TY - JOUR
T1 - Intraoperative electrocorticography using high-frequency oscillations or spikes to tailor epilepsy surgery in the Netherlands (the HFO trial)
T2 - a randomised, single-blind, adaptive non-inferiority trial
AU - Zweiphenning, Willemiek
AU - Klooster, Maryse A.van t.
AU - van Klink, Nicole E.C.
AU - Leijten, Frans S.S.
AU - Ferrier, Cyrille H.
AU - Gebbink, Tineke
AU - Huiskamp, Geertjan
AU - van Zandvoort, Martine J.E.
AU - van Schooneveld, Monique M.J.
AU - Bourez, M.
AU - Goemans, Sophie
AU - Straumann, Sven
AU - van Rijen, Peter C.
AU - Gosselaar, Peter H.
AU - van Eijsden, Pieter
AU - Otte, Willem M.
AU - van Diessen, Eric
AU - Braun, Kees P.J.
AU - Zijlmans, Maeike
AU - Bloemen-Carlier, Eltje M.
AU - Cibulková, Veronika
AU - de Munnink, Renee
AU - van der Salm, Sandra
AU - Eijkemans, Martinus J.C.
AU - Ophorst-van Eck, Janine M.
AU - Velders, Anouk
AU - van Asch, Charlotte J.J.
AU - Zwemmer, Jack
AU - van Regteren-van Griethuysen, Renate
AU - Smeding, Henriette
AU - van der Berg, Lydia
AU - de Bresser, Jeroen
AU - de Kort, Gérard A.P.
AU - Dankbaar, Jan Willem
N1 - Funding Information:
Funding for the HFO trial is provided by UMC Utrecht Alexandre Suermann Stipendium (to WZ), the Dutch Epilepsy Foundation (2012–04; to MAvtK), the Rudolf Magnus Institute Talent Fellowship (to MZ), the European Research Council (starting grant 803880, to MAvtK and MZ), and the MING fund (to WMO). This was an investigator-initiated study sponsored by the UMC Utrecht, Netherlands. We thank participating families, the technicians of the clinical neurophysiology department, and operating room personnel at UMC Utrecht who contributed to this study. We thank the members of the IDMC: Ton Feuth (Chair and biostatistician; Radboud University Nijmegen Medical Center, Nijmegen, Netherlands), Geert Jan Rutten (neurosurgeon; Elisabeth-Tweesteden Hospital, Tilburg, Netherlands), Erik D Gommer (clinical physicist, clinical neurophysiology; Maastricht University Medical Center, Maastricht, Netherlands), and Paul A M Hofman (neuroradiologist; Maastricht University Medical Center). We also thank Wim G C Kraan (head of data management, VUmc Amsterdam, Amsterdam, Netherlands) for support with the ALEA randomisation software during the trial; and Ley Sander (Stichting Epilepsie Instellingen Nederland and University College London Queen Square Institute of Neurology, London, UK), and a language editor, for final review of the manuscript.
Funding Information:
Funding for the HFO trial is provided by UMC Utrecht Alexandre Suermann Stipendium (to WZ), the Dutch Epilepsy Foundation (2012–04; to MAvtK), the Rudolf Magnus Institute Talent Fellowship (to MZ), the European Research Council (starting grant 803880, to MAvtK and MZ), and the MING fund (to WMO). This was an investigator-initiated study sponsored by the UMC Utrecht, Netherlands. We thank participating families, the technicians of the clinical neurophysiology department, and operating room personnel at UMC Utrecht who contributed to this study. We thank the members of the IDMC: Ton Feuth (Chair and biostatistician; Radboud University Nijmegen Medical Center, Nijmegen, Netherlands), Geert Jan Rutten (neurosurgeon; Elisabeth-Tweesteden Hospital, Tilburg, Netherlands), Erik D Gommer (clinical physicist, clinical neurophysiology; Maastricht University Medical Center, Maastricht, Netherlands), and Paul A M Hofman (neuroradiologist; Maastricht University Medical Center). We also thank Wim G C Kraan (head of data management, VUmc Amsterdam, Amsterdam, Netherlands) for support with the ALEA randomisation software during the trial; and Ley Sander (Stichting Epilepsie Instellingen Nederland and University College London Queen Square Institute of Neurology, London, UK), and a language editor, for final review of the manuscript.
Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2022/11
Y1 - 2022/11
N2 - Background: Intraoperative electrocorticography is used to tailor epilepsy surgery by analysing interictal spikes or spike patterns that can delineate epileptogenic tissue. High-frequency oscillations (HFOs) on intraoperative electrocorticography have been proposed as a new biomarker of epileptogenic tissue, with higher specificity than spikes. We prospectively tested the non-inferiority of HFO-guided tailoring of epilepsy surgery to spike-guided tailoring on seizure freedom at 1 year. Methods: The HFO trial was a randomised, single-blind, adaptive non-inferiority trial at an epilepsy surgery centre (UMC Utrecht) in the Netherlands. We recruited children and adults (no age limits) who had been referred for intraoperative electrocorticography-tailored epilepsy surgery. Participants were randomly allocated (1:1) to either HFO-guided or spike-guided tailoring, using an online randomisation scheme with permuted blocks generated by an independent data manager, stratified by epilepsy type. Treatment allocation was masked to participants and clinicians who documented seizure outcome, but not to the study team or neurosurgeon. Ictiform spike patterns were always considered in surgical decision making. The primary endpoint was seizure outcome after 1 year (dichotomised as seizure freedom [defined as Engel 1A–B] vs seizure recurrence [Engel 1C–4]). We predefined a non-inferiority margin of 10% risk difference. Analysis was by intention to treat, with prespecified subgroup analyses by epilepsy type and for confounders. This completed trial is registered with the Dutch Trial Register, Toetsingonline ABR.NL44527.041.13, and ClinicalTrials.gov, NCT02207673. Findings: Between Oct 10, 2014, and Jan 31, 2020, 78 individuals were enrolled to the study and randomly assigned (39 to HFO-guided tailoring and 39 to spike-guided tailoring). There was no loss to follow-up. Seizure freedom at 1 year occurred in 26 (67%) of 39 participants in the HFO-guided group and 35 (90%) of 39 in the spike-guided group (risk difference –23·5%, 90% CI –39·1 to –7·9; for the 48 patients with temporal lobe epilepsy, the risk difference was –25·5%, –45·1 to –6·0, and for the 30 patients with extratemporal lobe epilepsy it was –20·3%, –46·0 to 5·4). Pathology associated with poor prognosis was identified as a confounding factor, with an adjusted risk difference of –7·9% (90% CI –20·7 to 4·9; adjusted risk difference –12·5%, –31·0 to 5·9, for temporal lobe epilepsy and 5·8%, –7·7 to 19·5, for extratemporal lobe epilepsy). We recorded eight serious adverse events (five in the HFO-guided group and three in the spike-guided group) requiring hospitalisation. No patients died. Interpretation: HFO-guided tailoring of epilepsy surgery was not non-inferior to spike-guided tailoring on intraoperative electrocorticography. After adjustment for confounders, HFOs show non-inferiority in extratemporal lobe epilepsy. This trial challenges the clinical value of HFOs as an epilepsy biomarker, especially in temporal lobe epilepsy. Further research is needed to establish whether HFO-guided intraoperative electrocorticography holds promise in extratemporal lobe epilepsy. Funding: UMCU Alexandre Suerman, EpilepsieNL, RMI Talent Fellowship, European Research Council, and MING Fund.
AB - Background: Intraoperative electrocorticography is used to tailor epilepsy surgery by analysing interictal spikes or spike patterns that can delineate epileptogenic tissue. High-frequency oscillations (HFOs) on intraoperative electrocorticography have been proposed as a new biomarker of epileptogenic tissue, with higher specificity than spikes. We prospectively tested the non-inferiority of HFO-guided tailoring of epilepsy surgery to spike-guided tailoring on seizure freedom at 1 year. Methods: The HFO trial was a randomised, single-blind, adaptive non-inferiority trial at an epilepsy surgery centre (UMC Utrecht) in the Netherlands. We recruited children and adults (no age limits) who had been referred for intraoperative electrocorticography-tailored epilepsy surgery. Participants were randomly allocated (1:1) to either HFO-guided or spike-guided tailoring, using an online randomisation scheme with permuted blocks generated by an independent data manager, stratified by epilepsy type. Treatment allocation was masked to participants and clinicians who documented seizure outcome, but not to the study team or neurosurgeon. Ictiform spike patterns were always considered in surgical decision making. The primary endpoint was seizure outcome after 1 year (dichotomised as seizure freedom [defined as Engel 1A–B] vs seizure recurrence [Engel 1C–4]). We predefined a non-inferiority margin of 10% risk difference. Analysis was by intention to treat, with prespecified subgroup analyses by epilepsy type and for confounders. This completed trial is registered with the Dutch Trial Register, Toetsingonline ABR.NL44527.041.13, and ClinicalTrials.gov, NCT02207673. Findings: Between Oct 10, 2014, and Jan 31, 2020, 78 individuals were enrolled to the study and randomly assigned (39 to HFO-guided tailoring and 39 to spike-guided tailoring). There was no loss to follow-up. Seizure freedom at 1 year occurred in 26 (67%) of 39 participants in the HFO-guided group and 35 (90%) of 39 in the spike-guided group (risk difference –23·5%, 90% CI –39·1 to –7·9; for the 48 patients with temporal lobe epilepsy, the risk difference was –25·5%, –45·1 to –6·0, and for the 30 patients with extratemporal lobe epilepsy it was –20·3%, –46·0 to 5·4). Pathology associated with poor prognosis was identified as a confounding factor, with an adjusted risk difference of –7·9% (90% CI –20·7 to 4·9; adjusted risk difference –12·5%, –31·0 to 5·9, for temporal lobe epilepsy and 5·8%, –7·7 to 19·5, for extratemporal lobe epilepsy). We recorded eight serious adverse events (five in the HFO-guided group and three in the spike-guided group) requiring hospitalisation. No patients died. Interpretation: HFO-guided tailoring of epilepsy surgery was not non-inferior to spike-guided tailoring on intraoperative electrocorticography. After adjustment for confounders, HFOs show non-inferiority in extratemporal lobe epilepsy. This trial challenges the clinical value of HFOs as an epilepsy biomarker, especially in temporal lobe epilepsy. Further research is needed to establish whether HFO-guided intraoperative electrocorticography holds promise in extratemporal lobe epilepsy. Funding: UMCU Alexandre Suerman, EpilepsieNL, RMI Talent Fellowship, European Research Council, and MING Fund.
UR - https://www.scopus.com/pages/publications/85140083904
U2 - 10.1016/S1474-4422(22)00311-8
DO - 10.1016/S1474-4422(22)00311-8
M3 - Article
C2 - 36270309
SN - 1474-4422
VL - 21
SP - 982
EP - 993
JO - The Lancet. Neurology
JF - The Lancet. Neurology
IS - 11
ER -