GRAY MATTERS compared to outcomes of BDT without VNS in matched pairs.4 Also the recently published PuLsE study provided a more realistic picture of what adjunctive VNS may specifically achieve as compared to BDT only.5 To provide further evidence for the supposed specificity of the obtained improvements, Orosz et al. are the first to report a correlation between total electric stimulation intensity and seizure efficacy. However, evaluating the relevance of this effect is difficult as no effect sizes were reported. Furthermore, the effect was not found any more at 24 months of follow-up. The validity of the authors final conclusion is further challenged by the selected outcome measures. Deviant from the established standard, seizure response and freedom rates were reported with regard to the predominant seizure type only; furthermore, the respective percentages were calculated on the basis of lower sample sizes at the follow-up. In consequence, the respective percentages become larger and increasing efficacy over time seems to be suggested. However, for implanted patients (N = 347) the initial chance to experience >50% reduction in the frequency of seizures of the predominant type at 2 years of follow-up was 26%, not 44% (n = 91). In addition, the doctors rating of quality of life changes in patients is an unpublished measure with unknown psychometric properties (e.g., reliability and clinical validity). Regarding the authors favorable evaluation of VNS tolerability in children, the outcome report appears biased by not reporting occurrence rates of well-known VNS-specific side effects such as hoarseness or coughing during stimulation. Furthermore, the risk of surgical revisions (>10%) as well as the unavoidable irreversible diagnostic restrictions on high-field nuclear magnetic resonance brain imaging after VNS implantation are played down. The majority of studies on VNS, also the present study, was supported by Cyberonics Inc., as the manufacturer of the VNS system (e.g. medical writing, financial relationships to several academic authors, coauthoring employees, and data analysis). To avert any suspicion of a manufacturer bias in such cases, more rigorous review is required in the future. Physicians, patients, and parents are entitled to credible information about the possible benefits and risks of an invasive and costly treatment. DISCLOSURE OF CONFLICTS OF INTEREST C. Hoppe and C.E. Elger received grants from Cyberonics Inc. for former scientific projects. No other conflicts of interest relevant to this research activity have to be disclosed. We confirm that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Christian Hoppe Christoph Helmstaedter Christian E. Elger [email protected] Epilepsia, 56(2):319–328, 2015
Department of Epileptology, University of Bonn Medical Center, Bonn, Germany REFERENCES 1. 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;55:1576–1584. 2. Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013;81:1453–1459. 3. Callaghan B, Schlesinger M, Rodemer W, et al. Remission and relapse in a drug-resistant epilepsy population followed prospectively. Epilepsia 2011;52:619–626. 4. Hoppe C, Wagner L, Hoffmann JM, et al. Comprehensive long-term outcome of best drug treatment with or without add-on vagus nerve stimulation for epilepsy: a retrospective matched pairs case–control study. Seizure 2013;22:109–115. 5. Ryvlin P, Gilliam FG, Nguyen DK, et al. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia 2014;55:893–900.
In response: Vagus nerve stimulation for epilepsy treatment in children To the Editors: We thank Dr. Hoppe and colleagues for their valuable comments on our paper. We do agree that our study remains a pure observational study; the study design was explicitly described in the article. It is very difficult, both clinically and ethically, to conduct a regular placebo-controlled long-term trial with vagus nerve stimulation (VNS). This is particularly true with respect to the majority of the population involved in our study: those with severe childhood epilepsies, often with multiple types of daily seizures. All experienced childhood epileptologists agree that often some of these seizure types (atypical absences, myoclonic seizures, and short tonic seizures) are of such a high frequency that they are difficult to count. Given the well-known and published shortcomings of patient/caregiver-reported seizure counts, we focused on the predominant seizure type, with the expectation that these are more reliably tracked and reported, leading to a better assessment of the therapys overall clinical impact.1,2 This is preferable to hoping that every single absence seizure or myoclonic jerk will be counted adequately, as is done in many short-term controlled trials for new drugs. This is a major difference with focal drug-resistant epilepsies of adulthood. We appreciate the authors affirmation of the value of the recently published results of the PuLsE study (in which these authors participated), which demonstrated outcomes for VNS therapy similar to those of our study.3 The PuLsE trial confirms the added benefit of VNS in drug-resistant
324
GRAY MATTERS epilepsy. In addition, we believe that our results cannot be explained by the natural history of the disease. A sustained seizure reduction of 30–40% for 2 years is rarely seen in drug-resistant childhood epilepsy syndromes and, to our knowledge, has never been demonstrated in the peerreviewed literature. We also agree that the data on the relationship between total charge and outcome remains preliminary and will benefit from further study, but it seems an important first step in finding out the proper dosage of VNS, and it was presented as such in our article. We agree that the rate of common side effects was lower than anticipated in this study. However, this was addressed to the best of our ability by also reporting safety data collected from the companys complaint database, as was explicitly described in the article. Magnetic resonance imaging (MRI), both 1.5 and 3.0 Tesla, can be performed safely in patients with VNS under specified conditions.4 It is a pity that the authors of this letter seem to express any doubt about the integrity of the collaborating authors and suggest that Cyberonics would have influenced the data processing and writing process. All analyses were done by the senior authors and approved by all other investigators. Nowadays, as everybody realizes, it is difficult to run such a large multicenter trial without the logistics support of a company. We also regret that the peer-review process of the respectable International League Against Epilepsy (ILAE) Journal Epilepsia is questioned. Overall, it seems that some people want to continue to deny the possible beneficial effects of add-on VNS in drug-resistant childhood epilepsies.
