Objective
High‐frequency oscillations are considered among the most promising interictal biomarkers of the epileptogenic zone in patients suffering from pharmacoresistant focal epilepsy. However, ...there is no clear definition of pathological high‐frequency oscillations, and the existing detectors vary in methodology, performance, and computational costs. This study proposes relative entropy as an easy‐to‐use novel interictal biomarker of the epileptic tissue.
Methods
We evaluated relative entropy and high‐frequency oscillation biomarkers on intracranial electroencephalographic data from 39 patients with seizure‐free postoperative outcome (Engel Ia) from three institutions. We tested their capability to localize the epileptogenic zone, defined as resected contacts located in the seizure onset zone. The performance was compared using areas under the receiver operating curves (AUROCs) and precision‐recall curves. Then we tested whether a universal threshold can be used to delineate the epileptogenic zone across patients from different institutions.
Results
Relative entropy in the ripple band (80–250 Hz) achieved an average AUROC of .85. The normalized high‐frequency oscillation rate in the ripple band showed an identical AUROC of .85. In contrast to high‐frequency oscillations, relative entropy did not require any patient‐level normalization and was easy and fast to calculate due to its clear and straightforward definition. One threshold could be set across different patients and institutions, because relative entropy is independent of signal amplitude and sampling frequency.
Significance
Although both relative entropy and high‐frequency oscillations have a similar performance, relative entropy has significant advantages such as straightforward definition, computational speed, and universal interpatient threshold, making it an easy‐to‐use promising biomarker of the epileptogenic zone.
Highlights • EEG-fMRI study of temporal lobe spikes to assess mesial and lateral structures. • T-values were higher in mesial temporal structures than in neocortex in most cases. • Spikes start in ...mesial structures, propagate to neocortex where scalp EEG records them.
Epileptic spikes are the traditional interictal electroencephalographic (EEG) biomarker for epilepsy. Given their low specificity for identifying the epileptogenic zone (EZ), they are given only ...moderate attention in presurgical evaluation. This study aims to demonstrate that it is possible to identify specific spike features in intracranial EEG that optimally define the EZ and predict surgical outcome.
We analyzed spike features on stereo-EEG segments from 83 operated patients from 2 epilepsy centers (37 Engel IA) in wakefulness, non-rapid eye movement sleep, and rapid eye movement sleep. After automated spike detection, we investigated 135 spike features based on rate, morphology, propagation, and energy to determine the best feature or feature combination to discriminate the EZ in seizure-free and non-seizure-free patients by applying 4-fold cross-validation.
The rate of spikes with preceding gamma activity in wakefulness performed better for surgical outcome classification (4-fold area under receiver operating characteristics curve AUC = 0.755 ± 0.07) than the seizure onset zone, the current gold standard (AUC = 0.563 ± 0.05, p = 0.015) and the ripple rate, an emerging seizure-independent biomarker (AUC = 0.537 ± 0.07, p = 0.006). Channels with a spike-gamma rate exceeding 1.9/min had an 80% probability of being in the EZ. Combining features did not improve the results.
Resection of brain regions with high spike-gamma rates in wakefulness is associated with a high probability of achieving seizure freedom. This rate could be applied to determine the minimal number of spiking channels requiring resection. In addition to quantitative analysis, this feature is easily accessible to visual analysis, which could aid clinicians during presurgical evaluation. ANN NEUROL 2023;93:522-535.
Summary
Objective
To increase the diagnostic power of scalp electroencephalography (EEG) by investigating whether lesion type and location influence the morphology of interictal epileptic discharges ...(IEDs) and the likelihood that IEDs and high‐frequency oscillations (HFOs) are present.
Methods
We studied EEG activity in epilepsy patients with lesional epilepsy. Lesions were classified by type and by location (region and depth). We marked a maximum of 50 IEDs during deep non–rapid eye movement sleep. IEDs were identified as spikes or sharp waves with or without slow waves, or bursts of spikes or sharp waves with or without slow waves. We analyzed HFOs in the studies showing at least 50 IEDs.
Results
In 192 scalp EEG studies, the differences in the percentage of studies showing IEDs in each depth‐related group were not statistically significant, whereas HFOs (55 studies) predominated in patients exhibiting superficial lesions (p<0.001). Sharp waves, as predominant pattern, were more prevalent in hippocampal abnormalities (p < 0.001), whereas bursts predominated in patients with malformations of cortical development (p < 0.001).
Significance
The depth of the lesion does not influence the presence of IEDs, as one might expect, but it influences that of HFOs. This is explained as follows. HFOs are generated in the epileptogenic region, do not propagate, and hence are only visible on scalp EEG with superficial lesions. IEDs can result from a nearby focus or propagate from a deep generator and are therefore equally present with deep, intermediate, and superficial lesions. Additionally, IED morphology provides information in determining the lesion type.
Objective
Developmental epileptic encephalopathies (DEEs) are genetically heterogeneous severe childhood‐onset epilepsies with developmental delay or cognitive deficits. In this study, we explored ...the pathogenic mechanisms of DEE‐associated de novo mutations in the CACNA1A gene.
Methods
We studied the functional impact of four de novo DEE‐associated CACNA1A mutations, including the previously described p.A713T variant and three novel variants (p.V1396M, p.G230V, and p.I1357S). Mutant cDNAs were expressed in HEK293 cells, and whole‐cell voltage‐clamp recordings were conducted to test the impacts on CaV2.1 channel function. Channel localization and structure were assessed with immunofluorescence microscopy and three‐dimensional (3D) modeling.
