Abstract
Brázdil M, Pail M, Halámek J, Plešinger F, Cimbálník J, Roman R, Klimeš P, Daniel P, Chrastina J, Brichtová E, Rektor I, Worrell GA, Jurák P. Ann Neurol 2017;82:299–310.
OBJECTIVE: In the present study, we aimed to investigate depth electroencephalographic (EEG) recordings in a large cohort of patients with drug-resistant epilepsy and to focus on interictal very high-frequency oscillations (VHFOs) between 500Hz and 2kHz. We hypothesized that interictal VHFOs are more specific biomarkers for epileptogenic zone compared to traditional HFOs. METHODS: Forty patients with focal epilepsy who underwent pre-surgical stereo-EEG (SEEG) were included in the study. SEEG data were recorded with a sampling rate of 25kHz, and a 30-minute resting period was analyzed for each patient. Ten patients met selected criteria for analyses of correlations with surgical outcome: detection of interictal ripples (Rs), fast ripples (FRs), and VHFOs; resective surgery; and at least 1 year of postoperative follow-up. Using power envelope computation and visual inspection of power distribution matrixes, electrode contacts with HFOs and VHFOs were detected and analyzed. RESULTS: Interictal very fast ripples (VFRs; 500–1,000Hz) were detected in 23 of 40 patients and ultrafast ripples (UFRs; 1,000–2,000Hz) in almost half of investigated subjects (n = 19). VFRs and UFRs were observed only in patients with temporal lobe epilepsy and were recorded exclusively from mesiotemporal structures. The UFRs were more spatially restricted in the brain than lower-frequency HFOs. When compared to R oscillations, significantly better outcomes were observed in patients with a higher percentage of removed contacts containing FRs, VFRs, and UFRs. INTERPRETATION: Interictal VHFOs are relatively frequent abnormal phenomena in patients with epilepsy and appear to be more specific biomarkers for epileptogenic zone when compared to traditional HFOs.
van ‘t WJEM, Leijten FSS, Zelmann R, Ferrier CH, van Rijen PC, Otte WM, Braun KPJ, Huiskamp GJM, Zijlmans M. Ann Neurol 2017;81:664–676.
OBJECTIVE: Intraoperative electrocorticography (ECoG) can be used to delineate the resection area in epilepsy surgery. High-frequency oscillations (HFOs; 80–500 Hz) seem better biomarkers for epileptogenic tissue than spikes. We studied how HFOs and spikes in combined pre- and postresection ECoG predict surgical outcome in different tailoring approaches. METHODS: We, retrospectively, marked HFOs, divided into fast ripples (FRs; 250–500 Hz) and ripples (80–250 Hz), and spikes in pre- and postresection ECoG sampled at 2,048 Hz in people with refractory focal epilepsy. We defined four groups of electroencephalography (EEG) event occurrence: pre+post− (+/−), pre+post+ (+/+), pre−post+ (−/+) and pre−post− (−/−). We subcategorized three tailoring approaches: hippocampectomy with tailoring for neocortical involvement; lesionectomy of temporal lesions with tailoring for mesiotemporal involvement; and lesionectomy with tailoring for surrounding neocortical involvement. We compared the percentage of resected pre-EEG events, time to recurrence, and the different tailoring approaches to outcome (seizure-free vs recurrence). RESULTS: We included 54 patients (median age, 15.5 years; 25 months of follow-up; 30 seizure free). The percentage of resected FRs, ripples, or spikes in pre-ECoG did not predict outcome. The occurrence of FRs in post-ECoG, given FRs in pre-ECoG (+/−, +/+), predicted outcome (hazard ratio, 3.13; confidence interval = 1.22–6.25; p = 0.01). Seven of 8 patients without spikes in pre-ECoG were seizure free. The highest predictive value for seizure recurrence was presence of FRs in post-ECoG for all tailoring approaches. INTERPRETATION: FRs that persist before and after resection predict poor postsurgical outcome. These findings hold for different tailoring approaches. FRs can thus be used for tailoring epilepsy surgery with repeated intraoperative ECoG measurements.
