Association between Interictal Spike Rate and Seizure Frequency in a Large Epilepsy Cohort

Background and Objectives: Tracking and predicting seizure frequency in patients with epilepsy is important for prognostication and therapy management. Interictal spikes have been proposed as a biomarker of seizure burden, but their association with seizure frequency has not been well quantified across epilepsy subtypes. Our objective was to measure the association between spike rate and seizure frequency and how this varies by epilepsy subtype. Methods: We studied 3,614 consecutive routine outpatient EEGs from 3,245 patients with epilepsy followed for a median of 2.8 years. A validated automated detector (SpikeNet2) estimated spike frequency. Validated large language models performed natural language processing on outpatient clinic notes to extract seizure frequency and epilepsy subtype. We measured Spearman correlation between spike frequency (spikes/hour) and seizure frequency (seizures/month) for all patients with epilepsy and for patients with generalized epilepsy, temporal lobe epilepsy, and frontal lobe epilepsy. Results: Overall, spike frequency was modestly associated with seizure frequency (N = 3,245, ρ = 0.11 [95% CI 0.07-0.14], p < 0.001). Significant positive associations were observed in generalized epilepsy (N = 625, ρ = 0.23 [0.15-0.30], Bonferroni-adjusted p < 0.001) and temporal lobe epilepsy (N = 834, ρ = 0.12 [0.05-0.19], p = 0.0013), but not in frontal lobe epilepsy (N = 263, ρ = 0.11 [-0.02-0.24], p = 0.22). A mixed-effects model revealed a stronger spike-seizure association for clinic visits close in time to EEGs (OR=0.983 [0.967-0.999], p = 0.03), suggesting that spike rate may be a time-varying biomarker of seizure frequency. Discussion: In this large outpatient cohort, higher interictal spike rates on routine EEG were associated with higher seizure frequencies, with the strongest relationship observed in generalized epilepsy. These associations support interictal spike rate as a quantitative EEG marker of seizure burden. Spike rate may have clinical utility for risk stratification at diagnosis and for monitoring longitudinal changes in seizure burden in response to therapy.