In drug-resistant focal epilepsy, planning surgical resection can involve presurgical intracranial EEG (iEEG) recordings to detect seizures and other iEEG patterns to improve postsurgical seizure outcome. We hypothesized that resection of tissue generating interictal high-frequency oscillations (HFOs, 80-500 Hz) in the iEEG predicts surgical outcome. In eight international epilepsy centres, iEEG was recorded during the presurgical evaluation of patients. The patients were of all ages, had epilepsy of all types, and underwent surgical resection of a single focus aiming at seizure freedom. In a prospective analysis, we applied a fully automated definition of HFO that was independent of the dataset. Using an observational cohort design that was blinded to postsurgical seizure outcome, we analysed HFO rates during non-rapid-eye-movement sleep. If channels had consistently high rates over multiple epochs, they were labelled the 'HFO area'. After HFO analysis, centres provided the electrode contacts located in the resected volume and the seizure outcome at follow-up ≥24 months after surgery. The study was registered at www.clinicaltrials.gov (NCT05332990). We received 160 iEEG datasets. In 146 datasets (91%), the HFO area could be defined. The patients with a completely resected HFO area were more likely to achieve seizure freedom in comparison to those without [odds ratio 2.61, 95% confidence interval (CI) 1.15-5.91, P = 0.02]. Among seizure-free patients, the HFO area was completely resected in 31 and not completely resected in 43. Among patients with recurrent seizures, the HFO area was completely resected in 14 and not completely resected in 58. When predicting seizure freedom, the negative predictive value of the HFO area (68%, CI 52-81) was higher than that for the resected volume as a predictor by itself (51%, CI 42-59, P = 4 × 10-5). The sensitivity and specificity for complete HFO area resection were 0.88 (CI 0.72-0.98) and 0.39 (CI 0.25-0.54), respectively, and the area under the curve was 0.83 (CI 0.58-0.97), indicating good predictive performance. In a blinded cohort study from independent epilepsy centres, applying a previously validated algorithm for HFO marking without the need for adjusting to new datasets allowed us to validate the clinical relevance of HFOs to plan the surgical resection.

Alberta Children's Hospital Research Institute Hotchkiss Brain Institute Cumming School of Medicine University of Calgary Calgary Alberta T2N 4N1 Canada

Brno Epilepsy Center 1st Department of Neurology St Anne ́s University Hospital and Faculty of Medicine Masaryk University 602 00 Brno Czech Republic member of ERN EpiCARE

Department of Biomedical Engineering University of Michigan Ann Arbor MI 48109 USA

Department of Neurology and BioInterfaces Institute University of Michigan Ann Arbor MI 48109 USA

Department of Neurology and Biomedical Engineering Duke University Durham NC 27705 USA

Department of Neurology and Neurosurgery University Medical Centre Utrecht Brain Center Part of ERN EpiCARE P O box 85500 3508 GA Utrecht The Netherlands

Department of Neurology Thomas Jefferson University Philadelphia PA 19107 USA

Department of Neurosurgery University of Nebraska Medical Center Omaha NE 68198 USA

Department of Pediatrics University of Michigan Ann Arbor MI 48109 USA

Epilepsy Center Frankfurt Rhine Main and Department of Neurology Goethe University 60590 Frankfurt am Main Germany

Klinik für Neurochirurgie Universitätsspital Zürich Universität Zürich 8091 Zurich Switzerland

Montreal Neurological Institute and Hospital McGill University Montreal Quebec H3A 2B4 Canada

Neuroscience Research Jane and John Justin Institute for Mind Health Cook Children's Health Care System Fort Worth TX 76104 USA

Stichting Epilepsie Instellingen Nederland Postbus 540 2130 AM Hoofddorp The Netherlands

Swiss Epilepsy Center Clinic Lengg 8008 Zurich Switzerland

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