Refractory Neocortical Epilepsy Research Articles

Interictal magnetoencephalography abnormalities to guide intracranial electrode implantation and predict surgical outcome.

Intracranial EEG is the gold standard technique for epileptogenic zone localization but requires a preconceived hypothesis of the location of the epileptogenic tissue. This placement is guided by qualitative interpretations of seizure semiology, MRI, EEG and other imaging modalities, such as magnetoencephalography. Quantitative abnormality mapping using magnetoencephalography has recently been shown to have potential clinical value. We hypothesized that if quantifiable magnetoencephalography abnormalities were sampled by intracranial EEG, then patients' post-resection seizure outcome may be better. Thirty-two individuals with refractory neocortical epilepsy underwent magnetoencephalography and subsequent intracranial EEG recordings as part of presurgical evaluation. Eyes-closed resting-state interictal magnetoencephalography band power abnormality maps were derived from 70 healthy controls as a normative baseline. Magnetoencephalography abnormality maps were compared to intracranial EEG electrode implantation, with the spatial overlap of intracranial EEG electrode placement and cerebral magnetoencephalography abnormalities recorded. Finally, we assessed if the implantation of electrodes in abnormal tissue and subsequent resection of the strongest abnormalities determined by magnetoencephalography and intracranial EEG corresponded to surgical success. We used the area under the receiver operating characteristic curve as a measure of effect size. Intracranial electrodes were implanted in brain tissue with the most abnormal magnetoencephalography findings-in individuals that were seizure-free postoperatively (T = 3.9, P = 0.001) but not in those who did not become seizure-free. The overlap between magnetoencephalography abnormalities and electrode placement distinguished surgical outcome groups moderately well (area under the receiver operating characteristic curve = 0.68). In isolation, the resection of the strongest abnormalities as defined by magnetoencephalography and intracranial EEG separated surgical outcome groups well, area under the receiver operating characteristic curve = 0.71 and area under the receiver operating characteristic curve = 0.74, respectively. A model incorporating all three features separated surgical outcome groups best (area under the receiver operating characteristic curve = 0.80). Intracranial EEG is a key tool to delineate the epileptogenic zone and help render individuals seizure-free postoperatively. We showed that data-driven abnormality maps derived from resting-state magnetoencephalography recordings demonstrate clinical value and may help guide electrode placement in individuals with neocortical epilepsy. Additionally, our predictive model of postoperative seizure freedom, which leverages both magnetoencephalography and intracranial EEG recordings, could aid patient counselling of expected outcome.

High Frequency Stimulation of the Centromedian Thalamic Nucleus to Abort Seizures and Interictal Discharges During Stereoelectroencephalography Evaluation (P5-1.007)

