Epileptogenicity In Patients Research Articles

Prediction of epileptogenicity in patients with tuberous sclerosis complex using multimodal cerebral MRI

ObjectiveEpilepsy is the most common complication and cause of morbidity and mortality in tuberous sclerosis complex (TSC). Surgery is associated with an increased probability of achieving seizure-freedom. However, the preoperative noninvasive localisation of epileptogenic tubers remains challenging. This study aimed to identify multimodal magnetic resonance imaging (MRI) biomarkers of epilepsy in patients with TSC and develop a prediction model of epileptogenicity in these patients. MethodsPatients with TSC, with or without epilepsy, were recruited. All patients underwent MRI scanning, including T1WI, T2WI, T2W-FLAIR, DTI, and multi-parametric MR with a flexible design (MULTIPLEX). We compared the multimodal cerebral MRI characteristics of the cortical tubers, subependymal nodules, and perilesional tissue between patients with TSC with or without epilepsy and developed a prediction model for epileptogenicity. ResultsAmong the patients with TSC, 32 with and 16 without epilepsy underwent MRI. Higher proton-density mapping (PD) of cortical tubers and decreased fractional anisotropy (FA), increased mean diffusivity (MD), and increased radial diffusivity (RD) of subependymal nodules were associated with epileptogenicity in both the centre and perilesional tissue, independent of TSC gene variation. Based on the above findings, we developed a prediction model for epileptogenicity with an area under the curve of 0.973, specificity of 0.909, and sensitivity of 0.963 (P < 0.001). ConclusionIn patients with TSC, high PD of the cortical tubers, decreased FA, and elevated MD/RD of the subependymal nodules were significantly associated with epileptogenicity. A prediction model based on multimodal cerebral MRI characteristics has the potential to evaluate the likelihood of epilepsy in patients with TSC.

Oscillatory and nonoscillatory sleep electroencephalographic biomarkers of the epileptic network.

In addition to the oscillatory brain activity, the nonoscillatory (scale-free) components of the background electroencephalogram (EEG) may provide further information about the complexity of the underlying neuronal network. As epilepsy is considered a network disease, such scale-free metrics might help to delineate the epileptic network. Here, we performed an analysis of the sleep oscillatory (spindle, slow wave, and rhythmic spectral power) and nonoscillatory (H exponent) intracranial EEG using multiple interictal features to estimate whether and how they deviate from normalcy in 38 adults with drug-resistant epilepsy. To quantify intracranial EEG abnormalities within and outside the seizure onset areas, patients' values were adjusted based on normative maps derived from the open-access Montreal Neurological Institute open iEEG Atlas. In a subset of 29 patients who underwent resective surgery, we estimated the predictive value of these features to identify the epileptogenic zone in those with a good postsurgical outcome. We found that distinct sleep oscillatory and nonoscillatory metrics behave differently across the epileptic network, with the strongest differences observed for (1) a reduction in spindle activity (spindle rates and rhythmic sigma power in the 10-16 Hz band), (2) a higher rhythmic gamma power (30-80 Hz), and (3) a higher H exponent (steeper 1/f slope). As expected, epileptic spikes were also highest in the seizure onset areas. Furthermore, in surgical patients, the H exponent achieved the highest performance (balanced accuracy of .76) for classifying resected versus nonresected channels in good outcome patients. This work suggests that nonoscillatory components of the intracranial EEG signal could serve as promising interictal sleep candidates of epileptogenicity in patients with drug-resistant epilepsy. Our findings further advance the understanding of epilepsy as a disease, whereby absence or loss of sleep physiology may provide information complementary to pathological epileptic processes.

Modification of brain conductivity in human focal epilepsy: A model-based estimation from stereoelectroencephalography.

