Targeting interictal low‐entropy zones during epilepsy surgery predicts successful outcomes in pediatric drug‐resistant epilepsy

Approximately 40% of children undergoing epilepsy surgery have postoperative seizures, underscoring the need for enhanced estimators of the epileptogenic zone (EZ). We hypothesize that visually imperceptible low-entropy activity in the interictal periods, even in the absence of conventional spikes, is a robust signature of the EZ. To test this, we mapped interictal "low-entropy zones" using intracranial electroencephalography (iEEG) in children with drug-resistant epilepsy (DRE) and assessed their value for postsurgical outcome prediction when targeted during surgery, along with their stability over prolonged periods. We analyzed iEEG data of 75 DRE children, including brief (5 min) data from patients with known Engel outcome (N = 59; used for outcome prediction) plus prolonged data from a separate recent cohort (N = 16; used for stability assessment). We estimated each contact's entropy across various frequencies (delta to fast-ripple), pinpointed low-entropy zones, and assessed whether their removal predicts outcome (3-fold cross-validation). In addition, the predictive value of entropy during non-epileptiform (spike-free) epochs was also assessed. Furthermore, established interictal estimators (spikes-on-ripple, fast ripples) were tested for outcome prediction. Using the prolonged dataset, we tested whether entropy distribution over brief epochs was similar to prolonged (3 h) data. High overlap between low-entropy zones and resection correlated with low Engel class (p < 0.0001, R = -0.54, N = 59), also during non-epileptiform epochs (R = -0.52). Low-entropy-zone removal predicted outcomes with F1 score of 87% (p < 0.0001, N = 51; Engel I vs III-IV) outperforming spikes-on-ripple (F1 score = 82%, p = 0.002) or fast ripples (F1 score = 80%, p = 0.01). Low-entropy zones retained high predictive value when non-epileptiform epochs were used (F1 score = 89%, N = 44). Entropy distribution over brief epochs was strongly correlated with prolonged data (R > 0.8, p < 0.0001), and its relationship with seizure-onset zone did not differ (brief vs prolonged data: p > 0.6). Surgically targeting low-entropy zones accurately predicts the postoperative seizure outcomes of children with DRE. Mapping low-entropy activity using brief iEEG segments shows consistency with using prolonged data and could enhance surgical planning in pediatric DRE.