Protocol for multicentre comparison of interictal high-frequency oscillations as a predictor of seizure freedom.

In drug-resistant focal epilepsy, interictal high-frequency oscillations (HFOs) recorded from intracranial EEG (iEEG) may provide clinical information for delineating epileptogenic brain tissue. The iEEG electrode contacts that contain HFO are hypothesized to delineate the epileptogenic zone; their resection should then lead to postsurgical seizure freedom. We test whether our prospective definition of clinically relevant HFO is in agreement with postsurgical seizure outcome. The algorithm is fully automated and is equally applied to all data sets. The aim is to assess the reliability of the proposed detector and analysis approach. We use an automated data-independent prospective definition of clinically relevant HFO that has been validated in data from two independent epilepsy centres. In this study, we combine retrospectively collected data sets from nine independent epilepsy centres. The analysis is blinded to clinical outcome. We use iEEG recordings during NREM sleep with a minimum of 12 epochs of 5 min of NREM sleep. We automatically detect HFO in the ripple (80-250 Hz) and in the fast ripple (250-500 Hz) band. There is no manual rejection of events in this fully automated algorithm. The type of HFO that we consider clinically relevant is defined as the simultaneous occurrence of a fast ripple and a ripple. We calculate the temporal consistency of each patient's HFO rates over several data epochs within and between nights. Patients with temporal consistency <50% are excluded from further analysis. We determine whether all electrode contacts with high HFO rate are included in the resection volume and whether seizure freedom (ILAE 1) was achieved at ≥2 years follow-up. Applying a previously validated algorithm to a large cohort from several independent epilepsy centres may advance the clinical relevance and the generalizability of HFO analysis as essential next step for use of HFO in clinical practice.

Blinded study: prospectively defined high-frequency oscillations predict seizure outcome in individual patients.

Interictal high-frequency oscillations are discussed as biomarkers for epileptogenic brain tissue that should be resected in epilepsy surgery to achieve seizure freedom. The prospective classification of tissue sampled by individual electrode contacts remains a challenge. We have developed an automated, prospective definition of clinically relevant high-frequency oscillations in intracranial EEG from Montreal and tested it in recordings from Zurich. We here validated the algorithm on intracranial EEG that was recorded in an independent epilepsy centre so that the analysis was blinded to seizure outcome. We selected consecutive patients who underwent resective epilepsy surgery in Geneva with post-surgical follow-up > 12 months. We analysed long-term recordings during sleep that we segmented into intervals of 5 min. High-frequency oscillations were defined in the ripple (80-250 Hz) and the fast ripple (250-500 Hz) frequency bands. Contacts with the highest rate of ripples co-occurring with fast ripples designated the relevant area. As a validity criterion, we calculated the test-retest reliability of the high-frequency oscillations area between the 5 min intervals (dwell time ≥50%). If the area was not fully resected and the patient suffered from recurrent seizures, this was classified as a true positive prediction. We included recordings from 16 patients (median age 32 years, range 18-53 years) with stereotactic depth electrodes and/or with subdural electrode grids (median follow-up 27 months, range 12-55 months). For each patient, we included several 5 min intervals (median 17 intervals). The relevant area had high test-retest reliability across intervals (median dwell time 95%). In two patients, the test-retest reliability was too low (dwell time < 50%) so that outcome prediction was not possible. The area was fully included in the resected volume in 2/4 patients who achieved post-operative seizure freedom (specificity 50%) and was not fully included in 9/10 patients with recurrent seizures (sensitivity 90%), leading to an accuracy of 79%. An additional exploratory analysis suggested that high-frequency oscillations were associated with interictal epileptic discharges only in channels within the relevant area and not associated in channels outside the area. We thereby validated the automated procedure to delineate the clinically relevant area in each individual patient of an independently recorded dataset and achieved the same good accuracy as in our previous studies. The reproducibility of our results across datasets is promising for a multicentre study to test the clinical application of high-frequency oscillations to guide epilepsy surgery.