We have developed a novel method for estimating brain tissue electrical conductivity using low-intensity pulse stereoelectroencephalography (SEEG) stimulation coupled with biophysical modeling. We evaluated the hypothesis that brain conductivity is correlated with the degree of epileptogenicity in patients with drug-resistant focal epilepsy. We used bipolar low-intensity biphasic pulse stimulation (.2 mA) followed by a postprocessing pipeline for estimating brain conductivity. This processing is based on biophysical modeling of the electrical potential induced in brain tissue between the stimulated contacts in response to pulse stimulation. We estimated the degree of epileptogenicity using a semi-automatic method quantifying the dynamic of fast discharge at seizure onset: the epileptogenicity index (EI). We also investigated how the location of stimulation within specific anatomical brain regions or within lesional tissue impacts brain conductivity. We performed 1034 stimulations of 511 bipolar channels in 16 patients. We found that brain conductivity was lower in the epileptogenic zone (EZ; unpaired median difference = .064, p < .001) and inversely correlated with the epileptogenic index value (p < .001, Spearman rho = -.32). Conductivity values were also influenced by anatomical site, location within lesion, and delay between SEEG electrode implantation and stimulation, and had significant interpatient variability. Mixed model multivariate analysis showed that conductivity is significantly associated with EI (F = 13.45, p < .001), anatomical regions (F = 5.586, p < .001), delay since implantation (F = 14.71, p = .003), and age at SEEG (F = 6.591, p = .027), but not with the type of lesion (F = .372, p = .773) or the delay since last seizure (F = 1.592, p = .235). We provide a novel model-based method for estimating brain conductivity from SEEG low-intensity pulse stimulations. The brain tissue conductivity is lower in EZ as compared to non-EZ. Conductivity also varies significantly across anatomical brain regions. Involved pathophysiological processes may include changes in the extracellular space (especially volume or tortuosity) in epileptic tissue.

Iatrogenic Epileptogenicity Caused by CNS Drugs: A Short Case Series and Narrative Review.

Multiple medications are known to increase epileptogenicity in patients with and without an underlying seizure disorder. Paradoxically, some of these medications include anti-seizure medications (ASMs) and other medications, such as psychotropics, that act on the central nervous system (CNS). This article aims to discuss 3 clinical cases that highlight the gamut of epileptogenic reactivity secondary to CNS drugs ranging from increased epileptogenicity in the form of interictal epileptiform discharges (IEDs) without seizures, increased epileptogenicity on electroencephalogram (EEG) with associated non-epileptic movement disorders, and frank, de novo seizures. We also analyze the relevant literature on the impact of CNS medications on epileptogenicity.

Differential gene expression underlying epileptogenicity in patients with gliomas.

Seizures are a common sequela for patients suffering from gliomas. Molecular properties are known to influence the initiation of seizures that may influence tumor growth. Different levels of gene expression with seizures related to gliomas remain unclear. We analyzed RNA sequencing of gliomas to further probe these differences. Total RNA sequencing was obtained from The Cancer Genome Atlas-Lower-Grade Glioma project, comprised of 2021 World Health Organization classification low-grade gliomas, including IDH-mutant and IDH-wild type, to distinguish differential expression in patients who did and did not experience seizures. Utilizing QIAGEN Ingenuity Pathways Analysis, we identified canonical and functional pathways to characterize differential expression. Of 289 patients with gliomas, 83 (28.7%) had available information regarding seizure occurrence prior to intervention and other pertinent variables of interest. Of these, 50 (60.2%) were allocated to the seizure group. When comparing the level of RNA expression from these tumors between the seizure and non-seizure groups, 52 genes that were significantly differentially regulated were identified. We found canonical pathways that were altered, most significantly RhoGDI and semaphorin neuronal repulsive signaling. Functional gene analysis revealed tumors that promoted seizures had significantly increased functional gene sets involving neuronal differentiation and synaptogenesis. In the setting of gliomas, differences in tumor gene expression exist between individuals with and without seizures, despite similarities in patient demographics and other tumor characteristics. There are significant differences in gene expression associated with neuron development and synaptogenesis, ultimately suggesting a mechanistic role of a tumor-neuron synapse in seizure initiation.

Long-Term Intracranial EEG Lateralization of Epileptogenicity in Patients With Confirmed or Suspected Bilateral Mesial Temporal Lobe Onsets During Epilepsy Surgical Evaluation.

