Can we use intraoperative high-frequency oscillations to guide tumor-related epilepsy surgery?

OBJECTIVE: In people with low-grade intrinsic brain tumors, an epileptic focus is often located close to the lesion. High-frequency oscillations (HFOs) in electrocorticography (ECoG) might help to delineate this focus. We investigated the relationship between HFOs and low-grade brain tumors and their potential value for tumor-related epilepsy surgery. METHODS: We analyzed pre- and postresection intraoperative ECoG in 41 patients with refractory epilepsy and a low-grade lesion. Electrodes were designated as overlying the tumor, adjacent resected tissue (peritumoral), or outside the resection bed using magnetic resonance imaging (MRI) and intraoperative photographs. We then used a semiautomated approach to detect HFOs as either ripples (80-250 Hz) or fast ripples (250-500 Hz). RESULTS: The rate of fast ripples was higher in electrodes covering tumor and peritumoral tissue than outside the resection (p = .04). Mesiotemporal tumors showed more ripples (p = .002), but not more fast ripples (p = .07), than superficial tumors. Rates of fast ripples were higher in glioma and extraventricular neurocytoma than in ganglioglioma or dysembryoplastic neuroepithelial tumor (DNET). The rate of ripples and fast ripples in postresection ECoG was not higher in patients with residual tumor tissue on MRI than those without. The rate of ripples in postresection ECoG was higher in patients with good than bad seizure outcome (p = .03). Fast ripples outside the resection and in post-ECoG seem related to seizure recurrence. SIGNIFICANCE: Fast ripples in intraoperative ECoG can be used to help guide resection in tumor-related epilepsy surgery. Preresection fast ripples occur predominantly in epileptogenic tumor and peritumoral tissue. Fast ripple rates are higher in glioma and extraventricular neurocytoma than in ganglioglioma and DNET.

Increased gamma and decreased fast ripple connections of epileptic tissue: A high-frequency directed network approach.

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 [PPV]good  = 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.

Tailoring epilepsy surgery with fast ripples in the intraoperative electrocorticogram.

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. Ann Neurol 2017;81:664-676.

Ripples on rolandic spikes: A marker of epilepsy severity.

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.

High-frequency oscillations in scalp EEG: A systematic review of methodological choices and clinical findings.

OBJECTIVE: Pathological high-frequency oscillations (HFOs) in intracranial EEG are promising biomarkers of epileptogenic tissue, and their physiological counterparts play a role in sensorimotor and cognitive function. HFOs have also been found in scalp EEG, but an overview of all studies is lacking. In this systematic review, we assessed the methodology to detect scalp HFOs and their clinical potential. METHODS: We searched PubMed, Embase and the Cochrane Library for studies on HFOs in scalp EEG, and extracted methodological and clinical data. RESULTS: We included 60 studies with data from 1149 unique individuals. Two-thirds of studies analyzed HFOs visually in the time or time-frequency domain, and one-third automatically with visual validation. Most studies evaluated interictal ripples during sleep in children. Pathological HFOs were overall better than spikes in localizing the epileptogenic zone and predicting outcome, correlated negatively with cognition and positively with disease activity and severity, and decreased after medical and surgical treatment. CONCLUSIONS: The methodologies of the 60 studies were heterogeneous, but pathological scalp HFOs were clinically valuable as biomarkers in various situations, particularly in children with epilepsy. SIGNIFICANCE: This systematic review gives an extensive overview of methodological and clinical data on scalp HFOs, establishing their clinical potential and discussing their limitations.

High frequency oscillations associate with neuroinflammation in low-grade epilepsy associated tumors.

OBJECTIVE: High frequency oscillations (HFOs) in intraoperative electrocorticography (ioECoG) are thought to be generated by hyperexcitable neurons. Inflammation may promote neuronal hyperexcitability. We investigated the relation between HFOs and inflammation in tumor-related epilepsy. METHODS: We identified HFOs (ripples 80-250 Hz, fast ripples 250-500 Hz) in the preresection ioECoG of 32 patients with low-grade tumors. Localization of recorded HFOs was classified based on magnetic resonance imaging reconstructions: in tumor, in resected non-tumorous area and outside the resected area. We tested if the following inflammatory markers in the tumor or peritumoral tissue were related to HFOs: activated microglia, cluster of differentiation 3 (CD3)-positive T-cells, interleukin 1-beta (IL1ß), toll-like receptor 4 (TLR4) and high mobility group box 1 protein (HMGB1). RESULTS: Tumors that generated ripples were infiltrated by more CD3-positive cells than tumors without ripples. Ripple rate outside the resected area was positively correlated with IL1ß/TLR4/HMGB1 pathway activity in peritumoral area. These two areas did not directly overlap. CONCLUSIONS: Ripple rates may be associated with inflammatory processes. SIGNIFICANCE: Our findings support that ripple generation and spread might be associated with synchronized fast firing of hyperexcitable neurons due to certain inflammatory processes. This pilot study provides arguments for further investigations in HFOs and inflammation.

