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Blinded study: prospectively defined high-frequency oscillations predict seizure outcome in individual patients.

ABSTRACT: Interictal high-frequency oscillations are discussed as biomarkers for epileptogenic brain tissue that should be resected in epilepsy surgery to achieve seizure freedom. The prospective classification of tissue sampled by individual electrode contacts remains a challenge. We have developed an automated, prospective definition of clinically relevant high-frequency oscillations in intracranial EEG from Montreal and tested it in recordings from Zurich. We here validated the algorithm on intracranial EEG that was recorded in an independent epilepsy centre so that the analysis was blinded to seizure outcome. We selected consecutive patients who underwent resective epilepsy surgery in Geneva with post-surgical follow-up > 12 months. We analysed long-term recordings during sleep that we segmented into intervals of 5 min. High-frequency oscillations were defined in the ripple (80-250 Hz) and the fast ripple (250-500 Hz) frequency bands. Contacts with the highest rate of ripples co-occurring with fast ripples designated the relevant area. As a validity criterion, we calculated the test-retest reliability of the high-frequency oscillations area between the 5 min intervals (dwell time ≥50%). If the area was not fully resected and the patient suffered from recurrent seizures, this was classified as a true positive prediction. We included recordings from 16 patients (median age 32 years, range 18-53 years) with stereotactic depth electrodes and/or with subdural electrode grids (median follow-up 27 months, range 12-55 months). For each patient, we included several 5 min intervals (median 17 intervals). The relevant area had high test-retest reliability across intervals (median dwell time 95%). In two patients, the test-retest reliability was too low (dwell time < 50%) so that outcome prediction was not possible. The area was fully included in the resected volume in 2/4 patients who achieved post-operative seizure freedom (specificity 50%) and was not fully included in 9/10 patients with recurrent seizures (sensitivity 90%), leading to an accuracy of 79%. An additional exploratory analysis suggested that high-frequency oscillations were associated with interictal epileptic discharges only in channels within the relevant area and not associated in channels outside the area. We thereby validated the automated procedure to delineate the clinically relevant area in each individual patient of an independently recorded dataset and achieved the same good accuracy as in our previous studies. The reproducibility of our results across datasets is promising for a multicentre study to test the clinical application of high-frequency oscillations to guide epilepsy surgery.

SUBMITTER: Dimakopoulos V

PROVIDER: S-EPMC8445392 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:High frequency oscillations have been proposed as a clinically useful biomarker of seizure generating sites. We used a unique set of human microelectrode array recordings (four patients, 10 seizures), in which propagating seizure wavefronts could be readily identified, to investigate the basis of ictal high frequency activity at the cortical (subdural) surface. Sustained, repetitive transient increases in high gamma (80-150 Hz) amplitude, phase-locked to the low-frequency (1-25 Hz) ictal rhythm, correlated with strong multi-unit firing bursts synchronized across the core territory of the seizure. These repetitive high frequency oscillations were seen in recordings from subdural electrodes adjacent to the microelectrode array several seconds after seizure onset, following ictal wavefront passage. Conversely, microelectrode recordings demonstrating only low-level, heterogeneous neural firing correlated with a lack of high frequency oscillations in adjacent subdural recording sites, despite the presence of a strong low-frequency signature. Previously, we reported that this pattern indicates a failure of the seizure to invade the area, because of a feedforward inhibitory veto mechanism. Because multi-unit firing rate and high gamma amplitude are closely related, high frequency oscillations can be used as a surrogate marker to distinguish the core seizure territory from the surrounding penumbra. We developed an efficient measure to detect delayed-onset, sustained ictal high frequency oscillations based on cross-frequency coupling between high gamma amplitude and the low-frequency (1-25 Hz) ictal rhythm. When applied to the broader subdural recording, this measure consistently predicted the timing or failure of ictal invasion, and revealed a surprisingly small and slowly spreading seizure core surrounded by a far larger penumbral territory. Our findings thus establish an underlying neural mechanism for delayed-onset, sustained ictal high frequency oscillations, and provide a practical, efficient method for using them to identify the small ictal core regions. Our observations suggest that it may be possible to reduce substantially the extent of cortical resections in epilepsy surgery procedures without compromising seizure control.

Project description:PurposeTo investigate the characteristics of intracranial ictal high-frequency oscillations (HFOs).MethodsAmong 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 findingsOf 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).SignificanceOur 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.

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Blinded study: prospectively defined high-frequency oscillations predict seizure outcome in individual patients.

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