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-11 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. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd

Clinical neurophysiological correlates of histopathological abnormalities in epilepsy surgery

In search for variables that determine outcome in patients with pharmacoresistant epilepsy who undergo epilepsy surgery, we identified specific combinations of clinical neurophysiological findings with their underlying histopathology. These findings may have important surgical consequences. In a sample of patients with frontal lobe epilepsy, about 50% had an underlying diagnosis of focal cortical dysplasia. The pathology was not related to the surgical outcome. However, we found that contralateral head version, eye deviation and autonomic manifestions as ictal symptoms were associated with a poor outcome, whereas a focal abnormality on neuroimaging was related to a favourable outcome. Intraoperative electrocorticography (ECoG) in these patients revealed that dense epileptiform patterns (consisting of continuous spiking, bursts of spikes or recruiting discharges) in the preresection recordings were associated with a diagnosis of focal cortical dysplasia (sensitvity 94%, specificity 75%, positive predictive value 80%). The abolition of these patterns on postresection recordings was associated with a favourable outcome, whereas persistence of sporadic spikes and incomplete removal of histopathological abnormalities did not affect outcome. When studying the ECoG and histopathological findings in a sample of patients with neurodevelopmental lesions, we found that dense epileptiform ECoG patterns occurred in patients with focal cortical dysplasia, but also in those with a glioneuronal tumour (ganglioglioma or dysembryoplastic neuroepithelial tumour). One of these patterns, i.e. continuous spiking, was seen significantly more often in focal cortical dysplasia and this pattern was highly specific (96%) for the presence of a disorganized cortical architecture in the whole sample of patients. When studying patients with a cavernoma we found that dense epileptiform patterns occurred to a similar degree as in those with a neurodevelopmental lesion. In both patients with a neurodevelopmental lesion and cavernoma continuous spiking in the neocortex seems characteristic of early onset of seizures and such patterns may involve the hippocampus in time. We thus concluded that, in general, such patterns are not specific for neurodevelopmental lesions. We consider the expression of continuous neocortical spiking in the ECoG to be a marker of early disruption of functional systems in the developing brain. To investigate whether unilateral recognition memory was related to the neuronal integrity of the mesial temporal structures, metabolite ratios [NAA/(Cr+PCr), NAA/Cho, and NAA/(Cr+PCr+Cho)] from proton MR Spectroscopy were correlated with hemispheric memory scores from the Wada test. The total memory score, memory for objects and faces, and NAA/(Cr+PCr) were significantly lower for the hemisphere ipsilateral to the resection. Furthermore, we found positive correlations between unilateral memory for words and the NAA/(Cr+PCr) ratio from medial temporal structures in patients with mesial temporal sclerosis. The findings suggest that medial temporal structures play a significant role in recognition memory in humans, particularly for words and raise the question whether MR Spectroscopy can be used for presurgical memory lateralisation

Single Pulse Electrical Stimulation to identify epileptogenic cortex: Clinical information obtained from early evoked responses

Objective: Single Pulse Electrical Stimulation (SPES) probes epileptogenic cortex during electrocorticography. Two SPES responses are described: pathological delayed responses (DR, >100 ms) associated with the seizure onset zone (SOZ) and physiological early responses (ER, 80 Hz, in the SOZ and seizure propagation areas. Methods: We used data from 12 refractory epilepsy patients. SPES consisted of 10 pulses of 1 ms, 4–8 mA and 5 s interval on adjacent electrodes pairs. Data were available at 2048 samples/s for six and 512 samples/s (22 bits) for eight patients and analyzed in the time–frequency (TF) and time-domain (TD). Results: Electrodes with ERs were stronger associated with SOZ than non-SOZ electrodes. ERs with frequency content >80 Hz exist and are specific for SOZ channels. ERs evoked by stimulation of seizure onset electrodes were associated with electrodes involved in seizure propagation. Conclusion: Analysis of ERs can reveal aspects of pathology, manifested by association with seizure propagation and areas with high ER numbers that coincide with the SOZ. Significance: Not only DRs, but also ERs could have clinical value for mapping epileptogenic cortex and help to unravel aspects of the epileptic network

