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Objective: The most common medically resistant epilepsy (MRE) involves the temporal lobe (TLE), and children designated as temporal plus epilepsy (TLE+) have a five-times increased risk of postoperative surgical failure. This retrospective, blinded, cross-sectional study aimed to correlate visual and computational analyses of magnetoencephalography (MEG) virtual sensor waveforms with surgical outcome and epilepsy classification (TLE and TLE+)., Methods: Patients with MRE who underwent MEG and iEEG monitoring and had at least 1 year of postsurgical follow-up were included in this retrospective analysis. User-defined virtual sensor (UDvs) beamforming was completed with virtual sensors placed manually and symmetrically in the bilateral amygdalohippocampi, inferior/middle/superior temporal gyri, insula, suprasylvian operculum, orbitofrontal cortex, and temporoparieto-occipital junction. Additionally, MEG effective connectivity was computed and quantified using eigenvector centrality (EC) to identify hub regions. More conventional MEG methods (equivalent current dipole [ECD], standardized low-resolution brain electromagnetic tomography, synthetic aperture magnetometry beamformer), UDvs beamformer, and EC hubs were compared to iEEG., Results: Eighty patients (38 female, 42 male) with MRE (mean age = 11.3 ± 6.2 years, range = 1.0-31.5) were identified and included. Twenty-five patients (31.3%) were classified as TLE, whereas 55 (68.8%) were TLE+. When modeling the association between MEG method, iEEG, and postoperative surgical outcome (odds of a worse [International League Against Epilepsy (ILAE) class > 2] outcome), a significant result was seen only for UDvs beamformer (odds ratio [OR] = 1.22, 95% confidence interval [CI] = 1.01-1.48). Likewise, when the relationship between MEG method, iEEG, and classification (TLE and TLE+) was modeled, only UDvs beamformer had a significant association (OR = 1.47, 95% CI = 1.13-1.92). When modeling the association between EC hub location and resection/ablation to postoperative surgical outcome (odds of a good [ILAE 1-2] outcome), a significant association was seen (OR = 1.22, 95% CI = 1.05-1.43)., Significance: This study demonstrates a concordance between UDvs beamforming and iEEG that is related to both postsurgical seizure outcome and presurgical classification of epilepsy (TLE and TLE+). UDvs beamforming could be a complementary approach to the well-established ECD, improving invasive electrode and surgical resection planning for patients undergoing epilepsy surgery evaluations and treatments., (© 2024 International League Against Epilepsy.)

Objective: We evaluated changes in cognitive domains after neurosurgical lesioning of cortical sites with significant high-gamma power modulations (HGM) during a visual naming task, although these sites were found language-negative on standard-of-care electrical stimulation mapping (ESM)., Methods: In drug-resistant epilepsy patients who underwent resection/ablation after stereo-electroencephalography (SEEG), we computed reliable change indices (RCIs) from a battery of presurgical and 1-year postsurgical neuropsychological assessments. We modeled RCIs as a function of lesioning even one HGM language site, number of HGM language sites lesioned, and the magnitude of naming-related HGM. The analyses were adjusted for 1-year seizure freedom, operated hemispheres, and the volumes of surgical lesions., Results: In 37 patients with 4455 SEEG electrode contacts (1839 and 2616 contacts in right and left hemispheres, respectively), no ESM language sites were lesioned. Patients with lesioning of even one HGM language site showed significantly lower RCIs for Peabody Picture Vocabulary Test (PPVT), working memory, and verbal learning immediate (VLI) scores. RCI declines with higher number of HGM language sites lesioned were seen in PPVT (slope [β] = -.10), working memory (β = -.10), VLI (β = -.14), and letter-word identification (LWI; β = -.14). No neuropsychological domains improved after lesioning of HGM language sites. Significant effects of the HGM magnitude at lesioned sites were seen on working memory (β = -.31), story memory immediate (β = -.27), verbal learning recognition (β = -.18), LWI (β = -.16), spelling (β = -.49), and passage comprehension (β = -.33). Because working memory was significantly affected in all three analyses, patients with maximal working memory decline were examined post hoc, revealing that all such patients had HGM naming sites lesioned in the posterior quadrants of either hemisphere., Significance: HGM language mapping should be used as an adjunct to ESM in clinical practice and may help counsel patients/families about postsurgical cognitive deficits., (© 2024 International League Against Epilepsy.)

Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy., Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician., Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants., Significance: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG., (© 2023 International League Against Epilepsy.)

Objective: To determine whether automated, electronic alerts increased referrals for epilepsy surgery., Methods: We conducted a prospective, randomized controlled trial of a natural language processing-based clinical decision support system embedded in the electronic health record (EHR) at 14 pediatric neurology outpatient clinic sites. Children with epilepsy and at least two prior neurology visits were screened by the system prior to their scheduled visit. Patients classified as a potential surgical candidate were randomized 2:1 for their provider to receive an alert or standard of care (no alert). The primary outcome was referral for a neurosurgical evaluation. The likelihood of referral was estimated using a Cox proportional hazards regression model., Results: Between April 2017 and April 2019, at total of 4858 children were screened by the system, and 284 (5.8%) were identified as potential surgical candidates. Two hundred four patients received an alert, and 96 patients received standard care. Median follow-up time was 24 months (range: 12-36 months). Compared to the control group, patients whose provider received an alert were more likely to be referred for a presurgical evaluation (3.1% vs 9.8%; adjusted hazard ratio [HR] = 3.21, 95% confidence interval [CI]: 0.95-10.8; one-sided p = .03). Nine patients (4.4%) in the alert group underwent epilepsy surgery, compared to none (0%) in the control group (one-sided p = .03)., Significance: Machine learning-based automated alerts may improve the utilization of referrals for epilepsy surgery evaluations., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Electrical stimulation mapping (ESM) is the clinical standard for functional localization with subdural electrodes (SDE). As stereoelectroencephalography (SEEG) has emerged as an alternative option, we compared functional responses, afterdischarges (ADs), and unwanted ESM-induced seizures (EISs) between the two electrode types., Methods: Incidence and current thresholds for functional responses (sensory, motor, speech/language), ADs, and EISs were compared between SDE and SEEG using mixed models incorporating relevant covariates., Results: We identified 67 SEEG ESM and 106 SDE ESM patients (7207 and 4980 stimulated contacts, respectively). We found similar incidence of language and motor responses between electrode types; however, more SEEG patients reported sensory responses. ADs and EISs occurred less commonly with SEEG than SDE. Current thresholds for language, face motor, and upper extremity (UE) motor responses and EIS significantly decreased with age. However, they were not affected by electrode type, premedication, or dominant hemispheric stimulation. AD thresholds were higher with SEEG than with SDE. For SEEG ESM, language thresholds remained below AD thresholds up to 26 years of age, whereas this relationship was inverse for SDE. Also, face and UE motor thresholds fell below AD thresholds at earlier ages for SEEG than SDE. AD and EIS thresholds were not affected by premedication., Significance: SEEG and SDE have clinically relevant differences for functional brain mapping with electrical stimulation. Although evaluation of language and motor regions is comparable between SEEG and SDE, SEEG offers a higher likelihood of identifying sensory areas. A lower incidence of ADs and EISs, and a favorable relationship between functional and AD thresholds suggest superior safety and neurophysiologic validity for SEEG ESM than SDE ESM., (© 2023 International League Against Epilepsy.)

