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Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and hemimegalencephaly. Recent advances in sequencing and variant calling technologies have identified several genetic causes, including both short/single nucleotide and structural somatic variation. In this review, we aim to provide a comprehensive overview of the methodological advancements in this field while highlighting the unresolved technological and computational challenges that persist, including ultra-low variant allele fractions in bulk tissue, low availability of paired control samples, spatial variability of mutational burden within the lesion, and the issue of false-positive calls and validation procedures. Information from genetic testing in focal epilepsy may be integrated into clinical care to inform histopathological diagnosis, postoperative prognosis, and candidate precision therapies., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the longitudinal evolution of EEG findings in children with Zika related-microcephaly (ZRM) and to evaluate the associations of these patterns with the children's clinical and neuroimaging characteristics., Methods: As part of the follow-up of the Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC) in Recife, Brazil, we performed serial EEG recordings in a subgroup of children with ZRM to evaluate changes in background rhythms and epileptiform activity (EA). Latent class analysis was used to identify patterns in the evolution of EA over time; clinical and neuroimaging findings were compared across the identified groups., Results: Out of the 72 children with ZRM who were evaluated during 190 EEGs/videoEEGs, all participants presented with abnormal background activity, 37.5% presented with an alpha-theta rhythmic activity, and 25% presented with sleep spindles, which were less commonly observed in children with epilepsy. EA changed over time in 79.2% of children, and three distinct trajectories were identified: (i) multifocal EA over time, (ii) no discharges/focal EA evolving to focal/multifocal EA, and (iii) focal/multifocal EA evolving to epileptic encephalopathy patterns (e.g., hypsarrhythmia or continuous EA in sleep). The multifocal EA over time trajectory was associated with periventricular and thalamus/basal ganglia calcifications, brainstem and corpus callosum atrophy and had less focal epilepsy, whereas the children in the trajectory which evolved to epileptic encephalopathy patterns had more frequently focal epilepsy., Significance: These findings suggest that, in most children with ZRM, trajectories of changes in EA can be identified and associated with neuroimaging and clinical features., Competing Interests: Declaration of Competing Interest None of the authors has any conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

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.)

Polymicrogyria (PMG) is a malformation of cortical development that occurs mostly in the perisylvian region bilaterally (60-70%), most often presenting with epilepsy. Unilateral cases are much rarer with hemiparesis being the predominant symptom. We report a case of a 71-year-old man with right perirolandic PMG with ipsilateral hypoplasia and contralateral hyperplasia of the brainstem, with only non-progressive left-sided mild spastic hemiparesis. This imaging pattern is thought to occur due to the normal process of withdrawal of the axons of the corticospinal tract (CST) connected to aberrant cortex, possibly with compensatory contralateral CST hyperplasia. However, the majority of cases is additionally present with epilepsy. We believe it is worthwhile to investigate imaging patterns of PMG with symptoms' correlation, particularly with the help of techniques such as advanced brain imaging to assist in the study of cortical development along with adaptive somatotopic organization of the cerebral cortex in MCD with possible clinical applications., (© 2023. Fondazione Società Italiana di Neurologia.)

Hippocampal dentation (HD) refers to a series of ridges (dentes) seen on the inferior aspect of the hippocampus. The degree of HD varies dramatically across healthy individuals, and hippocampal pathology may result in loss of HD. Existing studies show associations between HD and memory performance in healthy adults as well as temporal lobe epilepsy (TLE) patients. However, until now studies relied on visual assessment of HD as no objective methods to quantify HD have been described. In this work, we describe a method to objectively quantify HD by transforming the characteristic 3D surface morphology of HD into a simplified 2D plot for which area under the curve (AUC) was calculated. This was applied to T1w scans of 59 TLE subjects, each with one epileptic hippocampus and one normal appearing hippocampus. Results showed that AUC significantly correlated with the number of dentes based on visual inspection (p < .05) and correctly sorted a set of hippocampi from least to most prominently dentated. Intra- and inter-rater reliability was nearly perfect (ICC ≥ 0.99). AUC values were significantly lower in epileptic hippocampi compared to contralateral hippocampi (p = .00019), consistent with previously published findings. In the left TLE group, the AUC values from the contralateral hippocampi showed a positive trend (p = .07) with verbal memory acquisition scores but was not statistically significant. The proposed approach is the first objective, quantitative measurement of dentation described in the literature. The AUC values numerically capture the complex surface contour information of HD and will enable future study of this interesting morphologic feature., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Valproic acid is prescribed for epilepsy and as prophylaxis for bipolar disorder and migraine headaches. It has also been implicated as a cause of a kidney tubular injury., Methods: We undertook a review of the literature to characterize the biochemical and histopathological features of the overt kidney tubular injury and to evaluate the possible existence of a pauci-symptomatic injury. The pre-registered review (CRD42022360357) was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Searches were conducted in Excerpta Medica, the National Library of Medicine, and Web of Science. The gray literature was also considered., Results: For the final analysis, we retained 36 articles: 28 case reports documented 48 individuals with epilepsy on valproic acid for 7 months or more and presenting with features consistent with an overt kidney tubular injury. The following disturbances were noted: hypophosphatemia (N = 46), normoglycemic glycosuria (N = 46), total proteinuria (N = 45), metabolic acidosis (N = 36), hypouricemia (N = 27), tubular proteinuria (N = 27), hypokalemia (N = 23), and hypocalcemia (N = 8). A biopsy, obtained in six cases, disclosed altered proximal tubular cells with giant and dysmorphic mitochondria. Eight case series addressed the existence of a pauci- or even asymptomatic kidney injury. In the reported 285 subjects on valproic acid for 7 months or more, an isolated tubular proteinuria, mostly N-acetyl-β-glucosaminidase, was often noted., Conclusions: Valproic acid may induce an overt kidney tubular injury, which is associated with a proximal tubular mitochondrial toxicity. Treatment for 7 months or more is often associated with a pauci- or oligosymptomatic kidney tubular injury. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s).)

