Pharmacoresistant Focal Epilepsy Research Articles

Subject-based assessment of large-scale integration dynamics in epileptic brain networks: insights from the intrinsic ignition framework.

This study examined the dynamic properties of brain regions involved in the genesis and spread of seizures in 10 individuals diagnosed with pharmacoresistant focal epilepsy. The patients and 30 healthy controls underwent resting-state functional magnetic resonance imaging scans and the brain's functional network dynamics were analyzed using the intrinsic ignition framework. Comparative statistical analyses examined the differences in the integration and metastability measures in both groups in the whole brain and specific local brain regions. Invasive electroencephalography evaluations validated the findings of significant global and regional changes in the patient's brain network dynamics. There was a marked increase in global integration and metastability across the brain, reflecting substantial alterations in the overall connectivity and flexibility of the functional networks. Specific brain regions exhibited paradoxical dynamics within the seizure onset zone, with decreased intrinsic ignition and increased metastability. Increased intrinsic ignition was observed in remote brain regions, suggesting a reorganization of the brain network hubs and potential pathways for seizure propagation. Using the intrinsic ignition framework provided insights into dynamic alterations in the brain networks of patients with epilepsy. These have increased our understanding of the mechanisms underlying epileptic seizures and may guide the development of diagnostic biomarkers and targeted therapeutic interventions.

Mapping Functional Connectivity Signatures of Pharmacoresistant Focal Cortical Dysplasia-Related Epilepsy.

To determine common network alterations in focal cortical dysplasia pharmacoresistant epilepsy (FCD-PRE) using functional connectivity analysis of resting-state functional magnetic resonance imaging (rsfMRI). This is a retrospective imaging cohort from Children's National Hospital (Washington, DC, USA) from January, 2011 to January, 2022. Patients with 3-T MRI-confirmed FCD-PRE underwent rsfMRI as part of routine clinical care. Patients were included if they were age 5-22 years at the time of the scan, and had a minimum of 18 months of follow-up. Healthy, typically-developing controls were included from Children's National Hospital (n = 16) and matched from Human Connectome Project-Development public dataset (n = 100). A total of 42 FCD-PRE patients (20 M:22 F, aged 14.2 ± 4.1 years) and 116 healthy controls (56 M:60 F, aged 13.7 ± 3.3 years) with rsfMRI were included. Seed-based functional connectivity maps were generated for each FCD, and each seed was used to generate a patient-specific z-scored connectivity map on 116 controls. FCD-PRE patients had mutual altered connectivity in regions of dorsal attention, default mode, and control networks. Functional connectivity was diminished within the FCD dominant functional network, as well as in homotopic regions. Cluster specific connectivity patterns varied by pathological subtype. Higher FCD connectivity to the limbic network was associated with increased odds of Engel I outcome. This study demonstrates diminished functional connectivity patterns in FCD-PRE, which may represent a neuromarker for the disease, independent of FCD location, involving the dorsal attention, default mode, and control functional networks. Higher connectivity to the limbic network is associated with a seizure-free outcome. Future multicenter, prospective studies are needed to allow for much earlier detection of signatures of treatment-resistant epilepsy. ANN NEUROL 2024.

Neurorehabilitation after epilepsy surgery in the temporal lobe in patients with specific neurocognitive risk profiles

In case of pharmacoresistant focal epilepsy, surgery is often the only way to achieve seizure freedom. These operations may result in cognitive deficits, especially with surgery in the left temporal lobe. The aim of this study was to determine whether patients operated in the left or right temporal lobe, respectively, have different cognitive outcomes. Furthermore, it was investigated if there was a positive influence of occupational therapy on neurorehabilitation in epilepsy patients. In all patients cognitive performance was assessed preoperatively and six months postoperatively. Patient groups with surgery in the right and left temporal lobe were compared. Additionally, single cases of patients who had undergone extensive pre- and postoperative occupational therapy were analyzed. There was a significantly better cognitive outcome in patients who underwent surgery in their right temporal lobe. Occupational therapy was highly beneficial in patients after left temporal lobe surgery. Occupational therapy after left temporal lobe surgery is adapted to find individual solutions for the patient's problems and to implement effective cognitive training strategies.

Combining magnetic resonance fingerprinting with voxel-based morphometric analysis to reduce false positives for focal cortical dysplasia detection.