<h3>Objective:</h3> To assess whether high frequency stimulation of the centromedian nucleus of the thalamus can disrupt seizures and/or interictal discharges. <h3>Background:</h3> There is growing evidence that subcortical structures, including the thalamus, are involved in seizure networks in patients with neocortical epilepsy. Responsive neurostimulation of the centromedian nucleus of the thalamus (CMT) has been shown to terminate seizures in case reports of patients with generalized and focal neocortical epilepsy [Burdette, et al. <i>Epilepsy and Behavior</i>, 2020]. However, to our knowledge, no prior reports have demonstrated the utility of stimulating the thalamus during a sEEG evaluation. We present two patients with refractory neocortical epilepsy who underwent sEEG evaluation including an electrode in the CMT. <h3>Design/Methods:</h3> Both patients underwent real-time high frequency stimulation (HFS) at CMT during runs of interictal discharges. Patient 1 was also stimulated during seizures. Stimulation settings for both patients were 50Hz, 0.3msec pulse duration, for 3 seconds. Patient 1 underwent stimulation at 2mA while Patient 2 was 1mA. For patient 1, seizure characteristics before and after stimulation were compared using a student’s t-test (duration) and Fisher exact test (apnea). <h3>Results:</h3> For Patient 1, HFS of the CMT successfully aborted 4 seizures. Compared to 11 seizures prior to stimulation, those with HFS were significantly shorter (9.5 vs. 20.5 seconds, p=0.018). The patient did not develop clinical apnea in any of the 4 seizures aborted with HFS, but did with all of the 11 seizures without stimulation (p=0.001). Stimulation during runs of interictal discharges was inconclusive. In Patient 2, HFS aborted runs of inter-ictal discharges in all 10 attempts. <h3>Conclusions:</h3> These cases demonstrate that stimulation of the CMT during sEEG evaluation can abort electroclinical seizures and potentially interictal discharges. This supports the idea that the CMT is involved in focal neocortical epilepsy networks. Stimulation during sEEG may be useful in predicting efficacy of thalamic neurostimulation. <b>Disclosure:</b> Dr. Nathan has nothing to disclose. Dr. Adney has received research support from NINDS. Joshua M Rosenow, MD, FAANS, FACS has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Boston Scientific Neuromodulation. Dr. Schuele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Monteris. Dr. Schuele has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurelis. Dr. Schuele has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for SK Life Science. Dr. Schuele has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Jazz. Dr. Schuele has received personal compensation in the range of $50,000-$99,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Clinical Neurophysiology. Dr. Schuele has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Thomas Needham. Dr. Schuele has received research support from National Institute of Health. Dr. Gerard has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Greenwich Pharmaceuticals. The institution of Dr. Gerard has received research support from NIH/NINDS. The institution of Dr. Gerard has received research support from Xenon Pharmaceuticals. The institution of an immediate family member of Dr. Gerard has received research support from NIH. The institution of an immediate family member of Dr. Gerard has received research support from Novo Nordisk. The institution of Dr. Gerard has received research support from Eisai, Inc. (via Stanford University).

MEG abnormalities and mechanisms of surgical failure in neocortical epilepsy.

Epilepsy surgery fails to achieve seizure freedom in 30%-40% of cases. It is not fully understood why some surgeries are unsuccessful. By comparing interictal magnetoencephalography (MEG) band power from patient data to normative maps, which describe healthy spatial and population variability, we identify patient-specific abnormalities relating to surgical failure. We propose three mechanisms contributing to poor surgical outcome: (1) not resecting the epileptogenic abnormalities (mislocalization), (2) failing to remove all epileptogenic abnormalities (partial resection), and (3) insufficiently impacting the overall cortical abnormality. Herein we develop markers of these mechanisms, validating them against patient outcomes. Resting-state MEG recordings were acquired for 70 healthy controls and 32 patients with refractory neocortical epilepsy. Relative band-power spatial maps were computed using source-localized recordings. Patient and region-specific band-power abnormalities were estimated as the maximum absolute z-score across five frequency bands using healthy data as a baseline. Resected regions were identified using postoperative magnetic resonance imaging (MRI). We hypothesized that our mechanistically interpretable markers would discriminate patients with and without postoperative seizure freedom. Our markers discriminated surgical outcome groups (abnormalities not targeted: area under the curve [AUC]=0.80, p=.003; partial resection of epileptogenic zone: AUC=0.68, p=.053; and insufficient cortical abnormality impact: AUC=0.64, p=.096). Furthermore, 95% of those patients who were not seizure-free had markers of surgical failure for at least one of the three proposed mechanisms. In contrast, of those patients without markers for any mechanism, 80% were ultimately seizure-free. The mapping of abnormalities across the brain is important for a wide range of neurological conditions. Here we have demonstrated that interictal MEG band-power mapping has merit for the localization of pathology and improving our mechanistic understanding of epilepsy. Our markers for mechanisms of surgical failure could be used in the future to construct predictive models of surgical outcome, aiding clinical teams during patient pre-surgical evaluations.

WGCNA combined with GSVA to explore biomarkers of refractory neocortical epilepsy.

