Seizure localization using ictal phase-locked high gamma: A retrospective surgical outcome study

Abstract

Objective: To determine whether resection of areas with evidence of intense, synchronized neural firing during seizures is an accurate indicator of postoperative outcome.

Methods: Channels meeting phase-locked high gamma (PLHG) criteria were identified retrospectively from intracranial EEG recordings (102 seizures, 46 implantations, 45 patients). Extent of removal of both the seizure onset zone (SOZ) and PLHG was correlated with seizure outcome, classified as good (Engel class I or II, n = 32) or poor (Engel class III or IV, n = 13).

Results: Patients with good outcomes had significantly greater proportions of both SOZ and the first 4 (early) PLHG sites resected. Improved outcome classification was noted with early PLHG, as measured by the area under the receiver operating characteristic curves (PLHG 0.79, SOZ 0.68) and by odds ratios for resections including at least 75% of sites identified by each measure (PLHG 9.7 [95% CI: 2.3-41.5], SOZ 5.3 [95% CI: 1.2-23.3]). Among patients with resection of at least 75% of the SOZ, 78% (n = 30) had good outcomes, increasing to 91% when the resection also included at least 75% of early PLHG sites (n = 22).

Conclusions: This study demonstrates the localizing value of early PLHG, which is comparable to that provided by the SOZ. Incorporation of PLHG into the clinical evaluation may improve surgical efficacy and help to focus resections on the most critical areas.

Figure 1. Diagnostic algorithm using the SOZ and PLHG metrics, and resulting surgical outcome classification

The chart combines data from both the contributing centers (Columbia University Medical Center and University College London). “Limited coverage” indicates exclusion of wide-area (e.g., bihemispheric) surveys, and “noisy data” refers to cases with too few usable channels or reference noise that could not be removed with blind source separation. Classification was based on resection extent of 75% of electrode sites for each measure, averaged across analyzed seizures for each patient. The best results were achieved by combining criteria based on the SOZ and the early-recruited (first 4 channels) PLHG sites. PLHG = phase-locked high gamma; SOZ = seizure onset zone.

Figure 2. Surgically sparing early ictal PLHG sites is associated with seizure recurrence

(A) Three-dimensional brain reconstruction of patient 16 who had an Engel class III outcome following resection (purple) of a left temporal lesion and the complete SOZ (green trace). PLHG sites identified by 22.8 seconds after seizure onset are shown in red, and the remainder of the lateral temporal grid electrodes in black. (B) EEG segment from an early PLHG channel (top, red) demonstrating high gamma oscillations phase locked to the negative peaks of the ictal discharges (black arrow). The increased high gamma signal is evident in the corresponding 80- to 150-Hz filtered trace (peak amplitude of approximately 100 μV), and in the Morlet wavelet spectrogram calculated from the unfiltered data segment and demonstrating islands of increased power in the high gamma band. (C) EEG segment from an SOZ electrode that did not meet PLHG recruitment criteria (top, black) exhibiting an ictal rhythm of similar amplitude but lacking discrete high gamma oscillations, as is evident in the corresponding filtered high gamma trace and spectrogram. PLHG = phase-locked high gamma; SOZ = seizure onset zone.

Figure 3. Delayed onset and limited extent of amplitude-modulated high gamma activity

(A) Seizure recorded from patient 16 (EEG, blue, top) and the corresponding 80- to 150-Hz filtered trace (red, middle) shows the contrast between early, steady high gamma activity and late-onset bursting activity that tracks the low-frequency rhythm. The PLHG time series metric (black, bottom) does not increase past the recruitment threshold (cyan dotted line) until shortly after high gamma bursting begins. (B) Line scan of ictal PLHG values for the same seizure, with the top 14 channels ranked in their recruitment sequence. Note the sharp demarcation between recruited and nonrecruited channels, the equally sharp transition to recruitment, and the delayed appearance (17 seconds after seizure onset) of the earliest suprathreshold PLHG values. (C) Corresponding line scan of line-length values calculated from the 2- to 25-Hz bandpass-filtered EEG signals, demonstrating more diffuse activity. Seizure onset zone channels are marked by green bars along the y-axis. (D) Across all implantations and seizures, fewer channels were recruited over the entire seizure duration based on the PLHG measure, compared with 2- to 25-Hz line length (n = 102, p < 0.001, paired t test). (E) The PLHG recruitment sequence demonstrated a greater degree of stereotypy (i.e., decreased normalized edit distance) than was the case for line length, across all implantations in which multiple seizures were recorded (n = 31 implantations, 86 seizures, p < 0.01, Wilcoxon rank sum test). PLHG = phase-locked high gamma.

Figure 4. Delayed spread of PLHG sites positioned inside resection boundaries

(A) Three-dimensional brain reconstructions including electrode sites (yellow) and resection (blue) for a patient (42) with Engel class 1A outcome. The wideband EEG trace from an electrode positioned within the SOZ demonstrated an initial pattern of increased repetitive spiking (top). Cyan vertical lines indicate the times of the 3 activity snapshots below, shown as 3-dimensional brain reconstructions with superimposed electrode positions (yellow) and resected region (blue). Line length recruited sites (left images, green disks) quickly spread to the entire resection area and beyond. Early PLHG (right images, red disks) was first seen in proximal depth electrodes (black arrows) inside the SOZ, with spreading PLHG recruitment remaining within the resection boundaries through 21 seconds after seizure onset. PLHG = phase-locked high gamma; SOZ = seizure onset zone.

Figure 5. Surgical outcome classification by extent of SOZ vs early PLHG resection

(A) Box plots of the percentage of electrode sites resected according to surgical outcome for the SOZ (left, blue) and early, late, and total PLHG (red, right). There was a significant difference in the proportion of SOZ and early PLHG (first 4 channels) resection between patients with good outcome (Engel class I/II) and poor outcome (Engel class III/IV). This difference was less evident when late PLHG (first 8 channels) and the full set of PLHG channels were considered. (B) Receiver operating characteristic curves comparing the sensitivity and specificity of seizure outcome classification using SOZ (blue), early PLHG (red), and a 2-stage analysis using both measures (green). Results at each data point were based on resections exceeding the corresponding cutoff proportion for each measure (inset). AUROCs for SOZ and early PLHG were 0.68 and 0.79, respectively. The solid black line indicates random performance, with an AUROC of 0.5. The differences in the SOZ and early PLHG curves are most striking at cutoff values of 75% and higher. Combining both measures resulted in a measurable improvement in outcome classification, with an AUROC of 0.86. AUROC = area under the receiver operating characteristic curve; PLHG = phase-locked high gamma; SOZ = seizure onset zone.