FULL-LENGTH ORIGINAL RESEARCH
Vagus nerve stimulation for drug-resistant epilepsy: A European long-term study up to 24 months in 347 children *Iren Orosz, †David McCormick, ‡Nelia Zamponi, §Sophia Varadkar, ¶Martha Feucht, #Dominique Parain, **Roger Griens, ††Louis Vall ee, ‡‡Paul Boon, §§Christopher Rittey, ¶¶Amara K. Jayewardene, ¶¶Mark Bunker, ##Alexis Arzimanoglou, and ***Lieven Lagae Epilepsia, 55(10):1576–1584, 2014 doi: 10.1111/epi.12762
SUMMARY
Dr. Iren Orosz is a pediatric neurologist at the Pediatric Clinic of the Medical University €beck, Germany of Lu and currently works as a Visiting Assistant Professor in the Department of Radiological Sciences at the David Geffen School of Medicine at University California Los Angeles.
Objective: To gain insight into the long-term impact of vagus nerve stimulation (with VNS Therapy) in children with drug-resistant epilepsy, we conducted the largest retrospective multicenter study to date over an extended follow-up period of up to 24 months. Methods: The primary objective was to assess change in seizure frequency of the predominant seizure type (defined as the most disabling seizure) following VNS device implantation. Treating physicians collected data from patient records from baseline to 6, 12, and 24 months of follow-up. Results: The analysis population included 347 children (aged 6 months to 17.9 years at the time of implant). At 6, 12, and 24 months after implantation, 32.5%, 37.6%, and 43.8%, respectively, of patients had ≥50% reduction in baseline seizure frequency of the predominant seizure type. The responder rate was higher in a subgroup of patients who had no change in antiepileptic drugs (AEDs) during the study. Favorable results were also evident for all secondary outcome measures including changes in seizure duration, ictal severity, postictal severity, quality of life, clinical global impression of improvement, and safety. Post hoc analyses demonstrated a statistically significant correlation between VNS total charge delivered per day and an increase in response rate. VNS Therapy is indicated as adjunctive therapy in children with focal, structural epilepsies, who for any reason are not good candidates for surgical treatment following the trial of two or more AEDs. Children with predominantly generalized seizures from genetic, structural epilepsies, like Dravet syndrome or Lennox-Gastaut syndrome, could also benefit from VNS Therapy. Significance: The results demonstrate that adjunctive VNS Therapy in children with drug-resistant epilepsy reduces seizure frequency and is well tolerated over a 2-year follow-up period. No new safety issues were identified. A post hoc analysis revealed a dose–response correlation for VNS in patients with epilepsy. KEY WORDS: Clinical trial, Epilepsy, Pediatrics, Quality of life, Vagus nerve stimulation.
Accepted July 22, 2014; Early View publication September 17, 2014. *Department of Neuropediatrics, Children's Hospital, University of Leubeck, Leubeck, Germany; †King's College Hospital, London, United Kingdom; ‡Department of Pediatric Neurology, Riuniti Hospital, Ancona, Italy; §UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; ¶Department of Pediatric Neurology, University of Medicine, Wien, Vienna, Austria; #Charles Nicolle Department of Neurophysiology, Rouen University Hospital, Rouen, France; **Medisch Spectrum Twente, Enschede, The Netherlands; ††Pole Child Neuropediatrics Service, Roger-Salengro Hospital, CHRU-University of North France, Lille, France; ‡‡Department of Neurology, Ghent University Hospital, Ghent, Belgium; §§Sheffield Children's Hospital, Sheffield, United Kingdom; ¶¶Cyberonics, Inc., Houston, Texas, U.S.A.; ##Epilepsy, Sleep and Pediatric Neurophysiology Department, University Hospitals of Lyon (HCL) and Lyon Neurosciences Research Center (CRNL), Lyon, France; and ***Gasthuisberg University Hospital, Leuven, Belgium Address correspondence to Lieven Lagae, Department of Pediatric Neurology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] and Alexis Arzimanoglou, Epilepsy, Sleep, and Pediatric Neurophysiology Department, HFME – University Hospitals of Lyon (HCL), 59 Boulevard Pinel, 69677 Lyon, France. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
1576
1577 Long-Term VNS in Pediatric Epilepsy Effective treatment of epilepsy is especially important in children, since uncontrolled seizures can have detrimental effects on normal functional neurodevelopment and subsequent quality of life.1 However, one third of patients with epilepsy do not respond to antiepileptic drugs (AEDs) and are considered to have drug-resistant epilepsy.2–5 Vagus nerve stimulation (VNS Therapy, Cyberonics) is an approved adjunctive therapy for refractory epilepsy. To date, >70,000 patients worldwide have been treated with VNS Therapy for both epilepsy and depression, representing >500,000 patient-years of treatment experience. Efficacy of VNS Therapy in the treatment of epilepsy is now well-established, showing improvement in seizure control and quality of life, and having a positive impact on health care utilization,6–14 but there remained a need to evaluate safety and efficacy from a long-term follow-up study in large cohorts of children, including children
Vagus nerve stimulation for drug-resistant epilepsy: A European long-term study up to 24 months in 347 children *Iren Orosz, †David McCormick, ‡Nelia Zamponi, §Sophia Varadkar, ¶Martha Feucht, #Dominique Parain, **Roger Griens, ††Louis Vall ee, ‡‡Paul Boon, §§Christopher Rittey, ¶¶Amara K. Jayewardene, ¶¶Mark Bunker, ##Alexis Arzimanoglou, and ***Lieven Lagae Epilepsia, 55(10):1576–1584, 2014 doi: 10.1111/epi.12762
SUMMARY
Dr. Iren Orosz is a pediatric neurologist at the Pediatric Clinic of the Medical University €beck, Germany of Lu and currently works as a Visiting Assistant Professor in the Department of Radiological Sciences at the David Geffen School of Medicine at University California Los Angeles.