Over the past 10 years, the drive to improve outcomes from epilepsy surgery has stimulated widespread interest in methods to quantitatively guide epilepsy surgery from intracranial EEG (iEEG). Many patients fail to achieve seizure freedom, in part due to the challenges in subjective iEEG interpretation. To address this clinical need, quantitative iEEG analytics have been developed using a variety of approaches, spanning studies of seizures, interictal periods, and their transitions, and encompass a range of techniques including electrographic signal analysis, dynamical systems modeling, machine learning and graph theory. Unfortunately, many methods fail to generalize to new data and are sensitive to differences in pathology and electrode placement. Here, we critically review selected literature on computational methods of identifying the epileptogenic zone from iEEG. We highlight shared methodological challenges common to many studies in this field and propose ways that they can be addressed. One fundamental common pitfall is a lack of open-source, high-quality data, which we specifically address by sharing a centralized high-quality, well-annotated, multicentre dataset consisting of >100 patients to support larger and more rigorous studies. Ultimately, we provide a road map to help these tools reach clinical trials and hope to improve the lives of future patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The hippocampal formation plays a central role in the development of temporal lobe epilepsy (TLE), a disease characterized by recurrent, unprovoked epileptic discharges. TLE is a neurologic disorder characterized by acute long-lasting seizures (i.e., abnormal electrical activity in the brain) or seizures that occur in close proximity without recovery, typically after a brain injury or status epilepticus. After status epilepticus, epileptogenic hyperexcitability develops gradually over the following months to years, resulting in the emergence of chronic, recurrent seizures. Acting as a filter or gate, the hippocampal dentate gyrus (DG) normally prevents excessive excitation from propagating through the hippocampus, and is considered a critical region in the progression of epileptogenesis in pathological conditions. Importantly, lipid-derived endogenous cannabinoids (endocannabinoids), which are produced on demand as retrograde messengers, are central regulators of neuronal activity in the DG circuit. In this review, we summarize recent findings concerning the role of the DG in controlling hyperexcitability and propose how DG regulation by cannabinoids (CBs) could provide avenues for therapeutic interventions. We also highlight possible pathways and manipulations that could be relevant for the control of hyperexcitation. The use of CB compounds to treat epilepsies is controversial, as anecdotal evidence is not always validated by clinical trials. Recent publications shed light on the importance of the DG as a region regulating incoming hippocampal excitability during epileptogenesis. We review recent findings concerning the modulation of the hippocampal DG circuitry by CBs and discuss putative underlying pathways. A better understanding of the mechanisms by which CBs exert their action during seizures may be useful to improve therapies., (© 2023 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).)

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown., Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE., Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022., Exposures: Drug-resistant MTLE., Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex., Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism., Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

Background and Purpose: Spatial registration is crucial in establishing correspondence between anatomic brain regions for research and clinical purposes. The insular cortex (IC) and gyri (IG) are implicated in various functions and pathologies including epilepsy. Optimizing registration of the insula to a common atlas can improve the accuracy of group-level analyses. Here, we compared six nonlinear, one linear, and one semiautomated registration algorithms (RAs) for registering the IC and IG to the Montreal Neurologic Institute standard space (MNI152)., Methods: 3T images acquired from 20 controls and 20 temporal lobe epilepsy patients with mesial temporal sclerosis underwent automated segmentation of the insula. This was followed by manual segmentation of the entire IC and six individual IGs. Consensus segmentations were created at 75% agreement for IC and IG before undergoing registration to MNI152 space with eight RAs. Dice similarity coefficients (DSCs) were calculated between segmentations after registration and the IC and IG in MNI152 space. Statistical analysis involved the Kruskal-Wallace test with Dunn's test for IC and two-way analysis of variance with Tukey's honest significant difference test for IG., Results: DSCs were significantly different between RAs. Based on multiple pairwise comparisons, we report that certain RAs performed better than others across population groups. Additionally, registration performance differed according to specific IG., Conclusion: We compared different methods for registering the IC and IG to MNI152 space. We found differences in performance between RAs, which suggests that algorithm choice is important factor in analyses involving the insula., (© 2023 American Society of Neuroimaging.)