About two-thirds of epilepsy patients relapse within five years after surgery. It is significant to note that the limitations of current treatments stem from a lack of understanding of molecular mechanisms. In this study, Weighted Gene Co-expression Network Analysis (WGCNA) and Gene set variation analysis (GSVA) methods were used to analyze the total RNA data from 20 surgical removal samples (epileptogenic zone and irritative zone, EZ and IZ) of 10 Chinese patients with refractory neocortical epilepsy downloaded from the original microarray dataset (GSE31718) of the National Center for Biological Information -Gene Expression Omnibus database (NCBI-GEO). The late stages of the estrogen response pathway, the IL6-JAK-STAT3-signal pathway and G2 checkpoints are correlated with the EZ, whereas the early stages of the estrogen response pathway and TGF-β signal are more strongly expressed in the IZ. The allogeneic rejection, apical surface and the TGF-β signal are relevant to the high seizure frequency, the unfolded protein response and MYC-target are mostly expressed in patients with low-frequency seizures. Genes with high gene significance(GS) values that were correlated with seizure frequency include OSR2, CABP4, CAPSL, CYP4F8, and FRK in the pink module, and SH3GLB2, CHAC1 and DDX23 in the yellow module. The occurrence of EZ and IZ act on different biological mechanisms. The upregulated genes associated with seizure frequency include OSR2, CABP4, CAPSL, CYP4F8, and FRK, and the downregulated genes include SH3GLB2, CHAC1 and DDX23. The evidence of key genes and differential pathways obtained by WGCNA and GSVA may be biomarkers for novel preventive and pharmacological interventions in clinical practice.

Continuous thetaburst stimulation for the treatment of refractory neocortical epilepsy

Continuous thetaburst stimulation for the treatment of refractory neocortical epilepsy

Randomized crossover sham‐controlled clinical trial of targeted low‐frequency transcranial magnetic stimulation comparing a figure‐8 and a round coil to treat refractory neocortical epilepsy

Determine the efficacy and side effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) to treat refractory neocortical epilepsy and study differences in effect between a figure-8 and round coil type. This single-center randomized sham-controlled crossover trial (NCT01745952 on ClinicalTrials.gov) included 11 patients with well-defined focal epilepsy. rTMS (0.5 Hz) was targeted to the focus during three treatment conditions consisting of 1,500 stimulations/day for 10 weekdays at 90% of resting motor threshold (rMT) followed by a 10-week observation period. Patients were randomized for the order in which the figure-8, round, and sham coil were used. Outcome assessors and patients were blinded to the type of coil used. The primary outcome measure was the percentage of seizure reduction after active rTMS treatment. Other outcome measures were responder rate, quality of life, and side effects. There was no difference between a figure-8 and round coil. None of the patients achieved an overall 50% seizure reduction. One patient responded during 1 month after treatment with either active coil, followed by a significant increase in seizure frequency. Another patient had a fourfold increase in seizure frequency during rTMS treatment. This study provides evidence that rTMS is on average not effective for reducing seizure frequency. No difference in effectiveness between the different coil types was observed. It can, however, exacerbate seizures during treatment and lead to a rebound in seizure frequency after an initial reduction.

26. Functional organization of the irritative zone in neocortical epilepsy

Rationale The irritative zone is an area of the brain generating interictal epileptiform discharges (IEDs) that is used together with other results when planning epilepsy surgery. This zone possesses relatively low diagnostic value due to lack of a specific marker that would identify IEDs generated within the epileptogenic tissue. To increase diagnostic yield of irritative zone, we examined its functional organization. Methods Intracranial EEG recordings from 14 patients with refractory neocortical epilepsy were analysed using an algorithm that separates IEDs according to their spatial distribution into clusters. Analysis of cluster properties enabled to determine: (1) activity – percentage contribution to all IEDs in the given recording; (2) origins – the contacts where cluster initiates and (3) active region – the area of the most common propagation. Results On average 16,868 ± 16,813 IEDs per patient were analysed. The results demonstrated that in all patients the irritative zone was composed of multiple clusters with an average number of 12.5 ± 4.7 clusters per patient. The strongest cluster generated 43.5 ± 18.9% of all IEDs Average size of active region was 4.5 ± 4.5 contacts and contained 2.2 ± 1.7 origins. Evaluation of the cluster resection with the outcome suggested that the topology of the irritative zone may determine the success of the resection. Conclusion This study demonstrates the complex organization and modular nature of the neocortical irritative zone in epilepsy patients. It can be stratified into functional components, each with distinct pathophysiological and clinical significance. The ability to identify the key components of this network and its topology has potential to improve the results of epilepsy surgery. Supported by grants from IGA NT11460, NT13357, NT14489, GACR 14-02634S and Neuron Fund (NFKJ 10/2012).