2. Poepel A, Elger CE. Epilepsy: accuracy of patient seizure counts. Arch Neurol 2007;64:1595–1599. 3. Ryvlin P, Gilliam FG, Nguyen DK, et al. The long- term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia 2014;55:893– 900. 4. VNS Therapyâ System Physicians Manual. www.cyberonics.com/ manuals
ANNOUNCEMENTS 31st International Epilepsy Congress 5–9 September, 2015; Istanbul, Turkey. Abstract submission is now open! Please see the congress website: www.epilepsyistanbul2015.org
Regional Congresses 3rd East Mediterranean Epilepsy Congress 19–21 March, 2015; Amman, Jordan. Website: www.epilepsyamman2015.org
12th European Congress on Epileptology 11–15 September, 2016; The Prague Congress Centre, Czech Republic. Website: www.epilepsyprague2016.org
CONFLICT OF INTEREST A. Arzimanoglou received grant support and speaker honoraria from Cyberonics, UCB, GlaxoSmithKline, Eisai, and Viropharma. L. Lagae received grant support and speaker honoraria form Cyberonics, UCB, Viropharma, Brabant Pharma, and Eisai. We confirm that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Lieven Lagae1 [email protected] Alexis Arzimanoglou2 1 Department of Development and Regeneration—Section Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium; and 2 Institute for Children and Adolescents with Epilepsy— IDEE University Hospitals of Lyon and INSERM U821, Lyon, France REFERENCES 1. Poochikian-Sarkissian S, Tai P, del Campo M, et al. Patient awareness of seizures as documented in the epilepsy monitoring unit. Can J Neurosci Nurs 2009;31:22–23.
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Upcoming Chapter Congresses The Annual Emirates League Epilepsy Meeting 22–23 May, 2015; Dubai, UAE.
5th SEIN Course on Clinical Epileptology 8–19 June, 2015; Stichting Epilepsie Instellingen Nederland (SEIN), the Netherlands. The course objective is to improve diagnosis and treatment of epilepsy in the students own clinical setting by offering young doctors the opportunity to follow a short, yet comprehensive and practically oriented training in clinical epileptology in both lectures and interactive workshops/discussion sessions. Information: [email protected] Epilepsia, 56(2):319–328, 2015
Christian Hoppe Christoph Helmstaedter Christian E. Elger [email protected] Epilepsia, 56(2):319–328, 2015
Department of Epileptology, University of Bonn Medical Center, Bonn, Germany REFERENCES 1. 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;55:1576–1584. 2. Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013;81:1453–1459. 3. Callaghan B, Schlesinger M, Rodemer W, et al. Remission and relapse in a drug-resistant epilepsy population followed prospectively. Epilepsia 2011;52:619–626. 4. Hoppe C, Wagner L, Hoffmann JM, et al. Comprehensive long-term outcome of best drug treatment with or without add-on vagus nerve stimulation for epilepsy: a retrospective matched pairs case–control study. Seizure 2013;22:109–115. 5. Ryvlin P, Gilliam FG, Nguyen DK, et al. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia 2014;55:893–900.