Focal and generalized epilepsies are associated with robust differences in magnetic resonance imaging (MRI) measures of subcortical structures, gray matter, and white matter. However, it is unknown whether such structural brain differences reflect the cause or consequence of epilepsy or its treatment. Analyses of common genetic variants underlying both common epilepsy risk and variability in structural brain measures can give further insights, as such inherited variants are not influenced by disease or treatment. Here, we performed genetic correlation analyses using data from the largest genome-wide association study (GWAS) on common epilepsy (n = 27 559 cases and 42 436 controls) and GWASs on MRI measures of white (n = 33 292) or gray matter (n = 51 665). We did not detect any significant genetic correlation between any type of common epilepsy and any of 280 measures of gray matter, white matter, or subcortical structures. These results suggest that there are distinct genetic bases underlying risk of common epilepsy and for structural brain measures. This would imply that the genetic basis of normal structural brain variation is unrelated to that of common epilepsy. Structural changes in epilepsy could rather be the consequence of epilepsy, its comorbidities, or its treatment, offering a cumulative record of disease., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: When magnetic resonance imaging (MRI) fails to detect an underlying epileptogenic lesion, the odds of a good outcome after epilepsy surgery are significantly lower (20%-65% compared with 60%-90% if a lesion is detected). We investigated the possible effects of introducing hybrid 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET)/MRI into the decision algorithm for patients with lesioned and nonlesioned drug-resistant epilepsy., Methods: Three databases were searched from January 1990 to October 2022. We registered the protocol with International Platform of Registered Systematic Review and Meta-analysis Protocols. Studies in which 18 F-FDG PET/MRI was conducted with ≥12 months of postsurgical follow-up in patients with refractory epilepsy. Random-effects meta-analysis was used to calculate the proportion of patients with good outcomes. Metaregression was used to investigate sources of heterogeneity., Results: We identified 8105 studies, of which 23 (1292 patients in total) were included. The overall good postoperative outcome rate was 71% (95% confidence interval 63.6-74.9). Good outcome was associated with the location of the refractory epileptic lesion (temporal lobe or extratemporal; risk ratio 1.27 [95% confidence interval 1.01-1.52], P = 0.009); Length of postoperative follow-up ≥40 months included in the same study accounted for 0.6% of the observed heterogeneity., Conclusions: Seventy-one percent of patients with refractory epilepsy and 18 F-FDG PET/MRI epileptogenic lesion features had a good outcome of epilepsy after surgery. Our findings can be incorporated into routine preoperative consultations and emphasize the importance of the complete resection of the temporal lobe epileptogenic zone for 18 F-FDG PET/MRI detection when safe and feasible., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: We examined the clinical, semiological, scalp electroencephalographic (EEG), and neuropsychological features of patients with amygdalar hamartoma-like lesion (AHL) without hippocampal sclerosis (HS)., Methods: This retrospective study included 9 patients with mesial temporal lobe epilepsy (MTLE) who had an amygdalar lesion on preoperative MRI; underwent mesial temporal resection; were diagnosed with amygdalar hamartoma-like lesion (AHL) without hippocampal sclerosis (HS); were followed up for at least 2 years after surgery; and had a favourable postoperative seizure outcome (Engel Class I). There were 5 women and 4 men, and age at surgery ranged from 19 to 54 (mean, 36.6) years. Clinical characteristics, auras, video-recorded seizure semiology, interictal and ictal EEG, and preoperative neuropsychological data were reviewed. Twenty patients with MTLE with HS who had favourable postoperative seizure outcomes (Engel Class I) were selected as controls., Results: Age at seizure onset was significantly higher in patients with AHL without HS than in those with HS. Fear was more frequently seen in patients with AHL (44 %) than in those with HS (5 %) (P = 0.022). There were no significant differences in interictal epileptiform discharges or ictal EEG pattern. Preoperative full-scale IQ score was significantly higher in the AHL group than in the HS group (mean, 92.9 v. 74.8, P = 0.004), as was preoperative memory quotient score (mean 100.7 v. 85.1, P = 0.028)., Conclusion: We clarified the clinical, semiological, and neuropsychological features of patients with MTLE-AHL. These findings may be useful for preoperative evaluation, especially of patients with suspected MTLE but without apparent HS on preoperative MRI., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Dendritic spines are the postsynaptic sites for most excitatory glutamatergic synapses. We previously demonstrated a severe spine loss and synaptic reorganization in human neocortices presenting Type II focal cortical dysplasia (FCD), a developmental malformation and frequent cause of drug-resistant focal epilepsy. We extend the findings, investigating the potential role of complement components C1q and C3 in synaptic pruning imbalance. Data from Type II FCD were compared with those obtained in focal epilepsies with different etiologies. Neocortical tissues were collected from 20 subjects, mainly adults with a mean age at surgery of 31 years, admitted to epilepsy surgery with a neuropathological diagnosis of: cryptogenic, temporal lobe epilepsy with hippocampal sclerosis, and Type IIa/b FCD. Dendritic spine density quantitation, evaluated in a previous paper using Golgi impregnation, was available in a subgroup. Immunohistochemistry, in situ hybridization, electron microscopy, and organotypic cultures were utilized to study complement/microglial activation patterns. FCD Type II samples presenting dendritic spine loss were characterized by an activation of the classical complement pathway and microglial reactivity. In the same samples, a close relationship between microglial cells and dendritic segments/synapses was found. These features were consistently observed in Type IIb FCD and in 1 of 3 Type IIa cases. In other patient groups and in perilesional areas outside the dysplasia, not presenting spine loss, these features were not observed. In vitro treatment with complement proteins of organotypic slices of cortical tissue with no sign of FCD induced a reduction in dendritic spine density. These data suggest that dysregulation of the complement system plays a role in microglia-mediated spine loss. This mechanism, known to be involved in the removal of redundant synapses during development, is likely reactivated in Type II FCD, particularly in Type IIb; local treatment with anticomplement drugs could in principle modify the course of disease in these patients., (© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

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.)

While seizures are undoubtedly neuronal events, an ensemble of auxiliary brain cells profoundly shapes synaptic transmission in health and disease conditions. Endothelial-astrocyte-pericyte assemblies at the blood-brain barrier (BBB) and neuroglia within the neuro-glio-vascular unit (NGVU) finely tune brain parenchymal homeostasis, safeguarding the ionic and molecular compositions of the interstitial fluid. BBB permeability with neuroinflammation and the resulting loss of brain homeostatic control are unifying mechanisms sustaining aberrant neuronal discharges, with temporal specificities linked to acute (head trauma, stroke, infections) and pre-existent (genetic) or chronic ( dysplasia, tumors, neurodegenerative disorders) pathological conditions. Within this research template, one hypothesis is that the topography of BBB damage and neuroinflammation could associate with symptoms, e.g., limbic structures for seizures or pre-frontal for psychiatric episodes. Another uncharted matter is whether seizure activity, without tissue lesions or sclerosis, is sufficient to promote stable cellular-level maladaptations in networks. Contingent to localization and duration, BBB damage and inflammation forecast pathological trajectories, and the concept of an epileptic NGVU could enable time-sensitive biomarkers to predict disease progression. The coherence between electrographic, imaging and molecular NGVU biomarkers could be established from the epileptogenic to the propagating zones. This paradigm shift could lead to new diagnostic and therapeutic modalities germane to specific epilepsies or when seizure activity represents a comorbidity., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Objective: Sleep strongly activates interictal epileptic activity through an unclear mechanism. We investigated how scalp sleep slow waves (SSWs), whose positive and negative half-waves reflect the fluctuation of neuronal excitability between the up and down states, respectively, modulate interictal epileptic events in focal epilepsy., Methods: Simultaneous polysomnography was performed in 45 patients with drug-resistant focal epilepsy during intracranial electroencephalographic recording. Scalp SSWs and intracranial spikes and ripples (80-250 Hz) were detected; ripples were classified as type I (co-occurring with spikes) or type II (occurring alone). The Hilbert transform was used to analyze the distributions of spikes and ripples in the phases of SSWs., Results: Thirty patients with discrete seizure-onset zone (SOZ) and discernable sleep architecture were included. Intracranial spikes and ripples accumulated around the negative peaks of SSWs and increased with SSW amplitude. Phase analysis revealed that spikes and both ripple subtypes in SOZ were similarly facilitated by SSWs exclusively during down state. In exclusively irritative zones outside SOZ (EIZ), SSWs facilitated spikes and type I ripples across a wider range of phases and to a greater extent than those in SOZ. The type II and type I ripples in EIZ were modulated by SSWs in different patterns. Ripples in normal zones decreased specifically during the up-to-down transition and then increased after the negative peak of SSW, with a characteristically high post-/pre-negative peak ratio., Significance: SSWs modulate interictal events in an amplitude-dependent and region-specific pattern. Pathological ripples and spikes were facilitated predominantly during the cortical down state. Coupling analysis of SSWs could improve the discrimination of pathological and physiological ripples and facilitate seizure localization., (© 2023 International League Against Epilepsy.)

