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Background: Epilepsy surgery can potentially cure pharmacoresistant temporal lobe epilepsy (TLE) in children. However, surgical failures, where patients continue to experience seizures, still exist. We evaluated outcomes in pediatric patients after resective temporal lobe surgery to identify risk factors for failure., Methods: Data on pediatric patients with TLE who underwent surgery were prospectively collected at our institution. Minimum follow-up (FU) was three years after surgery. Resections were stratified into extended resections, i.e., anterior temporal lobectomies, and sparing resections, i.e., lesionectomies and selective amygdalohippocampectomies. Ongoing seizures and relapses within the first three years were considered surgical failures., Results: We included 96 patients after 43 sparing and 52 extended resections from 1993 to 2019 with a median FU of 10.1 years (range 3.0 to 28.3 years). Pathohistology most frequently revealed epilepsy-associated tumors (44.8%), hippocampal sclerosis (37.5%), and focal cortical dysplasias (12.5%). One year postoperatively, 69.8% were seizure free, increasing to 78.5% after five and 72.9% after 10 years. Sparing resections increased the odds for surgical failure in a multivariate analysis (odds ratio: 4.63, P = 0.006). Preoperative focal onset to bilateral tonic-clonic seizures increased the likelihood of seizure relapses (hazard ratio: 3.89, P = 0.006) and contributed to higher odds of surgical failure (odds ratio: 2.79, P = 0.002)., Conclusions: Pediatric patients with TLE undergoing surgery have high rates of long-lasting favorable seizure outcomes. Resection strategy is a prognostic factor for early surgical success in favor of larger resections. Relapses were more frequent in children with focal onset to bilateral tonic-clonic seizures beforesurgery., Competing Interests: Declaration of competing interest For article titled “Predictors of epilepsy surgery failure in pediatric lesional temporal lobe epilepsy surgery” by Tomschik M. et al. the authors have no conflict of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives/hypothesis: Given the complex pathology underlying unilateral vocal fold paralysis (UVFP), there has been limited systematic exploration of curative treatments in humans. Central to the investigation of experimental therapies includes establishing a reliable and analogous large animal model. The study goal was to create a standardized porcine model of UVFP by establishing characteristic pathophysiology and functional outcomes., Methods: Four female Yucatan minipigs underwent transection of the right recurrent laryngeal nerve (R-RLN). Measurements of acoustic vocalization data, bilateral nerve conduction studies, and laryngeal adductor pressure (LAP) were obtained prior to transection (baseline) and 7weeks after transection. Laryngeal adductor muscle complex volume was analyzed via 3D ultrasound. Histological analysis with myofiber diameter measurement of bilateral thyroarytenoid muscles was conducted at study conclusion., Results: Stimulation of the R-RLN 7weeks after transection demonstrated reduction of motor unit action potentials. In addition, there was a statistically significant reduction in LAP compared to preinjury when stimulating the R-RLN. Voice analysis notably revealed decreased intensity and frequency ranges at 7weeks postinjury, and statistically lower average intensity and frequency of glottic phonations. Denervated right-sided laryngeal muscle volume was statistically lower compared to noninjured side. Morphological changes consistent with denervation, including smaller myofibril diameters and decreased nerve-to-muscle contact, were observed in right thyroarytenoid muscle and associated neuromuscular junctions., Conclusions: Given that our porcine model yielded histopathological and functional changes consistent with human UVFP, it has potential to serve as a viable model for systematic and controlled studies of potential treatments for UVFP., Level of Evidence: NA., 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. Published by Elsevier Inc.)

