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Object: Tumors in the temporo-mesial region often extend into the insula and vice versa. The present study investigated the results of a surgical strategy that combines principles of tumor and epilepsy surgery., Methods: We retrospectively analyzed 157 consecutive patients with intrinsic brain tumors in the temporo-mesial region, with varying degrees of extensions into the insula (44 patients, 28.0%). The surgical strategy utilized "anatomy-guided resection," targeting specific anatomical compartments infiltrated by the tumor (e.g., temporal pole, anterior temporo-mesial region = uncus and hippocampal head, posterior temporo-mesial, insula) rather than treating the tumor as a single mass., Results: The most frequent histologies were ganglioglioma CNS WHO grade 1 (55 patients, 35.0%) and IDH1 wildtype glioblastoma (36 patients, 22.9%). Tumor infiltration was most commonly found in the anterior temporo-mesial compartment (145 patients, 92.4%). An anterior temporal lobectomy was part of the surgical strategy in 131 cases (83.4%). Seventy-six patients (48.4%) with drug-resistant epilepsy underwent a formal presurgical epilepsy work-up, including depth electrode placement in three cases. Complete resections were achieved in 117 patients (74.5%), with supramarginal resections performed in 89 cases (56.7%). Four patients experienced non-temporary neurological complications (CTCAE grade 3-5). At 6 months, 127 of 147 assessable patients (86.4%) were free from seizures or auras (ILAE class 1), excluding early postoperative seizures (<30 days). At 24 months, 122 of 144 assessable cases (84.7%) remained seizure-free (ILAE class 1). Kaplan-Meier estimates for 5-year overall survival were 98.5% for non-recurrent glioneuronal tumors. The 2-year overall survival estimates were 96.0% for 24 primary diffuse CNS WHO grade 2 and 3 gliomas and 55.2% for 30 patients undergoing first surgeries for glioblastomas/astrocytomas CNS WHO grade 4., Conclusion: Combining both epilepsy and tumor surgery concepts in the surgical treatment of intrinsic brain tumors involving the mesial temporal lobe, often extending into the insula, led to more extensive resections, improved seizure outcomes, and potentially even better patient survival outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Alkassm, Grote, Berger, Woermann, Ersoy, Coras, Kalbhenn and Simon.)

Objective: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE)., Methods: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff., Results: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months)., Significance: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The computational capabilities of neuronal networks are fundamentally constrained by their specific connectivity. Previous studies of cortical connectivity have mostly been carried out in rodents; whether the principles established therein also apply to the evolutionarily expanded human cortex is unclear. We studied network properties within the human temporal cortex using samples obtained from brain surgery. We analyzed multineuron patch-clamp recordings in layer 2-3 pyramidal neurons and identified substantial differences compared with rodents. Reciprocity showed random distribution, synaptic strength was independent from connection probability, and connectivity of the supragranular temporal cortex followed a directed and mostly acyclic graph topology. Application of these principles in neuronal models increased dimensionality of network dynamics, suggesting a critical role for cortical computation.

Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure., Research Question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy., Material and Methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines., Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported., Discussion and Conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe., Competing Interests: 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., (© 2024 The Authors.)

Focal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype-phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study. Clinical data were directly available from each contributing centre. Histopathological analyses were performed from formalin-fixed, paraffin-embedded tissue samples using haematoxylin-eosin and immunohistochemistry for NF-SMI32, NeuN, pS6, p62, and vimentin. Ten individuals carried loss-of-function variants in the GATOR1 complex encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function variants in MTOR (n = 7). Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e., lack of balloon cells, individuals with MTOR variants presented with both histopathology subtypes, FCDIIa and FCDIIb. Interestingly, 50% of GATOR1-positive cases showed a unique and predominantly vacuolizing phenotype with p62 immunofluorescent aggregates in autophagosomes. All cases with GATOR1 alterations had neurosurgery in the frontal lobe and the majority was confined to the cortical ribbon not affecting the white matter. This pattern was reflected by subtle or negative MRI findings in seven individuals with GATOR1 variants. Nonetheless, all individuals were seizure-free after surgery except four individuals carrying a DEPDC5 variant. We describe a yet underrecognized genotype-phenotype correlation of GATOR1 variants with FCDIIa in the frontal lobe. These lesions were histopathologically characterized by abnormally vacuolizing cells suggestive of an autophagy-altered phenotype. In contrast, individuals with FCDIIb and brain somatic MTOR variants showed larger lesions on MRI including the white matter, suggesting compromised neural cell migration., (© 2023. The Author(s).)