The data resulting from epilepsy surgical evaluation are occasionally unclear in cases of mesial temporal lobe (MTL) epilepsy. Long-term intracranial EEG (iEEG) collected by the Responsive Neurostimulation (RNS) System may be an approach for capturing additional seizure data while treating patients with neurostimulation. We reviewed iEEG seizure lateralization and clinical outcomes in bilateral MTL patients at University of Utah. Long-term RNS System iEEG seizure lateralization was compared with pre-RNS System lateralization obtained during surgical evaluation. Safety and clinical outcomes were extracted retrospectively from patient records. Twenty-six patients received an RNS System with bilateral MTL leads. Fifteen of the patients had adequate follow-up to report clinical outcomes ( > 1 year), and 25 patients had enough recorded data ( > 6 months) to perform iEEG analysis. Median percent reduction in clinical seizures at last follow-up was 58%, and 40% reported being seizure-free at last follow-up, for variable durations. The electrographic seizure lateralization (unilateral vs. bilateral) differed between surgical evaluation and long-term iEEG in 44% of our patients. In the subset of eight patients (32%) who had only unilateral seizures recorded during surgical evaluation, but were implanted with bilateral MTL leads based on bilateral interictal epileptiform discharges, 62% (5/8) had bilateral seizures recorded on long-term iEEG. Interestingly, in the 18 patients who had bilateral seizures recorded during surgical evaluation, 28% (5/18) were found to be unilateral on long-term iEEG. Our data suggest that RNS System implantation in suspected bilateral MTL cases may be an option to assess a patient's true seizure lateralization on long-term iEEG. Responsive neuromodulation should be considered before resection or ablation in cases that have evaluation data suggesting bilaterality.

Effect of current conduction for local epileptiform discharges in patients with temporal lobe epilepsy.

The effects of current conduction were researched to confirm that it can decrease focal epileptogenicity in patients with temporal lobe epilepsy (TLE). Data from 13 patients with mesial TLE were collected. After no less than two habitual seizures were captured during stereo-electroencephalogram monitoring, current conduction was measured in the hippocampus to a homemade, zero potential circuit board. The interictal spike, ripple, fast ripple, and ictal epileptogenicity index (EI) changes were analyzed in the hippocampus, amygdala, and anterior and middle temporal neocortex regions. Significant differences were found in the percentage of patients without spikes in the temporal neocortex between pre- and post-current conduction. Significant decreases in average ripple rates were found in the hippocampus and amygdala after current conduction. The percentage of fast ripple rate decrease in the hippocampus and amygdala was significantly higher than that in the temporal neocortex, and significant decreases were found in the fast ripple rate in the hippocampus from post- to pre-current conduction. Significant decreases were found in the EI values after current conduction in the amygdala and middle temporal lobe compared to the EI values before current conduction. After current conduction in patients with TLE, the spike rate decreases in the hippocampus, amygdala, and anterior and middle temporal neocortex, the ripple rate decreases in the hippocampus and amygdala, the fast ripple decreases in the hippocampus, and the EI decreases in the amygdala and middle temporal neocortex. Current conduction can reduce epileptogenicity in the hippocampus in mesial TLE.

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients

Focal cortical dysplasia (FCD) is a malformation of the cerebral cortex with poorly-defined epileptogenic zones (EZs), and poor surgical outcome in FCD is associated with inaccurate localization of the EZ. Hence, identifying novel epileptogenic markers to aid in the localization of EZ in patients with FCD is very much needed. High-throughput gene expression studies of FCD samples have the potential to uncover molecular changes underlying the epileptogenic process and identify novel markers for delineating the EZ. For this purpose, we, for the first time performed RNA sequencing of surgically resected paired tissue samples obtained from electrocorticographically graded high (MAX) and low spiking (MIN) regions of FCD type II patients and autopsy controls. We identified significant changes in the MAX samples of the FCD type II patients when compared to non-epileptic controls, but not in the case of MIN samples. We found significant enrichment for myelination, oligodendrocyte development and differentiation, neuronal and axon ensheathment, phospholipid metabolism, cell adhesion and cytoskeleton, semaphorins, and ion channels in the MAX region. Through the integration of both MAX vs non-epileptic control and MAX vs MIN RNA sequencing (RNA Seq) data, PLP1, PLLP, UGT8, KLK6, SOX10, MOG, MAG, MOBP, ANLN, ERMN, SPP1, CLDN11, TNC, GPR37, SLC12A2, ABCA2, ABCA8, ASPA, P2RX7, CERS2, MAP4K4, TF, CTGF, Semaphorins, Opalin, FGFs, CALB2, and TNC were identified as potential key regulators of multiple pathways related to FCD type II pathology. We have identified novel epileptogenic marker elements that may contribute to epileptogenicity in patients with FCD and could be possible markers for the localization of EZ.