Commentary
Intracranial EEG presents two major challenges: 1) the risks increase in rate as a function of duration of recording (1) and 2) the chance of sustained seizure freedom after surgery is only 30 to 80 percent depending on the epileptic region and resected sites (2, 3), suggesting that current methods of localization are not optimal. Hence, identifying reliable biomarkers of epileptogenicity in the interictal phase without the need to record seizures (that is, shorter evaluations) is of great interest. In addition, increasing the specificity of localization and identifying markers of ongoing epileptogenesis or dormant sites may prove beneficial in improving long-term outcomes.
There has been a growing interest in the utility of interictal high-frequency oscillations HFOs (80–500 Hz, classically) for localization of the epileptic focus (4). Several challenges arose because similar oscillations have been associated with specific tasks or occur naturally during sleep (5), and no signal parameter can reliably distinguish between physiologic and epileptogenic subtypes in a given individual (5, 6). Hence, interictal HFOs, although useful, are not highly specific and do not replace current standards. Ironically, it appears, to date, that the most effective factor that increases specificity of HFOs for detection of pathology is their co-occurrence with other known markers of pathology, such as spikes (7, 8).
With the advancing technology of EEG acquisition systems, higher sampling rates, and greater computational power, it is now possible to record very high-frequency oscillations (VH-FOs; oscillations >500 Hz). Some recent important (yet limited) studies suggest that VHFOs are more specific for the epileptic regions (9). In this commentary, we will discuss two recent studies on the utility of interictal VHFOs and HFOs for localization of epileptic foci in extraoperative (10) and intraoperative (11) settings.
Study 1: Brázdil et al
Brázdil and colleagues tested their hypothesis that interictal VHFOs are specific for the localization of the epileptic focus in patients undergoing epilepsy surgery evaluation, including intracranial stereo-EEG (SEEG) evaluations, comparing performance to that of “standard” HFOs. In addition to more commonly recognized ripples (R; 80–200 Hz) and fast ripples (FR; 200–500 Hz), the authors also subdivided VHFOs into very fast ripples (VFRs; 500–1,000 Hz) and ultrafast ripples (UFRs; 1,000–2,000 Hz). They evaluated 40 patients undergoing stereo-EEG (28 temporal and 12 extratemporal), of whom only 10 met the inclusion criteria: Detection of both HFOs and VHFOs, surgical intervention, and 1-year postsurgical follow-up. Of these 10, 7 were seizure-free after 1 year of follow-up. As expected, HFOs were encountered more frequently than VHFOs. The latter were found exclusively in the mesiotemporal structures occurring within the same regions as HFOs, often as spikes. Despite the small N, the ratio of the number of removed to nonremoved contacts for FRs, VFRs, and UFRs was significantly higher in seizure-free patients but was not significant for ripples. In the seizure-free patients, 95% of contacts containing UFRs were removed, in contrast with 28% of UFR contacts in the three patients with persistent seizures. In the FR range, average percentages for good and poor outcomes were 72% and 19%, respectively. UFR analysis exhibited a trend with twice as many contacts with detected events in patients with poor outcomes, suggesting more widespread epileptogenicity. In the 30 patients who did not meet the inclusion criteria, 17 subjects did not have VHFOs, of whom 8 had resective surgeries with adequate follow-up. Of interest, all but one had persistent seizures, supporting by inference the authors’ hypothesis and perhaps suggesting that the relevant brain regions were not adequately sampled. The authors recognized that they never detected VHFOs outside the mesial temporal lobe, unlike other studies, and argued that this is likely due to SEEG resolution and the relatively small sample size. They discussed possible generators of VHFOs, which exceed the firing rate of single neurons and likely represent a rhythm generated by in- and out-of-phase action potentials of neuron clusters.
The authors should be commended for the rigorous approach regarding signal acquisition and processing and optimizing the detection of true oscillatory activity rather than artifacts. They used Hilbert transformation followed by power distribution matrices and thresholding to remove false detections. Not surprisingly, the number of false detections was the highest in the VFR and UFR bands. The authors used a 192-channel system powered by a battery to eliminate the noise of alternating current cycles and then subtracted the averaged signal in the white matter from all signals, providing additional noise reduction and an optimal reference in theory. We suggest considering these techniques, especially if studies demonstrate significant improvement in signal:noise ratio with their use. The authors recognized that the small sample size would limit statistical analyses and conclusions. It is unclear why the authors chose awake segments for their analysis. The relation of VHFOs to the time of recording seizures and of anti-seizure medication withdrawal would have been of interest.