Objective: Completeness as a predictor of seizure freedom is broadly accepted in epilepsy surgery. We focused on the requirements for a complete hemispherotomy and hypothesized that the disconnection of the insula contributes to a favorable postoperative seizure outcome. We analyzed surgical and nonsurgical predictors influencing long-term seizure outcome before and after a modification of our hemispherotomy technique., Methods: We retrospectively studied surgical procedures, electroclinical parameters, magnetic resonance imaging (MRI) results, and follow-up data in all children who had undergone hemispherotomy between 2001 and 2018 at our institution. We used logistic regression models to analyze the influence of different factors on seizure outcome., Results: A total of 152 patients were eligible for seizure outcome analysis only. Of these, 140 cases had complete follow-up data for ≥24 months and provide the basis for the following results. The median age at surgery was 4.3 years (range = .3-17.9 years). Complete disconnection (including the insular tissue) was achieved in 63.6% (89/140). At 2-year follow-up, seizure freedom (Engel class IA) was observed in 34.8% (8/23) with incomplete insular disconnection, whereas this was achieved in 88.8% (79/89) with complete surgical disconnection (p < .001, odds ratio [OR] = 10.41). In the latter group (n = 89), a potentially epileptogenic contralateral MRI lesion was the strongest predictor for postoperative seizure recurrence (OR = 22.20)., Significance: Complete surgical disconnection is the most important predictor of seizure freedom following hemispherotomy and requires disconnection of the insular tissue at the basal ganglia level. Even if the hemispherotomy is performed surgically completely, a potentially epileptogenic contralateral lesion on preoperative MRI significantly reduces the chances of postoperative seizure freedom., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy., (© 2023. The Author(s).)

Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed 'second hit' disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21-q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Seizure outcome after extratemporal lobe epilepsy (exTLE) surgery has often been poorer than after temporal lobe epilepsy (TLE) surgery, but recent improvements in diagnostics and surgery may have changed this. Our aim was to analyze the changes in presurgical and surgical volumes and seizure outcome 2 years after surgery for patients with exTLE compared with those with TLE., Methods: We performed a retrospective, single-center cohort study including patients from the Bethel presurgical-surgical-postsurgical database from 1990 to 2017. We used logistic regression to analyze factors influencing the odds for surgery and the odds for seizure freedom after surgery., Results: We included 3,822 patients with presurgical evaluation, 2,404 of whom had subsequently undergone surgery. The proportion of patients with exTLE in presurgical evaluation increased from 41% between 1990 and 1993 to 64% in 2014-2017. The odds for surgery decreased over time (2003-2011: odds ratio [OR] 0.50 [95% CI 0.36-0.70]; 2012-2017: OR 0.24 [CI 0.17-0.35]; reference: 1990-2002) and patients with exTLE had lower odds for surgery than patients with TLE, but this difference diminished over time (exTLE vs TLE 1990-2002: OR 0.14 [CI 0.09-0.20]; 2003-2011: OR 0.32 [CI 0.24-0.44]; 2012-2017: OR 0.46 [CI 0.34-0.63]). Etiology, the side of the epileptogenic lesion, and invasive recordings influenced the odds for surgery. The most frequent reasons for not undergoing surgery were missing identification of a circumscribed epileptogenic zone or an unacceptable risk of postsurgical deficits in patients with exTLE and the patient's decision in patients with TLE. Compared with patients with TLE, the odds for seizure freedom after surgery started lower for patients with exTLE in earlier years, but increased (≤2 lobes 1990-2002: OR 0.47 [CI 0.33-0.68]; 2003-2011: OR 0.62 [CI 0.44-0.87]; 2012-2017: OR 0.78 [CI 0.53-1.15]; ≥3 lobes 1990-2002: OR 0.37 [CI 0.22-0.62]; 2003-2011: OR 0.73 [CI 0.43-1.23]; 2012-2017: OR 1.46 [CI 0.91-2.42]). Etiology, age at surgery, and invasive recordings were further predictors for the odds for seizure freedom., Discussion: Over the past 28 years, the success of resective surgery for patients with exTLE has improved. At the same time, the number of patients with exTLE being evaluated for surgery increased, as well as their odds for undergoing surgery., (© 2022 American Academy of Neurology.)