Dyk-Davidoff-Masson Syndrome (DDMS) is one of the rare neurological conditions attributed to the development of drug-resistant epilepsy (DRE). The DDMS condition is characterized by cerebral hemisphere asymmetry, where atrophy occurs on one side of the brain and clinically manifests as hemiparesis, seizure disorder, mental retardation, and facial asymmetry. In addition, the condition has various perinatal or postnatal etiologies. Herein, we report the case of a 29-year-old right-handed male with Dyke-Davidoff Masson syndrome and mild right-side weakness. The patient experiences attacks of seizures with stiffness in his right arm and right leg, sometimes experiencing agitation and abnormal movement of the body parts. The MRI of the brain showed asymmetry with atrophic changes involving the left hippocampus, consisting of mesial temporal sclerosis. Additionally, the results showed the presence of gyral hyperintensities over the left parietal region. Therefore, the patient's case is reported with a literature review to support it., (Copyright: © Neurosciences.)

Background: Lesional posterior cortex epilepsy (PCE) is often drug resistant and may benefit from surgical intervention. In this study, we aimed to identify potential predictive factors associated with seizure recurrence after epilepsy surgery in lesional PCE., Methods: We retrospectively reviewed patients with PCE who underwent surgery between 1998 and 2021. They were divided into 2 groups according to seizure outcome; the seizure-free group (group 1) and the non-seizure-free group (group 2). The relationship among clinical factors, electroencephalography (EEG) or cranial magnetic resonance imaging findings, disease, and seizure outcome was investigated., Results: A total of 60 patients, with a mean age of 27.26 ± 12.35 years (range, 9-61 years), were included in the study. There were 31 patients (51.66%) in group 1 (Engel class I) and 29 patients (48.33%) in group 2 (13 [21.66%], 10 [16.66%], and 6 [10%] patients in Engel class II, III, and IV, respectively), with a mean follow-up of 8.95 ± 6.96 years (range, 1-24 years). No difference was observed regarding age, gender, age at seizure onset, operation type, treatment gap, and presence of bilateral lesions between the groups (P > 0.05). However, bilateral findings on interictal EEG and gliosis as the underlying disease were predictors of seizure recurrence (P < 0.05)., Conclusions: More than half of the patients (including 2 with bilateral magnetic resonance imaging lesions) were seizure free at long-term follow-up. However, patients with bilateral findings on interictal EEG and gliosis were more likely to have recurrent seizures after surgery. Because lesional PCE is almost always drug resistant and has a potential for favorable outcomes, epilepsy surgery should be considered early., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Dynamic diffusion magnetic resonance imaging (ddMRI) metrics can assess transient microstructural alterations in tissue diffusivity but requires additional scan time hindering its clinical application., Purpose: To determine whether a diffusion gradient table can simultaneously acquire data to estimate dynamic and diffusion tensor imaging (DTI) metrics., Study Type: Prospective., Subjects: Seven healthy subjects, 39 epilepsy patients (15 female, 31 male, age ± 15)., Field Strength/sequence: Two-dimensional diffusion MRI (b = 1000 s/mm 2 ) at a field strength of 3 T. Sessions in healthy subjects-standard ddMRI (30 directions), standard DTI (15 and 30 directions), and nested cubes scans (15 and 30 directions). Sessions in epilepsy patients-two 30 direction (standard ddMRI, 10 nested cubes) or two 15 direction scans (standard DTI, 5 nested cubes)., Assessment: Fifteen direction DTI was repeated twice for within-session test-retest measurements in healthy subjects. Bland-Altman analysis computed bias and limits of agreement for DTI metrics using test-retest scans and standard 15 direction vs. 5 nested cubes scans. Intraclass correlation (ICC) analysis compared tensor metrics between 15 direction DTI scans (standard vs. 5 nested cubes) and the coefficients of variation (CoV) of trace and apparent diffusion coefficient (ADC) between 30 direction ddMRI scans (standard vs. 10 nested cubes)., Statistical Tests: Bland-Altman and ICC analysis using a P-value of 0.05 for statistical significance., Results: Correlations of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were strong and significant in gray (ICC > 0.95) and white matter (ICC > 0.95) between standard vs. nested cubes DTI acquisitions. Correlation of white matter fractional anisotropy was also strong (ICC > 0.95) and significant. ICCs of the CoV of dynamic ADC measured using repeated cubes and nested cubes acquisitions were modest (ICC >0.60), but significant in gray matter., Conclusion: A nested cubes diffusion gradient table produces tensor-based and dynamic diffusion measurements in a single acquisition., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 1., (© 2022 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Nodding syndrome is an enigmatic recurrent epidemic neurologic disease that affects children in East Africa. The illness begins with vertical nodding of the head and can progress to grand mal seizures and death after several years. The most recent outbreak of nodding syndrome occurred in northern Uganda. We now describe the clinicopathologic spectrum of nodding syndrome in northern Uganda. The neuropathologic findings of 16 children or young adults with fatal nodding syndrome were correlated with the onset, duration and progression of their neurological illness. The affected individuals ranged in age from 14 to 25 years at the time of death with a duration of illness ranging from 6-15 years. All 16 cases had chronic seizures. In 10 cases, detailed clinical histories were available and showed that three individuals had a clinical course that was predominantly characterized by epilepsy, whereas the other seven individuals had progressive cognitive, behavioural and motor decline, in addition to epilepsy. The main neuropathologic findings included: tau pathology (16/16 cases), cerebellar degeneration (11/16 cases) and white matter degeneration (7/16 cases). The tau pathology was characterized by filamentous tau-positive deposits in the form of neurofibrillary tangles, pre-tangles and dot-like grains and threads in the neuropil. All cases showed some degree of tau pathology in the neocortex and in the locus coeruleus with frequent involvement of the substantia nigra and tegmental nuclei and lesser involvement of other grey matter sites, but there was a lack of glial tau pathology. The tau pathology in the neocortex showed a multifocal superficial laminar pattern. We conclude that nodding syndrome is a clinicopathological entity associated consistently with tau pathology, but our observations did not establish the cause of the disease, or an explanation for the tau pathology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: Epilepsy is a common symptom in patients with frontal lobe glioma. Tumor-related epilepsy was recently considered a type of network disease. Glioma can severely influence the integrity of the white matter network. The association between white matter network changes and presurgical epilepsy remains unclear in glioma patients. This study aims to identify alterations to the subcortical brain networks caused by glioma and glioma-related epilepsy., Methods: Sixty-one patients with frontal lobe gliomas were enrolled and stratified into the epileptic and non-epileptic groups. Additionally, 14 healthy participants were enrolled after matching for age, sex, and education level. All participants underwent diffusion tensor imaging. Graph theoretical analysis was applied to reveal topological changes in their white matter networks. Regions affected by tumors were excluded from the analysis., Results: Global efficiency was significantly decreased (p = 0.008), while the shortest path length increased (p = 0.02) in the left and right non-epileptic groups compared to the controls. A total of five edges exhibited decreased fiber count in the non-epileptic group (p < 0.05, false discovery rate-corrected). The topological properties and connectional edges showed no significant differences when comparing the epileptic groups and the controls. Additionally, the degree centrality of several nodes connected to the alternated edges was also diminished., Conclusions: Compared to the controls, the epilepsy groups showed raletively intact WM networks, while the non-epileptsy groups had damaged network with lower efficiency and longer path length. These findings indicated that the occurrence of glioma related epilepsy have association with white matter network intergrity., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: The concept of 'developmental and epileptic encephalopathy (DEE)' recognises that in infants presenting with severe early-onset epilepsy, neurodevelopmental comorbidity may be attributable to both the underlying cause and to adverse effects of uncontrolled epileptic activity. There is no direct genotype - phenotype correlation in DEEs. This study aimed to report the genetic and phenotypic differences in patients with DEE., Methods: Genetic evaluations of the patients were performed due to epilepsy combined with developmental delay, epileptic encephalopathy, motor deficits, autistic features, or cognitive impairment. Patients were assessed for demographic characteristics, medical history, family history, psychomotor development, seizure control interventions, electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings., Results: This study included 20 children aged 0-16 years who were diagnosed as having DEE.The types of DEE detected in our study were DEE 2, 4, 6B, 7, 11, 26, 30, 33, 35, 42, 58, 62, and 67.Status epilepticus was recorded in only DEE7. The most common EEG abnormality was multifocal epileptic discharges (35%,) followed by burst-suppression patterns in patients with neonatal-onset seizures. Thirteen of the children were aged over 2 years, two (15%) were non-ambulatory and six (46%) were non-verbal. MRI scans were normal in 80% of the patients. Refractory epilepsy seen in 33% of cases.De-novo mutation, microcephaly and dysmorphic findings accompany resistant seizures and are associated with poor prognosis., Discussion: For patients with movement disorders, developmental delay, autism, and ID with or without epilepsy in any period of their life, next-generation sequencing is the only diagnostic technique available, with genetic analysis often being the only diagnostic method.