We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis. We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-testswere performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level. MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients. This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting invivo pathological changes. © 2024 International League Against Epilepsy.

Seizure Cycles under Pharmacotherapy.

This study was undertaken to determine the effects of antiseizure medications (ASMs) on multidien (multiday) cycles of interictal epileptiform activity (IEA) and seizures and evaluate their potential clinical significance. We retrospectively analyzed up to 10 years of data from 88 of the 256 total adults with pharmacoresistant focal epilepsy who participated in the clinical trials of the RNS System, an intracranial device that keeps records of IEA counts. Following adjunctive ASM trials, we evaluated changes over months in (1) rates of self-reported disabling seizures and (2) multidien IEA cycle strength (spectral power for periodicity between 4 and 40 days). We used a survival analysis and the receiver operating characteristics to assess changes in IEA as a predictor of seizure control. Among 56 (33.3%) of the 168 adjunctive ASM trials suitable for analysis, ASM introduction was followed by an average 50 to 70% decrease in multidien IEA cycle strength and a concomitant 50 to 70% decrease in relative seizure rate for up to 12 months. Individuals with a ≥50% decrease in IEA cycle strength in the first 3 months of an ASM trial had a higher probability of remaining seizure responders (≥50% seizure rate reduction, p < 10-7) or super-responders (≥90%, p < 10-8) over the next 12 months. In this large cohort, a decrease in multidien IEA cycle strength following initiation of an adjunctive ASM correlated with seizure control for up to 12 months, suggesting that fluctuations in IEA mirror "disease activity" in pharmacoresistant focal epilepsy and may have clinical utility as a biomarker to predict treatment response. ANN NEUROL 2024;95:743-753.

Insular lobe epilepsy. Part 2: presurgical evaluation & surgical interventions with stereo-electroencephalography

Identification of insular lobe epilepsy (ILE) presents a major clinical challenge in the diagnosis and treatment of drug-resistant focal epilepsies. ILE has diverse clinical presentations due to the multifaceted functions of the insula. Surface EEG findings do not provide straightforward information to predict this deeply-situated origin of seizures; they are even misleading, masquerading as those of other focal epilepsies, such as temporal and frontal ones. Non-invasive imagings may disclose insular abnormalities, but extra-insular abnormalities can coexist or even stand out. Careful reading and a second-look guided by other clinical information are crucial in order not to miss subtle insulo-opercular abnormalities. Furthermore, a possible insular origin of seizures should be considered in MRI-negative frontal/temporal/parietal epilepsies. Therefore, exploration/exclusion of insular-origin seizures is necessary for a great majority of surgical candidates. As for the stereo-electroencephalography, considered as the gold standard method for intra-cranial EEG investigations with suspicion of ILE, planning of electrode positions/trajectories require sufficient knowledge of the functional localization and anatomo-functional connectivity of the insula. Dense sampling within the insula is required in patients with probable ILE, because the seizure-onset zone can be restricted to a single insular gyrus or even a part of it. It is also crucial to explore extra-insular regions on the basis of non-invasive investigation results while considering their anatomo-functional relationships with the insula. From a surgical perspective, differentiating seizures strictly confined to the insula from those extending to the opercula is of particular importance. Pure insular seizures can be treated with less invasive measures, such as radiofrequency thermocoagulation. To conclude, close attention must be paid to the possibility of ILE throughout the diagnostic workup. The precise identification/exclusion of ILE is a prerequisite to provide appropriate and effective surgical treatment in pharmaco-resistant focal epilepsies.

SEEG electrode shaft affects amplitude and latency of potentials evoked with single pulse electrical stimulation

BackgroundLong and thin shaft electrodes are implanted intracerebrally for stereoelectroencephalography (SEEG) in patients with pharmacoresistant focal epilepsies. Two adjacent contacts of one of such electrodes can deliver a train of single pulse electrical stimulations (SPES), and evoked potentials (EPs) are recorded on other contacts. In this study we assess if stimulating and recording on the same shaft, as opposed to different shafts, has an impact on common EP features. New methodWe leverage the large volume of SEEG data gathered in the F-TRACT database and analyze data from nearly one thousand SEEG implantations in order to verify whether stimulation and recording from the same shaft influence the EP pattern. ResultsWe found that when the stimulated and the recording contacts were located on the same shaft, the mean and median amplitudes of an EP are greater, and its mean and median latencies are smaller than when the contacts were located on different shafts. This effect is small (Cohen’s d ∼ 0.1), but robust (p-value < 10-3) across the SEEG database. Comparison with existing method(s)Our study is the first one to address this question. Due to the choice of commonly used EP features, our method is congruent with other studies. ConclusionsThe magnitude of the reported effect does not obligate all standard analyses to correct for it, unless they aim at high precision. The source of the effect is not clear. Manufacturers of SEEG electrodes could examine it and potentially minimize the effect in their future products.

