Spikes on ripples are better interictal biomarkers of epilepsy than spikes or ripples

Spikes are the most established interictal epilepsy biomarkers. Yet, they suffer from low specificity since they are partially concordant with the epileptogenic zone and are often found in non-epileptogenic areas. High-frequency oscillations, classified as ripples and fast ripples, are considered more specific biomarkers compared with spikes. Ripples occur more often than fast ripples but are believed to be less specific, since they are more frequently generated by physiological mechanisms. Here, we examine the temporal relationship between spikes, ripples and fast ripples, and assess the ability of these biomarkers (and their combinations) to delineate the epileptogenic zone and predict outcome. We hypothesize that spikes on ripples (temporal co-occurrence of spikes and ripples) can identify the epileptogenic zone and predict outcome better than spikes or ripples. We analysed intracranial EEG data from 40 children with drug-resistant epilepsy. Spikes, ripples and fast ripples were classified based on their temporal occurrence. Their rates were compared with resection by performing a receiver operating characteristic analysis. The resection ratio, quantifying the extent of each biomarker's removal, was computed, and correlated with patients' outcome. Spikes on ripples were seen in all patients; fast ripples were seen in 43% of patients. In good outcome patients, fast ripple and spike on ripple rates were higher inside resection (P = 0.027; P = 0.003, respectively). Fast ripples and spikes on ripples resection ratio predicted outcome (P < 0.05). For fast ripples, outcome was predicted in 82% of patients; this proportion was higher than the one for spikes (48%, P = 0.015) and ripples (40%, P = 0.003), and spikes on ripples (53%, P = 0.034). Fast ripples were the most accurate (82%) to predict outcome; spikes on ripples were the most precise (positive predictive value = 90%). Spike rate and spikes on ripples performance to predict the epileptogenic zone were correlated (r = 0.36, P = 0.035). For patients with frequent spikes, spikes on ripples accuracy to predict outcome reached 70%. Fast ripples are the best biomarker, but they can be seen in only half of patients with drug-resistant epilepsy. Spikes on ripples are a good alternative with more universal applicability since they can be seen in all patients while their resection predicts good outcome; their performance is improved in patients with frequent spikes. Overall, in the absence of fast ripples, spike on ripple areas should be targeted during surgery.