Search

Focal cortical dysplasia (FCD) is recognized as a significant etiological factor in pharmacoresistant intractable epilepsy, linked with disturbances in neurovascular metabolism. Our study investigated regulation of glucose-transporter1 (GLUT1) and cerebral hypometabolism within FCD subtypes. Surgically excised human brain specimens underwent histopathological categorization. A subset of samples (paired with matching blood) was assessed for DNA methylation changes of glucose metabolism-related genes. We evaluated GLUT1, VEGFα, MCT2, and mTOR expression by western blot analysis, measured glucose-lactate concentrations, and established correlations with patients' demographic and clinical profiles. Furthermore, we investigated the impact of DNA methylation inhibitor decitabine and hypometabolic condition on the uptake of [ 3 H]-2-deoxyglucose and ATPase in epileptic brain endothelial cells (EPI-EC). We observed hypermethylation of GLUT1 and glucose metabolic genes in FCD brain/blood samples and could distinguish FCDIIa/b from mMCD, MOGHE and non-lesional types in brain. Low GLUT1 and glucose-lactate ratios corresponded to elevated VEGFα and MCT2 in FCDIIa/b vs non-lesional tissues, independent of age, gender, seizure-onset, or duration of epilepsy. Increased mTOR signaling in FCDIIa/b tissues was evident. Decitabine stimulation increased GLUT1, decreased VEGFα expression, restored glucose uptake and ATPase activity in EPI-ECs and reduced mTOR and MCT2 levels in HEK cells. We demonstrated: 1) hypermethylation of glucose regulatory genes distinguish FCDIIa/b from mMCD, MOGHE and non-lesional types, 2) glucose uptake reduction is due to GLUT1 suppression mediated possibly by a GLUT1-mTOR mechanism; and 3) DNA methylation regulates cellular glucose update and metabolism. Together, these studies may lead to GLUT1-mediated biomarkers, glucose metabolism and identify early intervention strategies in FCD., Competing Interests: Conflict of Interest I.N. serves on the speakers’ bureau and as a member of ad hoc advisory board for SK Life. None of the other authors have any potential conflict of interest to disclose.

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Objective: Demographic and disease factors are associated with cognitive deficits and postoperative cognitive declines in adults with pharmacoresistant temporal lobe epilepsy (TLE), but the role of genetic factors in cognition in TLE is not well understood. Polygenic scores (PGS) for neurological and neuropsychiatric disorders and IQ have been associated with cognition in patient and healthy populations. In this exploratory study, we examined the relationship between PGS for Alzheimer's disease (AD), depression, and IQ and cognitive outcomes in adults with TLE., Methods: 202 adults with pharmacoresistant TLE had genotyping and completed neuropsychological evaluations as part of a presurgical work-up. A subset (n = 116) underwent temporal lobe resection and returned for postoperative cognitive testing. Logistic regression was used to determine if PGS for AD, depression, and IQ predicted baseline domain-specific cognitive function and cognitive phenotypes as well as postoperative language and memory decline., Results: No significant findings survived correction for multiple comparisons. Prior to correction, higher PGS for AD and depression (i.e., increased genetic risk for the disorder), but lower PGS for IQ (i.e., decreased genetic likelihood of high IQ) appeared possibly associated with baseline cognitive impairment in TLE. In comparison, higher PGS for AD and IQ appeared as possible risk factors for cognitive decline following temporal lobectomy, while the possible relationship between PGS for depression and post-operative cognitive outcome was mixed., Significance: We did not observe any relationships of large effect between PGS and cognitive function or postsurgical outcome; however, results highlight several promising trends in the data that warrant future investigation in larger samples better powered to detect small genetic effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The significance of ictal magnetoencephalography (MEG) is not well appreciated. We evaluated the relationships between ictal MEG, MRI, intracranial electroencephalography (ICEEG), surgery and postoperative seizure outcome., Methods: A total of 45 patients (46 cases) with ictal MEG who underwent epilepsy surgery was included. We examined the localization of each modality, surgical resection area and seizure freedom after surgery., Results: Twenty-one (45.7%) out of 46 cases were seizure-free at more than 6 months follow-up. Median duration of postoperative follow-up was 16.5 months. The patients in whom ictal, interictal single equivalent current dipole (SECD) and MRI lesion localization were completely included in the resection had a higher chance of being seizure-free significantly (p < 0.05). Concordance between ictal and interictal SECD localizations was significantly associated with seizure-freedom. Concordance between MRI lesion and ictal SECD, concordance between ictal ICEEG and ictal and interictal SECD, as well as concordance between ictal ICEEG and MRI lesion were significantly associated with seizure freedom., Conclusions: Ictal MEG can contribute useful information for delineating the resection area in epilepsy surgery., Significance: Resection should include ictal, interictal SECDs and MRI lesion localization, when feasible. Concordant ictal and interictal SECDs on MEG can be a favorable predictor of seizure freedom., Competing Interests: Conflicts of interest The authors report no competing interests., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Memory dysfunction is prevalent in temporal lobe epilepsy (TLE), but little is known about the underlying molecular etiologies. Single-nucleus RNA sequencing technology was used to examine differences in cellular heterogeneity among left (language-dominant) temporal neocortical tissues from patients with TLE with (n = 4) or without (n = 2) impairment in verbal episodic memory. We observed marked cell heterogeneity between memory phenotypes and identified numerous differentially expressed genes across all brain cell types. The most notable differences were observed in glutamatergic (excitatory) and GABAergic (inhibitory) neurons with an overrepresentation of genes associated with long-term potentiation, long-term depression, and MAPK signaling, processes known to be essential for episodic memory formation., (© 2022. The Author(s).)