Background and Objectives: To identify predictors of postoperative intelligence and developmental quotients (IQ/DQ) and develop and validate clinically applicable IQ/DQ prediction models., Methods: We retrospectively analyzed neuropsychological outcomes and their possible determinants for children treated in Bethel and Utrecht since 1990. We performed separate analyses for patients with IQ and those with only DQ available. We developed prediction models based on presurgical determinants to predict dichotomized levels of performance (IQ ≥85, IQ ≥70, DQ ≥50)., Results: IQ/DQ data before and 2 years after surgery were available for 492 patients (IQ n = 365, DQ n = 127). At a cutoff level ±10 points, the chance of improvement was considerably higher than the chance of deterioration (IQ 37.3% vs 6.6% and DQ 31.5% vs 15.0%, respectively). Presurgical IQ/DQ was the strongest predictor of postoperative cognition (IQ r = 0.85, p <0.001; DQ r = 0.57, p <0.001). Two IQ models were developed in the Bethel cohort (n = 258) and externally validated in the Utrecht cohort (n = 102). For DQ, we developed the model in the Bethel cohort and used 10-fold cross-validation. Models allowed good prediction at all 3 cutoff levels (correct classification for IQ ≥85 = 86%, IQ ≥70 = 91%, DQ ≥50 = 76%). External validation of the IQ models showed high accuracy (IQ ≥85: 0.82, confidence interval [CI] 0.75-0.91; IQ ≥70: 0.84, CI 0.77-0.92) and excellent discrimination (receiver operating characteristic curves: IQ ≥85: area under the curve [AUC] 0.90, CI 0.84-0.96; IQ ≥70: AUC 0.92, CI 0.87-0.97)., Discussion: After epilepsy surgery in children, the risk of cognitive deterioration is very low. Presurgical development has a strong effect on the postoperative trajectory. The presented models can improve presurgical counseling of patients and parents by reliably predicting cognitive outcomes., Classification of Evidence: This study provides Class II evidence that for children undergoing epilepsy surgery presurgical IQ/DQ was the strongest predictor of postoperative cognition., (© 2021 American Academy of Neurology.)

Malformations of cortical development (MCD) comprise a broad spectrum of structural brain lesions frequently associated with epilepsy. Disease definition and diagnosis remain challenging and are often prone to arbitrary judgment. Molecular classification of histopathological entities may help rationalize the diagnostic process. We present a retrospective, multi-center analysis of genome-wide DNA methylation from human brain specimens obtained from epilepsy surgery using EPIC 850 K BeadChip arrays. A total of 308 samples were included in the study. In the reference cohort, 239 formalin-fixed and paraffin-embedded (FFPE) tissue samples were histopathologically classified as MCD, including 12 major subtype pathologies. They were compared to 15 FFPE samples from surgical non-MCD cortices and 11 FFPE samples from post-mortem non-epilepsy controls. We applied three different statistical approaches to decipher the DNA methylation pattern of histopathological MCD entities, i.e., pairwise comparison, machine learning, and deep learning algorithms. Our deep learning model, which represented a shallow neuronal network, achieved the highest level of accuracy. A test cohort of 43 independent surgical samples from different epilepsy centers was used to test the precision of our DNA methylation-based MCD classifier. All samples from the test cohort were accurately assigned to their disease classes by the algorithm. These data demonstrate DNA methylation-based MCD classification suitability across major histopathological entities amenable to epilepsy surgery and age groups and will help establish an integrated diagnostic classification scheme for epilepsy-associated MCD., (© 2021. The Author(s).)