Implementation of a 7T Epilepsy Task Force consensus imaging protocol for routine presurgical epilepsy work-up: effect on diagnostic yield and lesion delineation

ObjectiveRecently, the 7 Tesla (7 T) Epilepsy Task Force published recommendations for 7 T magnetic resonance imaging (MRI) in patients with pharmaco-resistant focal epilepsy in pre-surgical evaluation. The objective of this study was to implement and evaluate this consensus protocol with respect to both its practicability and its diagnostic value/potential lesion delineation surplus effect over 3 T MRI in the pre-surgical work-up of patients with pharmaco-resistant focal onset epilepsy.MethodsThe 7 T MRI protocol consisted of T1-weighted, T2-weighted, high-resolution-coronal T2-weighted, fluid-suppressed, fluid-and-white-matter-suppressed, and susceptibility-weighted imaging, with an overall duration of 50 min. Two neuroradiologists independently evaluated the ability of lesion identification, the detection confidence for these identified lesions, and the lesion border delineation at 7 T compared to 3 T MRI.ResultsOf 41 recruited patients > 12 years of age, 38 were successfully measured and analyzed. Mean detection confidence scores were non-significantly higher at 7 T (1.95 ± 0.84 out of 3 versus 1.64 ± 1.19 out of 3 at 3 T, p = 0.050). In 50% of epilepsy patients measured at 7 T, additional findings compared to 3 T MRI were observed. Furthermore, we found improved border delineation at 7 T in 88% of patients with 3 T-visible lesions. In 19% of 3 T MR-negative cases a new potential epileptogenic lesion was detected at 7 T.ConclusionsThe diagnostic yield was beneficial, but with 19% new 7 T over 3 T findings, not major. Our evaluation revealed epilepsy outcomes worse than ILAE Class 1 in two out of the four operated cases with new 7 T findings.

Effects of inverse methods and spike phases on interictal high-density EEG source reconstruction

ObjectiveTo determine the effect of inverse methods and timepoints of interictal epileptic discharges (IEDs) used for high-density electric source imaging (hd-ESI) in pharmacoresistant focal epilepsies. MethodsWe retrospectively evaluated the hd-ESI and [18F]fluorodeoxyglucose positron emission tomography (18FDG-PET) of 21 operated patients with pharmacoresistant focal epilepsy (Engel I). Volumetric hd-ESI was performed with three different inverse methods such as the inverse solution linearly constrained minimum variance (LCMV, a beamformer method), standardized low resolution electromagnetic tomography (sLORETA) and weighted minimum-norm estimation (wMNE) and at different IED phases. Hd-ESI accuracy was determined by volumetric overlap and distance between hd-ESI source maximum, as well as 18FDG-PET hypometabolic region relative to the resection zone (RZ). ResultsIn our cohort, the shortest distances and greatest volumetric overlaps to the RZ were found in the half-rise and peak-phase for all inverse methods. The distance to the RZ was not different between the centroid of the clinical hypothesis-based cluster and the source maximum in peak-phase. However, the distance of the hypothesis-based cluster was significantly shorter compared to the cluster selected by the smallest p-value. ConclusionsHd-ESI provides the greatest accuracy in determining the RZ at the IED half-rise and peak-phase for all applied inverse methods, whereby sLORETA and LCMV were equally accurate. SignificanceOur results offer guidance in selecting inverse methods and IED phases for hd-ESI, compare the performance of hd-ESI and 18FDG-PET and encourage future studies in investigating the relationship between interictal ESI and 18FDG-PET hypometabolism.

Cell-type specific and multiscale dynamics of human focal seizures in limbic structures.