Objective: To gain insight into the long-term impact of vagus nerve stimulation (with VNS Therapy) in children with drug-resistant epilepsy, we conducted the largest retrospective multicenter study to date over an extended follow-up period of up to 24 months. Methods: The primary objective was to assess change in seizure frequency of the predominant seizure type (defined as the most disabling seizure) following VNS device implantation. Treating physicians collected data from patient records from baseline to 6, 12, and 24 months of follow-up. Results: The analysis population included 347 children (aged 6 months to 17.9 years at the time of implant). At 6, 12, and 24 months after implantation, 32.5%, 37.6%, and 43.8%, respectively, of patients had ≥50% reduction in baseline seizure frequency of the predominant seizure type. The responder rate was higher in a subgroup of patients who had no change in antiepileptic drugs (AEDs) during the study. Favorable results were also evident for all secondary outcome measures including changes in seizure duration, ictal severity, postictal severity, quality of life, clinical global impression of improvement, and safety. Post hoc analyses demonstrated a statistically significant correlation between VNS total charge delivered per day and an increase in response rate. VNS Therapy is indicated as adjunctive therapy in children with focal, structural epilepsies, who for any reason are not good candidates for surgical treatment following the trial of two or more AEDs. Children with predominantly generalized seizures from genetic, structural epilepsies, like Dravet syndrome or Lennox-Gastaut syndrome, could also benefit from VNS Therapy. Significance: The results demonstrate that adjunctive VNS Therapy in children with drug-resistant epilepsy reduces seizure frequency and is well tolerated over a 2-year follow-up period. No new safety issues were identified. A post hoc analysis revealed a dose–response correlation for VNS in patients with epilepsy. KEY WORDS: Clinical trial, Epilepsy, Pediatrics, Quality of life, Vagus nerve stimulation.
Accepted July 22, 2014; Early View publication September 17, 2014. *Department of Neuropediatrics, Children's Hospital, University of Leubeck, Leubeck, Germany; †King's College Hospital, London, United Kingdom; ‡Department of Pediatric Neurology, Riuniti Hospital, Ancona, Italy; §UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; ¶Department of Pediatric Neurology, University of Medicine, Wien, Vienna, Austria; #Charles Nicolle Department of Neurophysiology, Rouen University Hospital, Rouen, France; **Medisch Spectrum Twente, Enschede, The Netherlands; ††Pole Child Neuropediatrics Service, Roger-Salengro Hospital, CHRU-University of North France, Lille, France; ‡‡Department of Neurology, Ghent University Hospital, Ghent, Belgium; §§Sheffield Children's Hospital, Sheffield, United Kingdom; ¶¶Cyberonics, Inc., Houston, Texas, U.S.A.; ##Epilepsy, Sleep and Pediatric Neurophysiology Department, University Hospitals of Lyon (HCL) and Lyon Neurosciences Research Center (CRNL), Lyon, France; and ***Gasthuisberg University Hospital, Leuven, Belgium Address correspondence to Lieven Lagae, Department of Pediatric Neurology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] and Alexis Arzimanoglou, Epilepsy, Sleep, and Pediatric Neurophysiology Department, HFME – University Hospitals of Lyon (HCL), 59 Boulevard Pinel, 69677 Lyon, France. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
1576
1577 Long-Term VNS in Pediatric Epilepsy Effective treatment of epilepsy is especially important in children, since uncontrolled seizures can have detrimental effects on normal functional neurodevelopment and subsequent quality of life.1 However, one third of patients with epilepsy do not respond to antiepileptic drugs (AEDs) and are considered to have drug-resistant epilepsy.2–5 Vagus nerve stimulation (VNS Therapy, Cyberonics) is an approved adjunctive therapy for refractory epilepsy. To date, >70,000 patients worldwide have been treated with VNS Therapy for both epilepsy and depression, representing >500,000 patient-years of treatment experience. Efficacy of VNS Therapy in the treatment of epilepsy is now well-established, showing improvement in seizure control and quality of life, and having a positive impact on health care utilization,6–14 but there remained a need to evaluate safety and efficacy from a long-term follow-up study in large cohorts of children, including children