Memory dysfunction is prevalent in temporal lobe epilepsy, but little is known about the underlying pathophysiological etiologies. Here, we use spatial quantitation to examine differential expression of targeted proteins and transcripts in four brain regions essential for episodic memory (dentate gyrus, CA3, CA1, neocortex) between temporal lobe epilepsy patients with and without episodic memory impairment. Brain tissues were obtained from dominant temporal lobectomies in 16 adults with pharmacoresistant temporal lobe epilepsy associated with hippocampal sclerosis. Verbal memory tests from routine pre-operative clinical care were used to classify episodic memory as impaired or intact. Digital spatial profiling of a targeted protein panel and the whole transcriptome was performed using tissue sections from the temporal neocortex and hippocampus. We performed differential expression and pathway enrichment analysis between the memory groups within each temporal lobe region. Several proteins associated with neurodegenerative disease were overexpressed in the neocortex of patients with impaired memory, corroborating our prior findings using bulk transcriptomics. Spatial transcriptomics identified numerous differentially expressed transcripts in both neocortical and hippocampal subregions between memory groups, with little overlap across subregions. The strongest molecular signal was observed in the CA3 hippocampal subregion, known to play an essential role in memory encoding. Enrichment analyses revealed BDNF as a central hub in CA3-related networks regulating phenotype-relevant processes such as cognition, memory, long-term potentiation and neuritogenesis ( P adj < 0.05). Results suggest memory impairment in temporal lobe epilepsy with hippocampal sclerosis is associated with molecular alterations within temporal lobe subregions that are independent from hippocampal cell loss, demographic variables and disease characteristics. Importantly, each temporal subregion shows a unique molecular signature associated with memory impairment. While many differentially expressed transcripts and proteins in the neocortex have been associated with neurodegenerative disorders/processes, differentially expressed transcripts in hippocampal subregions involve genes associated with neuritogenesis and long-term potentiation, processes essential for new memory formation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: We aim to provide detailed imaging-electroclinicopathologic characterization of the black line sign, a novel MRI marker for focal cortical dysplasia (FCD) IIB., Methods: 7T T2*-weighted gradient-echo (T2*w-GRE) images were retrospectively reviewed in a consecutive cohort of patients with medically intractable epilepsy with pathology-proven FCD II, for the occurrence of the black line sign. We examined the overlap between the black line region and the seizure-onset zone (SOZ) defined by intracranial EEG (ICEEG) and additionally assessed whether complete inclusion of the black line region in the surgical resection was associated with postoperative seizure freedom. The histopathologic specimen was aligned with the MRI to investigate the pathologic underpinning of the black line sign. Region-of-interest-based quantitative MRI (qMRI) analysis on the 7T T1 map was performed in the black line region, entire lesional gray matter (GM), and contralateral/ipsilateral normal gray and white matter (WM)., Results: We included 20 patients with FCD II (14 IIB and 6 IIA). The black line sign was identified in 12/14 (85.7%) of FCD IIB and 0/6 of FCD IIA on 7T T2*w-GRE. The black line region was highly concordant with the ICEEG-defined SOZ (5/7 complete and 2/7 partial overlap). Seizure freedom was seen in 8/8 patients whose black line region was completely included in the surgical resection; in the 2 patients whose resection did not completely include the black line region, both had recurring seizures. Inclusion of the black line region in the surgical resection was significantly associated with seizure freedom ( p = 0.02). QMRI analyses showed that the T1 mean value of the black line region was significantly different from the WM ( p < 0.001), but similar to the GM. Well-matched histopathologic slices in one case revealed accumulated dysmorphic neurons and balloon cells in the black line region., Discussion: The black line sign may serve as a noninvasive marker for FCD IIB. Both MRI-pathology and qMRI analyses suggest that the black line region was an abnormal GM component within the FCD. Being highly concordant with ICEEG-defined SOZ and significantly associated with seizure freedom when included in resection, the black line sign may contribute to the planning of ICEEG/surgery of patients with medically intractable epilepsy with FCD IIB., Classification of Evidence: This study provides Class II evidence that in individuals with intractable focal epilepsy undergoing resection who have a 7T MRI with adequate image quality, the presence of the black line sign may suggest FCD IIB, be concordant with SOZ from ICEEG, and be associated with more seizure freedom if fully included in resection., (© 2022 American Academy of Neurology.)

The glucocorticoid receptor (GR) at the blood−brain barrier (BBB) is involved in the pathogenesis of drug-resistant epilepsy with focal cortical dysplasia (FCD); however, the roles of GR isoforms GRα and GRβ in the dysplastic brain have not been revealed. We utilized dysplastic/epileptic and non-dysplastic brain tissue from patients who underwent resective epilepsy surgery to identify the GRα and GRβ levels, subcellular localization, and cellular specificity. BBB endothelial cells isolated from the dysplastic brain tissue (EPI-ECs) were used to decipher the key BBB proteins related to drug regulation and BBB integrity compared to control and transfected GRβ-overexpressed BBB endothelial cells. GRβ was upregulated in dysplastic compared to non-dysplastic tissues, and an imbalance of the GRα/GRβ ratio was significant in females vs. males and in patients > 45 years old. In EPI-ECs, the subcellular localization and expression patterns of GRβ, Hsp90, CYP3A4, and CYP2C9 were consistent with GRβ+ brain endothelial cells. Active matrix metalloproteinase levels and activity increased, whereas claudin-5 levels decreased in both EPI-ECs and GRβ+ endothelial cells. In conclusion, the GRβ has a major effect on dysplastic BBB functional proteins and is age and gender-dependent, suggesting a critical role of brain GRβ in dysplasia as a potential biomarker and therapeutic target in epilepsy.

Focal cortical dysplasia (FCD) is associated with blood-brain barrier (BBB) dysfunction in patients with difficult-to-treat epilepsy. However, the underlying cellular and molecular factors in cortical dysplasia (CD) associated with progressive neurovascular challenges during the pro-epileptic phase, post-seizure, and during epileptogenesis remain unclear. We studied the BBB function in a rat model of congenital (in utero radiation-induced, first hit) CD and longitudinally examined the cortical brain tissues at baseline and the progressive neurovascular alterations, glucose transporter-1 (GLUT1) expression, and glucose metabolic activity at 2, 15, and 30 days following a second hit using pentylenetetrazole-induced seizure. Our study revealed through immunoblotting, immunohistochemistry, and biochemical analysis that (1) altered vascular density and prolongation of BBB albumin leakages in CD rats continued through 30 days post-seizure; (2) CD brain tissues showed elevated matrix metalloproteinase-9 levels at 2 days post-seizure and microglial overactivation through 30 days post-seizure; (3) BBB tight junction protein and GLUT1 levels were decreased and neuronal monocarboxylate transporter-2 (MCT2) and mammalian target of rapamycin (mTOR) levels were increased in the CD rat brain: (4) ATPase activity is elevated and a low glucose/high lactate imbalance exists in CD rats; and (5) the mTOR pathway is activated and MCT2 levels are elevated in the presence of high lactate during glucose starvation in vitro. Together, this study suggests that BBB dysfunction, including decreased GLUT1 expression and metabolic disturbance, may contribute to epileptogenesis in this CD rat model through multiple mechanisms that could be translated to FCD therapy in medically refractory epilepsy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To develop and externally validate models to predict the probability of postoperative verbal memory decline in adults after temporal lobe resection (TLR) for epilepsy using easily accessible preoperative clinical predictors., Methods: Multivariable models were developed to predict delayed verbal memory outcome on 3 commonly used measures: Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) and Verbal Paired Associates (VPA) subtests from Wechsler Memory Scale-Third Edition. With the use of the Harrell step-down procedure for variable selection, models were developed in 359 adults who underwent TLR at the Cleveland Clinic and validated in 290 adults at 1 of 5 epilepsy surgery centers in the United States or Canada., Results: Twenty-nine percent of the development cohort and 26% of the validation cohort demonstrated significant decline on at least 1 verbal memory measure. Initial models had good to excellent predictive accuracy (calibration [c] statistic range 0.77-0.80) in identifying patients with memory decline; however, models slightly underestimated decline in the validation cohort. Model coefficients were updated with data from both cohorts to improve stability. The model for RAVLT included surgery side, baseline memory score, and hippocampal resection. The models for LM and VPA included surgery side, baseline score, and education. Updated model performance was good to excellent (RAVLT c = 0.81, LM c = 0.76, VPA c = 0.78). Model calibration was very good, indicating no systematic overestimation or underestimation of risk., Conclusions: Nomograms are provided in 2 easy-to-use formats to assist clinicians in estimating the probability of verbal memory decline in adults considering TLR for treatment of epilepsy., Classification of Evidence: This study provides Class II evidence that multivariable prediction models accurately predict verbal memory decline after TLR for epilepsy in adults., (© 2021 American Academy of Neurology.)