The CA2 pyramidal cells are mostly resistant to cell death in mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis, but they are aberrantly integrated into the epileptic hippocampal network via mossy fiber sprouting. Furthermore, they show increased excitability in vitro in hippocampal slices obtained from human MTLE specimens or animal epilepsy models. Although these changes promote CA2 to contribute to epileptic activity (EA) in vivo, the role of CA2 in the epileptic network within and beyond the sclerotic hippocampus is still unclear. We used the intrahippocampal kainate mouse model for MTLE, which recapitulates most features of the human disease including pharmacoresistant epileptic seizures and hippocampal sclerosis, with preservation of dentate gyrus (DG) granule cells and CA2 pyramidal cells. In vivo recordings with electrodes in CA2 and the DG showed that EA occurs at high coincidence between the ipsilateral DG and CA2 and current source density analysis of silicon probe recordings in dorsal ipsilateral CA2 revealed CA2 as a local source of EA. Cell-specific viral tracing in Amigo2-icreERT2 mice confirmed the preservation of the axonal projection from ipsilateral CA2 pyramidal cells to contralateral CA2 under epileptic conditions and indeed, EA propagated from ipsi- to contralateral CA2 with increasing likelihood with time after KA injection, but always at lower intensity than within the ipsilateral hippocampus. Furthermore, we show that CA2 presents with local theta oscillations and like the DG, shows a pathological reduction of theta frequency already from 2 days after KA onward. The early changes in activity might be facilitated by the loss of glutamic acid decarboxylase 67 (Gad67) mRNA-expressing interneurons directly after the initial status epilepticus in ipsi- but not contralateral CA2. Together, our data highlight CA2 as an active player in the epileptic network and with its contralateral connections as one possible router of aberrant activity., (© 2022 The Authors. Hippocampus published by Wiley Periodicals LLC.)