Introduction: Optimizing patient safety and quality improvement is increasingly important in surgery. Benchmarks and clinical quality registries are being developed to assess the best achievable results for several surgical procedures and reduce unwarranted variation between different centers. However, there is no clinical database from international centers for establishing standardized reference values of patients undergoing surgery for mesial temporal lobe epilepsy. Design: The Enhancing Safety in Epilepsy Surgery (EASINESS) study is a retrospectively conducted, multicenter, open registry. All patients undergoing mesial temporal lobe epilepsy surgery in participating centers between January 2015 and December 2019 are included in this study. The patient characteristics, preoperative diagnostic tools, surgical data, postoperative complications, and long-term seizure outcomes are recorded. Outcomes: The collected data will be used for establishing standardized reference values ("benchmarks") for this type of surgical procedure. The primary endpoints include seizure outcomes according to the International League Against Epilepsy (ILAE) classification and defined postoperative complications. Discussion: The EASINESS will define robust and standardized outcome references after amygdalohippocampectomy for temporal lobe epilepsy. After the successful definition of benchmarks from an international cohort of renowned centers, these data will serve as reference values for the evaluation of novel surgical techniques and comparisons among centers for future clinical trials. Clinical trial registration: This study is indexed at clinicaltrials.gov (NT 04952298)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Drexler, Ben-Haim, Bien, Borger, Cardinale, Carpentier, Cendes, Chandra, Clusmann, Colon, Curtis, Delev, Didato, Dührsen, Farah, Guenot, Ghatan, Haegelen, Hamer, Hauptmann, Jeffree, Kalbhenn, Kegele, Krayenbühl, Lang, Mathon, Naros, Onken, Panov, Raftopoulos, Ricklefs, Rijkers, Rizzi, Rössler, Schijns, Schneider, Spyrantis, Strzelczyk, Stodieck, Tripathi, Vadera, Alonso-Vanegas, Vaz, Wellmer, Wehner, Westphal and Sauvigny.)