Objective: Previous retrospective studies have reported vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), although clinical impact is unknown. We evaluated the association between vigabatrin and predefined brain magnetic resonance imaging (MRI) changes in a large homogenous tuberous sclerosis complex (TSC) cohort and assessed to what extent VABAM-related symptoms were reported in TSC infants., Methods: The Dutch TSC Registry and the EPISTOP cohort provided retrospective and prospective data from 80 TSC patients treated with vigabatrin (VGB) before the age of 2 years and 23 TSC patients without VGB. Twenty-nine age-matched non-TSC epilepsy patients not receiving VGB were included as controls. VABAM, specified as T2/fluid-attenuated inversion recovery hyperintensity or diffusion restriction in predefined brain areas, were examined on brain MRI before, during, and after VGB, and once in the controls (at approximately age 2 years). Additionally, the presence of VABAM accompanying symptoms was evaluated., Results: Prevalence of VABAM in VGB-treated TSC patients was 35.5%. VABAM-like abnormalities were observed in 13.5% of all patients without VGB. VGB was significantly associated with VABAM (risk ratio [RR] = 3.57, 95% confidence interval [CI] = 1.43-6.39), whereas TSC and refractory epilepsy were not. In all 13 VGB-treated patients with VABAM for whom posttreatment MRIs were available, VABAM entirely resolved after VGB discontinuation. The prevalence of symptoms was 11.7% in patients with VABAM or VABAM-like MRI abnormalities and 4.3% in those without, implicating no significant association (RR = 2.76, 95% CI = .68-8.77)., Significance: VABAM are common in VGB-treated TSC infants; however, VABAM-like abnormalities also occurred in children without either VGB or TSC. The cause of these MRI changes is unknown. Possible contributing factors are abnormal myelination, underlying etiology, recurrent seizures, and other antiseizure medication. Furthermore, the presence of VABAM (or VABAM-like abnormalities) did not appear to be associated with clinical symptoms. This study confirms that the well-known antiseizure effects of VGB outweigh the risk of VABAM and related symptoms., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose: Upper airway stimulation (UAS) is a treatment option for moderate-to-severe OSA, in which electrical stimulation is applied to the hypoglossal nerve via an electrode cuff. In this study, we assess the effect of electrode cuff positioning on UAS outcomes, in particular device adherence., Methods: Patients at a single academic institution who met the Food and Drug Administration criteria for UAS between 2016 and 2021 were included. The electrode position was documented as superior (cuff spine up) or inferior (cuff spine down) to the hypoglossal nerve based on postoperative lateral neck X-ray. Patients underwent titration polysomnography 2-6 months following surgery. The most recent postoperative variables from sleep studies following titration polysomnogram were used for statistical analysis. Adherence data was downloaded from the UAS device., Results: 327 patients met inclusion criteria. The average age of patients was 60.9 ± 11.1 years, with 105 (32.1%) females. Cuff spine up position was present in 169 (51.7%) patients as compared to 158 (48.3%) with cuff spine down. UAS adherence was significantly higher among cuff spine down patients (45.4 vs. 41.0 h device use/week, p = 0.015). Cuff position was not significantly associated with therapeutic amplitude, change in apnea hypopnea index, or change in symptoms as measured by the Epworth Sleepiness Scale. On multivariable linear regression analysis, cuff spine down position (β = 3.7, CI [1.3, 7.4], p = 0.038) and increased age (β = 0.22, CI [0.07, 0.38], p = 0.005) were associated with increased adherence., Conclusions: UAS cuff spine down position is associated with increased device adherence. Further investigation into cuff positioning is warranted., Competing Interests: Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the University of Kansas Medical Center and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Approved by the University of Kansas Medical Center IRB. Conflicts of interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Imaging and resection strategies for pediatric gangliogliomas (GG) and dysembryoplastic neuroepitheliomas (DNET) presenting with epilepsy were retrospectively analyzed in a consecutive institutional series of surgically treated patients., Methods: Twenty-two children (median 8 years, 3-18 years) presented with seizures for 30 months median (14-55.2 months) due to a histologically verified GG/DNET., Results: There were 20 GG and 2 DNT, 68 % located temporal, 32 % extra-temporal. Seizure history was significantly longer in temporal cases (38 versus 14 months median, p < 0.01). MRI contrast enhancement was present in 50 % and methionine (MET) positron emission tomography (PET) uptake in 70 % (standard uptake values (SUVs) 2.92 mean, from 1.6 to 6.4). 27 % had glucose PET hypometabolism. Primarily, in temporal GG, ECoG (electrocorticography) -guided lesionectomies were performed in 87 % and antero-mesial temporal lobe resections (AMTLR) in 13 %, whereas in extra-temporal GG/DNETs, lesionectomies were performed in 100 %. ILAE Class 1 seizure outcome was primarily achieved in 73 % of the temporal cases, and was increased to 93 % by performing six repeat surgeries using AMTLR. Extratemporal patients experienced ILAE Class 1 seizure outcomes in 86 % without additional surgeries, although harboring significantly more residual tumor (p < 0.005, mean follow-up 28 months)., Conclusion: In children, MET PET imaging for suspected GG is proposed preoperatively showing a high diagnostic sensitivity and an option to delineate the lesions for navigated resection, whereas MRI contrast behavior was of no differential diagnostic use. As a surgical strategy we propose primarily lesionectomies for extratemporal but AMTLR for temporal GG respecting eloquent brain areas., Competing Interests: Declaration of competing interest The authors declare, that there is no conflict of interest according to the submitted manuscript titled Seizure outcome in surgically treated pediatric gangliogliomas and dysembrioplastic neuroepitheliomas according to imaging and resection strategies., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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: This study aimed to assess reporting quality of machine learning (ML) algorithms in the head and neck oncology literature using the TRIPOD-AI criteria., Data Sources: A comprehensive search was conducted using PubMed, Scopus, Embase, and Cochrane Database of Systematic Reviews, incorporating search terms related to "artificial intelligence," "machine learning," "deep learning," "neural network," and various head and neck neoplasms., Review Methods: Two independent reviewers analyzed each published study for adherence to the 65-point TRIPOD-AI criteria. Items were classified as "Yes," "No," or "NA" for each publication. The proportion of studies satisfying each TRIPOD-AI criterion was calculated. Additionally, the evidence level for each study was evaluated independently by two reviewers using the Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence. Discrepancies were reconciled through discussion until consensus was reached., Results: The study highlights the need for improvements in ML algorithm reporting in head and neck oncology. This includes more comprehensive descriptions of datasets, standardization of model performance reporting, and increased sharing of ML models, data, and code with the research community. Adoption of TRIPOD-AI is necessary for achieving standardized ML research reporting in head and neck oncology., Conclusion: Current reporting of ML algorithms hinders clinical application, reproducibility, and understanding of the data used for model training. To overcome these limitations and improve patient and clinician trust, ML developers should provide open access to models, code, and source data, fostering iterative progress through community critique, thus enhancing model accuracy and mitigating biases., Level of Evidence: NA Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Tuberous sclerosis complex (TSC) is caused by variants in TSC1/TSC2, leading to constitutive activation of the mammalian target of rapamycin (mTOR) complex 1. Therapy with everolimus has been approved for TSC, but variations in success are frequent. Recently, caudal late interneuron progenitor (CLIP) cells were identified as a common origin of the TSC brain pathologies such as subependymal giant cell astrocytomas (SEGA) and cortical tubers (CT). Further, targeting the epidermal growth factor receptor (EGFR) with afatinib, which is expressed in CLIP cells, reduces cell growth in cerebral TSC organoids. However, investigation of clinical patient-derived data is lacking., Aims: Observation of EGFR expression in SEGA, CT and focal cortical dysplasia (FCD) 2B human brain specimen and investigation of whether its inhibition could be a potential therapeutic intervention for these patients., Methods: Brain specimens of 23 SEGAs, 6 CTs, 20 FCD2Bs and 17 controls were analysed via immunohistochemistry to characterise EGFR expression, cell proliferation (via Mib1) and mTOR signalling. In a cell-based assay using primary patient-derived cells (CT n = 1, FCD2B n = 1 and SEGA n = 4), the effects of afatinib and everolimus on cell proliferation and cell viability were observed., Results: EGFR overexpression was observed in histological sections of SEGA, CT and FCD2B patients. Both everolimus and afatinib decreased the proliferation and viability in primary SEGA, tuber and FCD2B cells., Conclusion: Our study demonstrates that EGFR suppression might be an effective alternative treatment option for SEGAs and tubers, as well as other mTOR-associated malformations of cortical development, including FCD2B., (© 2024 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Background and Objective: Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied., Methods: We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen., Results: Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed., Discussion: This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.