Initial delta and delayed theta/alpha pattern in the temporal region on ictal EEG suggests purely hippocampal epileptogenicity in patients with mesial temporal lobe epilepsy

ObjectiveTo determine whether the ictal scalp EEG findings suggest purely hippocampal epileptogenicity in patients with mesial temporal lobe epilepsy (mTLE) associated with hippocampal sclerosis (HS). MethodsTwenty-three patients with mTLE with pathologically confirmed HS were divided into 12 with epileptogenicity only in the hippocampus (HS only group) and 11 with epileptogenicity in both the hippocampus and temporal neocortex or other locations (HS plus group), based on the combination of surgical procedures, postoperative outcome, and pathological findings. Sixteen underwent selective amygdalohippocampectomy (SelAH) and 7 received anterior temporal lobectomy. Ictal scalp EEG findings of 79 focal impaired awareness seizures were compared between the HS only and HS plus groups. We focused on the 1–4 Hz rhythmic delta activity at ictal onset followed by 5–9 Hz rhythmic theta/alpha activity 10–30 s after the onset in the temporal region. ResultsThe initial delta and delayed theta/alpha (ID-DT) pattern was observed in 8 of 12 patients in the HS only group, but in none of 11 patients in the HS plus group (p < 0.01). ConclusionsID-DT pattern on ictal EEG suggests purely hippocampal epileptogenicity in mTLE with HS. SignificancePatients with the ID-DT pattern are likely to become seizure-free after SelAH.

Seizure outcomes in relation to the extent of resection of the perifocal fluorodeoxyglucose and flumazenil PET abnormalities in anteromedial temporal lobectomy.

BackgroundThe area of predominant perifocal [18F]fluorodeoxyglucose (18F-FDG) hypometabolism and reduced [11C]flumazenil (11C-FMZ) -binding on PET scans is currently considered to contain the epileptogenic zone and corresponds anatomically to the area localizing epileptogenicity in patients with temporal lobe epilepsy (TLE). The question is whether the volume of the perifocal pre-operative PET abnormalities, the extent of their resection, and the volume of the non-resected abnormalities affects the post-operative seizure outcome.MethodsThe sample group consisted of 32 patients with mesial temporal sclerosis who underwent anteromedial temporal lobe resection for refractory TLE. All patients had pathologic perifocal findings on both of the PET modalities as well as on the whole-brain MRI. The volumetric data of the PET and MRI abnormalities within the resected temporal lobe were estimated by automated quantitative voxel-based analysis. The obtained volumetric data were investigated in relation to the outcome subgroups of patients (Engel classification) determined at the 2-year post-operative follow-up.ResultsThe mean volume of the pre-operative perifocal 18F-FDG- and 11C-FMZ PET abnormalities in the volumes of interest (VOI) of the epileptogenic temporal lobe, the mean resected volume of these PET abnormalities, the mean volume of the non-resected PET abnormalities, and the mean MRI-derived resected volume were not significantly related to the outcome subgroups and had a low prediction for individual freedom from seizures.ConclusionsThe extent of pre-surgical perifocal PET abnormalities, the extent of their resection, and the extent of non-resected abnormalities were not useful predictors of individual freedom from seizures in patients with TLE.