Focal epilepsy (FE) is clinically highly heterogeneous. It has been shown recently that not only rare but also a subset of common genetic variants confer risk for FE. The relatively modest power of genetic studies in FE suggests a high genetic heterogeneity of FE when grouped as one disorder. We hypothesize that the clinical heterogeneity of FE is correlated with genetic heterogeneity on a common risk variant level. To test the hypothesis, we used an FE polygenic risk score "FE-PRS" that combines small effect sizes of thousands of common variants from the largest FE-GWAS (genome-wide association study) into a single measure. We grouped 414 individuals with FE according to common clinical features into subgroups, either by one feature at a time or by all features combined in a cluster analysis. We examined their association with FE-PRS compared to 20 435 matched population controls and observed heterogeneous FE-PRS burden among the subgroups. The highest phenotypic variance explained by FE-PRS was identified in a cluster analysis-defined FE subgroup where all individuals had unknown etiologies and psychiatric comorbidities, and the majority had early onset seizures. Our results indicate that genetic factors associated with FE have differential burden among FE subtypes. Future studies using better-powered FE-PRS might have clinical utility., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Pharmacoresistance in epilepsy is a major challenge to successful clinical therapy. Glucocorticoid receptor (GR) dysregulation can affect the underlying disease pathogenesis. We recently reported that local drug biotransformation at the blood-brain barrier is upregulated by GR, which controls drug-metabolizing enzymes (e.g., cytochrome P450s, CYPs) and efflux drug transporters (MDR1) in human epileptic brain endothelial cells (EPI-ECs). Here, we establish that this mechanism is influenced upstream by GR and its association with heat shock proteins/co-chaperones (Hsps) during maturation, which differentially affect human epileptic (EPI) tissue and brain endothelial cells. Overexpressed GR, Hsp90, Hsp70, and Hsp40 were found in EPI vs. NON-EPI brain regions. Elevated neurovascular GR expression and co-localization with Hsps was evident in the EPI regions with cortical dysplasia, predominantly in the brain micro-capillaries and neurons. A corresponding increase in ATPase activity (*p < 0.05) was found in the EPI regions. The GR-Hsp90/Hsp70 binding patterns indicated a faster chaperone-promoted maturation of GR, leading to its overactivation in both the tissue and EPI-ECs derived from EPI/focal regions and GR silencing in EPI-ECs slowed such GR-Hsp interactions. Significantly accelerated GR nuclear translocation was determined in EPI-ECs following treatment with GR modulators/ligands dexamethasone, rifampicin, or phenytoin. Our findings reveal that overexpressed GR co-localizes with Hsps in the neurovasculature of EPI brain, increased GR maturation by Hsps accelerates EPI GR machinery, and furthermore this change in EPI and NON-EPI GR-Hsp interaction alters with the age of seizure onset in epileptic patients, together affecting the pathophysiology and drug regulation in the epileptic brain endothelium.

Objective: Memory dysfunction is prevalent in many neurological disorders and can have a significant negative impact on quality of life. The genetic contributions to memory impairment in epilepsy, particularly temporal lobe epilepsy (TLE), remain poorly understood. Here, we compare the brain transcriptome between TLE patients with and without verbal memory impairments to identify genes and signaling networks important for episodic memory., Methods: Brain tissues were resected from 23 adults who underwent dominant temporal lobectomy for treatment of pharmacoresistant epilepsy. To control for potential effects of APOE on memory, only those homozygous for the APOE ε3 allele were included. A battery of memory tests was performed, and patients were stratified into two groups based on preoperative memory performance. The groups were well matched on demographic and disease-related variables. Total RNA-Seq and small RNA-Seq were performed on RNA extracted from the brain tissues. Pathway and integrative analyses were subsequently performed., Results: We identified 1092 differentially expressed transcripts (DETs), with the majority (71%) being underexpressed in brain tissues from patients with impaired memory compared to those from patients with intact memory. Enrichment analysis revealed overrepresentation of genes in pathways pertaining to brain-related neurological dysfunction, including a subset associated with neurodegenerative diseases, memory, and cognition (APP, MAPT, PINK1). Despite including patients with identical APOE genotypes, we identify APOE as a differentially expressed gene associated with memory status. Small RNA-Seq identified four differentially expressed microRNAs (miRNAs) that were predicted to target a subset (22%) of all DETs. Integrative analysis showed that these miRNA-predicted DET targets impact brain-related pathways and biological processes also pertinent to memory and cognition., Significance: TLE-associated memory status may be influenced by differences in gene expression profiles within the temporal lobe. Upstream processes influencing differential expression signatures, such as miRNAs, could serve as biomarkers and potential treatment targets for memory impairment in TLE., (© 2020 International League Against Epilepsy.)

Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. Little is known about the molecular pathology of PNES, much less about possible underlying genetic factors. We generated whole-exome sequencing and whole-genome genotyping data to identify rare, pathogenic (P) or likely pathogenic (LP) variants in 102 individuals with PNES and 448 individuals with focal (FE) or generalized (GE) epilepsy. Variants were classified for all individuals based on the ACMG-AMP 2015 guidelines. For research purposes only, we considered genes associated with neurological or psychiatric disorders as candidate genes for PNES. We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). Notably, the burden of P/LP variants among the individuals with PNES was similar and not significantly different to the burden observed in the individuals with FE (3.05%) or GE (1.82%) (PNES vs. FE vs. GE (3 × 2 χ 2 ), P = 0.30; PNES vs. epilepsy (2 × 2 χ 2 ), P = 0.14). The presence of variants in genes associated with monogenic forms of neurological and psychiatric disorders in individuals with PNES shows that genetic factors are likely to play a role in PNES or its comorbidities in a subset of individuals. Future large-scale genetic research studies are needed to further corroborate these interesting findings in PNES.