Purpose: The aim of this prospective cohort study was to assess the factual accuracy, completeness of medical information, and potential harmfulness of incorrect conclusions by medical professionals in automatically generated texts of varying complexity (1) using ChatGPT, Furthermore, patients without a medical background were asked to evaluate comprehensibility, information density, and conclusion possibilities (2)., Methods: In the study, five different simplified versions of MRI findings of the knee of different complexity (A: simple, B: moderate, C: complex) were each created using ChatGPT. Subsequently, a group of four medical professionals (two orthopedic surgeons and two radiologists) and a group of 20 consecutive patients evaluated the created reports. For this purpose, all participants received a group of simplified reports (simple, moderate, and severe) at intervals of 1 week each for their respective evaluation using a specific questionnaire. Each questionnaire consisted of the original report, the simplified report, and a series of statements to assess the quality of the simplified reports. Participants were asked to rate their level of agreement with a five-point Likert scale., Results: The evaluation of the medical specialists showed that the findings produced were consistent in quality depending on their complexity. Factual correctness, reproduction of relevant information and comprehensibility for patients were rated on average as "Agree". The question about possible harm resulted in an average of "Disagree". The evaluation of patients also revealed consistent quality of reports, depending on complexity. Simplicity of word choice and sentence structure was rated "Agree" on average, with significant differences between simple and complex findings (p = 0.0039) as well as between moderate and complex findings (p = 0.0222). Participants reported being significantly better at knowing what the text was about (p = 0.001) and drawing the correct conclusions the more simplified the report of findings was (p = 0.013829). The question of whether the text informed them as well as a healthcare professional was answered as "Neutral" across all findings., Conclusion: By using ChatGPT, MRI reports can be simplified automatically with consistent quality so that the relevant information is understandable to patients. However, a report generated in this way does not replace a thorough discussion between specialist and patient., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Recently, the 7 Tesla (7 T) Epilepsy Task Force published recommendations for 7 T magnetic resonance imaging (MRI) in patients with pharmaco-resistant focal epilepsy in pre-surgical evaluation. The objective of this study was to implement and evaluate this consensus protocol with respect to both its practicability and its diagnostic value/potential lesion delineation surplus effect over 3 T MRI in the pre-surgical work-up of patients with pharmaco-resistant focal onset epilepsy., Methods: The 7 T MRI protocol consisted of T1-weighted, T2-weighted, high-resolution-coronal T2-weighted, fluid-suppressed, fluid-and-white-matter-suppressed, and susceptibility-weighted imaging, with an overall duration of 50 min. Two neuroradiologists independently evaluated the ability of lesion identification, the detection confidence for these identified lesions, and the lesion border delineation at 7 T compared to 3 T MRI., Results: Of 41 recruited patients > 12 years of age, 38 were successfully measured and analyzed. Mean detection confidence scores were non-significantly higher at 7 T (1.95 ± 0.84 out of 3 versus 1.64 ± 1.19 out of 3 at 3 T, p = 0.050). In 50% of epilepsy patients measured at 7 T, additional findings compared to 3 T MRI were observed. Furthermore, we found improved border delineation at 7 T in 88% of patients with 3 T-visible lesions. In 19% of 3 T MR-negative cases a new potential epileptogenic lesion was detected at 7 T., Conclusions: The diagnostic yield was beneficial, but with 19% new 7 T over 3 T findings, not major. Our evaluation revealed epilepsy outcomes worse than ILAE Class 1 in two out of the four operated cases with new 7 T findings., (© 2023. The Author(s).)