Objective: Delay to resective epilepsy surgery results in avoidable disease burden and increased risk of mortality. The objective was to prospectively validate a natural language processing (NLP) application that uses provider notes to assign epilepsy surgery candidacy scores., Methods: The application was trained on notes from (1) patients with a diagnosis of epilepsy and a history of resective epilepsy surgery and (2) patients who were seizure-free without surgery. The testing set included all patients with unknown surgical candidacy status and an upcoming neurology visit. Training and testing sets were updated weekly for 1 year. One- to three-word phrases contained in patients' notes were used as features. Patients prospectively identified by the application as candidates for surgery were manually reviewed by two epileptologists. Performance metrics were defined by comparing NLP-derived surgical candidacy scores with surgical candidacy status from expert chart review., Results: The training set was updated weekly and included notes from a mean of 519 ± 67 patients. The area under the receiver operating characteristic curve (AUC) from 10-fold cross-validation was 0.90 ± 0.04 (range = 0.83-0.96) and improved by 0.002 per week (P < .001) as new patients were added to the training set. Of the 6395 patients who visited the neurology clinic, 4211 (67%) were evaluated by the model. The prospective AUC on this test set was 0.79 (95% confidence interval [CI] = 0.62-0.96). Using the optimal surgical candidacy score threshold, sensitivity was 0.80 (95% CI = 0.29-0.99), specificity was 0.77 (95% CI = 0.64-0.88), positive predictive value was 0.25 (95% CI = 0.07-0.52), and negative predictive value was 0.98 (95% CI = 0.87-1.00). The number needed to screen was 5.6., Significance: An electronic health record-integrated NLP application can accurately assign surgical candidacy scores to patients in a clinical setting., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Racial disparities in the utilization of epilepsy surgery are well documented, but it is unknown whether a natural language processing (NLP) algorithm trained on physician notes would produce biased recommendations for epilepsy presurgical evaluations. To assess this, an NLP algorithm was trained to identify potential surgical candidates using 1097 notes from 175 epilepsy patients with a history of resective epilepsy surgery and 268 patients who achieved seizure freedom without surgery (total N = 443 patients). The model was tested on 8340 notes from 3776 patients with epilepsy whose surgical candidacy status was unknown (2029 male, 1747 female, median age = 9 years; age range = 0-60 years). Multiple linear regression using demographic variables as covariates was used to test for correlations between patient race and surgical candidacy scores. After accounting for other demographic and socioeconomic variables, patient race, gender, and primary language did not influence surgical candidacy scores (P > .35 for all). Higher scores were given to patients >18 years old who traveled farther to receive care, and those who had a higher family income and public insurance (P < .001, .001, .001, and .01, respectively). Demographic effects on surgical candidacy scores appeared to reflect patterns in patient referrals., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objective: We studied age-related dynamics of information sharing among cortical language regions with electrocorticographic high-gamma modulation during picture-naming and story-listening tasks., Methods: Seventeen epilepsy patients aged 4-19 years, undergoing extraoperative monitoring with left-hemispheric subdural electrodes, were included. Mutual information (MI), a nondirectional measure of shared information, between 16 pairs of cortical regions of interest, was computed from trial-averaged 70-150 Hz power modulations during language tasks. Impact of age on pairwise MI between language regions and their determinants were ascertained with regression analysis., Results: During picture naming, significant increase in MI with age was seen between pairwise combinations of Broca's area, inferior precentral gyrus (iPreC), and frontal association cortex (FAC); Wernicke's area and posterior association cortex (PAC); and Broca's and Wernicke's areas. During story listening, significant age-related increase in MI was seen between Wernicke's area and either Broca's area, FAC, or PAC; and between Broca's area and FAC. Significant impact of baseline intelligence quotient was seen on the relationship between age and MI for all pairs, except between Broca's area and iPreC. The mean MI was higher during naming compared to listening for pairs including iPreC with Broca's area, FAC, or PAC and was lower for pairs of Wernicke's area or PAC with anterior language regions., Significance: Information sharing matures with age "within" frontal and temporoparietal language cortices, and "between" Broca's and Wernicke's areas. This study provides evidence for distinct patterns of developmental plasticity within perisylvian language cortex and has implications for planning epilepsy surgery., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objective: This prospective study compared the topography of high-gamma modulation (HGM) during a story-listening task requiring negligible patient cooperation, with the