Pharmacoresistance is a major clinical challenge for approximately 30% of patients with epilepsy. Previous studies indicate nuclear receptors (NRs), drug efflux transporters, and cytochrome P450 enzymes (CYPs) control drug passage across the blood-brain barrier (BBB) in drug-resistant epilepsy. Here, we (1) evaluate BBB changes, neurovascular nuclear receptors, and drug transporters in lesional/epileptic (EPI) and non-lesional/non-epileptic (NON-EPI) regions of the same brain, (2) examine regional CYP expression and activity, and (3) investigate the association among CYP brain expression, seizure frequency, duration of epilepsy, and antiepileptic drug (AED) combination. We used surgically resected brain specimens from patients with medically intractable epilepsy (n = 22) where the epileptogenic loci were well-characterized by invasive and non-invasive methods; histology confirmed distinction of small NON-EPI regions from EPI tissues. NRs, transporters, CYPs, and tight-junction proteins were assessed by western blots/immunohistochemistry, and CYP metabolic activity was determined and compared. The relationship of CYP expression with seizure frequency, duration of epilepsy, and prescribed AEDs was evaluated. Decreased BBB tight-junction proteins accompanied IgG leakage in EPI regions and correlated with upregulated NR and efflux transporter levels. CYP expression and activity significantly increased in EPI compared to NON-EPI tissues. Change in EPI and NON-EPI CYP3A4 expression increased in patients taking AEDs that were CYP substrates, was downregulated when CYP- and non-CYP-substrate AEDs were given together, and correlated with seizure frequency. Our studies suggest focal neurovascular CYP-NR-transporter alterations, as demonstrated by the relationship of seizure frequency and AED combination to brain CYP3A4, might together impact biotransformation machinery of human pharmacoresistant epilepsy.

Objective: To evaluate the localization value and prognostic significance of subclinical seizures (SCSs) on scalp video-electroencephalography monitoring (VEEG) in comparison to clinical seizures (CSs) in patients who had epilepsy surgery., Methods: We included 123 consecutive patients who had SCSs and CSs during scalp-VEEG evaluation. All patients had subsequent epilepsy surgery and at least 1-year follow-up. Concordance between SCSs and CSs was summarized into five categories: complete, partial, overlapping, no concordance, or indeterminate. Using the same scheme, we analyzed the relationship between resection and SCS/CS localizations. The concordance measures, along with demographic, electroclinical, and other presurgical evaluation data, were evaluated for their associations with postoperative seizure outcome., Results: Sixty-nine patients (56.1%) had seizure-free outcome at 1-year follow-up. In 68 patients (55.3%), the localizations of SCSs and CSs were completely concordant. Multivariate logistic analysis showed that complete SCS/CS concordance was independently associated with seizure-free outcome at 1-year (P = .020) and 2-year follow-up (P = .040). In the temporal lobe epilepsy (TLE) seizure-free group, SCS localization was completely contained within the resection in 44.4% and CS localization was completely contained within the resection in 41.7%; in the extratemporal lobe epilepsy (ETLE) seizure-free group, SCS localization was completely contained within the resection in 54.5% and CS localization was completely contained within the resection in 57.6%., Significance: Complete concordance between CS and SCS localization is a positive prognostic factor for 1-year and 2-year postoperative seizure-free outcome. Localization value of SCSs on scalp VEEG is similar to that of CSs for TLE and ETLE. Although SCSs cannot replace CSs, localization information from SCSs should not be ignored., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: The objective of this study was to determine whether three common genetic polymorphisms [apolipoprotein (APOE) ε4 (rs42938 and rs7412), brain derived neurotrophic factor (BDNF) Met (rs6265), and catechol-O-methyltransferase (COMT) Val (rs4680)] are associated with increased psychiatric symptomatology in individuals with pharmacoresistant epilepsy., Methods: One hundred forty-eight adults (M age  = 38 years; 53% female) with refractory epilepsy completed self-report measures of mood, anxiety, and/or personality/psychopathology. Mann-Whitney U, t-tests, and Fisher's exact tests were used to determine if APOE4, BDNF Val66Met, or COMT Val158Met are associated with increased psychiatric symptomatology in people with epilepsy., Results: As a group, BDNF Met carriers reported greater symptoms of depression on the Personality Assessment Inventory (PAI) than those without a Met allele (p = 0.004); COMT Val carriers reported greater symptoms on the PAI Schizophrenia (p = 0.007), Antisocial Features (p = 0.04), and Alcohol Problems (p = 0.03) scales than noncarriers. On the individual level, a significantly greater proportion of BDNF Met carriers demonstrated elevated PAI Depression scores compared to those without a Met allele (p = 0.046). There was also a larger proportion of COMT Val carriers with elevated PAI Anxiety scores as compared to those without a Val allele (p = 0.036)., Significance: This retrospective cross-sectional study provides preliminary evidence for a genetic basis of psychiatric comorbidities in epilepsy and suggests that BDNF and COMT may play an important role in the pathophysiology of mental health problems in this vulnerable population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Presurgical evaluation of patients with operculoinsular epilepsy and negative MRI presents major challenges. Here the authors examined the yield of noninvasive modalities such as voxel-based morphometric MRI postprocessing, FDG-PET, subtraction ictal SPECT coregistered to MRI (SISCOM), and magnetoencephalography (MEG) in a cohort of patients with operculoinsular epilepsy and negative MRI., Methods: Twenty-two MRI-negative patients were included who had focal ictal onset from the operculoinsular cortex on intracranial EEG, and underwent focal resection limited to the operculoinsular cortex. MRI postprocessing was applied to presurgical T1-weighted volumetric MRI using a morphometric analysis program (MAP). Individual and combined localization yields of MAP, FDG-PET, MEG, and SISCOM were compared with the ictal onset location on intracranial EEG. Seizure outcomes were reported at 1 year and 2 years (when available) using the Engel classification., Results: Ten patients (45.5%, 10/22) had operculoinsular abnormalities on MAP; 5 (23.8%, 5/21) had operculoinsular hypometabolism on FDG-PET; 4 (26.7%, 4/15) had operculoinsular hyperperfusion on SISCOM; and 6 (30.0%, 6/20) had an MEG cluster (3 tight, 3 loose) within the operculoinsular cortex. The highest yield of a 2-test combination was 59.1%, seen with MAP and SISCOM, followed by 54.5% with MAP and FDG-PET, and also 54.5% with MAP and MEG. The highest yield of a 3-test combination was 68.2%, seen with MAP, MEG, and SISCOM. The yield of the 4-test combination remained at 68.2%. When all other tests were negative or nonlocalizing, unique information was provided by MAP in 5, MEG in 1, SISCOM in 2, and FDG-PET in none of the patients. One-year follow-up was available in all patients, and showed 11 Engel class IA, 4 class IB, 4 class II, and 3 class III/IV. Two-year follow-up was available in 19 patients, and showed 9 class IA, 3 class IB, 1 class ID, 3 class II, and 3 class III/IV., Conclusions: This study highlights the individual and combined values of multiple noninvasive modalities for the evaluation of nonlesional operculoinsular epilepsy. The 3-test combination of MAP, MEG, and SISCOM represented structural, interictal, and ictal localization information, and constituted the highest yield. MAP showed the highest yield of unique information when other tests were negative or nonlocalizing.