High frequency oscillations in intra-operative electrocorticography before and after epilepsy surgery

Objective Removal of brain tissue showing high frequency oscillations (HFOs; ripples: 80–250 Hz and fast ripples: 250–500 Hz) in preresection electrocorticography (preECoG) in epilepsy patients seems a predictor of good surgical outcome. We analyzed occurrence and localization of HFOs in intra-operative preECoG and postresection electrocorticography (postECoG). Methods HFOs were automatically detected in one-minute epochs of intra-operative ECoG sampled at 2048 Hz of fourteen patients. Ripple, fast ripple, spike, ripples on a spike (RoS) and not on a spike (RnoS) rates were analyzed in pre- and postECoG for resected and nonresected electrodes. Results Ripple, spike and fast ripple rates decreased after resection. RnoS decreased less than RoS (74% vs. 83%; p = 0.01). Most fast ripples in preECoG were located in resected tissue. PostECoG fast ripples occurred in one patient with poor outcome. Patients with good outcome had relatively high postECoG RnoS rates, specifically in the sensorimotor cortex. Conclusions Our observations show that fast ripples in intra-operative ECoG, compared to ripples, may be a better biomarker for epileptogenicity. Further studies have to determine the relation between resection of epileptogenic tissue and physiological ripples generated by the sensorimotor cortex. Significance Fast ripples in intra-operative ECoG can help identify the epileptogenic zone, while ripples might also be physiological

Landscape of chromosomal copy number aberrations in gangliogliomas and dysembryoplastic neuroepithelial tumours

Item does not contain fulltextAIM: Gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumours (DNTs) represent the most common histological entities within the spectrum of glioneuronal tumours (GNTs). The wide variability of morphological features complicates histological classification, including discrimination from prognostically distinct diffuse low-grade astrocytomas (AIIs). This study was performed to increase our understanding of these tumours. METHODS: We studied chromosomal copy number aberrations (CNAs) by genome-wide sequencing in a large cohort of GNTs and linked these to comprehensive histological analysis and clinical characteristics. One hundred fourteen GNTs were studied: 50 GGs and 64 DNTs. Also, a data set of CNAs from 38 diffuse AIIs was included. RESULTS: The most frequent CNAs in both GGs and DNTs were gains at chromosomes 5 and 7, often concurrent, and gain at chromosome 6. None of the CNAs was linked to histological subtype, immunohistochemical features or to clinical characteristics. Comparison of AIIs and diffuse GNTs revealed that gain at whole chromosome 5 is only observed in GNTs. CNA patterns indicative of chromothripsis were detected in three GNTs. CONCLUSION: We conclude that GNTs with diverse morphologies share molecular features, and our findings support the need to improve classification and differential diagnosis of tumour entities within the spectrum of GNTs, as well as their distinction from other gliomas

Is Fish Oil Good or Bad for Heart Disease? Two Trials with Apparently Conflicting Results

Two successive randomized trials examined the effect of an increased intake of fatty fish, or the use of fish oil supplements, in reducing mortality in men with heart disease. The Diet and Reinfarction Trial (DART) was conducted in 2033 men who were recovering from acute myocardial infarction (MI). Those who were advised to eat fatty fish (or who opted to take fish oil capsules instead) had a 29% reduction in all-cause mortality over the following two years compared with those not so advised. The effect appeared in the first few months of the trial. The Diet and Angina Randomized Trial (DART 2) involved 3114 men with stable angina. Advice to eat fatty fish did not reduce mortality, and taking fish oil capsules was associated with a higher risk of cardiac and sudden death. The adverse effects of fish or fish oil were restricted to men not taking β-blockers or dihydropyridine calcium-channel blockers, and were greater in those taking digoxin. Evidence from other sources strongly suggests an anti-arrhythmic action of fish oil, particularly after MI or in the presence of acute ischemia. The apparently conflicting results of the two trials may reflect different actions of n-3 fatty acids in acute and chronic conditions, together with different effects of eating fish and taking fish oil capsules. A mechanism is proposed that could account for these findings