Summary
Modern electroencephalographic (EEG) technology contributed to the appreciation that the EEG signal outside the classical Berger frequency band contains important information. In epilepsy, ...research of the past decade focused particularly on interictal high‐frequency oscillations (HFOs) > 80 Hz. The first large application of HFOs was in the context of epilepsy surgery. This is now followed by other applications such as assessment of epilepsy severity and monitoring of antiepileptic therapy. This article reviews the evidence on the clinical use of HFOs in epilepsy with an emphasis on the latest developments. It highlights the growing literature on the association between HFOs and postsurgical seizure outcome. A recent meta‐analysis confirmed a higher resection ratio for HFOs in seizure‐free versus non–seizure‐free patients. Residual HFOs in the postoperative electrocorticogram were shown to predict epilepsy surgery outcome better than preoperative HFO rates. The review further discusses the different attempts to separate physiological from epileptic HFOs, as this might increase the specificity of HFOs. As an example, analysis of sleep microstructure demonstrated a different coupling between HFOs inside and outside the epileptogenic zone. Moreover, there is increasing evidence that HFOs are useful to measure disease activity and assess treatment response using noninvasive EEG and magnetoencephalography. This approach is particularly promising in children, because they show high scalp HFO rates. HFO rates in West syndrome decrease after adrenocorticotropic hormone treatment. Presence of HFOs at the time of rolandic spikes correlates with seizure frequency. The time‐consuming visual assessment of HFOs, which prevented their clinical application in the past, is now overcome by validated computer‐assisted algorithms. HFO research has considerably advanced over the past decade, and use of noninvasive methods will make HFOs accessible to large numbers of patients. Prospective multicenter trials are awaited to gather information over long recording periods in large patient samples.
We studied whether residual high-frequency oscillations (80-500 Hz; ripples, 80-250 Hz), especially fast ripples (FRs, 250-500 Hz), in post-resection intraoperative electrocorticography (ECoG) ...predicted seizure recurrence in comparison to residual interictal spikes and ictiform spike patterns.
We studied, retrospectively, ECoG recorded at 2,048 Hz after resection in a cohort of patients with refractory focal epilepsy. We analyzed occurrence and number of residual FRs, ripples, interictal spikes, and ictiform spike patterns within the last minute of each recording and compared these to seizure recurrence.
We included 54 patients (median age 15.5 years) with 25 months median follow-up. Twenty-four patients had recurrent seizures. We found residual FRs, ripples, spikes, and ictiform spike patterns in 12, 51, 38, and 9 patients. Nine out of 12 patients with residual FRs had recurrent seizures (p = 0.016, positive predictive value 75%). Other ECoG events did not predict seizure recurrence. Patients with seizures had higher FR rates than seizure-free patients (p = 0.022). FRs near the resection and in distant pathologic areas could have changed the resection in 8 patients without harming functionally eloquent areas. One seizure-free patient had FRs in distant functionally eloquent areas.
Residual FRs in post-resection ECoG are prognostic markers for seizure recurrence, especially if their number is high. Tailoring could rely on FRs, but requires careful assessment of the ECoG, as FRs in functionally eloquent areas might not be pathologic.
Intraoperative electrocorticography is used to tailor epilepsy surgery by analysing interictal spikes or spike patterns that can delineate epileptogenic tissue. High-frequency oscillations (HFOs) on ...intraoperative electrocorticography have been proposed as a new biomarker of epileptogenic tissue, with higher specificity than spikes. We prospectively tested the non-inferiority of HFO-guided tailoring of epilepsy surgery to spike-guided tailoring on seizure freedom at 1 year.
The HFO trial was a randomised, single-blind, adaptive non-inferiority trial at an epilepsy surgery centre (UMC Utrecht) in the Netherlands. We recruited children and adults (no age limits) who had been referred for intraoperative electrocorticography-tailored epilepsy surgery. Participants were randomly allocated (1:1) to either HFO-guided or spike-guided tailoring, using an online randomisation scheme with permuted blocks generated by an independent data manager, stratified by epilepsy type. Treatment allocation was masked to participants and clinicians who documented seizure outcome, but not to the study team or neurosurgeon. Ictiform spike patterns were always considered in surgical decision making. The primary endpoint was seizure outcome after 1 year (dichotomised as seizure freedom defined as Engel 1A–B vs seizure recurrence Engel 1C–4). We predefined a non-inferiority margin of 10% risk difference. Analysis was by intention to treat, with prespecified subgroup analyses by epilepsy type and for confounders. This completed trial is registered with the Dutch Trial Register, Toetsingonline ABR.NL44527.041.13, and ClinicalTrials.gov, NCT02207673.