The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the transition to seizure is complex, potentially leading to imprecise delineation of epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing and others suggesting reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principle applies in limbic structures. We analysed simultaneous electrocorticography (ECoG) and neuronal recordings of 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, which at times co-existed within seizures. Overall, 156 single units were isolated, subclassified by cell-type and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (P < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition, with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (P = 0.014). This study provides evidence for entrained high-gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, reduced neuronal firing suggested preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or indicates a 'seizure-responsive' state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help to refine the surgical treatment of mesial temporal lobe epilepsy.

The probability of achieving remission after correction of therapy in patients with pharmacoresistant focal epilepsy

Drug-resistant forms of epilepsy are an important medical and social problem.Goal of the work. Evaluation of the probability of achieving remission after correction of therapy in patients with drug-resistant focal epilepsy.Material and methods. The study included 309 patients divided into three heterogeneous groups: a group of patients with focal pharmacoresistant epilepsy; a group of patients with super refractory focal epilepsy; control group – patients who had not previously received treatment. The examination included history taking, clinical and neurological examination, routine EEG and/or EEG video monitoring, MRI of the brain, and analysis of medical records. Therapy was adjusted.Results. After correction of therapy, remission in patients in Group 1 was achieved in 27.8% of patients, improvement – in 27.1%, no effect – in 45.1%; in Group 2, remission was achieved in 13.2% of patients, improvement – in 28.6%, no effect – in 58.2%; in Group 3, remission was achieved in 41.2% of patients, improvement – in 32.9%, no effect – in 25.9%. Negative prognostic factors did not show a significant correlation with the lack of effect of therapy.Conclusion. After correction of therapy, remission was achieved in several patients with drug-resistant focal epilepsy, while negative prognostic factors do not exclude the possibility of achieving remission.

Ipsilateral preictal alpha rhythm attenuation (IPARA): An EEG sign of side of seizure onset in temporal lobe epilepsy

PurposeIdentification of the seizure onset zone is critically important for outlining the surgical plan in the treatment of pharmacoresistant focal epilepsy. In patients with temporal lobe epilepsy (TLE), bilateral ictal scalp EEG changes frequently occur and can make lateralization of the seizure onset zone difficult. We investigated the incidence and clinical utility of unilateral preictal alpha rhythm attenuation as a lateralizing sign of seizure onset in TLE. MethodsScalp EEG recordings of the seizures acquired during presurgical video-EEG monitoring of 57 consecutive patients with TLE were reviewed retrospectively. Included patients had interictal baseline recordings demonstrating symmetrical posterior alpha rhythm and seizures occurring during wakefulness. ResultsWe identified a total of 649 seizures in the 57 patients, of which 448 seizures in 53 patients fulfilled the inclusion criteria. Among the 53 included patients, 7 patients (13.2%) exhibited a distinct attenuation of the posterior alpha rhythm prior to the first ictal EEG changes, in 26 of 112 (23.2%) included seizures. Preictal alpha rhythm attenuation in these seizures was ipsilateral to the ultimately determined side of seizure onset (based on video-EEG or intracranial EEG findings) in 22 (84.6%) of these seizures and bilateral in 4 (15.4%), and occurred on average 5.9 ± 2.6 s prior to ictal EEG onsets. ConclusionOur findings suggest that in some patients with TLE lateralized preictal attenuation of the posterior alpha rhythm may be a useful indicator of side of seizure onset, presumably due to early disruption of thalamo-temporo-occipital network function, likely mediated through the thalamus.

Feasibility of high-density electric source imaging in the presurgical workflow: Effect of number of spikes and automated spike detection.