The blood-brain barrier (BBB) is a physiological barrier maintaining a specialized brain micromilieu that is necessary for proper neuronal function. Endothelial tight junctions and specific transcellular/efflux transport systems provide a protective barrier against toxins, pathogens, and immune cells. The barrier function is critically supported by other cell types of the neurovascular unit, including pericytes, astrocytes, microglia, and interneurons. The dysfunctionality of the BBB is a hallmark of neurological diseases, such as ischemia, brain tumors, neurodegenerative diseases, infections, and autoimmune neuroinflammatory disorders. Moreover, BBB dysfunction is critically involved in epilepsy, a brain disorder characterized by spontaneously occurring seizures because of abnormally synchronized neuronal activity. While resistance to antiseizure drugs that aim to reduce neuronal hyperexcitability remains a clinical challenge, drugs targeting the neurovasculature in epilepsy patients have not been explored. The use of novel imaging techniques permits early detection of BBB leakage in epilepsy; however, the detailed mechanistic understanding of causes and consequences of BBB compromise remains unknown. Here, we discuss the current knowledge of BBB involvement in temporal lobe epilepsy with the emphasis on the neurovasculature as a therapeutic target., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Bilateral Temporal lobe epilepsy (BTLE) cases may result in poor surgical outcomes due to the difficulty in determining/localizing the epileptogenic zone. In this study, we investigated whether hippocampal volume (HV) would be useful for the determination of the best resection side in BTLE. Eighteen cases of BTLE determined by a scalp video electroencephalogram (SVEEG) underwent resection via intracranial electroencephalography (IVEEG). Patients with lesions or semiologically determined focus lateralization were excluded. In addition to SVEEG, an epilepsy protocol magnetic resonance imaging (MRI) including hippocampus fluid-attenuated inversion recovery (FLAIR) and HV, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), single-photon emission computed tomography with 123I-iomazenil (IMZ-SPECT), and magnetoencephalography (MEG) were performed for the preoperative evaluation of the lateralization. The resection side was determined based on the IVEEG results, and the seizure outcome at two years postoperatively was classified as either a well-controlled seizure outcome (Engel class I), or residual (classes II-V). We used a Fisher's exact test to compare the concordance between the determination of the epileptic focus by each modality and the resected side where patients achieved a well-controlled seizure outcome. Seizures were well controlled in 9/18 patients after surgery. Eight out of 11 patients (72.7%), in whom the HV results (strongly atrophic side) and the resection side were matched, had well-controlled seizure outcomes (P = 0.0498). The concordance of other presurgical evaluations with the resection side was not significantly related to a well-controlled seizure outcome. HV may be a useful method to determine the optimal resection side of the epileptic focus/foci in cases of suspected BTLE., (© 2023. The Author(s).)

Understanding the neuronal basis of epileptic activity is a major challenge in neurology. Cellular integration into larger scale networks is all the more challenging. In the local field potential, interictal epileptic discharges can be associated with fast ripples (200-600 Hz), which are a promising marker of the epileptogenic zone. Yet, how neuronal populations in the epileptogenic zone and in healthy tissue are affected by fast ripples remain unclear. Here, we used a novel 'hybrid' macro-micro depth electrode in nine drug-resistant epileptic patients, combining classic depth recording of local field potentials (macro-contacts) and two or three tetrodes (four micro-wires bundled together) enabling up to 15 neurons in local circuits to be simultaneously recorded. We characterized neuronal responses (190 single units) with the timing of fast ripples (2233 fast ripples) on the same hybrid and other electrodes that target other brain regions. Micro-wire recordings reveal signals that are not visible on macro-contacts. While fast ripples detected on the closest macro-contact to the tetrodes were always associated with fast ripples on the tetrodes, 82% of fast ripples detected on tetrodes were associated with detectable fast ripples on the nearest macro-contact. Moreover, neuronal recordings were taken in and outside the epileptogenic zone of implanted epileptic subjects and they revealed an interlay of excitation and inhibition across anatomical scales. While fast ripples were associated with increased neuronal activity in very local circuits only, they were followed by inhibition in large-scale networks (beyond the epileptogenic zone, even in healthy cortex). Neuronal responses to fast ripples were homogeneous in local networks but differed across brain areas. Similarly, post-fast ripple inhibition varied across recording locations and subjects and was shorter than typical inter-fast ripple intervals, suggesting that this inhibition is a fundamental refractory process for the networks. These findings demonstrate that fast ripples engage local and global networks, including healthy tissue, and point to network features that pave the way for new diagnostic and therapeutic strategies. They also reveal how even localized pathological brain dynamics can affect a broad range of cognitive functions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Plastic change of the neuronal system has traditionally been assumed to be governed primarily by the long-term potentiation/depression mechanisms of synaptic transmission. However, a rather simple shift in the ambient ion, transmitter and metabolite concentrations could have a pivotal role in generating plasticity upon the physiological process of learning and memory. Local brain environment and metabolic changes could also be the cause and consequences of the pathogenesis leading to epilepsy. Governing of the local brain environment is the primal function of astrocytes. The metabolic state of the entire brain is strongly linked to the activity of the lateral hypothalamus. In this study, plastic change of astrocyte reactions in the lateral hypothalamus was examined using epileptogenesis as an extreme form of plasticity. Fluorescent sensors for calcium or pH expressed in astrocytes were examined for up to one week by in vivo fibre photometry in freely moving transgenic male mice. Optical fluctuations on a timescale of seconds is difficult to assess because these signals are heavily influenced by local brain blood volume changes and pH changes. Using a newly devised method for the analysis of the optical signals, changes in Ca2+ and pH in astrocytes and changes in local brain blood volume associated with hippocampal-stimulated epileptic seizures were extracted. Following a transient alkaline shift in the astrocyte triggered by neuronal hyperactivity, a prominent acidic shift appeared in response to intensified seizure which developed with kindling. The acidic shift was unexpected as transient increase in local brain blood volume was observed in response to intensified seizures, which should lead to efficient extrusion of the acidic CO2. The acidic shift could be a result of glutamate transporter activity and/or due to the increased metabolic load of astrocytes leading to increased CO2 and lactate production. This acidic shift may trigger additional gliotransmitter release from astrocytes leading to the exacerbation of epilepsy. As all cellular enzymic reactions are influenced by Ca2+ and pH, changes in these parameters could also have an impact on the neuronal circuit activity. Thus, controlling the astrocyte pH and/or Ca2+ could be a new therapeutic target for treatment of epilepsy or prevention of undesired plasticity associated with epileptogenesis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Refractory subhemispheric epilepsy has been traditionally treated by resection. The last few decades have seen the emergence of disconnective techniques, for both hemispheric and subhemispheric disease. The aim of this study was to describe the technique for a disconnective surgery for large epileptogenic lesions involving the central (perirolandic cortices), parietal, and occipital lobes. This junctional cortex within the hemisphere (in contrast to anterior and posterior quadrantotomies) presents unique challenges when contemplating a complete disconnection of the region. The surgical technique is achieved through six distinct steps: fronto-central, inferior frontoparietal, lateral temporo-occipital, medial frontal, basal temporo-occipital, and posterior parasagittal callosal disconnections. The functional neuroanatomy of each step is described, along with cadaveric dissections. The authors describe this technique and include a case description of a young girl who presented with childhood-onset intractable epilepsy associated with cognitive stagnation. The postoperative seizure outcome in this patient remains excellent at 2 years' follow-up, with gains in cognition and behavior. Excellent seizure outcomes can be achieved if the network encompassing the entire epileptogenic cortex is disconnected while ensuring preservation of fiber systems that link functionally eloquent uninvolved cortices adjacent to the central quadrant.