We investigated how pathological changes in newborn hippocampal dentate granule cells (DGCs) lead to epilepsy. Using a rabies virus-mediated retrograde tracing system and a designer receptors exclusively activated by designer drugs (DREADD) chemogenetic method, we demonstrated that newborn hippocampal DGCs are required for the formation of epileptic neural circuits and the induction of spontaneous recurrent seizures (SRS). A rabies virus-mediated mapping study revealed that aberrant circuit integration of hippocampal newborn DGCs formed excessive de novo excitatory connections as well as recurrent excitatory loops, allowing the hippocampus to produce, amplify, and propagate excessive recurrent excitatory signals. In epileptic mice, DREADD-mediated-specific suppression of hippocampal newborn DGCs dramatically reduced epileptic spikes and SRS in an inducible and reversible manner. Conversely, specific activation of hippocampal newborn DGCs increased both epileptic spikes and SRS. Our study reveals an essential role for hippocampal newborn DGCs in the formation and function of epileptic neural circuits, providing critical insights into DGCs as a potential therapeutic target for treating epilepsy.

Objective: To develop and externally validate models to predict the probability of postoperative naming decline in adults following temporal lobe epilepsy surgery using easily accessible preoperative clinical predictors., Methods: In this retrospective, prediction model development study, multivariable models were developed in a cohort of 719 patients who underwent temporal lobe epilepsy surgery at Cleveland Clinic and externally validated in a cohort of 138 patients who underwent temporal lobe surgery at one of 3 epilepsy surgery centers in the United States (Columbia University Medical Center, Emory University School of Medicine, University of Washington School of Medicine)., Results: The development cohort was 54% female with an average age at surgery of 36 years (SD 12). Twenty-six percent of this cohort experienced clinically relevant postoperative naming decline. The model included 5 variables: side of surgery, age at epilepsy onset, age at surgery, sex, and education. When applied to the external validation cohort, the model performed very well, with excellent calibration and a c statistic (reflecting discriminatory ability) of 0.81. A second model predicting moderate to severe postoperative naming decline included 3 variables: side of surgery, age at epilepsy onset, and preoperative naming score. This model generated a c statistic of 0.84 in the external validation cohort and showed good calibration., Conclusion: Externally validated nomograms are provided in 2 easy-to-use formats (paper version and online calculator) clinicians can use to estimate the probability of naming decline in patients considering epilepsy surgery for treatment of pharmacoresistant temporal lobe epilepsy., (© 2018 American Academy of Neurology.)

Background: Laser ablation surgery has had encouraging results in the treatment of multiple intracranial diseases including primary and metastatic brain tumors, radiation necrosis, and epilepsy. The use of the stereoelectroencephalography (SEEG) method in combination with laser thermocoagulation therapy with the goal of modulating epileptic networks in patients with neocortical nonlesional phamacoresistant epilepsy has not been previously described., Objective: To describe the novel methodological and conceptual aspects related to SEEG-guided laser ablations in patients with magnetic resonance imaging (MRI)-negative pharmacoresistant neocortical focal epilepsy., Methods: Guided by previous SEEG intracranial data, a laser ablation probe was inserted by using a robotic guidance device in a 17-yr-old medically refractory epilepsy patient with difficult to localize seizures and nonlesional MRI. The laser applicator position was confirmed by MRI, targeting the left mesial rostral superior frontal gyrus. The ablation was performed under multiplanar digital imaging views and real-time thermal imaging and treatment estimates in each plane. A postablation MRI (contrasted T1 sequence) confirmed the ablation's location and size., Results: The entire procedure was achieved in approximately 100 min. The actual ablation was performed in less than 3 min. Approximately, additional 30 min preoperatively were used for positioning and robot registration. Precise placement of laser application (in comparison with preplanned trajectories) was achieved using the robotic guidance and confirmed by the intraoperative magnetic resonance images. No complications were reported. The patient has been seizure-free since surgery. The follow-up period is 20 mo. Two additional patients, treated with similar methodology, are also described., Conclusion: The preliminary experience with the described method shows the feasibility of a unique combination of the SEEG methodology with laser thermocoagulation in patients with neocortical MRI-negative pharmacoresistant focal epilepsy.

Background and Purpose: Surgical management of patients with cingulate epilepsy (CE) is highly challenging, especially when the MRI is non-lesional. We aimed to use a voxel-based MRI post-processing technique, implemented in a morphometric analysis program (MAP), to facilitate detection of subtle epileptogenic lesions in CE, thereby improving surgical evaluation of patients with CE with non-lesional MRI by visual inspection. Methods: Included in this retrospective study were 9 patients with CE (6 with negative 3T MRI and 3 with subtly lesional 3T MRI) who underwent surgery and became seizure-free or had marked seizure improvement with at least 1-year follow-up. MRI post-processing was applied to pre-surgical T1-weighted volumetric sequence using MAP. The MAP finding was then coregistered and compared with other non-invasive imaging tests (FDG-PET, SPECT and MEG), intracranial EEG ictal onset, surgery location and histopathology. Results: Single MAP+ abnormalities were found in 6 patients, including 3 patients with negative MRI, and 3 patients with subtly lesional MRI. Out of these 6 MAP+ patients, 4 patients became seizure-free after complete resection of the MAP+ abnormalities; 2 patients didn't become seizure-free following laser ablation that only partially overlapped with the MAP+ abnormalities. All MAP+ foci were concordant with intracranial EEG ictal onset (when performed). The localization value of FDG-PET, SPECT and MEG was limited in this cohort. FCD was identified in all patients' surgical pathology except for two cases of laser ablation with no tissue available. Conclusion: MAP provided helpful information for identifying subtle epileptogenic abnormalities in patients with non-lesional cingulate epilepsy. MRI postprocessing should be considered to add to the presurgical evaluation test battery of non-lesional cingulate epilepsy.