Objectives: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy., Methods: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/)., Results: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%., Significance: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC., (© 2023. The Author(s).)

Children with tuberous sclerosis complex (TSC), may experience a variety of seizure types in the first year of life, most often focal seizure sand epileptic spasms. Drug resistance is seen early in many patients, and the management of TSC associated epilepsy remain a major challenge for clinicians. In 2018 clinical recommendations for the management of TSC associated epilepsy were published by a panel of European experts. In the last five years considerable progress has been made in understanding the neurobiology of epileptogenesis and three interventional randomized controlled trials have changed the therapeutic approach for the management of TSC associated epilepsy. Pre-symptomatic treatment with vigabatrin may delay seizure onset, may reduce seizure severity and reduce the risk of epileptic encephalopathy. The efficacy of mTOR inhibition with adjunctive everolimus was documented in patients with TSC associated refractory seizures and cannabidiol could be another therapeutic option. Epilepsy surgery has significantly improved seizure outcome in selected patients and should be considered early in all patients with drug resistant epilepsy. There is a need to identify patients who may have a higher risk of developing epilepsy and autism spectrum disorder (ASD). In the recent years significant progress has been made owing to the early identification of risk factors for the development of drug-resistant epilepsy. Better understanding of the mechanism underlying epileptogenesis may improve the management for TSC-related epilepsy. Developmental neurobiology and neuropathology give opportunities for the implementation of concepts related to clinical findings, and an early genetic diagnosis and use of EEG and MRI biomarkers may improve the development of pre-symptomatic and disease-modifying strategies., Competing Interests: Declaration of competing interest We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. N Specchio has served on scientific advisory boards for GW Pharma, BioMarin, Arvelle, Marinus and Takeda; has received speaker honoraria from Eisai, Biomarin, Livanova, Sanofi; has served as an investigator for Zogenix, Marinus, Biomarin, UCB, Roche. R Nabbout has served as principal investigators in clinical trials for Novartis, Nutricia, Eisai, UCB, GW Pharma, Livanova. She received consulting and lecturer honoraria from Biogene, BioMarin, Praxis, GW Pharma, Zogenix, Novartis, Nutricia, Stoke, Ionis, Targeon, Neuraxpharma, Takeda, Nutricia, Biocodex, Advicennes and Eisai. She received unrestricted research grants from Eisai, UCB, Livanova and GW Pharma and academic research grants from EJP-RD (horizons 2020). E Aronica has nothing to disclose. S Auvin is a deputy editor at Epilepsia and has received support from, and/or has served as a paid consultant for Biocodex, Eisai, Encoded, Jazz Pharmaceuticals, GRIN Therapeutics, Neuraxpharm, Nutricia, Orion Pharma, Supernus Pharmaceuticals, Takeda Pharmaceutical Company, UCB Pharma, Vitaflo, Xenon Pharmaceuticals, and Zogenix. M Feucht received speaker and advisory board honoraria as well as scientific grants from Biocodex, Eisai, Gerot, Livanova, Novartis, Nutricia, Shire, UCB and GW Pharma. F Jansen has served as a consultant for Jazz Pharmaceuticals, Nutricia, Novartis and UCB. She was an investigator of the GWEPCARE 1512 trial. L Lagae received grants and is a consultant and/or speaker for Zogenix; LivaNova, UCB, Shire, Eisai, Novartis, Takeda/Ovid, NEL, Epihunter. A Benvenuto, K Kotulska, S Jozwiak, P Curatolo report no conflicts of interest., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Objective: Magnetic resonance thermography-guided laser interstitial thermal therapy (LITT) provides a minimally invasive treatment option in children with central nervous system tumors or medically intractable epilepsy. However, transporting anesthetized children between an operating room (OR) and a radiologic suite creates logistical challenges. Thus we describe advantages of using a 2-room intraoperative magnetic resonance imaging (MRI) concept for LITT., Methods: Patients were pinned in a head frame that doubles as the lower part of the MRI head coil. Preoperative MRI was performed for accurate neuronavigation, after which laser fibers were stereotactically implanted. Transport between OR and MRI was achieved by sliding the top of the OR table onto a trolly., Results: We performed 12 procedures in 11 children, mean age 7.1 years (range: 2 to 14 years). Ten children suffered from medically intractable epilepsy, and 1 child had a pilocytic midbrain astrocytoma. Two fibers were placed in 8 and 1 fiber in 4 procedures. Mean entry point and target errors were 2.8 mm and 3.4 mm, respectively. Average transfer time from OR to MRI and vice versa was 9 minutes (±1 minute, 40 seconds). Altogether, 50% of the seizure patients were seizure free (Engel grade I) at 22 months' follow-up time. One hemorrhagic event, which could be managed nonoperatively, occurred. We recorded no surgical site or intracranial infections., Conclusions: All LITT procedures were successfully carried out with head frame in the sterile environment. The intraoperative MRI suite proved to be advantageous for minimally invasive procedures, especially in young children resulting in short transports while maintaining high accuracy and safety., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: FINCA disease (Fibrosis, Neurodegeneration and Cerebral Angiomatosis, OMIM 618278) is an infantile-onset neurodevelopmental and multiorgan disease. Since our initial report in 2018, additional patients have been described. FINCA is the first human disease caused by recessive variants in the highly conserved NHLRC2 gene. Our previous studies have shown that Nhlrc2 - null mouse embryos die during gastrulation, indicating the essential role of the protein in embryonic development. Defect in NHLRC2 leads to cerebral neurodegeneration and severe pulmonary, hepatic and cardiac fibrosis. Despite having a structure suggestive of an enzymatic role and the clinical importance of NHLRC2 in multiple organs, the specific physiological role of the protein is unknown., Methods: The clinical histories of five novel FINCA patients diagnosed with whole exome sequencing were reviewed. Segregation analysis of the biallelic, potentially pathogenic NHLRC2 variants was performed using Sanger sequencing. Studies on neuropathology and NHLRC2 expression in different brain regions were performed on autopsy samples of three previously described deceased FINCA patients., Results: One patient was homozygous for the pathogenic variant c.442G > T, while the other four were compound heterozygous for this variant and two other pathogenic NHLRC2 gene variants. All five patients presented with multiorgan dysfunction with neurodevelopmental delay, recurrent infections and macrocytic anemia as key features. Interstitial lung disease was pronounced in infancy but often stabilized. Autopsy samples revealed widespread, albeit at a lower intensity than the control, NHLRC2 expression in the brain., Conclusion: This report expands on the characteristic clinical features of FINCA disease. Presentation is typically in infancy, and although patients can live to late adulthood, the key clinical and histopathological features are fibrosis, infection susceptibility/immunodeficiency/intellectual disability, neurodevelopmental disorder/neurodegeneration and chronic anemia/cerebral angiomatosis (hence the acronym FINCA) that enable an early diagnosis confirmed by genetic investigations., 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 © 2023 Tallgren, Kager, O’Grady, Tuominen, Körkkö, Kuismin, Feucht, Wilson, Behunova, England, Kurki, Palotie, Hallman, Kaarteenaho, Laccone, Boztug, Hinttala and Uusimaa.)