P459: Electro-clinical features of focal epilepsy patients with postictal generalized EEG suppression

P459: Electro-clinical features of focal epilepsy patients with postictal generalized EEG suppression

Electrocorticographic–Histopathologic Correlations Implying Epileptogenicity of Dysembryoplastic Neuroepithelial Tumor

Based on intracranial-video electroencephalography (EEG), histopathological features, and postoperative seizure outcome, we elucidated the epileptogenicity in patients with dysembryoplastic neuroepithelial tumor (DNT). Five patients (P1–P5) pathologically diagnosed with DNT underwent intracranial-video EEG to identify the ictal onset zone and irritative zone. We evaluated the correlations of ictal onset zone and irritative zone with the magnetic resonance imaging-visible lesion (MRI-lesion) and their histopatho-logical features. Intracranial-video EEG located the ictal onset zone adjacent to the MRI-lesion margin in four patients with complex/simple forms of DNT subcategory, and on the MRI-lesion in P3 with a nonspecific DNT form. The irritative zone extended to surrounding regions of the ictal onset zone in all patients. Histopathologically, MRI-lesions were characterized by specific glioneuronal elements, whereas the ictal onset zone and irritative zone were represented with dysplastic cortex accompanying oligodendroglia-like cells in four (P1, P2, P4, and P5) of five patients. Cortical dysplasia was identified with typical histopathologic features in the irritative zone remote from the MRI-lesion in P5. P3, with a nonspecific form, indicated prominent component of dysplastic cortex with oligodendroglia-like cells scattered in the MRI-lesion. Lesionectomy of MRI-lesion with additional cortical resections (including the ictal onset zone and irritative zone) yielded postoperative seizure freedom (Engel Class I) in P3, P4, and P5, while P1 and P2 (with only lesionectomy) experienced postoperative residual seizure (Class II and III in each patient). Our results suggest the intrinsic epileptogenicity of DNT. The topographical correlation indicated that the dysplastic cortex accompanying oligodendroglia-like cells was more epileptogenic than the specific glioneuronal elements itself. Meticulous intracranial-video EEG analysis delineating the MRI nonvisible ictal onset zone and the irritative zone may yield better seizure outcome.

Gray matter loss correlates with mesial temporal lobe neuronal hyperexcitability inside the human seizure‐onset zone

Patient studies have not provided consistent evidence for interictal neuronal hyperexcitability inside the seizure-onset zone (SOZ). We hypothesized that gray matter (GM) loss could have important effects on neuronal firing, and quantifying these effects would reveal significant differences in neuronal firing inside versus outside the SOZ. Magnetic resonance imaging (MRI) and computational unfolding of mesial temporal lobe (MTL) subregions was used to construct anatomic maps to compute GM loss in presurgical patients with medically intractable focal seizures in relation to controls. In patients, these same maps were used to locate the position of microelectrodes that recorded interictal neuronal activity. Single neuron firing and burst rates were evaluated in relation to GM loss and MTL subregions inside and outside the SOZ. MTL GM thickness was reduced inside and outside the SOZ in patients with respect to controls, yet GM loss was associated more strongly with firing and burst rates in several MTL subregions inside the SOZ. Adjusting single neuron firing and burst rates for the effects of GM loss revealed significantly higher firing rates in the subregion consisting of dentate gyrus and CA2 and CA3 (CA23DG), as well as CA1 and entorhinal cortex (EC) inside versus outside the SOZ where normalized MRI GM loss was ≥1.40 mm. Firing rates were higher in subicular cortex inside the SOZ at GM loss ≥1.97 mm, whereas burst rates were higher in CA23DG, CA1, and EC inside than outside the SOZ at similar levels of GM loss. The correlation between GM loss and increased firing and burst rates suggests GM structural alterations in MTL subregions are associated with interictal neuronal hyperexcitability inside the SOZ. Significant differences in firing rates and bursting in areas with GM loss inside compared to outside the SOZ indicate that synaptic reorganization following cell loss could be associated with varying degrees of epileptogenicity in patients with intractable focal seizures.