Background: Many traumatic brain injury (TBI) survivors live with persistent disability from chronic motor deficits despite contemporary rehabilitation services, underscoring the need for novel treatment., Objective/hypothesis: We have previously shown that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN) can enhance post-stroke motor recovery and increase the expression of markers of long-term potentiation in perilesional cerebral cortex. We hypothesize that a similar beneficial effect will be for motor deficits induced by unilateral fluid percussion injury (FPI) in rodents through long-term potentiation- and anti-inflammatory based mechanisms., Methods: Male Long Evans rats with a DBS macroelectrode in the LCN underwent FPI over contralateral primary motor cortex. After 4 weeks of spontaneous recovery, DBS treatment was applied for 4 weeks, with the pasta matrix, cylinder, and horizontal ladder tests used to evaluate motor performance. All animals were euthanized and tissue harvested for further analysis by histology, immunohistochemistry, RNA microarray assay and Western Blot., Results: LCN DBS-treated animals experienced a significantly greater rate of motor recovery than untreated surgical controls, with treated animals showing enhanced expression of RNA and protein for excitability related genes, suppressed expression of pro-inflammatory genes, suppressed microglial and astrocytic activation, but proliferation of c-fos positive cells. Finally, our data suggest a possible role for anti-apoptotic effects with LCN DBS., Conclusion: LCN DBS enhanced the motor recovery following TBI, possibly by elevating the neuronal excitability at the perilesional area and mediating anti-apoptotic and anti-inflammatory effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Detection of focal cortical dysplasia (FCD) is of paramount importance in epilepsy presurgical evaluation. Our study aims at utilizing quantitative positron emission tomography (QPET) analysis to complement magnetic resonance imaging (MRI) postprocessing by a morphometric analysis program (MAP) to facilitate automated identification of subtle FCD., Methods: We retrospectively included a consecutive cohort of surgical patients who had a negative preoperative MRI by radiology report. MAP was performed on T1-weighted volumetric sequence and QPET was performed on PET/computed tomographic data, both with comparison to scanner-specific normal databases. Concordance between MAP and QPET was assessed at a lobar level, and the significance of concordant QPET-MAP + abnormalities was confirmed by postresective seizure outcome and histopathology. QPET thresholds of standard deviations (SDs) of -1, -2, -3, and -4 were evaluated to identify the optimal threshold for QPET-MAP analysis., Results: A total of 104 patients were included. When QPET thresholds of SD = -1, -2, and -3 were used, complete resection of the QPET-MAP + region was significantly associated with seizure-free outcome when compared with the partial resection group (P = 0.023, P < 0.001, P = 0.006) or the no resection group (P = 0.002, P < 0.001, P = 0.001). The SD threshold of -2 showed the best combination of positive rate (55%), sensitivity (0.68), specificity (0.88), positive predictive value (0.88), and negative predictive value (0.69). Surgical pathology of the resected QPET-MAP + areas revealed mainly FCD type I. Multiple QPET-MAP + regions were present in 12% of the patients at SD = -2., Significance: Our study demonstrates a practical and effective approach to combine quantitative analyses of functional (QPET) and structural (MAP) imaging data to improve identification of subtle epileptic abnormalities. This approach can be readily adopted by epilepsy centers to improve postresective seizure outcomes for patients without apparent lesions on MRI., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Objective: To investigate the neuroimaging and clinical features associated with sleep-related epilepsy (SRE) in patients with focal cortical dysplasia (FCD) type II., Methods: Patients with histopathologically proven FCD type II were included from three epilepsy centers. SRE was defined according to the video EEG findings and seizure history. Cortical surface reconstruction and volume calculation were performed using FreeSurfer. The lesions were manually delineated on T1 volumetric MRI using the ITK-SNAP software. The lesion volumes were normalized by the intracranial volume of each patient. The lesions were classified as small or large by placing a threshold based on quantitative (whether the lesion was detected on MRI report) and qualitative (volume) criteria., Results: A total of 77 consecutive patients were included. Of them, 36 had SRE and 41 had non-SRE. An earlier age of epilepsy onset, high seizure frequency, regional interictal EEG findings, and favorable surgical outcome were characteristic in both groups. Small lesions were defined as those having a volume <3,217 mm 3 . In total, 60.9% of the patients with SRE (25/41) had small FCD lesion, which was significantly higher than the non-SRE group (9/34, 26.5%, p  = 0.005). Small lesion size was the only predictor significantly associated with SRE in the overall type II group by multivariate analyses ( p  = 0.016). Although the proportion of patients who had frontal FCD and SRE was higher than non-frontal FCD (54.5 vs. 27.3%, p  = 0.043), the relationship between SRE and lesion location was not confirmed by multivariate analysis. Thalamic volume and seizure semiology were not statistically different between the SRE and non-SRE group. The significant association between lesion size and SRE was reproducible in type IIb and IIa subgroups., Significance: SRE is common in patients with FCD type II. Small FCD type II lesions are significantly associated with SRE. Although our findings cannot be applied to the entire spectrum of SRE, potential existence of small FCD lesions should be considered when evaluating patients with SRE, and utilization of all other supportive electroclinical information for lesion detection is highly desirable.

The Diagnostic Methods commission of the International League against Epilepsy (ILAE) released a first international consensus classification of Focal Cortical Dysplasia (FCD) in 2011. Since that time, this FCD classification has been widely used in clinical diagnosis and research (more than 740 papers cited in Pubmed between 1/1/2012 and 7/1/2017). Herein, we review the new data that will inform and revise the FCD classification. Many recent papers described molecular-genetic characteristics in FCD type II including multiple mutations in the mTOR pathway. In addition, the electro-clinico-imaging phenotype and surgical outcomes of FCD type II (in particular type IIb) were further defined and validated. These results pave the way for the design of an integrated clinico-pathological and genetic classification system, as recently recommended by the WHO for the classification of malignant brain tumours. On the other hand, little new information was acquired on FCD types I and III. Focal cortical dysplasia type I subtypes are still lacking a comprehensive description of clinical phenotypes, reproducible imaging characteristics, and specific molecular/genetic biomarkers. Associated FCD III subtypes also became rare in published literature. Despite temporal lobe epilepsy being the most common focal epilepsy in adults, we have not identified neurophysiological, imaging, histopathological and/or genetic biomarkers to reliably classify FCD III with or without hippocampal sclerosis. In respect of pathogenesis, FCD adjacent to a non-developmental, postnatally acquired lesion is difficult to explain and perhaps does not exist. This update may help foster shared efforts towards a better understanding of FCD, potential future updates of classification and novel targeted treatments., (© 2018 British Neuropathological Society.)

We previously showed increased growth associated protein 43 (GAP-43) expression in brain samples resected from patients with cortical dysplasia (CD), which was correlated with duration of epilepsy. Here, we used a rat model of CD to examine the regulation of GAP-43 in the brain and serum over the course of epileptogenesis. Baseline GAP-43 expression was higher in CD animals compared to control non-CD rats. An acute seizure increased GAP-43 expression in both CD and control rats. However, GAP-43 expression decreased by day 15 post-seizure in control rats, which did not develop spontaneous seizures. In contrast, GAP-43 remained up-regulated in CD rats, and over 50% developed chronic epilepsy with increased GAP-43 levels in their serum. GAP-43 protein was primarily located in excitatory neurons, suggesting its functional significance in epileptogenesis. Inhibition of GAP-43 expression by shRNA significantly reduced seizure duration and severity in CD rats after acute seizures with subsequent reduction in interictal spiking. Serum GAP-43 levels were significantly higher in CD rats that developed spontaneous seizures. Together, these results suggest GAP-43 as a key factor promoting epileptogenesis, a possible therapeutic target for treatment of progressive epilepsy and a potential biomarker for epilepsy progression in CD.