Objective: Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy., Methods: This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified., Results: A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity., Significance: Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response., (© 2021. The Author(s).)

The objective is to provide a treatment algorithm for pediatric patients with intracranial cavernous malformations (CMs) based on our experience. Patients < 18 years of age who were treated either surgically or conservatively at the authors' institution between 1982 and 2019 were retrospectively evaluated. A total of 61 pediatric patients were treated at the authors' institution: 39 with lobar CMs; 18 with deep CMs, including 12 in the brainstem and 6 in the basal ganglia; and 4 with CMs in the cerebellar hemispheres. Forty-two patients underwent surgery, and 19 were treated conservatively. The median follow-up time was 65 months (1-356 months). In surgically treated patients, lesions were larger (2.4 cm vs 0.9 cm, p < 0.001). In patients with lobar CMs, seizures were more common (72% vs 21%, p = 0.003) in the surgery group than in conservatively managed patients. In deep CMs, modified Rankin scale (mRS) was higher (4 vs 1, p = 0.003) in the surgery group than in conservatively treated patients. At the time of last follow-up, no differences in Wieser outcome class I were seen (86% vs 67%) in lobar CMs, and mRS scores had aligned between the treatment groups in deep CMs (1 vs 0). We encountered no new permanent neurological deficit at time of last follow-up. We propose a treatment algorithm according to lesion location and size, burden of symptoms, epilepsy workup, and further clinical course during observation. A conservative management is safe in pediatric patients with asymptomatic CMs. Gross total resection should be the aim in patients with symptomatic lobar CMs. A less aggressive approach with subtotal resection, when required to prevent neurological compromise, sustainably improves neurological outcome in patients with deep CMs., (© 2022. The Author(s).)