Intraoperative electrocorticography using high-frequency oscillations or spikes to tailor epilepsy surgery in the Netherlands (the HFO trial): a randomised, single-blind, adaptive non-inferiority trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: UMCU Alexandre Suerman, EpilepsieNL, RMI Talent Fellowship, European Research Council, and MING Fund.

Are HFOs in the Intra-operative ECoG Related to Hippocampal Sclerosis, Volume and IQ?

Temporal lobe epilepsy (TLE) is the most common form of refractory focal epilepsy and is often associated with hippocampal sclerosis (HS) and cognitive disturbances. Over the last decade, high frequency oscillations (HFOs) in the intraoperative electrocorticography (ioECoG) have been proposed to be biomarkers for the delineation of epileptic tissue but hippocampal ripples have also been associated with memory consolidation. Healthy hippocampi can show prolonged ripple activity in stereo- EEG. We aimed to identify how the HFO rates [ripples (80-250 Hz, fast ripples (250-500 Hz); prolonged ripples (80-250 Hz, 200-500 ms)] in the pre-resection ioECoG over subtemporal area (hippocampus) and lateral temporal neocortex relate to presence of hippocampal sclerosis, the hippocampal volume quantified on MRI and the severity of cognitive impairment in TLE patients. Volumetric measurement of hippocampal subregions was performed in 47 patients with TLE, who underwent ioECoG. Ripples, prolonged ripples, and fast ripples were visually marked and rates of HFOs were calculated. The intellectual quotient (IQ) before resection was determined. There was a trend toward higher rates of ripples and fast ripples in subtemporal electrodes vs. the lateral neocortex (ripples: 2.1 vs. 1.3/min; fast ripples: 0.9 vs. 0.2/min). Patients with HS showed higher rates of subtemporal fast ripples than other patients (Z = -2.51, p = 0.012). Prolonged ripples were only found in the lateral temporal neocortex. The normalized ratio (smallest/largest) of hippocampal volume was correlated to pre-resection IQ (r = 0.45, p = 0.015). There was no correlation between HFO rates and hippocampal volumes or HFO rates and IQ. To conclude, intra-operative fast ripples were a marker for HS, but ripples and fast ripples were not linearly correlated with either the amount of hippocampal atrophy, nor for pre-surgical IQ.

High-frequency oscillations recorded with surface EEG in neonates with seizures.

OBJECTIVE: Neonatal seizures are often the first symptom of perinatal brain injury. High-frequency oscillations (HFOs) are promising new biomarkers for epileptogenic tissue and can be found in intracranial and surface EEG. To date, we cannot reliably predict which neonates with seizures will develop childhood epilepsy. We questioned whether epileptic HFOs can be generated by the neonatal brain and potentially predict epilepsy. METHODS: We selected 24 surface EEGs sampled at 2048 Hz with 175 seizures from 16 neonates and visually reviewed them for HFOs. Interictal epochs were also reviewed. RESULTS: We found HFOs in thirteen seizures (7%) from four neonates (25%). 5025 ictal ripples (rate 10 to 1311/min; mean frequency 135 Hz; mean duration 66 ms) and 1427 fast ripples (rate 8 to 356/min; mean frequency 298 Hz; mean duration 25 ms) were marked. Two neonates (13%) showed interictal HFOs (285 ripples and 25 fast ripples). Almost all HFOs co-occurred with sharp transients. We could not find a relationship between neonatal HFOs and outcome yet. CONCLUSIONS: Neonatal HFOs co-occur with ictal and interictal sharp transients. SIGNIFICANCE: The neonatal brain can generate epileptic ripples and fast ripples, particularly during seizures, though their occurrence is not common and potential clinical value not evident yet.

High frequency oscillations relate to cognitive improvement after epilepsy surgery in children.

