title: High frequency oscillations in the intra-operative ECoG to guide epilepsy surgery ("The HFO Trial"): study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Intra-operative electrocorticography, based on interictal spikes and spike patterns, is performed to optimize delineation of the epileptogenic tissue during epilepsy surgery. High frequency oscillations (HFOs, 80-500 Hz) have been identified as more precise biomarkers for epileptogenic tissue. The aim of the trial is to determine prospectively if ioECoG-tailored surgery using HFOs, instead of interictal spikes, is feasible and will lead to an equal or better seizure outcome. METHODS\
  
  
  METHODS
  We present a single-blinded multi-center randomized controlled trial "The HFO Trial" including patients with refractory focal epilepsy of all ages who undergo surgery with intra-operative electrocorticography. Surgery is tailored by HFOs (arm 1) or interictal spikes (arm 2) in the intra-operative electrocorticography. Primary outcome is post-operative outcome after 1 year, dichotomized in seizure freedom (Engel 1A and 1B) versus seizure recurrence (Engel 1C-4). Secondary outcome measures are the volume of resected tissue, neurologic deficits, surgical duration and complications, cognition and quality of life. The trial has a non-inferiority design to test feasibility and at least equal performance in terms of surgical outcome. We aim to include 78 patients within 3 years including 1 year follow-up. Results are expected in 2018.
  
  
  CONCLUSIONS
  This trial provides a transition from observational research towards clinical interventions using HFOs. We address methodological difficulties in designing this trial. We expect that the use of HFOs as a biomarker for tailoring will increase the success rate of epilepsy surgery while reducing resection volume. This may reduce neurological deficits and yield a better quality of life. Future technical developments, such as validated automatic online HFO identification, could, together with the attained clinical knowledge, lead to a new objective tailoring approach in epilepsy surgery.
  
  
  BACKGROUND
  This trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT02207673 (31 July 2014) and the Central Committee on Research Involving Human Subjects, The Netherlands #NL44257.041.13 (18 March 2014).
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, PO Box 85500, 3504, Utrecht, GA, The Netherlands. m.a.vanhetklooster-2@umcutrecht.nl.
authors.forename: Maryse A
authors.initials: MA
authors.lastname: van 't Klooster
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, PO Box 85500, 3504, Utrecht, GA, The Netherlands. F.S.S.Leijten@umcutrecht.nl.
authors.forename: Frans S S
authors.initials: FS
authors.lastname: Leijten
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, PO Box 85500, 3504, Utrecht, GA, The Netherlands. G.J.M.Huiskamp@umcutrecht.nl.
authors.forename: Geertjan
authors.initials: G
authors.lastname: Huiskamp
authors.affiliation: Department of Clinical Neurophysiology and Magnetoencephalography Center, VU University Medical Center, Amsterdam, The Netherlands. HE.Ronner@vumc.nl.
authors.forename: Hanneke E
authors.initials: HE
authors.lastname: Ronner
authors.affiliation: Neurosurgical Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands. jc.baaijen@vumc.nl.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Baayen
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, PO Box 85500, 3504, Utrecht, GA, The Netherlands. P.v.Rijen@umcutrecht.nl.
authors.forename: Peter C
authors.initials: PC
authors.lastname: van Rijen
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. M.J.C.Eijkemans@umcutrecht.nl.
authors.forename: Martinus J C
authors.initials: MJ
authors.lastname: Eijkemans
authors.affiliation: Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. K.Braun@umcutrecht.nl.
authors.forename: Kees P J
authors.initials: KP
authors.lastname: Braun
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, PO Box 85500, 3504, Utrecht, GA, The Netherlands. G.J.M.Zijlmans@umcutrecht.nl.|SEIN-Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands. G.J.M.Zijlmans@umcutrecht.nl.
authors.forename: Maeike
authors.initials: M
authors.lastname: Zijlmans
mesh_terms: D001921:Brain / Q000503:physiopathology / Q000601:surgery*; D058256:Brain Waves; D002985:Clinical Protocols; D003071:Cognition; D000069280:Electrocorticography; D004827:Epilepsy / Q000175:diagnosis / Q000503:physiopathology / Q000523:psychology / Q000601:surgery*; D006801:Humans; D064795:Intraoperative Neurophysiological Monitoring / Q000379:methods*; D009426:Netherlands; D019635:Neurosurgical Procedures / Q000009:adverse effects; D011183:Postoperative Complications / Q000209:etiology; D011237:Predictive Value of Tests; D011788:Quality of Life; D012074:Remission Induction; D012107:Research Design; D016037:Single-Blind Method; D013997:Time Factors; D016896:Treatment Outcome