Objective: We describe for the first time clinical characteristics in a series of 20 pre-surgically investigated patients with mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE) who were operated on in our epilepsy center. We aimed to better diagnose this entity and help surgical planning., Methods: Data on 20 patients with histologically confirmed MOGHE were retrospectively evaluated as to age at epilepsy onset and operation, seizure semiology, magnetic resonance imaging (MRI) localization, electroencephalography (EEG) patterns, extent of the operative resection, and postoperative seizure outcome., Results: Epilepsy began mainly in early childhood; however, symptoms did not manifest until adolescence or adulthood in 30% of patients. All patients had pathologic MRI findings. In 45% of patients the lesion was initially overlooked. Most commonly, the lesion was seen in the frontal lobe. Seizure semiology was characterized as follows: (1) epileptic spasms at epilepsy onset were common and (2) nocturnal hyperkinetic seizures during the course of the disease were rare. EEG always showed frequent interictal epileptic discharges. Two peculiar patterns were observed: (1) during sleep stage I-II, sub-continuous repetitive (0.5-1.5/s) unilateral plump spike/polyspike slow waves were seen and (2) during wakefulness, unilateral paroxysms of 2-2.5/s spike-wave complexes occurred. In total, 60% of patients were seizure-free 1 year postoperatively. Postoperative seizure outcome was positively correlated with the extent of resection, age at epilepsy onset, and age at operation. Postoperative long-term outcomes remained stable in patients undergoing larger operations., Significance: MRI, EEG, and semiology already contribute to the diagnosis of probable MOGHE preoperatively. Because postoperative seizure outcomes depend on the extent of the resection, prior knowledge of a probable MOGHE helps to plan the resection and balance the risks and benefits of such an intervention. In patients undergoing larger operations, epilepsy surgery achieved good postoperative results; the first long-term outcome data were stable in these patients., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Presurgical evaluation has no established routine to assess reading competence and to identify essential "not to resect" reading areas. Functional models describe a visual word form area (VWFA) located in the midfusiform gyrus in the dominant ventral occipito-temporal cortex (vOTC) as essential for reading. We demonstrate the relevance and feasibility of invasive VWFA-mapping., Methods: Four patients with epilepsy received invasive VWFA-mapping via left temporo-basal strip-electrodes. Co-registration of the results and additional data from the literature led to the definition of a region of interest (ROI) for a retrospective assessment of postoperative reading deficits by a standardized telephone-interview in patients with resections in this ROI between 2004 and 2018., Results: Electrical cortical stimulation disturbed whole word recognition and reading in four patients with structural epilepsy. Stimulation results showed distribution in the basal temporal lobe (dorsal mesencephalon to preoccipital notch). We identified 34 patients with resections in the ROI of the dominant hemisphere. Of these, 15 (44.1%) showed a postoperative reading deficit with a mean duration of 18.2 months (+/-32.4, 0.5-122). Six patients suffered from letter-by-letter (LBL) reading. Two patients had permanent LBL reading after resection in the ROI., Significance: We present evidence on the functional relevance of the vOTC for reading by (1) extra-operative cortical stimulation of the VWFA and by (2) a retrospective case study of reading deficits in patients operated in this area. Reading assessments and data concerning essential reading structures should be included in the presurgical evaluation of patients with lesions in the left vOTC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Drug-resistant epilepsy is one of the major disease burdens in patients with tuberous sclerosis complex (TSC). Epilepsy surgery has been shown to be effective in TSC, but making a decision for surgery is often more complex than in other surgically amenable epilepsy syndromes and not all patients with TSC are eligible. We investigated long-term outcomes (after ≥one year; median, 6.4 years) with a special interest in general developmental level, health-related quality of life, parental concerns due to epilepsy, impact on family, and social adaptation in children who underwent epilepsy surgery and in children who were not eligible for surgery., Methods: Eighty-five children (median age at intervention: 3.3 years, interquartile range [IQR]: 1.8-6.3 years) with TSC-related epilepsy had a presurgical investigation, and 34 of this group underwent epilepsy surgery. At follow-up (median age: 11.5 years, IQR: 7.8-15.5 years), we assessed seizure outcome, health-related quality of life, social adaptation, parental concerns due to epilepsy, and general developmental level based on established questionnaires and a standardized interview. Generalized linear models were performed for statistical evaluation., Results: At follow-up, 53% (18/34) of the operated patients were seizure free for ≥12 months and 30% (15/50) of the patients non-eligible for epilepsy surgery (p = 0.037). In the surgical group, developmental level was significantly higher in seizure-free patients, in comparison to non-seizure-free patients (p = 0.004); this was also observed in the non-surgical group, but less marked (p = 0.089). Furthermore, developmental level was significantly (p ≤ 0.001) related to quality of life, social adaptation, impact on family, and parental concerns. In both cohorts, parental concerns were less pronounced if children became seizure free (p < 0.001 and p = 0.018, respectively)., Significance: In children with TSC-related epilepsy, quality of life, social adaptation, and impact on family were related to general developmental level, which in turn was significantly related to seizure freedom. Consequent epilepsy management aiming at seizure freedom, including presurgical evaluation and, if indicated, epilepsy surgery in a center specifically experienced with TSC-related epilepsy, is a worthwhile effort to improve quality of life in patients with TSC and their families., Competing Interests: Conflicts of interest C.G.B received research support from Deutsche Forschungsgemeinschaft (German Research Council, Bonn, Germany) and Gerd-Altenhof-Stiftung (Deutsches Stiftungs-Zentrum, Essen, Germany). T.P. reported personal fees from Novartis Pharma, Desitin Arzneimittel, Zogenix International, and UCB Pharma for work outside the submitted work. The other authors have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The number of patients requiring depth electrode implantation for invasive video EEG diagnostics increases in most epilepsy centres. Here we report on our institutional experience with frameless robot-assisted stereotactic placement of intracerebral depth electrodes using the Neuromate® stereotactic robot-system., Methods: We identified all patients who had undergone robot-assisted stereotactic placement of intracerebral depth electrodes for invasive extra-operative epilepsy monitoring between September 2013 and March 2020. We studied technical (placement) and diagnostic accuracy of the robot-assisted procedure, associated surgical complications and procedural time requirements., Results: We evaluated a total of 464 depth electrodes implanted in 74 patients (mean 6 per patient, range 1-12). There were 27 children and 47 adults (age range: 3.6-64.6 yrs.). The mean entry and target point errors were 1.82±1.15 and 1.98±1.05 mm. Target and entry point errors were significantly higher in paediatric vs. adult patients and for electrodes targeting the temporo-mesial region. There were no clinically relevant haemorrhages and no infectious complications. Mean time for the placement of one electrode was 37±14 min and surgery time per electrode decreased with the number of electrodes placed. 55 patients (74.3%) underwent definitive surgical treatment. 36/51 (70.1%) patients followed for >12 months or until seizure recurrence became seizure-free (ILAE I)., Conclusion: Frameless robot-guided stereotactic placement of depth electrodes with the Neuromate® stereotactic robot-system is safe and feasible even in very young children, with good in vivo accuracy and high diagnostic precision. The surgical workflow is time-efficient and further improves with increasing numbers of implanted electrodes., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Hyperkinetic seizures are described as seizure onset in the frontal or temporal lobe. Additional localizing information is important for diagnostic workup and surgical therapy. We describe diagnostic workup and surgical outcomes in three patients with pharmacoresistant focal emotional seizures with hyperkinetic elements., Methods/results: High-resolution 3 Tesla (T) magnetic resonance imaging (MRI) did not reveal clear-cut lesions. Invasive video-electroencephalography (EEG) with depth electrodes along the cingulate sulcus (bilateral; patients 1 and 3), right; patient 2 provided congruent results for a circumscribed seizure onset zone within the medial frontal lobe (right: patients 1 and 2; left: patient 3). Topectomies were performed in all patients. Histopathology revealed a small focal cortical dysplasia in the three cases (focal cortical dysplasia [FCD] IIA: patient 1; FCD IIB: patients 2 and 3). All patients remained completely seizure-free since surgery (Engel 1A; follow-up: 9-28 months)., Conclusion: Ictal fear associated with hyperkinetic semiology points to a seizure-onset zone within the anteromedial frontal lobe (anterior cingulate gyrus). Ictal semiology is crucial for the placement of depth electrodes, especially in MRI-negative cases. These cases illustrate a clinical advantage to the new International League against Epilepsy (ILAE) seizure classification, emphasizing initial clinical symptoms., Competing Interests: C.G.B. obtained honoraria for speaking engagements from UCB (Monheim, Germany), Desitin (Hamburg, Germany), and Euroimmun (Lübeck, Germany). He received research support from Deutsche Forschungsgemeinschaft (German Research Council, Bonn, Germany) and Gerd-Altenhof-Stiftung (Deutsches Stiftungs-Zentrum, Essen, Germany).T.C. was supported by a stipend from the Epilepsy Academy Berlin-Bethel, and from the von-Bodelschwingh Foundation in Bielefeld-Bethel. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Thieme. All rights reserved.)