Study 2: Van ‘t Klooster et al
Secondly, van ‘t Klooster and colleagues analyzed the utility of spikes, ripples, and fast ripples in pre- and postresection ECOG of 54 patients for different tailoring approaches in 4 subgroups of epilepsy surgery patients: mesial temporal, neocortical temporal, lesional extratemporal, and 4 nonlesional cases. The postresection sampling was guided by preresection findings. The authors concluded that the occurrence of FRs in post-ECoG (given FRs in pre-ECoG) predicted outcome (hazard ratio 3.13) and that percentage of resected spikes, ripples, and FRs in the pre-ECoG did not predict outcome. The highest predictive value for seizure recurrence was the presence of FRs in post-ECoG for all tailoring approaches. Of interest, they found that FRs on the pre-ECoG out of the resection area often disappear after resecting the primary focus. This may suggest that one may eliminate FRs without resecting everywhere they are seen and that this focal resection interrupts an important epileptogenic network; it also suggests that frequent ECoG samples during the resection (starting after resecting a smaller region) may be of utility if further studies confirm this. The authors cited a randomized controlled study currently underway (the HFO trial) and recognized its need to fill this critical gap. As the authors noted, the concept of tailoring resections itself is challengeable, especially in mesial and anterior temporal lobe epilepsies. It would be of interest to learn if the authors employed spectral methods to correct for false detections or relied on expert visual review of the filtered signal, which could be challenging, especially for fast ripples (10). The authors recognized that there are several confounding factors relating to inhomogeneity of the groups involved and numerous potentially confounding variables. Details of anesthesia and the choice of propofol could be debated.
One common denominator among studies reporting on HFOs is that the analysis is often performed at the group level and case-wise results are not always presented; perhaps the latter is more relevant for decision-making in clinical practice. Although the approach of assessing surgical resections and relatively short-term seizure-free outcomes is commonly employed, it has inherent limitations. This holds true especially in the concept of ongoing epileptogenicity and temporal patterns of seizure recurrences, even after seemingly successful resections (11).
Some of the variable results with HFOs and VHFOs in the existing literature stem from: 1) the extent of spatial sampling; 2) methods undertaken to exclude detections with filtering artifact (10); 3) review montage; 4) methods implemented in detection and analysis; 5) areas sampled; 6) size of contacts; and 7) time of analysis and relation to tasks/meds/seizures, among others. It is important to investigate the occurrence of VHFOs outside the epileptic regions, including in relation to normal physiology and cognitive neuroscience. The extent of spatial sampling at Yale, for instance, has led to detection of ripples and fast ripples at a consistently significantly higher rate outside the epileptic network (5).
In conclusion, both articles present exciting findings, with the important caveat that these analyses require special expertise in signal analysis and noise reduction to prevent misinterpretation. In general, these studies and others suggest that the faster the oscillations, the more restricted they are in space and the more specific they are for abnormal, potentially epileptogenic, tissue. Future studies may clarify further the differentiation between epileptic and physiologic oscillations and help in identifying regions at risk of potential relapses. It appears we are arriving at the time to integrate real-time detection of HFOs/spike-HFOs in clinical practice. Clinician-friendly and commercially available automatic real-time detection algorithms (highly specific) are needed. How to routinely store (and pay for) EEGs sampled at these very high rates—a rate >5K samples per second is needed for detection of VHFOs—is not a trivial issue, especially with a few hundred contacts. Additional studies that increase the reliability of interictal markers of epileptogenicity are always welcome and still badly needed, preferably as part of large, multicenter consortia. The findings of the current studies are two steps in the right direction. Based on the current state of affairs, the seizure-onset zone is here to stay for a little while longer as the best available marker of the epileptogenic zone. However, it is becoming a common practice to supplement the analysis of standard ictal onset with analysis of ictal HFOs and interictal high frequency events overriding spikes. Prime-time and widespread use of fast, ultrafast, and even faster oscillations may be approaching—hopefully, progress in this area will be ultrafast.