Intraoperative electrocorticography using high-frequency oscillations or spikes to tailor epilepsy surgery in the Netherlands (the HFO trial): a randomised, single-blind, adaptive non-inferiority trial

Willemiek Zweiphenning, Maryse A van 't Klooster, Nicole E C van Klink, Frans S S Leijten, Cyrille H Ferrier, Tineke Gebbink, Geertjan Huiskamp, Martine J E van Zandvoort, Monique M J van Schooneveld, M Bourez, Sophie Goemans, Sven Straumann, Peter C van Rijen, Peter H Gosselaar, Pieter van Eijsden, Willem M Otte, Eric van Diessen, Kees P J Braun, Maeike Zijlmans, HFO study group, Eltje M Bloemen-Carlier, Veronika Cibulková, Renee de Munnink, Sandra van der Salm, Martinus J C Eijkemans, Janine M Ophorst-van Eck, Anouk Velders, Charlotte J J van Asch, Jack Zwemmer, Renate van Regteren-van Griethuysen, Henriette Smeding, Lydia van der Berg, Jeroen de Bresser, Gérard A P de Kort, Jan-Willem Dankbaar, Willemiek Zweiphenning, Maryse A van 't Klooster, Nicole E C van Klink, Frans S S Leijten, Cyrille H Ferrier, Tineke Gebbink, Geertjan Huiskamp, Martine J E van Zandvoort, Monique M J van Schooneveld, M Bourez, Sophie Goemans, Sven Straumann, Peter C van Rijen, Peter H Gosselaar, Pieter van Eijsden, Willem M Otte, Eric van Diessen, Kees P J Braun, Maeike Zijlmans, HFO study group, Eltje M Bloemen-Carlier, Veronika Cibulková, Renee de Munnink, Sandra van der Salm, Martinus J C Eijkemans, Janine M Ophorst-van Eck, Anouk Velders, Charlotte J J van Asch, Jack Zwemmer, Renate van Regteren-van Griethuysen, Henriette Smeding, Lydia van der Berg, Jeroen de Bresser, Gérard A P de Kort, Jan-Willem Dankbaar

Abstract

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.

Conflict of interest statement

Declaration of interests We declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile HFOs=high frequency oscillations. SEEG=stereo-electroencephalography. *13 withheld consent because of the risk of the resection being too small, and four withdrew consent because of the uncertainty of the treatment assignment.
Figure 2
Figure 2
Forest plot of the primary analysis and prespecified subgroup analyses Results are absolute risk differences (dots) with a 90% CI (line) for the primary endpoint seizure freedom. Non-inferiority of tailoring based on HFOs would be shown if the lower limit of the 90% CI of the absolute risk difference was higher than the –10% non-inferiority margin (dotted line). HFOs=high frequency oscillations.
Figure 3
Figure 3
Intraoperative electrocorticography tailoring of surgery Flowcharts show findings of intraoperative electrocorticography during the surgical procedure for each treatment group and the effect on surgical decision making. HFOs=high frequency oscillations. *Included in per-protocol analysis. †Limited by function means that the extent of surgery was limited due to eloquent cortex; limited by distance means that the surgery was not extended because the identified EEG events were too distant from the surgical area.

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