Ictal high-frequency oscillations in neocortical epilepsy: implications for seizure localization and surgical resection

Abstract

Purpose: To investigate the characteristics of intracranial ictal high-frequency oscillations (HFOs).

Methods: Among neocortical epilepsy patients who underwent intracranial monitoring and surgery, we studied patients with well-defined, unifocal seizure onsets characterized by discrete HFOs (≥70 Hz). Patients with multifocal or bilateral independent seizure onsets, electroencephalography (EEG) acquired at <1,000 Hz sampling rate, and nonresective surgery were excluded. Based on a prospectively defined protocol, we defined the seizure-onset zone (SOZ) presurgically to include only those channels with HFOs that showed subsequent sustained evolution (HFOs+ channels) but not the channels that lacked evolution (HFOs- channels). We then resected the SOZ as defined above, 1 cm of the surrounding cortex, and immediate spread area, modified by the presence of eloquent cortex in the vicinity. For purposes of this study, we also defined the SOZ based on the conventional frequency activity (CFA, <70 Hz) at seizure onset, although that information was not considered for preoperative determination of the surgical boundary. We investigated the temporal and spatial characteristics of the ictal HFOs post hoc by visual and spectral methods, and also compared them to the seizure onset defined by the CFA.

Key findings: Of 14 consecutive neocortical epilepsy patients, six patients met the inclusion criteria. Magnetic resonance imaging (MRI) was normal or showed heterotopia. All had subdural electrodes, with additional intracerebral depth electrodes in some. Electrode coverage was extensive (median 94 channels), including limited contralateral coverage. Seizure onsets were lobar or multilobar. Resections were performed per protocol, except in two patients where complete resection of the SOZ could not be done due to overlap with speech area. Histology was abnormal in all patients. Postoperative outcome was class I/II (n = 5, 83%) or class III over a mean follow-up of 27 months. Post hoc analysis of 15 representative seizures showed that the ictal HFOs were widespread at seizure onset but evolved subsequently with different characteristics. In contrast to HFOs-, the HFOs+ were significantly higher in peak frequency (97.1 vs. 89.1 Hz, p = 0.001), more robust (nearly twofold higher peak power, p < 0.0001), and spatially restricted [mean 12.2 vs. 22.4 channels; odds ratio (OR) 0.51, 95% confidence interval (CI) 0.42-0.62; p < 0.0001]. The seizure onset defined by HFOs+ was earlier (by an average of 0.41 s), and occurred in a significantly different and smaller distribution (OR 0.27, 95% CI 0.21-0.34, p < 0.0001), than the seizure onset defined by the CFA. As intended, the HFOs+ channels were 10 times more likely to have been resected than the HFOs- channels (OR 9.7, 95% CI 5-17, p < 0.0001).

Significance: Our study demonstrates the widespread occurrence of ictal HFOs at seizure onset, outlines a practical method to localize the SOZ based on their restricted pattern of evolution, and highlights the differences between the SOZs defined by HFOs and CFA. We show that smaller resections, restricted mainly to the HFOs channels with evolution, can lead to favorable seizure outcome. Our findings support the notion of widespread epileptic networks underlying neocortical epilepsy.

Fig. 1

Localization of seizure onset using conventional setting. Selected channels of subdural recording of seizure 3 from patient F, visualized at 10 sec/page, 1.6–70 Hz bandpass/60 Hz notch filter, shows the point of occurrence of readily identifiable rhythmic activity indicating seizure spread (marker: RSSA). Reviewing backwards from this point reveals the seizure onset occurring a few seconds earlier, consisting of a sharp transient in multiple channels followed by slow waves with superimposed fast activity suggestive of high frequency oscillations (marker: HFOs?). At this filter setting, HFOs are seen as thick, dark waveforms initially in the LT (9–10, 10–11 and 11–12) and AT (2–3 and 3–4) channels with subsequent involvement of ST (3–4 and 4–5), AT (1–2) and LT (1–2, 2–3 and 3–4) channels. Earliest clinical change in this seizure (marker: cc), consisting of repetitive eye blinks, occurred several seconds after the electrical onset.

Fig. 2

Localization of seizure onset based on high frequency oscillations (HFOs). Selected adjacent channels of subdural recording of seizure 3 from patient F (same as Fig. 1), visualized at 2 sec/page, 53–300 Hz bandpass/60 Hz notch filter. The panels A, B and C are consecutive 2-sec epochs each whereas panel D is a 2-sec epoch which starts 4 sec after the end of epoch C. The preictal baseline (A) shows interictal HFOs superimposed on a background of relative attenuation. The seizure onset (B) shows ictal HFOs (marker: HFOs), which appear to involve all the 4 channels. However, the subsequent seizure evolution (C) shows that the ictal HFOs continue to evolve prominently in LT9-10 and LT10-11 (HFOs+ev channels) but not in LT1-2 and LT2-3 (HFOs-ev channels). Further evolution of the seizure (D) shows the transition of HFOs+ev channels into repetitive slower frequency spikes (marker: RSSA); at this time, repetitive spikes have already appeared in the HFOs-ev channels indicating spread of seizure activity to those channels. Although the ictal HFOs evolved in 2/4 channels, the seizure spread to involve all four channels as evidenced by the spikes. Earliest clinical change (i.e., repetitive eye blinks in this seizure) occurred about 2 sec after the end of epoch D (not shown). See text for details.

Fig. 3

Seizure localization by post-hoc spectral analysis. Selected channels of the subdural recording of seizure 1 from patient F, visualized with 50–300 Hz bandpass/60 Hz notch filter, shows the high frequency oscillations (HFOs) on the left side of the figure. Note that the block E1 enclosed by the square brackets is 2 sec long. A 400-ms epoch (highlighted in yellow) is placed at the beginning of this block. The fast Fourier transform-derived power spectra over this epoch (≥70 Hz in red, <70 Hz in black), the dominant frequencies (Hz) and power (µV²) are shown at the right side of the figure. Although all the depicted channels could be considered as potential ictal HFOs channels because of dominant frequencies ≥70 Hz, the three channels (RG35-36, RG57-58 and AT1-2) would not qualify as ictal HFOs channels because of their power being <median power. The channels with subsequent evolution of the ictal HFOs into slower frequency activity (i.e., HFOs+ev channels) are highlighted. See text for details.

Fig. 4

Spatial distribution of ictal high frequency oscillations (HFOs). Implanted electrodes over the right subtemporal and right hemispheric convexity in patient E are shown. RG, RT, SF and ST are subdural electrodes whereas RD, AD, MD and PD are intracerebral depth electrodes. Contacts containing the ictal HFOs with evolution (HFOs+ev) and without evolution (HFOs-ev) are indicated along with those resected. The contacts of the three HFOs+ev channels overlapping with the eloquent sensorimotor cortex that were not resected are also shown (arrows). See text for details.

Fig. 5

Likelihood of ictal high frequency oscillations (HFOs) in resected channels. The total number of resected channels is shown for each patient, broken down in terms of channels without HFOs, channels with ictal HFOs with subsequent evolution (HFOs+ev), and channels with ictal HFOs but without evolution (HFOs-ev). Resections in patients A and D did not include any of the HFOs-ev channels.