Aims: Epilepsy is one of the most prevalent neurological diseases. A third of patients with epilepsy remain drug-resistant. The exact aetiology of drug-resistant epilepsy (DRE) is still unknown. Neuronal tetraploidy has been associated with neuropathology. The aim of this study was to assess the presence of tetraploid neurons and astrocytes in DRE., Methods: For that purpose, cortex, hippocampus and amygdala samples were obtained from patients subjected to surgical resection of the epileptogenic zone. Post-mortem brain tissue of subjects without previous records of neurological, neurodegenerative or psychiatric diseases was used as control., Results: The percentage of tetraploid cells was measured by immunostaining of neurons (NeuN) or astrocytes (S100β) followed by flow cytometry analysis. The results were confirmed by image cytometry (ImageStream X Amnis System Cytometer) and with an alternative astrocyte biomarker (NDRG2). Statistical comparison was performed using univariate tests. A total of 22 patients and 10 controls were included. Tetraploid neurons and astrocytes were found both in healthy individuals and DRE patients in the three brain areas analysed: cortex, hippocampus and amygdala. DRE patients presented a higher number of tetraploid neurons (p = 0.020) and astrocytes (p = 0.002) in the hippocampus than controls. These results were validated by image cytometry., Conclusions: We demonstrated the presence of both tetraploid neurons and astrocytes in healthy subjects as well as increased levels of both cell populations in DRE patients. Herein, we describe for the first time the presence of tetraploid astrocytes in healthy subjects. Furthermore, these results provide new insights into epilepsy, opening new avenues for future treatment., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Aims: Focal cortical dysplasia (FCD) is a major cause of drug-resistant paediatric epilepsy and is amenable to successful neurosurgical resection. FCD ILAE Type IIb is the most common FCD subtype, and brain somatic mutations affecting the mTOR pathway play a major pathogenic role. The aim of this study was to comprehensively describe the genotype-phenotype association of 20 patients with histopathologically confirmed FCDIIb using next generation sequencing (NGS) of paired blood-brain samples., Methods: Clinical and neuropathological data were retrospectively reviewed from the hospital archive. The NGS panel included 11 mTOR-pathway-related genes with maximum coverage of 2000×. The detected variants were validated by digital droplet PCR., Results: Pathogenic MTOR variants were identified in 10 patients (50%). Further comparison with MTOR-wildtype FCDIIb suggested a profound genotype-phenotype association characterised by (1) a non-temporal lobe lesion on MRI, (2) a larger lesion volume occupying grey and white matter (3.032 ± 1.859 cm 3 vs 1.110 ± 0.856 cm 3 , p = 0.014), (3) more balloon cells (50.20 ± 14.40 BC/mm 2 vs 31.64 ± 30.56 BC/mm 2 , p = 0.099) and dysmorphic neurons (48.72 ± 19.47DN/mm 2 vs 15.28 ± 13.95DN/mm 2 , p = 0.000) and (4) a positive correlation between VAF and the lesion volume (r = 0.802, p = 0.017)., Conclusions: Our study identified frequent MTOR mutations in the cell-rich FCDIIb phenotype, clinically characterised by a non-temporal location and large lesion volume. Comprehensive genotype-phenotype associations will help us further explore and define the broad spectrum of FCD lesions to make more targeted therapies available in the realm of epileptology., (© 2022 British Neuropathological Society.)

Aims: We aimed to identify predictors of postoperative seizures in patients with diffuse low-grade glioma (DLGG)-related epilepsy after complete tumor resection in this study., Methods: We retrospectively collected data from individuals with DLGG-related epilepsy whose tumors were completely resected at Xiangya Hospital, Central South University between January 2014 and January 2020. The predictors of seizure outcomes were assessed by employing univariate analysis and a multivariate logistic regression model in a backward binary logistic regression model., Results: Among the 118 cases that met the inclusion criteria, 83.05% were seizure-free following an average follow-up of 4.27 ± 1.65 years, all of whom were classified as International League Against Epilepsy class I outcome. Univariate and multivariate analyses indicated that seizure duration of >6 years (odds ratio [OR], 6.62; 95% confidence interval [CI], 1.76-24.98; p = 0.005) and first clinical symptoms other than seizures (OR, 4.51; 95% CI, 1.43-14.23; p = 1.010) were both independent predictors of unfavorable seizure outcomes., Conclusion: Our results imply that satisfactory seizure outcomes can be achieved in most patients with DLGG-related epilepsy after complete tumor resection. Patients with seizure duration of >6 years or first clinical symptoms other than seizures were more likely to experience postoperative seizure recurrence., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: Our objective was to study the relationship between epilepsy and autoimmune diseases in two different types of epilepsy: idiopathic generalized epilepsies (IGEs) and mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). The contribution of the human leukocyte antigen (HLA) system to this relationship was analyzed., Methods: Adult patients with IGEs and MTLE-HS at a tertiary epilepsy center were consecutively enrolled between January 2016 and December 2020., Results: A total of 664 patients, 422 with IGEs and 242 with MTLE-HS, were included. Patients with IGEs were 15 years younger, on average, than patients with MTLE-HS (p < .001). The frequency of autoimmune diseases was 5.5% (n = 23) and 4.5% (n = 11) in patients with IGEs and MTLE-HS, respectively (p = .716). The mean age of autoimmune disease onset was 20 ± 15.6 years in patients with IGEs and 36.7 ± 16.5 years in patients with MTLE-HS (p < .05). Clinical manifestations of autoimmune diseases preceded epilepsy onset in 30.4% of patients with IGEs (i.e., in early childhood); in the other patients, epilepsy appeared before autoimmune disease onset. In all but one patient with MTLE-HS and autoimmune diseases, the autoimmune diseases appeared after epilepsy onset from adolescence onward., Significance: Our study indicates two relationship patterns: a bidirectional association between IGEs and autoimmune diseases and a unidirectional relationship between MTLE-HS and autoimmune diseases. The involvement of genetic susceptibility factors (such as the HLA system), autoinflammatory mechanisms, female sex, and antiseizure medications in these relationships are discussed., (© 2023 International League Against Epilepsy.)