Polymicrogyria (PMG) is a developmental cortical malformation characterized by an excess of small and frustrane gyration and abnormal cortical lamination. PMG frequently associates with seizures. The molecular pathomechanisms underlying PMG development are not yet understood. About 40 genes have been associated with PMG, and small copy number variations have also been described in selected patients. We recently provided evidence that epilepsy-associated structural brain lesions can be classified based on genomic DNA methylation patterns. Here, we analyzed 26 PMG patients employing array-based DNA methylation profiling on formalin-fixed paraffin-embedded material. A series of 62 well-characterized non-PMG cortical malformations (focal cortical dysplasia type 2a/b and hemimegalencephaly), temporal lobe epilepsy, and non-epilepsy autopsy controls was used as reference cohort. Unsupervised dimensionality reduction and hierarchical cluster analysis of DNA methylation profiles showed that PMG formed a distinct DNA methylation class. Copy number profiling from DNA methylation data identified a uniform duplication spanning the entire long arm of chromosome 1 in 7 out of 26 PMG patients, which was verified by additional fluorescence in situ hybridization analysis. In respective cases, about 50% of nuclei in the center of the PMG lesion were 1q triploid. No chromosomal imbalance was seen in adjacent, architecturally normal-appearing tissue indicating mosaicism. Clinically, PMG 1q patients presented with a unilateral frontal or hemispheric PMG without hemimegalencephaly, a severe form of intractable epilepsy with seizure onset in the first months of life, and severe developmental delay. Our results show that PMG can be classified among other structural brain lesions according to their DNA methylation profile. One subset of PMG with distinct clinical features exhibits a duplication of chromosomal arm 1q.

