Multicentre analysis of seizure outcome predicted by removal of high-frequency oscillations

Abstract

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.

Keywords: automated detection; epilepsy surgery; fast ripples; intracranial EEG; ripples.

Figure 1

STROBE flow chart of patient selection. HFO = high-frequency oscillation; iEEG = intracranial EEG; STROBE = strengthening the reporting of observational studies in epidemiology.

Figure 2

Complete resection of HFO area compared with postsurgical seizure outcome. There were 74 of 146 (51%) patients who achieved seizure freedom in clinical practice (ILAE1), in 31 of whom the HFO area was completely resected (crHFO-area, dark green field). There were 72 patients without seizure freedom (ILAE2–6), in 14 of whom the HFO-area was completely resected (red field). crHFO-area = completely resected HFO area; HFO = high-frequency oscillation; ILAE = International League Against Epilepsy.

Figure 3

The pooled ILAE1 proportion with crHFO-area. Each study centre is represented by a blue square; the size of the square represents the relative statistical weight of each study centre, with larger squares indicating study centres that carry greater statistical weight in the overall results. The pooled data with 95% confidence interval (CI) is shown by a red diamond. Note that centre JUH (Jefferson University Hospital) does not appear in this analysis because it had no patients with crHFO-area. crHFO-area = completely resected high-frequency oscillation area.

Figure 4

HFO-area resection and seizure freedom. (A) Association of crHFO-area and ILAE1. Each study centre is represented by a blue square. The size of the square represents the relative statistical weight of each study centre, with larger squares indicating study centres that carry greater statistical weight in the overall results. The pooled data with 95% CI is shown by a red diamond. The dotted vertical line represents the ‘line of null effect’. The likelihood of achieving ILAE1 was higher for crHFO-area compared with non-crHFO-area (OR = 2.67, CI 1.16–6.16, P = 0.02). (B) The predictive performance of crHFO-area for ILAE1. Red circles represent the study centres, where the size of the circle reflects the number of patients contributed by that centre. The model integrates the sensitivity and specificity across the centres and yields a summary receiver operating curve (SROC, black). The summary operating point is surrounded by the 95% confidence contour (blue). Note the wide spread between the centres, which might reflect the spread in iEEG recording set-ups and therapeutic strategies between centres. CI = confidence interval; crHFO-area = completely resected HFO area; HFO = high-frequency oscillation; ILAE = International League Against Epilepsy; iEEG = intracranial EEG; OR = odds ratio.