Purpose: Both acute ruptures of the anterior cruciate ligament (ACL) as well as chronic ACL insufficiency show a high association with focal cartilage defects of the knee. However, the results after combined ACL reconstruction and cartilage repair are not well investigated. The aim of the present study was to investigate the short-term outcomes after autologous chondrocyte implantation (ACI) in combination with ACL reconstruction and to compare the results with patients who underwent isolated ACI in ligament intact knees., Methods: All patients who were registered in the German Cartilage Registry with ACI for focal cartilage defects in the knee joint in combination with ACL reconstruction and who completed the 24 month follow-up were included in the study group. A matched-pair procedure according to gender, defect location, defect size, and age was used to create a control group of patients with isolated ACI in ACL intact joints. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the numeric analog scale for pain (NAS) were used to assess the preoperative state as well as the clinical outcomes 12 and 24 months after surgery., Results: A total of 34 patients were included in both the study group (age mean 33.3 ± SD 8.8 years) and the control group (33.6 ± 8.4 years) with a median defect size of 466 (25%-75% IQR 375-600) mm 2 and 425 (IQR 375-600) mm 2 , respectively. In comparison with the preoperative state (median 67, IQR 52-75), the study group showed a significant increase of the total KOOS after 12 months (78, IQR 70-86; p = 0.014) and after 24 months (81, IQR 70-84; p = 0.001). The NAS for pain did not change significantly in the postoperative course. In comparison with the control group there was no significant difference for the total KOOS neither preoperative (control group median 67, IQR 52-73) nor at any postoperative time point (12 months: 82, IQR 67-93; 24 months: 81, IQR 71-91)., Conclusion: The clinical short-term outcomes after ACI at the knee joint in combination with ACL reconstruction are good and similar to the results after isolated ACI in ligament intact knees., Level of Evidence: III., (© 2021. The Author(s).)

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients' serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients.

Objective. While it is well-known that epilepsy has a clear impact on the activity of both the central nervous system (CNS) and the autonomic nervous system (ANS), its role on the complex interplay between CNS and ANS has not been fully elucidated yet. In this work, pairwise and higher-order predictability measures based on the concepts of Granger Causality (GC) and partial information decomposition (PID) were applied on time series of electroencephalographic (EEG) brain wave amplitude and heart rate variability (HRV) in order to investigate directed brain-heart interactions associated with the occurrence of focal epilepsy. Approach. HRV and the envelopes of δ and α EEG activity recorded from ipsilateral (ipsi-EEG) and contralateral (contra-EEG) scalp regions were analyzed in 18 children suffering from temporal lobe epilepsy monitored during pre-ictal, ictal and post-ictal periods. After linear parametric model identification, we compared pairwise GC measures computed between HRV and a single EEG component with PID measures quantifying the unique, redundant and synergistic information transferred from ipsi-EEG and contra-EEG to HRV. Main results. The analysis of GC revealed a dominance of the information transfer from EEG to HRV and negligible transfer from HRV to EEG, suggesting that CNS activities drive the ANS modulation of the heart rhythm, but did not evidence clear differences between δ and α rhythms, ipsi-EEG and contra-EEG, or pre- and post-ictal periods. On the contrary, PID revealed that epileptic seizures induce a reorganization of the interactions from brain to heart, as the unique predictability of HRV originated from the ipsi-EEG for the δ waves and from the contra-EEG for the α waves in the pre-ictal phase, while these patterns were reversed after the seizure. Significance. These results highlight the importance of considering higher-order interactions elicited by PID for the study of the neuro-autonomic effects of focal epilepsy, and may have neurophysiological and clinical implications., (© 2022 IOP Publishing Ltd.)

Purpose: Focal, patellar cartilage defects are a challenging problem as most cases have an underlying multifactorial pathogenesis. This systematic review of current literature analysed clinical results after regenerative cartilage repair of the patella with a special focus on the assessment and treatment of existing patellofemoral malalignment., Methods: A systematic review was conducted to identify articles reporting clinical results after cartilage regenerative surgeries of the patella using the PubMed and Scopus database. The extracted data included patient-reported outcome measures (PROMS) and whether cartilage repair was performed alone or in combination with concomitant surgeries of underlying patellofemoral co-pathologies. In cases of isolated cartilage repair, specific exclusion criteria regarding underlying co-pathologies were screened. In cases of concomitant surgeries, the type of surgeries and their specific indications were extracted., Results: A total of 35 original articles were included out of which 27 (77%) were cohort studies with level IV evidence. The most frequently used technique for cartilage restoration of the patella was autologous chondrocyte implantation (ACI). Results after isolated cartilage repair alone were reported by 15 (43%) studies. Of those studies, 9 (60%) excluded patients with underlying patellofemoral malalignment a priori and 6 (40%) did not analyse underlying co-pathologies at all. Among the studies including combined surgeries, the most frequently reported concomitant procedures were release of the lateral retinaculum, reconstruction of the medial patellofemoral ligament (MPFL), and osteotomy of the tibial tubercle. In summary, these studies showed lower preoperative PROMS but similar final PROMS in comparison with the studies reporting on isolated cartilage repair. The most frequently used PROMS were the IKDC-, Lysholm- and the Modified Cincinnati Score., Conclusion: This comprehensive literature review demonstrated good clinical outcomes after patellar cartilage repair with no evidence of minor results even in complex cases with the need for additional patellofemoral realignment procedures. However, a meaningful statistical comparison between isolated patellar cartilage repair and combined co-procedures is not possible due to very heterogeneous patient cohorts and a lack of analysis of specific subgroups in recent literature., Level of Evidence: Level IV., (© 2021. The Author(s).)