Between Oct 10, 2014, and Jan 31, 2020, 78 individuals were enrolled to the study and randomly assigned (39 to HFO-guided tailoring and 39 to spike-guided tailoring). There was no loss to follow-up. Seizure freedom at 1 year occurred in 26 (67%) of 39 participants in the HFO-guided group and 35 (90%) of 39 in the spike-guided group (risk difference –23·5%, 90% CI –39·1 to –7·9; for the 48 patients with temporal lobe epilepsy, the risk difference was –25·5%, –45·1 to –6·0, and for the 30 patients with extratemporal lobe epilepsy it was –20·3%, –46·0 to 5·4). Pathology associated with poor prognosis was identified as a confounding factor, with an adjusted risk difference of –7·9% (90% CI –20·7 to 4·9; adjusted risk difference –12·5%, –31·0 to 5·9, for temporal lobe epilepsy and 5·8%, –7·7 to 19·5, for extratemporal lobe epilepsy). We recorded eight serious adverse events (five in the HFO-guided group and three in the spike-guided group) requiring hospitalisation. No patients died.
HFO-guided tailoring of epilepsy surgery was not non-inferior to spike-guided tailoring on intraoperative electrocorticography. After adjustment for confounders, HFOs show non-inferiority in extratemporal lobe epilepsy. This trial challenges the clinical value of HFOs as an epilepsy biomarker, especially in temporal lobe epilepsy. Further research is needed to establish whether HFO-guided intraoperative electrocorticography holds promise in extratemporal lobe epilepsy.
UMCU Alexandre Suerman, EpilepsieNL, RMI Talent Fellowship, European Research Council, and MING Fund.
Summary
Objective
Children with rolandic spikes may or may not have seizures, ranging from benign rolandic epilepsy to severe atypical rolandic epilepsy. We investigated whether ripples (80–250 Hz), ...superimposed on rolandic spikes in surface electroencephalography (EEG), can differentiate between different entities.
Methods
In this cohort study we analyzed the EEG studies of children with rolandic spikes without other EEG or magnetic resonance imaging (MRI) abnormalities. They were divided into the following three groups: (1) rolandic spikes but no epilepsy, (2) typical rolandic epilepsy, and (3) atypical and symptomatic rolandic epilepsy. Ripples superimposed on rolandic spikes were marked in 10 minutes of EEG, and compared to the number of seizures before the EEG. Receiver operating characteristic (ROC) curves were constructed to determine the predictive value of ripples and spikes for having epilepsy (groups 2 and 3) and for differentiating benign courses (groups 1 or 2) from atypical and symptomatic epilepsy (group 3). Ripples were also marked in the time frequency spectrum of averaged rolandic spikes.
Results
Ripples were found in 13 of 22 children. Children without epilepsy showed no ripples, except for a single child with only one ripple. The number of ripples showed a significant positive correlation with the number of seizures (ρ = 0.70, p = 0.001), whereas spikes had a borderline significant correlation (ρ = 0.43, p = 0.05). Presence of more than two ripples was a predictor for having seizures (area under the curve AUC 0.84), whereas spikes could not predict having seizures (AUC 0.53). More than five ripples predicted the difference between benign courses and atypical and symptomatic epilepsy (AUC 0.91, sensitivity 63%, specificity 100%). Ripples in the time frequency spectra appeared in all children and were not related to seizures.
Significance
Absence of ripples on top of rolandic spikes predicts a relative benign clinical entity, whereas in the presence of several ripples, the child is likely to have more seizures than classical rolandic epilepsy, and pharmacologic treatment might be needed.
Objective
New insights into high‐frequency electroencephalographic activity and network analysis provide potential tools to improve delineation of epileptic tissue and increase the chance of ...postoperative seizure freedom. Based on our observation of high‐frequency oscillations “spreading outward” from the epileptic source, we hypothesize that measures of directed connectivity in the high‐frequency range distinguish epileptic from healthy brain tissue.
Methods
We retrospectively selected refractory epilepsy patients with a malformation of cortical development or tumor World Health Organization grade I/II who underwent epilepsy surgery with intraoperative electrocorticography for tailoring the resection based on spikes. We assessed directed functional connectivity in the theta (4‐8 Hz), gamma (30‐80 Hz), ripple (80‐250 Hz), and fast ripple (FR; 250‐500 Hz) bands using the short‐time direct directed transfer function, and calculated the total, incoming, and outgoing propagation strength for each electrode. We compared network measures of electrodes covering the resected and nonresected areas separately for patients with good and poor outcome, and of electrodes with and without spikes, ripples, and FRs (group level: paired t test; patient level: Mann‐Whitney U test). We selected the measure that could best identify the resected area and channels with epileptic events using the area under the receiver operating characteristic curve, and calculated the positive and negative predictive value, sensitivity, and specificity.
