stimulation for another 19 weeks (add-on phase). Tryptophan metabolites were assessed in plasma and cerebrospinal fluid (CSF) by use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared between high- and low-output groups and between the end of both study phases and baseline. Seizure frequency was recorded using seizure diaries. Mood was assessed using Profile of Mood States (POMS) questionnaires.
  
  
  RESULTS
  Regarding tryptophan metabolites, anthranilic acid (AA) levels were significantly higher at the end of the add-on phase compared with baseline (p=0.002) and correlated significantly with improvement of mood (τ=-0.39, p=0.037) and seizure frequency reduction (τ=-0.33, p<0.01). No significant changes were found between high- and low-output groups regarding seizure frequency.
  
  
  CONCLUSIONS
  Vagus nerve stimulation induces a consistent increase in AA, a neuroprotective and anticonvulsant tryptophan metabolite. Moreover, increased AA levels are associated with improvement in mood and reduction of seizure frequency.
authors.affiliation: Department of Neurology, Maastricht University Medical Center, The Netherlands; School for Mental Health and Neuroscience, Maastricht University, The Netherlands. Electronic address: s.klinkenberg@mumc.nl.
authors.forename: S
authors.initials: S
authors.lastname: Klinkenberg
authors.affiliation: Epilepsy Center Kempenhaeghe, Heeze, The Netherlands.
authors.forename: C J H
authors.initials: CJ
authors.lastname: van den Borne
authors.affiliation: Department of Neurology, Maastricht University Medical Center, The Netherlands; School for Mental Health and Neuroscience, Maastricht University, The Netherlands.
authors.forename: M W
authors.initials: MW
authors.lastname: Aalbers
authors.affiliation: Epilepsy Center Kempenhaeghe, Heeze, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Verschuure
authors.affiliation: Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center, The Netherlands.
authors.forename: A G
authors.initials: AG
authors.lastname: Kessels
authors.affiliation: Epilepsy Center Kempenhaeghe, Heeze, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Leenen
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, The Netherlands; Department of Neurosurgery, Maastricht University Medical Center, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Rijkers
authors.affiliation: Department of Neurology, Maastricht University Medical Center, The Netherlands; Epilepsy Center Kempenhaeghe, Heeze, The Netherlands; Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: A P
authors.initials: AP
authors.lastname: Aldenkamp
authors.affiliation: Department of Neurology, Maastricht University Medical Center, The Netherlands; School for Mental Health and Neuroscience, Maastricht University, The Netherlands; Epilepsy Center Kempenhaeghe, Heeze, The Netherlands.
authors.forename: J S H
authors.initials: JS
authors.lastname: Vles
authors.affiliation: Department of Neurology, Maastricht University Medical Center, The Netherlands; School for Mental Health and Neuroscience, Maastricht University, The Netherlands; Epilepsy Center Kempenhaeghe, Heeze, The Netherlands.
authors.forename: H J M
authors.initials: HJ
authors.lastname: Majoie
mesh_terms: D000293:Adolescent; D000339:Affect; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D004351:Drug Resistance; D004567:Electrodes, Implanted; D004827:Epilepsy / Q000378:metabolism* / Q000628:therapy*; D005260:Female; D006801:Humans; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D012640:Seizures / Q000453:epidemiology / Q000517:prevention & control; D016896:Treatment Outcome; D014364:Tryptophan / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D055536:Vagus Nerve Stimulation / Q000379:methods*; D062367:ortho-Aminobenzoates / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007737:Kynurenine; D014364:Tryptophan
keywords: Anthranilic acid; Kynurenine; Pediatric; Therapy-resistant seizures; Tryptophan metabolic pathway; VNS