The TuberOus SClerosis registry to increase disease Awareness (TOSCA) Post-Authorization Safety Study (PASS) was a non-interventional, multicenter, safety substudy that assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) receiving everolimus for its licensed indications in the European Union (EU). This substudy also aimed to address TSC-associated neuropsychiatric disorders (TAND), sexual development, and male infertility. Eligible patients were enrolled from 39 sites across 11 countries in the EU. Outcomes of interest included the incidence of adverse events (AEs), serious adverse events (SAEs), treatment-related AEs (TRAEs), AEs leading to everolimus discontinuation, AEs of special interest (AESIs), the observed relationship between everolimus blood levels and incidence of AESIs, TAND, and reproductive clinical features. Herein, we present the final analysis results from this substudy (data cutoff date: 22 January 2020). At data cutoff, 179 patients were enrolled (female, 59.2%; age ≥18 years, 65.9%), of which the majority completed the study (76%). Overall, 121 patients (67.6%) had AEs regardless of causality. The most frequent TRAEs (≥5%) were stomatitis (7.8%), aphthous ulcer (6.7%), and hypercholesterolemia (6.1%). The most common treatment-related SAEs (>1%) were pneumonia (3.4%), influenza, pyelonephritis, aphthous ulcer, stomatitis, dyslipidemia, and hypercholesterolemia (1.1% each). Ten patients (5.6%) reported AEs leading to everolimus discontinuation. The common psychiatric disorders ( N = 179) were autism spectrum disorder (21.8%), anxiety disorder (12.8%), "other" psychiatric disorders (8.9%), attention-deficit hyperactivity disorder, and depressive disorder (7.8% each). Of 179 patients, 88 (49.2%) had ≥1 behavioral problem. Of these ( n = 88), the most common (>20%) were sleep difficulties (47.7%), anxiety (43.2%), mood swings (37.5%), depression mood (35.2%), impulsivity (30.7%), severe aggression (23.9%), and overactivity (22.7%). Of 179 patients, four (2.2%) reported abnormal puberty onset, and three (1.7%) reported other reproductive disorders. Of 106 females, 23 (21.7%) reported menstrual cycle disorders and 10 (9.4%) reported amenorrhea. Available data did not show delays in sexual maturation or an association between sexual development and infertility. The results demonstrate that everolimus has a manageable long-term safety profile in the TSC treatment setting. No new safety signals emerged. This substudy also contributed to the mapping of TAND and reproductive clinical features in patients with TSC., Competing Interests: Authors RM and YH are employees at Novartis and report stock ownership at Novartis. Author AR is an employee at Novartis. MF reports consulting fees for being part of the scientific advisory board and TOSCA working committee; received speaker honoraria, support for travel, and payment for expert testimony from Novartis; and reports leadership or fiduciary role in the following: ILAE task force epilepsy surgery, ERN EpiCARE, ÖGKN, and ÖGfE. AM received honoraria and support for travel from Novartis. BW reports honoraria for a lecture from Takeda. JK received honoraria, support for travel, and research grant from Novartis. The remaining 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 © 2022 Ruiz-Falcó Rojas, Feucht, Macaya, Wilken, Hahn, Maamari, Hirschberg, Ridolfi and Kingswood.)

Background and Objectives: Multiple factors have been found to contribute to the high risk of epilepsy in infants with tuberous sclerosis complex (TSC), including evolution of EEG abnormalities, TSC gene variant, and MRI characteristics. The aim of this prospective multicenter study was to identify early MRI biomarkers of epilepsy in infants with TSC aged <6 months and before seizure onset, and associate these MRI biomarkers with neurodevelopmental outcomes at 2 years of age. The study was part of the EPISTOP project., Methods: We evaluated brain MRIs performed in infants younger than 6 months with TSC. We used harmonized MRI protocols across centers and children were monitored closely with neuropsychological evaluation and serial video EEG. MRI characteristics, defined as tubers, radial migration lines, white matter abnormalities, cysts, calcifications, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA), were visually evaluated and lesions were detected semiautomatically. Lesion to brain volume ratios were calculated and associated with epilepsy and neurodevelopmental outcomes at 2 years., Results: Lesions were assessed on MRIs from 77 infants with TSC; 62 MRIs were sufficient for volume analysis. The presence of tubers and higher tuber-brain ratios were associated with the development of clinical seizures, independently of TSC gene variation and preventive treatment. Furthermore, higher tuber-brain ratios were associated with lower cognitive and motor development quotients at 2 years, independently of TSC gene variation and presence of epilepsy., Discussion: In infants with TSC, there is a significant association between characteristic TSC lesions detected on early brain MRI and development of clinical seizures, as well as neurodevelopmental outcomes in the first 2 years of life. According to our results, early brain MRI findings may guide clinical care for young children with TSC., Classification of Evidence: This study provides Class I evidence that in infants with TSC, there is a significant association between characteristic TSC lesions on early brain MRI and the development of clinical seizures and neurodevelopmental outcomes in the first 2 years of life., (© 2022 American Academy of Neurology.)