Epileptogenicity of a patient with the association of medullary venous malformation and cavernous malformation

We present a surgical case of a 53-year-old man with lesion-related epilepsy associated with medullary venous malformation (MVM) and cavernous malformation (CM) in the right frontal lobe. He had frequent secondary generalized seizures since developing a MVM-related intracerebral hemorrhage in the right frontal lobe at the age of 44. Intraoperative electrocorticography demonstrated frequent paroxysmal activities on the yellowish cortex above the CM. Anterior frontal lobectomy including the irritative cortex, CM, MVM and its tributaries was performed. The patient became seizure free after surgery. Pathologically, the irritative cortex above the CM had hemosiderin deposits and astrogliosis. The CM was surrounded by dilated veins of various sizes, indicating MVM, which confirmed the radiological findings of so-called caput medusae. Epileptogenicity in patients with CM and MVM is thought to be due to repeated hemorrhage from the CM. Surgical strategy is discussed.

Magnetoencephalographic Findings on Patients Having Symptomatic Localization‐Related Epilepsy with Dysembryoplastic Neuroepithelial Tumor as the Epileptogenic Lesion

Purpose: Dysembryoplastic neuroepithelial tumor (DNT) is one of the major pathologies that are related to the epileptogenicity in patients having symptomatic localization‐related epilepsy (SLE). Histopathological definition of DNT is as follows: (I) intracortical locations, (2) multinodular architecture, (3)heterogeneous cellular composition with astrocytes, oligodendrocytes, and neurons, and (4) foci of cortical dysplasia. There are many glial cells and very few neurons at the center of the MRI lesion of DNT, which shows low intensity in TI image and high in T2. This characteristic is in contrast with that of focal cortical dysplasia (FCD), with MRI lesions that show iso‐intensity in TI image and high in T2, wherein are found many giant neurons pathologically. Epileptogenicity related to FCD is supposed to be intrinsic, that is, to exist within the MRI lesion, because of existence of these giant new rons. We have previously confirmed that spike‐dipoles estimated by magnetoencephalography (MEG) in SLE patients with FCD are distributed within the MRI lesion, suggesting the intrinsic epileptogenicity of FCD. We, therefore, suppose that epileptogenicity related to DNT should exist in the foci of cortical dysplasia, which are rather distant from the center of the MRI lesion, and hypothesized that spike‐dipoles in SLE patients with DNT would be distributed out of the center of the MRI lesion. This study was performed to test the hypothesis. Methods: Subjects of this study were composed of 1 I SLE patients who underwent surgical treatment and received good outcome for seizure reduction, and histopathological diagnosis of DNT was confirmed postoperatively. Three patients were female and 8 were male. Age at the MEG study ranged from I to 35 years. As to the epileptic syndrome, 3 were frontal lobe epilepsy (FLE), 7 were temporal (TLE), and I patient was parietal (PLE). The lobe i n which DNT was found and from which the seizure was supposed to originate were the same in all of the patients. MEG measurement and dipole fitting of interictal spikes were performed using a 37+37‐channel dual sensor system (Biomag‐netic Technologies Inc.; San Diego, California, USA) preoperatively. Estimated spike‐dipoles were overlaid on the preoperative MRI image, and the topographical relationship between spike‐dipoles and MRI lesion was examined in each patient. Results: Estimated spike‐dipoles were distributed at the marginal area around thc MRI lesion in all of the FLE patients and 20 of the TLE patients. In the PLE patient spike‐dipoles were distributed at a rather distant area from the MRI lesion, although within the same lobe. Four of the TLE patients showed extended distribution of spike‐dipoles around the MRI lesion. One patient with TLE was found to have DNT only after surgery. This patient's spike‐dipoles were distributed in a pattern characteristic of the mesial type of TLE. Conclusions: Spike‐dipoles estimated by MEC were distributed not within the MRI lesion but in a marginal area surrounding the lesion, or rather a distant area of the cortex in the majority of cases. This result supports our hypothesis that epileptogenicity of DNT exists not at the center of the lesion, but around its margin.