In response: Vagus nerve stimulation for epilepsy treatment in children To the Editors: We thank Dr. Hoppe and colleagues for their valuable comments on our paper. We do agree that our study remains a pure observational study; the study design was explicitly described in the article. It is very difficult, both clinically and ethically, to conduct a regular placebo-controlled long-term trial with vagus nerve stimulation (VNS). This is particularly true with respect to the majority of the population involved in our study: those with severe childhood epilepsies, often with multiple types of daily seizures. All experienced childhood epileptologists agree that often some of these seizure types (atypical absences, myoclonic seizures, and short tonic seizures) are of such a high frequency that they are difficult to count. Given the well-known and published shortcomings of patient/caregiver-reported seizure counts, we focused on the predominant seizure type, with the expectation that these are more reliably tracked and reported, leading to a better assessment of the therapys overall clinical impact.1,2 This is preferable to hoping that every single absence seizure or myoclonic jerk will be counted adequately, as is done in many short-term controlled trials for new drugs. This is a major difference with focal drug-resistant epilepsies of adulthood. We appreciate the authors affirmation of the value of the recently published results of the PuLsE study (in which these authors participated), which demonstrated outcomes for VNS therapy similar to those of our study.3 The PuLsE trial confirms the added benefit of VNS in drug-resistant
324
GRAY MATTERS epilepsy. In addition, we believe that our results cannot be explained by the natural history of the disease. A sustained seizure reduction of 30–40% for 2 years is rarely seen in drug-resistant childhood epilepsy syndromes and, to our knowledge, has never been demonstrated in the peerreviewed literature. We also agree that the data on the relationship between total charge and outcome remains preliminary and will benefit from further study, but it seems an important first step in finding out the proper dosage of VNS, and it was presented as such in our article. We agree that the rate of common side effects was lower than anticipated in this study. However, this was addressed to the best of our ability by also reporting safety data collected from the companys complaint database, as was explicitly described in the article. Magnetic resonance imaging (MRI), both 1.5 and 3.0 Tesla, can be performed safely in patients with VNS under specified conditions.4 It is a pity that the authors of this letter seem to express any doubt about the integrity of the collaborating authors and suggest that Cyberonics would have influenced the data processing and writing process. All analyses were done by the senior authors and approved by all other investigators. Nowadays, as everybody realizes, it is difficult to run such a large multicenter trial without the logistics support of a company. We also regret that the peer-review process of the respectable International League Against Epilepsy (ILAE) Journal Epilepsia is questioned. Overall, it seems that some people want to continue to deny the possible beneficial effects of add-on VNS in drug-resistant childhood epilepsies.
2. Poepel A, Elger CE. Epilepsy: accuracy of patient seizure counts. Arch Neurol 2007;64:1595–1599. 3. Ryvlin P, Gilliam FG, Nguyen DK, et al. The long- term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia 2014;55:893– 900. 4. VNS Therapyâ System Physicians Manual. www.cyberonics.com/ manuals
ANNOUNCEMENTS 31st International Epilepsy Congress 5–9 September, 2015; Istanbul, Turkey. Abstract submission is now open! Please see the congress website: www.epilepsyistanbul2015.org
Regional Congresses 3rd East Mediterranean Epilepsy Congress 19–21 March, 2015; Amman, Jordan. Website: www.epilepsyamman2015.org
12th European Congress on Epileptology 11–15 September, 2016; The Prague Congress Centre, Czech Republic. Website: www.epilepsyprague2016.org
CONFLICT OF INTEREST A. Arzimanoglou received grant support and speaker honoraria from Cyberonics, UCB, GlaxoSmithKline, Eisai, and Viropharma. L. Lagae received grant support and speaker honoraria form Cyberonics, UCB, Viropharma, Brabant Pharma, and Eisai. We confirm that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Lieven Lagae1 [email protected] Alexis Arzimanoglou2 1 Department of Development and Regeneration—Section Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium; and 2 Institute for Children and Adolescents with Epilepsy— IDEE University Hospitals of Lyon and INSERM U821, Lyon, France REFERENCES 1. Poochikian-Sarkissian S, Tai P, del Campo M, et al. Patient awareness of seizures as documented in the epilepsy monitoring unit. Can J Neurosci Nurs 2009;31:22–23.
325
Upcoming Chapter Congresses The Annual Emirates League Epilepsy Meeting 22–23 May, 2015; Dubai, UAE.
5th SEIN Course on Clinical Epileptology 8–19 June, 2015; Stichting Epilepsie Instellingen Nederland (SEIN), the Netherlands. The course objective is to improve diagnosis and treatment of epilepsy in the students own clinical setting by offering young doctors the opportunity to follow a short, yet comprehensive and practically oriented training in clinical epileptology in both lectures and interactive workshops/discussion sessions. Information: [email protected] Epilepsia, 56(2):319–328, 2015