Objective: The goal of this study was to evaluate the feasibility, benefit, and safety of awake brain surgery (ABS) and intraoperative language mapping in children and adolescents with structural epilepsies. Whereas ABS is an established method to monitor language function in adults intraoperatively, reports of ABS in children are scarce., Methods: A retrospective chart review of pediatric patients ≤ 18 years of age who underwent ABS and cortical language mapping for supratentorial tumors and nontumoral epileptogenic lesions between 2008 and 2019 was conducted. The authors evaluated the global intellectual and specific language performance by using detailed neuropsychological testing, the patient's intraoperative compliance, results of intraoperative language mapping assisted by electrocorticography (ECoG), and postsurgical language development and seizure outcomes. Descriptive statistics were used for this study, with a statistical significance of p < 0.05., Results: Eleven children (7 boys) with a median age of 13 years (range 10-18 years) underwent ABS for a lesion in close vicinity to cortical language areas as defined by structural and functional MRI (left hemisphere in 9 children, right hemisphere in 2). Patients were neurologically intact but experiencing seizures; these were refractory to therapy in 9 patients. Compliance during the awake phase was high in 10 patients and low in 1 patient. Cortical mapping identified eloquent language areas in 6/10 (60%) patients and was concordant in 3/8 (37.5%), discordant in 3/8 (37.5%), and unclear in 2/8 (25%) patients compared to preoperative functional MRI. Stimulation-induced seizures occurred in 2 patients and could be interrupted easily. ECoG revealed that afterdischarge potentials (ADP) were involved in 5/9 (56%) patients with speech disturbances during stimulation. None of these patients harbored postoperative language dysfunction. Gross-total resection was achieved in 10/11 (91%) patients, and all were seizure free after a median follow-up of 4.3 years. Neuropsychological testing using the Wechsler Intelligence Scale for Children and the verbal learning and memory test showed an overall nonsignificant trend toward an immediate postoperative deterioration followed by an improvement to above preoperative levels after 1 year., Conclusions: ABS is a valuable technique in selected pediatric patients with lesions in language areas. An interdisciplinary approach, careful patient selection, extensive preoperative training of patients, and interpretation of intraoperative ADP are pivotal to a successful surgery.

Objective: Increasing evidence supports the contribution of inflammatory mechanisms to the neurological manifestations of epileptogenic developmental pathologies linked to mammalian target of rapamycin (mTOR) pathway dysregulation (mTORopathies), such as tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD). In this study, we aimed to investigate the expression pattern and cellular distribution of the complement factors C1q and C3 in resected cortical tissue of clinically well-characterized patients with TSC and FCD2B., Methods: We applied immunohistochemistry in TSC (n = 29) and FCD2B (n = 32) samples and compared them to autopsy and biopsy controls (n = 27). Furthermore, protein expression was observed via Western blot, and for descriptive colocalization studies immunofluorescence double labeling was performed., Results: Protein expression for C3 was significantly upregulated in TSC and FCD2B white and gray matter lesions compared to controls. Staining of the synaptic vesicle protein synaptophysin showed a remarkable increase in the white matter of both TSC and FCD2B. Furthermore, confocal imaging revealed colocalization of complement factors with astroglial, microglial, neuronal, and abnormal cells in various patterns., Significance: Our results demonstrate that the prominent activation of the complement pathway represents a common pathological hallmark of TSC and FCD2B, suggesting that complement overactivation may play a role in these mTORopathies., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.

Background: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70-80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes - cell-adhesion molecule contactin-3., Methods: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1-48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0-44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0-3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro., Results: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = - 0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of 0-3 years old (fold change = - 3.8, p < 0.001) as compared to the age-matched controls. In control brain tissue, contactin-3 gene and protein expression could be detected during fetal development, peaked around birth and during infancy and declined in the adult brain. CNTN3 expression was induced in the differentiated SH-SY5Y neuroblastoma cells in vitro (fold change = 6.2, p < 0.01)., Conclusions: Our data show a lower expression of contactin-3 in cortical tubers of TSC patients during early postnatal period as compared to controls, which may affect normal brain development and might contribute to neuropsychiatric co-morbidities observed in patients with TSC., (© 2022. The Author(s).)

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).)