Results
We found higher total and outstrength in the ripple and gamma bands in resected tissue in patients with good outcome (rippletotal: P = .01; rippleout: P = .04; gammatotal: P = .01; gammaout: P = .01). Channels with events showed lower total and instrength, and higher outstrength in the FR band, and higher total and outstrength in the ripple, gamma, and theta bands (FRtotal: P = .05; FRin: P < .01; FRout: P = .02; gammatotal: P < .01; gammain: P = .01; gammaout: P < .01; thetatotal: P = .01; thetaout: P = .01). The total strength in the gamma band was most distinctive at the channel level (positive predictive value PPVgood = 74%, PPVpoor = 43%).
Significance
Interictally, epileptic tissue is isolated in the FR band and acts as a driver up to the (fast) ripple frequency range. The gamma band total strength seems promising to delineate epileptic tissue intraoperatively.
Summary
Objective
Ripples (80–150 Hz) recorded from clinical macroelectrodes have been shown to be an accurate biomarker of epileptogenic brain tissue. We investigated coupling between epileptiform ...spike phase and ripple amplitude to better understand the mechanisms that generate this type of pathologic ripple (pRipple) event.
Methods
We quantified phase amplitude coupling (PAC) between epileptiform electroencephalography (EEG) spike phase and ripple amplitude recorded from intracranial depth macroelectrodes during episodes of sleep in 12 patients with mesial temporal lobe epilepsy. PAC was determined by (1) a phasor transform that corresponds to the strength and rate of ripples coupled with spikes, and a (2) ripple‐triggered average to measure the strength, morphology, and spectral frequency of the modulating and modulated signals. Coupling strength was evaluated in relation to recording sites within and outside the seizure‐onset zone (SOZ).
Results
Both the phasor transform and ripple‐triggered averaging methods showed that ripple amplitude was often robustly coupled with epileptiform EEG spike phase. Coupling was found more regularly inside than outside the SOZ, and coupling strength correlated with the likelihood a macroelectrode's location was within the SOZ (p < 0.01). The ratio of the rate of ripples coupled with EEG spikes inside the SOZ to rates of coupled ripples in non‐SOZ was greater than the ratio of rates of ripples on spikes detected irrespective of coupling (p < 0.05). Coupling strength correlated with an increase in mean normalized ripple amplitude (p < 0.01), and a decrease in mean ripple spectral frequency (p < 0.05).
Significance
Generation of low‐frequency (80–150 Hz) pRipples in the SOZ involves coupling between epileptiform spike phase and ripple amplitude. The changes in excitability reflected as epileptiform spikes may also cause clusters of pathologically interconnected bursting neurons to grow and synchronize into aberrantly large neuronal assemblies.
Intra-operative electrocorticography, based on interictal spikes and spike patterns, is performed to optimize delineation of the epileptogenic tissue during epilepsy surgery. High frequency ...oscillations (HFOs, 80-500 Hz) have been identified as more precise biomarkers for epileptogenic tissue. The aim of the trial is to determine prospectively if ioECoG-tailored surgery using HFOs, instead of interictal spikes, is feasible and will lead to an equal or better seizure outcome. METHODS\
We present a single-blinded multi-center randomized controlled trial "The HFO Trial" including patients with refractory focal epilepsy of all ages who undergo surgery with intra-operative electrocorticography. Surgery is tailored by HFOs (arm 1) or interictal spikes (arm 2) in the intra-operative electrocorticography. Primary outcome is post-operative outcome after 1 year, dichotomized in seizure freedom (Engel 1A and 1B) versus seizure recurrence (Engel 1C-4). Secondary outcome measures are the volume of resected tissue, neurologic deficits, surgical duration and complications, cognition and quality of life. The trial has a non-inferiority design to test feasibility and at least equal performance in terms of surgical outcome. We aim to include 78 patients within 3 years including 1 year follow-up. Results are expected in 2018.
This trial provides a transition from observational research towards clinical interventions using HFOs. We address methodological difficulties in designing this trial. We expect that the use of HFOs as a biomarker for tailoring will increase the success rate of epilepsy surgery while reducing resection volume. This may reduce neurological deficits and yield a better quality of life. Future technical developments, such as validated automatic online HFO identification, could, together with the attained clinical knowledge, lead to a new objective tailoring approach in epilepsy surgery.
This trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT02207673 (31 July 2014) and the Central Committee on Research Involving Human Subjects, The Netherlands #NL44257.041.13 (18 March 2014).
•Spikes and ripples had high rates over resected tissue in people with focal cortical dysplasia and post-surgical seizure-freedom.•Most of ripples and fast ripples occur before the spike peak and on ...the rising flank.•The ratio of ripples on spikes / all ripples was high over resected tissue and a potent marker for individual patient prediction.
Focal cortical dysplasias (FCD) are characterized by distinct interictal spike patterns and high frequency oscillations (HFOs; ripples: 80–250 Hz; fast ripples: 250–500 Hz) in the intra-operative electrocorticogram (ioECoG). We studied the temporal relation between intra-operative spikes and HFOs and their relation to resected tissue in people with FCD with a favorable outcome.
We included patients who underwent ioECoG-tailored epilepsy surgery with pathology confirmed FCD and long-term Engel 1A outcome. Spikes and HFOs were automatically detected and visually checked in 1-minute pre-resection-ioECoG. Channels covering resected and non-resected tissue were compared using a logistic mixed model, assessing event numbers, co-occurrence ratios, and time-based properties.
We found pre-resection spikes, ripples in respectively 21 and 20 out of 22 patients. Channels covering resected tissue showed high numbers of spikes and HFOs, and high ratios of co-occurring events. Spikes, especially with ripples, have a relatively sharp rising flank with a long descending flank and early ripple onset over resected tissue.
A combined analysis of event numbers, ratios, and temporal relationships between spikes and HFOs may aid identifying epileptic tissue in epilepsy surgery.
This study shows a promising method for clinically relevant properties of events, closely associated with FCD.
Epilepsy surgery depends on reliable pre-surgical markers of epileptogenic tissue. The current gold standard is the seizure onset zone in ictal, i.e. chronic, electrocorticography recordings. Single ...pulse electrical stimulation can evoke epileptic, spike-like responses in areas of seizure onset also recorded by electrocorticography. Recently, spontaneous pathological high-frequency oscillations (80-520 Hz) have been observed in the electrocorticogram that are related to epileptic spikes, but seem more specific for epileptogenic cortex. We wanted to see whether a quantitative electroencephalography analysis using time-frequency information including the higher frequency range could be applied to evoked responses by single pulse electrical stimulation, to enhance its specificity and clinical use. Electrocorticography data were recorded at a 2048-Hz sampling rate from 13 patients. Single pulse electrical stimulation (10 stimuli, 1 ms, 8 mA, 0.2 Hz) was performed stimulating pairs of adjacent electrodes. A time-frequency analysis based on Morlet wavelet transformation was performed in a −1 s : 1 s time interval around the stimulus and a frequency range of 10-520 Hz. Significant (P = 0.05) changes in power spectra averaged for 10 epochs were computed, resulting in event-related spectral perturbation images. In these images, time-frequency analysis of single pulse-evoked responses, in the range of 10-80 Hz for spikes, 80-250 Hz for ripples and 250-520 Hz for fast ripples, were scored by two observers independently. Sensitivity, specificity and predictive value of time-frequency single pulse-evoked responses in the three frequency ranges were compared with seizure onset zone and post-surgical outcome. In all patients, evoked responses included spikes, ripples and fast ripples. For the seizure onset zone, the median sensitivity of time-frequency single pulse-evoked responses decreased from 100% for spikes to 67% for fast ripples and the median specificity increased from 17% for spikes to 79% for fast ripples. A median positive predictive value for the evoked responses in the seizure onset zone of 17% was found for spikes, 26% for ripples and 37% for fast ripples. Five out of seven patients with <50% of fast ripples removed by resection had a poor outcome. A wavelet transform-based time-frequency analysis of single pulse electrical stimulation reveals evoked responses in the frequency range of spikes, ripples and fast ripples. We demonstrate that time-frequency analysis of single pulse electrical stimulation can assist in delineation of the epileptogenic cortex using time-frequency single pulse-evoked fast ripples as a potential new marker.
Highlights • An auto-regressive model residual modulation (ARRm) delineates epileptic tissue based on the non-harmonicity of the signal. • Tissue with high ARRm corresponds to fast ripples and ...removal of this tissue relates to outcome. • The ARRm can be used as real-time analysis tool during epilepsy surgery as it is fast and insensitive to subtle artefacts.
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