Objective: Epilepsy is a common neurologic disorder resulting in spontaneous, recurrent seizures. About 30-40% of patients are not responsive to pharmacologic therapies. This may be due to the differences between individual patients such as etiology, underlying pathophysiology, and seizure focus, and it highlights the importance of new drug discovery and testing in this field. Our goal was to determine the efficacy of lacosamide (LCM), a drug approved for the treatment of focal seizures, in a model of generalized epilepsy with cortical dysplasia (CD). We sought to compare LCM to levetiracetam (LEV), a drug that is currently used for the treatment of both partial and generalized epilepsy and to test its proficiency., Methods: Pregnant rats were irradiated to produce pups with malformed cortices in a model of CD, which will be referred to as the "first hit." Adult animals, developed normally (NL) and irradiated (XRT), were surgically implanted with electroencephalography (EEG) electrodes. Baseline EEG was recorded on all rats prior to pretreatments with either LCM, LEV, or placebo (PBO). After 30 min, all rats were injected with a subconvulsive dose of pentylenetetrazole (PTZ), a γ-aminobutyric acid receptor A (GABA A ) antagonist used to provoke generalized seizures as a "second hit.", Results: LCM and LEV were both effective against seizures induced by PTZ. XRT rats had a higher seizure incidence with longer and more severe seizures than NL rats. Seizure duration was decreased with both LCM and LEV in all animals. In XRT rats, there was a significant reduction in acute seizure incidence and severity with both LCM and LEV after PTZ injection., Significance: Our results suggest that LCM could be used as a potential treatment option for generalized epilepsy with CD as the underlying pathology., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Subtraction ictal and interictal single photon emission computed tomography can demonstrate complex ictal perfusion patterns. Regions with ictal hyperperfusion are suggested to reflect seizure onset and propagation pathways. The significance of ictal hypoperfusion is not well understood. The aim of this study was to verify whether ictal perfusion changes, both hyper- and hypoperfusion, correspond to electrically connected brain networks. A total of 36 subtraction ictal and interictal perfusion studies were analysed in 31 consecutive medically refractory focal epilepsy patients, evaluated by stereo-electroencephalography that demonstrated a single focal onset. Cortico-cortical evoked potential studies were performed after repetitive electrical stimulation of the ictal onset zone. Evoked responses at electrode contacts outside the stimulation site were used as a measure of connectivity. The evoked responses at these electrodes were compared to ictal perfusion values noted at these locations. In 67% of studies, evoked responses were significantly larger in hyperperfused compared to baseline-perfused areas. The majority of hyperperfused contacts also had significantly increased evoked responses relative to pre-stimulus electroencephalogram. In contrast, baseline-perfused and hypoperfused contacts mainly demonstrated non-significant evoked responses. Finally, positive significant correlations (P < 0.05) were found between perfusion scores and evoked responses in 61% of studies. When the stimulated ictal onset area was hyperperfused, 82% of studies demonstrated positive significant correlations. Following stimulation of hyperperfused areas outside seizure onset, positive significant correlations between perfusion changes and evoked responses could be seen, suggesting bidirectional connectivity. We conclude that strong connectivity was demonstrated between the ictal onset zone and hyperperfused regions, while connectivity was weaker in the direction of baseline-perfused or hypoperfused areas. In trying to understand a patient's epilepsy, one should consider the contribution of all hyperperfused regions, as these are likely not random, but represent an electrically connected epileptic network., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: This study aimed to identify the subtype of interictal ripples that help delineate the epileptogenic zone in neocortical epilepsy., Methods: Totally 25 patients with focal neocortical epilepsy who had invasive electroencephalography (EEG) evaluation and subsequent surgery were included. They were followed up for at least 2years. Interictal ripples (80-250Hz) and fast ripples (250-500Hz) during slow-wave sleep were identified. Neocortical ripples were defined as type I ripples when they were superimposed on epileptiform discharges, and as type II ripples when they occurred independently. Resection ratio was calculated to present the extent to which the cortical area showing an interictal event or the seizure onset zone (SOZ) was completely removed., Results: Fast ripples and types I and II ripples were found in 8, 19, and 21 patients, respectively. Only the higher resection ratio of interictal fast or type I ripples was correlated to the Engel 1a surgical outcome., Conclusions: Type I ripples could assist in localizing the epileptogenic zone in neocortical epilepsy., Significance: Type I and fast ripples both may be pathological high-frequency oscillations., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Recent evidence suggests a metabolic contribution of cytochrome P450 enzymes (CYPs) to the drug-resistant phenotype in human epilepsy. However, the upstream molecular regulators of CYP in the epileptic brain remain understudied. We therefore investigated the expression and function of pregnane xenobiotic (PXR) and glucocorticoid (GR) nuclear receptors in endothelial cells established from post-epilepsy surgery brain samples., Methods: PXR/GR localization was evaluated by immunohistochemistry in specimens from subjects who underwent temporal lobe resections to relieve drug-resistant seizures. We used primary cultures of endothelial cells obtained from epileptic brain tissues (EPI-ECs; n = 8), commercially available human brain microvascular endothelial cells (HBMECs; n = 8), and human hepatocytes (n = 3). PXR/GR messenger RNA (mRNA) levels in brain ECs was initially determined by complementary DNA (cDNA) microarrays. The expression of PXR/GR proteins was quantified by Western blot. PXR and GR silencing was performed in EPI-ECs (n = 4), and the impact on downstream CYP expression was determined., Results: PXR/GR expression was detected by immunofluorescence in ECs and neurons in the human temporal lobe samples analyzed. Elevated mRNA and protein levels of PXR and GR were found in EPI-ECs versus control HBMECs. Hepatocytes, used as a positive control, displayed the highest levels of PXR/GR expression. We confirmed expression of PXR/GR in cytoplasmic-nuclear subcellular fractions, with a significant increase of PXR/GR in EPI-ECs versus controls. CYP3A4, CYP2C9, and CYP2E1 were overexpressed in EPI-ECs versus control, whereas CYP2D6 and CYP2C19 were downregulated or absent in EPI-ECs. GR silencing in EPI-ECs led to decreased CYP3A4, CYP2C9, and PXR expression. PXR silencing in EPI-ECs resulted in the specific downregulation of CYP3A4 expression., Significance: Our results indicate increased PXR and GR in primary ECs derived from human epileptic brains. PXR or GR may be responsible for a local drug brain metabolism sustained by abnormal CYP regulation., (© 2017 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Objective: This retrospective cohort study characterized cognitive and motor outcomes in a large sample of adults who underwent frontal lobe resections for treatment of pharmacoresistant epilepsy., Methods: Ninety patients who underwent unilateral frontal lobe resection for epilepsy (42 language-dominant hemisphere/48 nondominant hemisphere) between 1989 and 2014 completed comprehensive preoperative and postoperative neuropsychological evaluations that included measures of verbal and nonverbal intellectual functioning, attention/working memory, processing speed, language, executive functioning, verbal and visual memory, and motor functioning. Objective methods were used to assess meaningful change across a wide range of abilities and to identify factors associated with neuropsychological decline following frontal lobectomy. Detailed postoperative neuroimaging analysis was conducted to characterize region, extent, and volume of resection., Results: Forty-eight percent of patients did not demonstrate meaningful postoperative declines in cognition and an additional 42% demonstrated decline in 1 or 2 cognitive domains. When cognitive decline was observed, it usually occurred on measures of intelligence, visuomotor processing speed, or executive functioning. Side and site of resection were unrelated to cognitive outcome, but played a role in decline of contralateral manual dexterity following supplementary motor area resection. Higher preoperative ability, older age at surgery, absence of a malformation of cortical development on MRI, and poor seizure outcome were related to cognitive decline on some measures, but had poor sensitivity in identifying at-risk patients., Conclusions: The vast majority of patients who undergo frontal lobectomy for treatment of pharmacoresistant epilepsy demonstrate good cognitive and motor outcomes., (© 2017 American Academy of Neurology.)