conventional electrical stimulation mapping (ESM) using a picture-naming task, for presurgical language localization in pediatric drug-resistant epilepsy., Methods: Patients undergoing extraoperative monitoring with subdural electrodes were included. Electrocorticographic signals were recorded during quiet baseline and a story-listening task. The likelihood of 70- to 150-Hz power modulation during the listening task relative to the baseline was estimated for each electrode and plotted on a cortical surface model. Sensitivity, specificity, accuracy, and diagnostic odds ratio (DOR) were estimated compared to ESM, using a meta-analytic framework., Results: Nineteen patients (10 with left hemisphere electrodes) aged 4-19 years were analyzed. HGM during story listening was observed in bilateral posterior superior temporal, angular, supramarginal, and inferior frontal gyri, along with anatomically defined language association areas. Compared to either cognitive or both cognitive and orofacial sensorimotor interference with naming during ESM, left hemisphere HGM showed high specificity (0.82-0.84), good accuracy (0.66-0.70), and DOR of 2.23 and 3.24, respectively. HGM was a better classifier of ESM language sites in the left temporoparietal cortex compared to the frontal lobe. Incorporating visual naming with the story-listening task substantially improved the accuracy (0.80) and DOR (13.61) of HGM mapping, while the high specificity (0.85) was retained. In the right hemisphere, no ESM sites for aphasia were seen, and the results of HGM and ESM comparisons were not significant., Significance: HGM associated with story listening is a specific determinant of left hemisphere ESM language sites. It can be used for presurgical language mapping in children who cannot cooperate with conventional language tasks requiring active engagement. Incorporation of additional language tasks, if feasible, can further improve the diagnostic accuracy of language localization with HGM., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Objective: This prospective study compared presurgical language localization with visual naming-associated high-γ modulation (HGM) and conventional electrical cortical stimulation (ECS) in children with intracranial electrodes., Methods: Patients with drug-resistant epilepsy who were undergoing intracranial monitoring were included if able to name pictures. Electrocorticography (ECoG) signals were recorded during picture naming (overt and covert) and quiet baseline. For each electrode the likelihood of high-γ (70-116 Hz) power modulation during naming task relative to the baseline was estimated. Electrodes with significant HGM were plotted on a three-dimensional (3D) cortical surface model. Sensitivity, specificity, and accuracy were calculated compared to clinical ECS., Results: Seventeen patients with mean age of 11.3 years (range 4-19) were included. In patients with left hemisphere electrodes (n = 10), HGM during overt naming showed high specificity (0.81, 95% confidence interval [CI] 0.78-0.85), and accuracy (0.71, 95% CI 0.66-0.75, p < 0.001), but modest sensitivity (0.47) when ECS interference with naming (aphasia or paraphasic errors) and/or oral motor function was regarded as the gold standard. Similar results were reproduced by comparing covert naming-associated HGM with ECS naming sites. With right hemisphere electrodes (n = 7), no ECS-naming deficits were seen without interference with oral-motor function. HGM mapping showed a high specificity (0.81, 95% CI 0.78-0.84), and accuracy (0.76, 95% CI 0.71-0.81, p = 0.006), but modest sensitivity (0.44) compared to ECS interference with oral-motor function. Naming-associated ECoG HGM was consistently observed over Broca's area (left posterior inferior-frontal gyrus), bilateral oral/facial motor cortex, and sometimes over the temporal pole., Significance: This study supports the use of ECoG HGM mapping in children in whom adverse events preclude ECS, or as a screening method to prioritize electrodes for ECS testing., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Invasive electroencephalographic monitoring with implantable subdural electrodes and intraparenchymal depth electrodes has become a basic tenet of epilepsy surgery. Improved localization of epileptic foci justifies the secondary procedure and monitoring period in many patients. Informed use of invasive monitoring in conjunction with imaging and functional studies makes epilepsy surgery a smaller, safer, and more effective endeavor. Herein we review the history, indications, implementation, and foreseeable future of grid, strip, and depth electrode use., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Objective: The predictive value of intraoperative electrocorticography (ECoG) in pediatric epilepsy surgery is unknown. In a population of children undergoing ECoG followed typically by invasive extraoperative monitoring (IEM) and resection, we aimed to determine the relationship between frequent ECoG abnormalities and the seizure onset zone and outcome after resection., Methods: We retrospectively identified 103 children with preresection ECoG of sufficient technical quality. ECoG records were scored based on electrode location and frequency, blinded to the seizure-onset zone and outcome. Electrographic seizure and spike locations were identified. Locations of seizures