Dense array EEG source estimation in neocortical epilepsy.

Rationale: Dense array EEG (dEEG) evenly covers the whole head surface with over 100 channels contributing to more accurate electrical source imaging due to the higher spatial and temporal resolution. Several studies have shown the clinical utility of dEEG in presurgical clinical evaluation of epilepsy. However validation studies measuring the accuracy of dEEG source imaging are still needed. This can be achieved through simultaneously recording both scalp dEEG with intracranial electrodes (icEEG), which is considered as the true measure of cortical activity at the source. The purpose of this study is to evaluate the accuracy of 256-channel dEEG electrical source estimation for interictal spikes.Methods: Four patients with medically refractory neocortical epilepsy, all surgical candidates, underwent subdural electrode implantation to determine ictal onset and define functional areas. One patient showed a lesion on the magnetic resonance imaging in the right parietal lobe. The patient underwent simultaneous recording of interictal spikes by both scalp 256-channelsvdEEG and icEEG. The dEEG was used to non-invasively estimate the source of the interictal spikes detected by the 256-channel dEEG array, which was then compared to the activity measured directly at the source by the icEEG.Results: From the four patients, a total of 287 interictal spikes were measured with the icEEG. One hundred fifty-five of the 287 spikes (54%) were visually detected by the dEEG upon examination of the 256 channel head surface array. The spike amplitudes detected by the 256-channel dEEG correlated with icEEG spike amplitudes (p < 0.01). All spikes detected in dEEG were localized to the same lobe correctly.Conclusion: Our study demonstrates that 256-channel dEEG can reliably detect interictal spikes and localize them with reasonable accuracy. Two hundred fifty-six-channel dEEG may be clinically useful in the presurgical workup for epilepsy and also reduce the need for invasive EEG evaluation.

Value of interictal magnetoencephalography in preoperative evaluation of nonlesional neocortical epilepsy

Objective To investigate whether interictal magnetoencephalography (MEG) consistent with surgical range could predict the surgical outcomes in patients with nonlesional refractory neocortical epilepsy (NE).Methods Twenty-five patients with nonlesional NE were studied.All patients had longterm intracranial video-electroencephalography (i-VEEG) monitoring and MEG examinations before surgery.According to the relationship between localization of interictal MEG and surgical range,we divided the participants into two groups,including concordance condition (MEG findings were concordant with surgical range) and discordance condition (MEG findings were discordant with surgical range).Epilepsy surgery was performed to the 25 patient.The surgical outcomes were assessed by neurosurgeons based on over one-year follow-up after surgery using the Engel classification system.Results The total seizurefree (Engel class IA) rate was 36％ (9/25),and the total effective rate was 68％ (17/25).The seizurefree rate of concordance condition was 57％ (8/14),and effective rate was 71％ (10/14).The seizure-free rate of discordance condition was 9％ (1/11),and effective rate was 64％ (7/11).Both the seizure-free rate and effective rate of concordance group were significantly better than those of discordance condition.A statistical difference was found between the seizure-free outcomes of patients with concordance condition and with discordance condition (P ＜ 0.05).Conclusions The study demonstrates that a favorable postsurgical outcome could be prodicted in most patients with concordance of MEG and surgical range. Key words: Magnetoencephalography ; Epilepsy surgery ; Neocortical epilepsy; Nonlesional

Interictal magnetoencephalographic findings related with surgical outcomes in lesional and nonlesional neocortical epilepsy