Presurgical high-density electric source imaging (hdESI) of interictal epileptic discharges (IEDs) is only used by few epilepsy centers. One obstacle is the time-consuming workflow both for recording as well as for visual review. Therefore, we analyzed the effect of (a) an automated IED detection and (b) the number of IEDs on the accuracy of hdESI and time-effectiveness. In 22 patients with pharmacoresistant focal epilepsy receiving epilepsy surgery (Engel 1) we retrospectively detected IEDs both visually and semi-automatically using the EEG analysis software Persyst in 256-channel EEGs. The amount of IEDs, the Euclidean distance between hdESI maximum and resection zone, and the operator time were compared. Additionally, we evaluated the intra-individual effect of IED quantity on the distance between hdESI maximum of all IEDs and hdESI maximum when only a reduced amount of IEDs were included. There was no significant difference in the number of IEDs between visually versus semi-automatically marked IEDs (74 ± 56 IEDs/patient vs 116 ± 115 IEDs/patient). The detection method of the IEDs had no significant effect on the mean distances between resection zone and hdESI maximum (visual: 26.07 ± 31.12 mm vs semi-automated: 33.6 ± 34.75 mm). However, the mean time needed to review the full datasets semi-automatically was shorter by 275 ± 46 min (305 ± 72 min vs 30 ± 26 min, P < 0.001). The distance between hdESI of the full versus reduced amount of IEDs of the same patient was smaller than 1 cm when at least a mean of 33 IEDs were analyzed. There was a significantly shorter intraindividual distance between resection zone and hdESI maximum when 30 IEDs were analyzed as compared to the analysis of only 10 IEDs (P < 0.001). Semi-automatized processing and limiting the amount of IEDs analyzed (~30-40 IEDs per cluster) appear to be time-saving clinical tools to increase the practicability of hdESI in the presurgical work-up.

Interictal Electrical Source Imaging.

Interictal electrical source imaging (ESI) determines the neuronal generators of epileptic activity in EEG occurring outside of seizures. It uses computational models to take anatomic and neuronal characteristics of the individual patient into account. The presented article provides an overview of application and clinical value of interictal ESI in patients with pharmacoresistant focal epilepsies undergoing evaluation for surgery. Neurophysiological constraints of interictal data are discussed and technical considerations are summarized. Typical indications are covered as well as issues of integration into clinical routine. Finally, an outlook on novel markers of epilepsy for interictal source analysis is presented. Interictal ESI provides diagnostic performance on par with other established methods, such as MRI, PET, or SPECT. Although its accuracy benefits from high-density recordings, it provides valuable information already when applied to EEG with only a limited number of electrodes with complete coverage. Novel oscillatory markers and the integration of frequency coupling and connectivity may further improve accuracy and efficiency.

Spatiotemporal spike-centered averaging reveals symmetry of temporal and spatial components of the spike-LFP relationship during human focal seizures

The electrographic manifestation of neural activity can reflect the relationship between the faster action potentials of individual neurons and the slower fluctuations of the local field potential (LFP). This relationship is typically examined in the temporal domain using the spike-triggered average. In this study, we add a spatial component to this relationship. Here we first derive a theoretical model of the spike-LFP relationship across a macroelectrode. This mathematical derivation showed a special symmetry in the spike-LFP relationship wherein a sinc function in the temporal domain predicts a sinc function in the spatial domain. We show that this theoretical result is observed in a real-world system by characterizing the spike-LFP relationship using microelectrode array (MEA) recordings of human focal seizures. To do this, we present a approach, termed the spatiotemporal spike-centered average (st-SCA), that allows for visualization of the spike-LFP relationship in both the temporal and spatial domains. We applied this method to 25 MEA recordings obtained from seven patients with pharmacoresistant focal epilepsy. Of the five patients with MEAs implanted in recruited territory, three exhibited spatiotemporal patterns consistent with a sinc function, and two exhibited spatiotemporal patterns resembling deep wells of excitation. These results suggest that in some cases characterization of the spike-LFP relationship in the temporal domain is sufficient to predict the underlying spatial pattern. Finally, we discuss the biological interpretation of these findings and propose that the sinc function may reflect the role of mid-range excitatory connections during seizure activity.

Artificial intelligence for the detection of focal cortical dysplasia: Challenges in translating algorithms into clinical practice.

Focal cortical dysplasias (FCDs) are malformations of cortical development and one of the most common pathologies causing pharmacoresistant focal epilepsy. Resective neurosurgery yields high success rates, especially if the full extent of the lesion is correctly identified and completely removed. The visual assessment of magnetic resonance imaging does not pinpoint the FCD in 30%-50% of cases, and half of all patients with FCD are not amenable to epilepsy surgery, partly because the FCD could not be sufficiently localized. Computational approaches to FCD detection are an active area of research, benefitting from advancements in computer vision. Automatic FCD detection is a significant challenge and one of the first clinical grounds where the application of artificial intelligence may translate into an advance for patients' health. The emergence of new methods from the combination of health and computer sciences creates novel challenges. Imaging data need to be organized into structured, well-annotated datasets and combined with other clinical information, such as histopathological subtypes or neuroimaging characteristics. Algorithmic output, that is, model prediction, requires a technically correct evaluation with adequate metrics that are understandable and usable for clinicians. Publication of code and data is necessary to make research accessible and reproducible. This critical review introduces the field of automatic FCD detection, explaining underlying medical and technical concepts, highlighting its challenges and current limitations, and providing a perspective for a novel research environment.