Results
We find that the G230V and I1357S mutations result in loss‐of‐function effects with reduced whole‐cell current densities and decreased channel expression at the cell membrane. By contrast, the A713T and V1396M variants resulted in gain‐of‐function effects with increased whole‐cell currents and facilitated current activation (hyperpolarized shift). The A713T variant also resulted in slower current decay. 3D modeling predicts conformational changes favoring channel opening for A713T and V1396M.
Significance
Our findings suggest that both gain‐of‐function and loss‐of‐function CACNA1A mutations are associated with similarly severe DEEs and that functional validation is required to clarify the underlying molecular mechanisms and to guide therapies.
Because seizures originate from different pathological substrates, the question arises of whether distinct or similar mechanisms underlie seizure generation across different pathologies. Better ...defining intracranial electroencephalographic morphological patterns at seizure-onset could improve the understanding of such mechanisms. To this end, we investigated intracranial electroencephalographic seizure-onset patterns associated with different epileptogenic lesions, and defined high-frequency oscillation correlates of each pattern. We analysed representative seizure types from 33 consecutive patients with drug-resistant focal epilepsy and a structural magnetic resonance imaging lesion (11 mesial temporal sclerosis, nine focal cortical dysplasia, six cortical atrophy, three periventricular nodular heterotopia, three polymicrogyria, and one tuberous sclerosis complex) who underwent depth-electrode electroencephalographic recordings (500 Hz filter, 2000 Hz sampling rate). Patients were included only if seizures arose from contacts located in lesional/peri-lesional tissue, and if clinical manifestations followed the electrographic onset. Seizure-onset patterns were defined independently by two reviewers blinded to clinical information, and consensus was reached after discussion. For each seizure, pre-ictal and ictal sections were selected for high-frequency oscillation analysis. Seven seizure-onset patterns were identified across the 53 seizures sampled: low-voltage fast activity (43%); low-frequency high-amplitude periodic spikes (21%); sharp activity at ≤13 Hz (15%); spike-and-wave activity (9%); burst of high-amplitude polyspikes (6%); burst suppression (4%); and delta brush (4%). Each pattern occurred across several pathologies, except for periodic spikes, only observed with mesial temporal sclerosis, and delta brush, exclusive to focal cortical dysplasia. However, mesial temporal sclerosis was not always associated with periodic spikes nor focal cortical dysplasia with delta brush. Compared to other patterns, low-voltage fast activity was associated with a larger seizure-onset zone (P = 0.04). Four patterns, sharp activity at ≤13 Hz, low-voltage fast activity, spike-and-wave activity and periodic spikes, were also found in regions of seizure spread, with periodic spikes only emerging from mesial temporal sclerosis. Each of the seven patterns was accompanied by a significant increase in high-frequency oscillations upon seizure-onset. Overall, our data indicate that: (i) biologically-distinct epileptogenic lesions share intracranial electroencephalographic seizure-onset patterns, suggesting that different pathological substrates can affect similarly networks or mechanisms underlying seizure generation; (ii) certain pathologies are associated with intracranial electroencephalographic signatures at seizure-onset, e.g. periodic spikes which may reflect mechanisms specific to mesial temporal sclerosis; (iii) some seizure-onset patterns, including periodic spikes, can also be found in regions of spread, which cautions against relying on the morphology of the initial discharge to define the epileptogenic zone; and (iv) high-frequency oscillations increase at seizure-onset, independently of the pattern.
Objective
Focal cortical dysplasia (FCD), hippocampal sclerosis (HS), nonspecific gliosis (NG), and normal tissue (NT) comprise the majority of histopathological results of surgically treated ...drug‐resistant epilepsy patients. Epileptic spikes, high‐frequency oscillations (HFOs), and connectivity measures are valuable biomarkers of epileptogenicity. The question remains whether they could also be utilized for preresective differentiation of the underlying brain pathology. This study explored spikes and HFOs together with functional connectivity in various epileptogenic pathologies.
Methods
Interictal awake stereoelectroencephalographic recordings of 33 patients with focal drug‐resistant epilepsy with seizure‐free postoperative outcomes were analyzed (15 FCD, 8 HS, 6 NT, and 4 NG). Interictal spikes and HFOs were automatically identified in the channels contained in the overlap of seizure onset zone and resected tissue. Functional connectivity measures (relative entropy, linear correlation, cross‐correlation, and phase consistency) were computed for neighboring electrode pairs.
Results
Statistically significant differences were found between the individual pathologies in HFO rates, spikes, and their characteristics, together with functional connectivity measures, with the highest values in the case of HS and NG/NT. A model to predict brain pathology based on all interictal measures achieved up to 84.0% prediction accuracy.
Significance
The electrophysiological profile of the various epileptogenic lesions in epilepsy surgery patients was analyzed. Based on this profile, a predictive model was developed. This model offers excellent potential to identify the nature of the underlying lesion prior to resection. If validated, this model may be particularly valuable for counseling patients, as depending on the lesion type, different outcomes are achieved after epilepsy surgery.
Highlights • Scalp ripples can be used as an additional tool to lateralize the epileptic focus in secondary bilateral synchrony. • In idiopathic generalized epilepsy scalp ripples are recordable and ...show an anterior dominance. • To differentiate focal patients with secondary bilateral synchrony from patients with idiopathic generalized epilepsy scalp ripples are not useful.
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