Objective: It has been suggested that multilobar epilepsies caused by lesions restricted to the posterior cerebral quadrant (ie, the parietal, temporal, and occipital lobes) can be treated successfully by a procedure termed posterior disconnection. The objective of the present paper was to identify determinants of the epileptological outcome following posterior disconnection surgery., Methods: The authors retrospectively analyzed a series of 29 consecutive patients undergoing posterior disconnection surgery between 2005 and 2017 for the treatment of refractory posterior quadrantic epilepsy. Specifically, all presurgical and postoperative magnetic resonance (MR) studies were reviewed to identify cases with an incomplete disconnection, or the presence of a more widespread pathology involving the whole hemisphere rather than only its posterior quadrant. In addition, we reevaluated all presurgical video-electroencephalography (EEG) reports., Results: Seizure-free (International League Against Epilepsy [ILAE] 1) after surgery were 3/3 patients with EEG findings restricted to the posterior quadrant, 0/7 patients who had propagation of epileptic activity to the contralateral frontal lobe, and 11/19 (57.9%) who showed propagation to ipsilateral frontal and/or contralateral posterior. Eleven of 13 (84.6%) patients with purely posterior quadrantic magnetic resonance imaging (MRI) findings (as retrospectively diagnosed by neuroimaging) vs 3/16 (18.8%) cases with additional subtle abnormalities outside the posterior quadrant became seizure-free (P = .001). Eleven of 16 (68.8%) patients with complete disconnections were seizure-free vs only 3/13 (23.0%) cases with leftover temporal lobe tissue with contact to the insula (P = .025, both Fisher's exact test)., Significance: A posterior disconnection is a technically demanding but very effective operation for posterior quadrantic epilepsy. Good epileptologic outcomes require not only that the epileptogenic lesion does not extend beyond the confines of the disconnected cerebral volume but also the absence of subtle MRI abnormalities, more widespread than the clear-cut lesion of the posterior quadrant. Hemispheric or contralateral (particularly frontal) propagation of the epileptic activity may also indicate the presence of a hemispheric rather than posterior quadrantic pathology., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objective: Surgical volumes at large epilepsy centers are decreasing. Pediatric cohorts, however, show a trend toward more resections and superior outcome. Differences in pediatric and adult epilepsy surgery were investigated in our cohort., Methods: The Bethel database between 1990 and 2014 was retrospectively analyzed., Results: A total of 1916 adults and 1300 children underwent presurgical workup. The most common etiologies were medial temporal sclerosis (35.4%) in adults, and focal cortical dysplasias (21.1%) and diffuse hemispheric pathologies (14.7%) in children. Only 1.4% of the total cohort had normal histopathology. A total of 1357 adults (70.8%) and 751 children (57.8%) underwent resections. Surgery types for children were more diverse and showed a higher proportion of extratemporal resections (32.8%) and functional hemispherectomies (20.8%). Presurgical evaluations increased in both groups; surgical numbers remained stable for children, but decreased in the adult group from 2007 on. The patients' decision against surgery in the adult nonoperated cohort increased over time (total = 44.9%, 27.4% in 1995-1998 up to 53.2% in 2011-2014; for comparison, in children, total = 22.1%, stable over time). Postsurgical follow-up data were available for 1305 adults (96.2%) and 690 children (91.9%) 24 months after surgery. The seizure freedom rate was significantly higher in children than in adults (57.8% vs 47.5%, P < 0.001) and significantly improved over time (P = 0.016)., Significance: Pediatric epilepsy surgery has stable surgical volumes and renders more patients seizure-free than epilepsy surgery in adults. A relative decrease in hippocampal sclerosis, the traditional substrate of epilepsy surgery, changes the focus of epilepsy surgery toward other pathologies., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

We describe five patients with frontal lobe epilepsy who underwent electrocortical stimulation (ES) for language localization and language functional magnetic resonance imaging (fMRI) prior to epilepsy surgery. Six months after surgery, three patients suffered from a drop of verbal fluency. In all of them, frontal areas with presurgical language fMRI activity were resected. Our results suggest that resection in regions of areas with presurgical fMRI activation is not without risk for a postsurgical loss of function, even when ES results were negative for language function in these areas. Using fMRI activations might be specifically helpful to plan the resection when ES delivered inconclusive results.

The histopathological spectrum of human epileptogenic brain lesions is widespread including common and rare variants of cortical malformations. However, 2-26% of epilepsy surgery specimens are histopathologically classified as nonlesional. We hypothesized that these specimens include also new diagnostic entities, in particular when presurgical magnetic resonance imaging (MRI) can identify abnormal signal intensities within the anatomical region of seizure onset. In our series of 1381 en bloc resected epilepsy surgery brain specimens, 52 cases could not be histopathologically classified and were considered nonlesional (3.7%). An increase of Olig2-, and PDGFR-alpha-immunoreactive oligodendroglia was observed in white matter and deep cortical layers in 22 of these patients (42%). Increased proliferation activity as well as heterotopic neurons in white matter were additional histopathological hallmarks. All patients suffered from frontal lobe epilepsy (FLE) with a median age of epilepsy onset at 4 years and 16 years at epilepsy surgery. Presurgical MRI suggested focal cortical dysplasia (FCD) in all patients. We suggest to classify this characteristic histopathology pattern as "mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE)." Further insights into pathomechanisms of MOGHE may help to bridge the diagnostic gap in children and young adults with difficult-to-treat FLE., (© 2016 International Society of Neuropathology.)