Relative entropy is an easy-to-use invasive electroencephalographic biomarker of the epileptogenic zone.

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. 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. 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. 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.

MEG Node Degree for Focus Localization: Comparison with Invasive EEG.

Epilepsy surgery is a viable therapy option for patients with pharmacoresistant focal epilepsies. A prerequisite for postoperative seizure freedom is the localization of the epileptogenic zone, e.g., using electro- and magnetoencephalography (EEG/MEG). Evidence shows that resting state MEG contains subtle alterations, which may add information to the workup of epilepsy surgery. Here, we investigate node degree (ND), a graph-theoretical parameter of functional connectivity, in relation to the seizure onset zone (SOZ) determined by invasive EEG (iEEG) in a consecutive series of 50 adult patients. Resting state data were subjected to whole brain, all-to-all connectivity analysis using the imaginary part of coherence. Graphs were described using parcellated ND. SOZ localization was investigated on a lobar and sublobar level. On a lobar level, all frequency bands except alpha showed significantly higher maximal ND (mND) values inside the SOZ compared to outside (ratios 1.11-1.20, alpha 1.02). Area-under-the-curve (AUC) was 0.67-0.78 for all expected alpha (0.44, ns). On a sublobar level, mND inside the SOZ was higher for all frequency bands (1.13-1.38, AUC 0.58-0.78) except gamma (1.02). MEG ND is significantly related to SOZ in delta, theta and beta bands. ND may provide new localization tools for presurgical evaluation of epilepsy surgery.

Gene Therapy for Epilepsy: Clinical Studies are on the Road

For more than 10 years, research has been conducted on gene therapies for the most severe forms of epilepsy, which until now have proven resistant to treatment. First gene therapies are now in clinical trials for pharmacoresistant focal epilepsies and Dravet syndrome. In this article, we describe how these and many more gene therapies work and what they target.

Evaluating whole-brain tissue-property changes in MRI-negative pharmacoresistant focal epilepsies using MR fingerprinting.

We aim to quantify whole-brain tissue-property changes in patients with magnetic resonance imaging (MRI)-negative pharmacoresistant focal epilepsy by three-dimensional (3D) magnetic resonance fingerprinting (MRF). We included 30 patients with pharmacoresistant focal epilepsy and negative MRI by official radiology report, as well as 40 age- and gender-matched healthy controls (HCs). MRF scans were obtained with 1 mm3 isotropic resolution. Quantitative T1 and T2 relaxometry maps were reconstructed from MRF and registered to the Montreal Neurological Institute (MNI) space. A two-sample t test was performed in Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) to evaluate significant abnormalities in patients comparing to HCs, with correction by the threshold-free cluster enhancement (TFCE) method. Subgroups analyses were performed for extra-temporal epilepsy/temporal epilepsy (ETLE/TLE), and for those with/without subtle abnormalities detected by morphometric analysis program (MAP), to investigate each subgroup's pattern of MRF changes. Correlation analyses were performed between the mean MRF values in each significant cluster and seizure-related clinical variables. Compared to HCs, patients exhibited significant group-level T1 increase ipsilateral to the epileptic origin, in the mesial temporal gray matter (GM) and white matter (WM), temporal pole GM, orbitofrontal GM, hippocampus, and amygdala, with scattered clusters in the neocortical temporal and insular GM. No significant T2 changes were detected. The ETLE subgroup showed a T1-increase pattern similar to the overall cohort, with additional involvement of the ipsilateral anterior cingulate GM. The subgroup of MAP+ patients also showed a T1-increase pattern similar to the overall cohort, with additional cluster in the ipsilateral lateral orbitofrontal GM. Higher T1 was associated with younger seizure-onset age, longer epilepsy duration, and higher seizure frequency. MRF revealed group-level T1 increase in limbic/paralimbic structures ipsilateral to the epileptic origin, in patients with pharmacoresistant focal epilepsy and no apparent lesions on MRI, suggesting that these regions may be commonly affected by seizures in the epileptic brain. The significant association between T1 increase and higher seizure burden may reflect progressive tissue damage.