and spike populations were then compared to the location of seizure-onset zone defined by IEM using subdural electrodes and resection margin., Results: Electrographic seizures were identified in 11 (11%) of 103 patients. A spike population of one or more was noted in 79 (77%) of 103 patients. In 50 (63%) of 79 patients, spike populations correlated with seizure-onset zone location. The overall surgical outcome was good (ILAE 1 to 3) in 53 (52%) of 101 patients. Outcome was good in seven (78%) of nine patients when electrographic seizure location was resected. The best outcomes were obtained with resection of both the seizure-onset zone and ECoG abnormalities to include seizures and spike locations (22/33 good outcome, 67%, p = 0.008). There was a significantly better outcome in children with complete resection of ECoG-identified spike populations (14/26, 62% good outcome) compared to when none were resected (4/14, 29%, p = 0.043)., Significance: Electrographic seizures and frequent spikes are frequently seen on pre-resection ECoG in children. The brain locations corresponding to these discharges are highly concordant with the seizure-onset zone; resection of these regions is correlated with good seizure outcome. Further research is needed to design interventions that increase the reliability of ECoG prediction of the epileptogenic zone and obviate the need for IEM., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Purpose: Determine if blood messenger RNA (mRNA) expression patterns in children with newly diagnosed untreated idiopathic epilepsy are different from those in healthy controls. Determine the differential expression patterns between epilepsy patients with generalized onset or partial onset seizures compared to healthy controls., Methods: Whole blood was obtained from otherwise healthy pediatric patients with newly diagnosed untreated idiopathic epilepsy along with healthy pediatric controls. mRNA was isolated and hybridized to Affymetrix HGU 133 2.0+ microarrays. Analysis was performed using Genespring. Differentially expressed gene lists resulted from comparison of (1) epilepsy and control groups and (2) seizure type subgroups with controls. Tissue expression and gene ontology analysis was performed using DAVID., Key Findings: Thirty-seven epilepsy patients and 28 controls were included. Overall, 575 genes were differentially expressed in subjects with epilepsy compared to controls. The generalized seizure subgroup versus control (GvC) gene list and the partial seizure subgroup versus control (PvC) gene list were different (p < 0.05). Tissue expression analysis identified almost half of the genes in GvC and PvC as brain based. Functional group analysis identified several biologically relevant pathways. In GvC, these included mitochondria and lymphocyte activation. In PvC, we identified apoptosis, inflammatory defense, and cell motion pathways., Significance: A unique, biologically meaningful mRNA expression pattern is detectable in whole blood of pediatric subjects with new-onset and untreated epilepsy. This analysis finds many similar pathways to those identified in brain studies examining lesional intractable epilepsy. Blood mRNA expression patterns show promise as a target for biomarker development in pediatric epilepsy., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Purpose: Intracranial electroencephalography (EEG) is performed as part of an epilepsy surgery evaluation when noninvasive tests are incongruent or the putative seizure-onset zone is near eloquent cortex. Determining the seizure-onset zone using intracranial EEG has been conventionally based on identification of specific ictal patterns with visual inspection. High-frequency oscillations (HFOs, >80 Hz) have been recognized recently as highly correlated with the epileptogenic zone. However, HFOs can be difficult to detect because of their low amplitude. Therefore, the prevalence of ictal HFOs and their role in localization of epileptogenic zone on intracranial EEG are unknown., Methods: We identified 48 patients who underwent surgical treatment after the surgical evaluation with intracranial EEG, and 44 patients met criteria for this retrospective study. Results were not used in surgical decision making. Intracranial EEG recordings were collected with a sampling rate of 2,000 Hz. Recordings were first inspected visually to determine ictal onset and then analyzed further with time-frequency analysis. Forty-one (93%) of 44 patients had ictal HFOs determined with time-frequency analysis of intracranial EEG., Key Findings: Twenty-two (54%) of the 41 patients with ictal HFOs had complete resection of HFO regions, regardless of frequency bands. Complete resection of HFOs (n = 22) resulted in a seizure-free outcome in 18 (82%) of 22 patients, significantly higher than the seizure-free outcome with incomplete HFO resection (4/19, 21%)., Significance: Our study shows that ictal HFOs are commonly found with intracranial EEG in our population largely of children with cortical dysplasia, and have localizing value. The use of ictal HFOs may add more promising information compared to interictal HFOs because of the evidence of ictal propagation and followed by clinical aspect of seizures. Complete resection of HFOs is a favorable prognostic indicator for surgical outcome., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)