Purpose To investigate whether interictal magnetoencephalography (MEG) concordant with other techniques can predict surgical outcome in patients with lesional and nonlesional refractory neocortical epilepsy (NE). Methods 23 Patients with lesional NE and 20 patients with nonlesional NE were studied. MEG was recorded for all patients with a 275 channel whole-head system. Synthetic aperture magnetometry (SAM) with excess kurtosis (g2) and conventional Equivalent Current Dipole (ECD) were used for MEG data analysis. 27 Patients underwent long-term extraoperative intracranial video electroencephalography (iVEEG) monitoring. Surgical outcomes were assessed based on more than 1-year of post-surgical follow-up using Engel classification system. Results As we expected, both favorable outcomes (Engel class I or II) and seizure freedom outcomes (Engel class IA) were higher for the concordance condition (MEG findings are concordant with MRI or iVEEG findings) versus the discordance condition. Also the seizure free rate was significantly higher ( χ 2 = 5.24, P < 0.05) for the patients with lesional NE than for the patients with nonlesional NE. In 30% of the patients with nonlesional NE, the MEG findings proved to be valuable for intracranial electrode implantation. Conclusions This study demonstrates that a favorable post-surgical outcome can be obtained in most patients with concordant MEG and MRI results even without extraoperative iVEEG monitoring, which indicates that the concordance among different modalities could indicate a likelihood of better postsurgical outcomes. However, extraoperative iVEEG monitoring remains prerequisite to the patients with discordant MEG and MRI findings. For nonlesional cases, our results showed that MEG could provide critical information in the placement of intracranial electrodes.

Quantitative brain surface mapping of an electrophysiologic/metabolic mismatch in human neocortical epilepsy

The spatial relationship between an intracranial EEG-defined epileptic focus and cortical hypometabolism on glucose PET has not been precisely described. In order to quantitatively evaluate the hypothesis that ictal seizure onset and/or rapid seizure propagation, detected by subdural EEG monitoring, commonly involves normometabolic cortex adjacent to hypometabolic cortical regions, we applied a novel, landmark-constrained conformal mapping approach in 14 children with refractory neocortical epilepsy. The 3D brain surface was parcellated into finite cortical elements (FCEs), and hypometabolism was defined using lobe- and side-specific asymmetry indices derived from normal adult controls. The severity and location of hypometabolic areas vs. ictal intracranial EEG abnormalities were compared on the 3D brain surface. Hypometabolism was more severe in the seizure onset zone than in cortical areas covered by non-onset electrodes. However, similar proportions of the onset electrodes were located over and adjacent to (within 2 cm) hypometabolic regions (46% vs. 41%, respectively), whereas rapid seizure spread electrodes preferred these "adjacent areas" rather than the hypometabolic area itself (51% vs. 22%). On average, 58% of the hypometabolic regions had no early seizure involvement. These findings strongly support that the seizure onset zone often extends from hypometabolic to adjacent normometabolic cortex, while large portions of hypometabolic cortex are not involved in seizure onset or early propagation. The clinical utility of FDG PET in guiding subdural electrode placement in neocortical epilepsy could be greatly enhanced by extending grid coverage to at least 2 cm beyond hypometabolic cortex, when feasible.

Metabolic characteristics of cortical malformations causing epilepsy

Cortical malformations (CMs) are increasingly recognized as the epileptogenic substrate in patients with medically refractory neocortical epilepsy (NE). The aim of this study was to test the hypotheses that: 1. CMs are metabolically heterogeneous. 2. The structurally normal appearing perilesional zone is characterized by similar metabolic abnormalities as the CM. Magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation was performed on eight patients with NE and CMs and 19 age matched controls. In controls, NAA, Cr, Cho,NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter content and thresholds for pathological values determined by calculating the 95% prediction intervals. These thresholds were used to identify metabolically abnormal voxels within the CM and in the perilesional zone. 30% of all voxels in the CMs were abnormal, most frequently because of decreases of NAA or increases of Cho. Abnormal voxels tended to form metabolically heterogeneous clusters interspersed in metabolically normal regions. Furthermore, 15% of all voxels in the perilesional zone were abnormal, the most frequent being decreases of NAA and Cr. In CMs metabolically normal regions are interspersed with metabolically heterogeneous abnormal regions. Metabolic abnormalities in the perilesional zone share several characteristics of CMs and might therefore represent areas with microscopic malformations and/or intrinsic epileptogenicity.