IDH1 and IDH2 mutations in postoperative diffuse glioma-associated epilepsy |
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| Institution: | 1. Department of Medicine, The University of Melbourne, Parkville, Australia;2. Department of Neurology, Royal Melbourne Hospital, Parkville, Australia;3. Department of Neuropathology, Royal Prince Alfred Hospital, NSW, Australia;4. Brain & Mind Centre, University of Sydney, NSW, Australia;5. Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville, Australia;6. Department of Surgery, The University of Melbourne, Parkville, Australia;7. Department of Neurosurgery, Royal Melbourne Hospital, Parkville, Australia;1. Refractory Epilepsy Unit, Neurology Service, University Hospital La Fe, Avenida Fernando Abril Martorell 106, 46026, Valencia, Spain;2. Department of Psychobiology/IDOCAL, University of Valencia, Avenida Blasco Ibáñez 21, 46010, Valencia, Spain;3. Biostatistics Unit, Health Research Institute La Fe, Avenida Fernando Abril Martorell 106, 46026, Valencia, Spain;4. Refractory Epilepsy Unit, Neurosurgery Service, University Hospital La Fe, Avenida Fernando Abril Martorell 106, 46026, Valencia, Spain;1. Department of Neurology, West China Hospital, Sichuan University, No. 37 Guoxue Road, Chengdu, Sichuan 610041, People''s Republic of China;2. West China Medical School, Sichuan University, No. 37 Guoxue Road, Chengdu, Sichuan 610041, People''s Republic of China;1. Graduate Program in Pharmacy and Health System, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand;2. Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand;3. Department of Pharmacy, Saraburi Hospital, Saraburi 18000, Thailand;4. Department of Neurology, Prasat Neurological Institute, Bangkok 10400, Thailand;5. Division of Neurology, Department of Medicine, Faculty of Medicine, Integrated Epilepsy Research Group, Khon Kaen University, Khon Kaen 40002, Thailand;1. Department of Neurophysiopathology, Azienda Ospedaliera di Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia, Italy;2. Cochrane Neurosciences Field, Direzione Salute Welfare, Region of Umbria, Perugia, Italy;3. Perugia Hospital, Neurophysiopathology Unit, Azienda Ospedaliera di Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia, Italy;4. School of Specialisation in Hospital Pharmacy, Dept. of Pharmaceutical Sciences, University of Milan, Italy;5. University of Kansas Medical Center, Department of Dietetics and Nutrition, USA;1. Epilepsiezentrum, Neurologische Klinik, Universitätsklinikum Erlangen, Germany;2. Gesellschaft für Epilepsieforschung e.V., Bielefeld, Germany;3. Epilepsiezentrum Bodensee, Weissenau, Germany;4. Epilepsiezentrum Rotenburg, Germany;5. Novartis Pharma GmbH, Nürnberg, Germany;6. Epilepsie-Zentrum Berlin-Brandenburg, Ev. Krankenhaus Königin Elisabeth Herzberge, Berlin, Germany;7. Bereich Neuropädiatrie, Klinik für Kinder- und Jugendmedizin, Allgemeine Pädiatrie, Universitätsklinikum Münster, Germany;8. Sächsisches Epilepsiezentrum Radeberg, Kleinwachau, Germany;9. Epilepsiezentrum Kork, Germany;10. Epilepsiezentrum Hamburg, Evangelisches Krankenhaus Alsterdorf, Germany;11. Epilepsie-Zentrum Berlin-Brandenburg, Epilepsieklinik Tabor, Bernau, Germany;12. Abteilung Neurologie mit Schwerpunkt Epileptologie, Hertie-Institut für klinische Hirnforschung, Universität Tübingen, Germany;13. Epilepsie-Zentrum Bethel, Krankenhaus Mara, Bielefeld, Germany |
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| Abstract: | ObjectiveIsocitrate dehydrogenase 1 and 2 mutations (IDH1/2) have an established association with preoperative seizures in patients with grades II–IV diffuse gliomas. Here, we examined if IDH1/2 mutations are a biomarker of postoperative seizure frequency.MethodsThis was a retrospective study. Patients with grades II–IV supratentorial diffuse glioma, immunohistochemistry results of IDH1-R132H, and antiepileptic drug (AED) prescribed postoperatively were included. The primary outcome was seizure frequency over the first 12 postoperative months: Group A — postoperative seizure freedom; Group B — 1–11 seizures over 12 months (less than one seizure per month); and Group C — greater than one seizure per month. Rates of IDH1-R132H mutation were compared between the three outcome groups in univariate and multivariate analyses. Subgroup analysis was performed in 64 patients with IDH1/2 pyrosequencing data.ResultsOne hundred cases were included in the analysis: 30.0% grade II, 20.0% grade III, and 50.0% grade IV gliomas. Group B patients averaged 1 seizure over 12 months, compared with 2 seizures per month in Group C. Isocitrate dehydrogense 1-R132H mutation was present in 29.3% (17/58) of Group A, 18.2% (14/22) of Group B, and 70.0% (14/20) of Group C patients (p = 0.001). On multivariate analysis, after controlling for preoperative seizure, grade, and temporal tumor location, IDH1-R132H was associated with Group C when compared with both Group A (RR 4.75, p = 0.032) and Group B (RR 9.70, p = 0.012). In the subgroup with IDH1/2 molecular data, an IDH1/2 mutation was present in 64.7% (22/34) of Group A, 28.6% (4/14) of Group C, and 87.5% (14/16) of Group C patients (p = 0.004).SignificanceIn patients with supratentorial diffuse gliomas, IDH1-R132H mutations are associated with a more severe phenotype of postoperative epilepsy. These findings support further research into IDH mutations, and the potential for an antiepileptic therapeutic effect of their inhibitors, in patients with glioma-associated epilepsy. |
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