OBJECTIVE: To investigate how high frequency oscillations (HFOs; ripples 80-250 Hz, fast ripples (FRs) 250-500 Hz) and spikes in intra-operative electrocorticography (ioECoG) relate to cognitive outcome after epilepsy surgery in children. METHODS: We retrospectively included 20 children who were seizure free after epilepsy surgery using ioECoG and determined their intelligence quotients (IQ) pre- and two years postoperatively. We analyzed whether the number of HFOs and spikes in pre- and postresection ioECoGs, and their change in the non-resected areas relate to cognitive improvement (with ≥ 5 IQ points increase considered to be clinically relevant (=IQ+ group) and < 5 IQ points as irrelevant (=IQ- group)). RESULTS: The IQ+ group showed significantly more FRs in the resected tissue (p = 0.01) and less FRs in the postresection ioECoG (p = 0.045) compared to the IQ- group. Postresection decrease of ripples on spikes was correlated with postoperative cognitive improvement (correlation coefficient = -0.62 with p = 0.01). CONCLUSIONS: Postoperative cognitive improvement was related to reduction of pathological HFOs signified by removing FR generating areas with subsequently less residual FRs, and decrease of ripples on spikes in the resection edge of the non-resected area. SIGNIFICANCE: HFOs recorded in ioECoG could play a role as biomarkers in the prediction and understanding of cognitive outcome after epilepsy surgery.

Non-harmonicity in high-frequency components of the intra-operative corticogram to delineate epileptogenic tissue during surgery.

OBJECTIVE: We aimed to test the potential of auto-regressive model residual modulation (ARRm), an artefact-insensitive method based on non-harmonicity of the high-frequency signal, to identify epileptogenic tissue during surgery. METHODS: Intra-operative electrocorticography (ECoG) of 54 patients with refractory focal epilepsy were recorded pre- and post-resection at 2048Hz. The ARRm was calculated in one-minute epochs in which high-frequency oscillations (HFOs; fast ripples, 250-500Hz; ripples, 80-250Hz) and spikes were marked. We investigated the pre-resection fraction of HFOs and spikes explained by the ARRm (h2-index). A general ARRm threshold was set and used to compare the ARRm to surgical outcome in post-resection ECoG (Pearson X2). RESULTS: ARRm was associated strongest with the number of fast ripples in pre-resection ECoG (h2=0.80, P<0.01), but also with ripples and spikes. An ARRm threshold of 0.47 yielded high specificity (95%) with 52% sensitivity for channels with fast ripples. ARRm values >0.47 were associated with poor outcome at channel and patient level (both P<0.01) in post-resection ECoG. CONCLUSIONS: The ARRm algorithm might enable intra-operative delineation of epileptogenic tissue. SIGNIFICANCE: ARRm is the first unsupervised real-time analysis that could provide an intra-operative, 'on demand' interpretation per electrode about the need to remove underlying tissue to optimize the chance of seizure freedom.

Brain areas with epileptic high frequency oscillations are functionally isolated in MEG virtual electrode networks.

OBJECTIVE: Previous studies have associated network hubs and epileptiform activity, such as spikes and high frequency oscillations (HFOs), with the epileptogenic zone. The epileptogenic zone is approximated by the area that generates interictal epileptiform activity: the irritative zone. Our aim was to determine the relation between network hubs and the irritative zone. METHODS: Interictal resting-state MEG recordings of 12 patients with refractory epilepsy were analysed. Beamformer-based virtual electrodes were calculated at 70 locations around the epileptic spikes (irritative zone) and in the contralateral hemisphere. Spikes and HFOs were marked in all virtual electrodes. A minimum spanning tree network was generated based on functional connectivity (phase lag index; PLI) between all virtual electrodes to calculate the betweenness centrality, an indicator of hub status of network nodes. RESULTS: Betweenness centrality was low, and PLI was high, in virtual electrodes close to the centre of the irritative zone, and in virtual electrodes with many spikes and HFOs. CONCLUSION: Node centrality increases with distance from brain areas with spikes and HFOs, consistent with the idea that the irritative zone is a functionally isolated part of the epileptic network during the interictal state. SIGNIFICANCE: A new hypothesis about a pathological hub located remotely from the irritative zone and seizure onset zone opens new ways for surgery when epileptogenic areas and eloquent cortex coincide.

Residual fast ripples in the intraoperative corticogram predict epilepsy surgery outcome.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.