Introduction: Despite the success of epilepsy surgery, recent reports suggest a decline in surgical numbers. We tested these trends in our cohort to elucidate potential reasons., Patients and Methods: Presurgical, surgical and postsurgical data of all patients undergoing presurgical evaluation in between 1990 and 2013 were retrospectively analysed. Patients were grouped according to the underlying pathology., Results: A total of 3060 patients were presurgically studied, and resective surgery was performed in 66.8% (n=2044) of them: medial temporal sclerosis (MTS): n=675, 33.0%; benign tumour (BT): n=408, 20.0%; and focal cortical dysplasia (FCD): n=284, 13.9%. Of these, 1929 patients (94.4%) had a follow-up of 2 years, and 50.8% were completely seizure free (Engel IA). Seizure freedom rate slightly improved over time. Presurgical evaluations continuously increased, whereas surgical interventions did not. Numbers for MTS, BT and temporal lobe resections decreased since 2009. The number of non-lesional patients and the need for intracranial recordings increased. More evaluated patients did not undergo surgery (more than 50% in 2010-2013) because patients were not suitable (mainly due to missing hypothesis: 4.5% in 1990-1993 up to 21.1% in 2010-2013, total 13.4%) or declined from surgery (maximum 21.0% in 2010-2013, total 10.9%). One potential reason may be that increasingly detailed information on chances and risks were given over time., Conclusions: The increasing volume of the presurgical programme largely compensates for decreasing numbers of surgically remediable syndromes and a growing rate of informed choice against epilepsy surgery. Although comprehensive diagnostic evaluation is offered to a larger group of epilepsy patients, surgical numbers remain stable., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: The etiology of focal cortical dysplasia type IIb (FCDIIb) remains enigmatic in patients suffering from drug-resistant epilepsy, and an aberrant activation of the mammalian target of rapamycin complex 1 signaling pathway (mTORC1) was detected in this developmental brain malformation. Recently, the human papillomavirus (HPV) oncoprotein E6 has been identified as a potent activator of mTORC1, and HPV16 E6 has been described to persist in balloon cells obtained from surgical FCDIIb specimens. Although this observation was replicated by an independent second report, it contradicts current knowledge of HPV biology. HPV infects the squamous or mucocutaneous epithelium; hematogenic spread into other tissues has not been observed. In addition, brain carcinogenesis has never been reported in FCDIIb patients. Herein, we have tried to confirm 2 previous reports of HPV16 E6 infection using an independent series of 14 surgical specimens with histopathologically confirmed FCDIIb., Methods: Snap-frozen FCDIIb specimens were tested for HPV DNA using the primer set for amplification of the complete E6 reading frame of HPV16 and 3 other sets of primers (2 consensus primer sets detecting multiple HPV genotypes, and another primer set specifically used for HPV16). Furthermore, formalin-fixed and paraffin-embedded histopathological preparations were immunohistochemically analyzed using previously described antibodies directed against the HPV E6 oncoprotein., Results: All 14 FCDIIb specimens were negative for HPV DNA with all 4 primer sets. Antibodies directed against the HPV E6 epitope showed weak labeling of cytoplasm in balloon cells, as previously described in FCDIIb, but also in other cell populations., Interpretation: Our data did not confirm previously reported evidence for HPV16 detection in FCDIIb., (© 2014 American Neurological Association.)

Background: In this study we have analyzed the local immunosuppression with budesonide, a topically selective glucocorticosteroid, in rats after orthotopic liver transplantation. Because of its high first-pass hepatic clearance budesonide can be given orally, achieving high intrahepatic and low systemic concentrations., Methods: Using an acute rejection model from Dark Agouti (DA) to Lewis rats, the histomorphological degree of rejection was assessed on histological sections at the ninth postoperative day., Results: Livers of the DA to Lewis study group without immunosuppression revealed severe allograft rejection with vast cellular infiltrates, massive endothelialitis, and hepatocyte necrosis. In the three budesonide study groups (250 microg, 500 microg, and 1 mg/kg/day) a moderate to mild liver allograft rejection was seen. Rejection was most prominent in the 250 microg group, whereas the 1 g group showed almost no signs of rejection, similar to the Lewis to Lewis control group. Aspartate and alanine transaminase (sGOT, sGPT) as well as alkaline phosphatase serum levels correlated with the degree of rejection, achieving highest levels in the DA to Lewis group without immunosuppression. Animals treated with 1 g of budesonide had serum levels similar to Lewis to Lewis control animals., Conclusions: These results implicate a beneficial effect of local immunosuppression with budesonide in rats based on the histomorphological degree of liver allograft rejection.