Objective: This retrospective, observational study examined the frequency and magnitude of change in naming ability as a function of side/site of epilepsy surgery and identified predictive factors to assist clinicians in identifying patients at low, moderate, or high risk of postoperative naming decline., Methods: A total of 875 adults with pharmacoresistant epilepsy (454 left/421 right; 763 temporal/87 frontal/25 posterior quadrant) met inclusion criteria and completed the Boston Naming Test before and after surgery. Clinically meaningful change in naming ability was assessed using reliable change indices for epilepsy. Demographic, cognitive, and seizure variables were examined to determine factors most predictive of naming decline and to develop a decision tree to assist with clinical decision-making., Results: Naming decline was rare in right-sided resections and did not exceed the level expected by chance (5% overall; 90% confidence interval [CI] ± 2%). Naming decline occurred in 41% (CI ± 5%) of patients after left temporal resection (TLR) compared to 10%-12% (CI ± 10%-19%) in other left-sided surgical groups. A sizable proportion of left TLR patients (17%; CI ± 4%) showed substantial declines in naming (>11 points). Decline following left TLR was related to later age at seizure onset, older age at surgery, and higher preoperative naming ability. These factors correctly predicted naming decline in 68% of patients and were associated with degree of decline following left TLR. A decision tree is provided to assist clinicians in identifying patients at low, moderate, or high risk for postoperative naming declines., Conclusions: In addition to discussions regarding risk for memory decline following left TLR, patients should be counseled about potential decline in word-finding ability., (© 2016 American Academy of Neurology.)

Traumatic brain injury (TBI) is a significant risk factor for development of epilepsy in humans. It is unclear, however, why some persons are at an increased risk of becoming epileptic, while others recover from the TBI seizure-free. We previously showed that the presence of a proepileptic pathology increases the risk of epilepsy in an animal model of cortical dysplasia (CD) after a secondary insult, which we described as the "second hit". Here we sought to evaluate the prevalence of epileptic activity and seizures in CD after a moderate TBI to determine the influence of dysplastic pathology on TBI-induced epileptogenesis. CD was generated in rats through in utero irradiation (the "first hit"). Nondysplastic and CD rats were surgically implanted with EEG electrodes. Craniotomies were performed over the pre-central cortex, and rats were given a moderate TBI using the lateral fluid percussion injury device. Rats were monitored with chronic EEG and video. EEG data were analyzed for the occurrence of interictal spikes and epileptic EEG seizure patterns. Brains were harvested and evaluated histologically. Spontaneous seizures are more prominent and occur earlier in rats with CD after a moderate TBI compared with nondysplastic control rats. All of the CD animals exhibited interictal spiking after TBI, while only a portion of nondysplastic animals produced spikes. These results suggest that the presence of a proepileptic pathology may increase the risk for the development of epilepsy after TBI. Diagnosis and treatment of TBI may depend on underlying pathologies contributing to epilepsy after a brain injury.

High-frequency oscillations (HFOs) are promising biomarkers for epileptic foci; however, their characteristic changes during the preictal period remain unclear. Here, the preictal HFOs were recorded and detected by an automated HFOs detection method in the mouse pilocarpine model as well as in patients with mesial temporal lobe epilepsy (mTLE) and neocortical epilepsy. A total of sixteen low-voltage fast (LVF) and fifty-three hypersynchronous-onset (HYP) seizures were recorded in ten mice. The rate of ripples (80-250Hz) decreased during 1min before the onset of LVF and HYP seizures, which was primarily due to the reduction of type II (independent of epileptiform discharges) rather than type I ripples (superimposed on epileptiform activities). The ripple rate decreased until 30s before HYP seizure, whereas it increased with a peak at 40s during the 1min preictal period of LVF seizures. Furthermore, the "ripple reduction" phenomenon was also observed in all twelve seizures from nine patients with mTLE but not in neocortical epilepsy. These results indicate that ripples may potentially be helpful for understanding the mechanisms of ictogenesis in mTLE, and the different modes of ripple changes during the minute before LVF and HYP seizures might also be beneficial for the diagnosis of seizure types., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Management of MRI-negative patients with intractable focal epilepsy after failed surgery is particularly challenging. In this study, we aim to investigate whether MRI post-processing could identify relevant targets for the re-evaluation of MRI-negative patients who failed the initial resective surgery. We examined a consecutive series of 56 MRI-negative patients who underwent resective surgery and had recurring seizures at 1-year follow-up. T1-weighted volumetric sequence from the pre-surgical MRI was used for voxel-based MRI post-processing which was implemented in a morphometric analysis program (MAP). MAP was positive in 15 of the 56 patients included in this study. In 5 patients, the MAP+ regions were fully resected. In 10 patients, the MAP+ regions were not or partially resected: two out of the 10 patients had a second surgery including the unresected MAP+ region, and both became seizure-free; the remaining 8 patients did not undergo further surgery, but the unresected MAP+ regions were concordant with more than one noninvasive modality in 7. In the 8 patients who had unresected MAP+ regions and intracranial-EEG before the previous surgery, the unresected MAP+ regions were concordant with ictal onset in 6. Our data suggest that scrutiny of the presurgical MRI guided by MRI post-processing may reveal relevant targets for reoperation in nonlesional epilepsies. MAP findings, when concordant with the patient's other noninvasive data, should be considered when planning invasive evaluation/reoperation for this most challenging group of patients.