Background: Hippocampal damage caused by status epilepticus (SE) can bring about cognitive decline and emotional disorders, which are common clinical comorbidities in patients with epilepsy. It is therefore imperative to develop a novel therapeutic strategy for protecting hippocampal damage after SE. Mitochondrial dysfunction is one of contributing factors in epilepsy. Given the therapeutic benefits of mitochondrial replenishment by exogenous mitochondria, we hypothesized that transplantation of mitochondria would be capable of ameliorating hippocampal damage following SE., Methods: Pilocarpine was used to induced SE in mice. SE-generated cognitive decline and emotional disorders were determined using novel object recognition, the tail suspension test, and the open field test. SE-induced hippocampal pathology was assessed by quantifying loss of neurons and activation of microglia and astrocytes. The metabolites underlying mitochondrial transplantation were determined using metabonomics., Results: The results showed that peripheral administration of isolated mitochondria could improve cognitive deficits and depressive and anxiety-like behaviors. Exogenous mitochondria blunted the production of reactive oxygen species, proliferation of microglia and astrocytes, and loss of neurons in the hippocampus. The metabonomic profiles showed that mitochondrial transplantation altered multiple metabolic pathways such as sphingolipid signaling pathway and carbon metabolism. Among potential affected metabolites, mitochondrial transplantation decreased levels of sphingolipid (d18:1/18:0) and methylmalonic acid, and elevated levels of D-fructose-1,6-bisphosphate., Conclusion: To the best of our knowledge, these findings provide the first direct experimental evidence that artificial mitochondrial transplantation is capable of ameliorating hippocampal damage following SE. These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy-associated psychiatric and cognitive disorders., (© 2023 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Temporal lobe epilepsy (TLE) is one of the most common subtypes of focal epilepsy, with mesial temporal sclerosis (MTS) being a common radiological and histopathological finding. Accurate identification of MTS during presurgical evaluation confers an increased chance of good surgical outcome. Here we propose the use of glutamate-weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) at 7 Tesla for mapping hippocampal glutamate distribution in epilepsy, allowing to differentiate lesional from non-lesional mesial TLE. We demonstrate that a directional asymmetry index, which quantifies the relative difference between GluCEST contrast in hippocampi ipsilateral and contralateral to the seizure onset zone, can differentiate between sclerotic and non-sclerotic hippocampi, even in instances where traditional presurgical MRI assessments did not provide evidence of sclerosis. Overall, our results suggest that hippocampal glutamate mapping through GluCEST imaging is a valuable addition to the presurgical epilepsy evaluation toolbox., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objectives: Cerebral hyaline protoplasmic astrocytopathy (HPA) is a clinicopathologic entity characterized by eosinophilic cytoplasmic inclusions within astrocytes. It has been observed in a subset of patients with early-onset epilepsy, brain malformations, and developmental delay. The exact association of this entity with epilepsy is still unknown. This report, with its review of the literature, aims to summarize HPA features to raise awareness regarding this entity., Methods: We report on 2 HPA cases and critically review the literature., Results: Approximately 42 cases of HPA have been reported, including the 2 cases presented here, consisting of 23 female and 19 male patients. Patient age ranged from 3 to 39 years. All patients had early-onset seizures (3-20 months of age), ranging from partial to generalized, that were refractory despite treatment with antiepileptic drugs. Postoperative follow-up intervals ranged from 2 to 93 months, and the clinical outcome was graded according to the Engel classification, showing variable results., Conclusions: Clinicians should consider HPA in differential diagnosis in patients with intractable seizures, especially when they are associated with developmental delay and brain malformations. Increasing awareness of this entity among pathologists may promote better understanding of this condition as well as better diagnosis and treatment for these patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Malformations of cortical development represent a major cause of epilepsy in childhood. However, the pathological substrate and dynamic changes leading to the development and progression of epilepsy remain unclear. Here, we characterized an etiology-relevant rat model of subcortical band heterotopia (SBH), a diffuse type of cortical malformation associated with drug-resistant seizures in humans. We used longitudinal electrographic recordings to monitor the age-dependent evolution of epileptiform discharges during the course of epileptogenesis in this model. We found both quantitative and qualitative age-related changes in seizures properties and patterns, accompanying a gradual progression towards a fully developed seizure pattern seen in adulthood. We also dissected the relative contribution of the band heterotopia and the overlying cortex to the development and age-dependent progression of epilepsy using timed and spatially targeted manipulation of neuronal excitability. We found that an early suppression of neuronal excitability in SBH slows down epileptogenesis in juvenile rats, whereas epileptogenesis is paradoxically exacerbated when excitability is suppressed in the overlying cortex. However, in rats with active epilepsy, similar manipulations of excitability have no effect on chronic spontaneous seizures. Together, our data support the notion that complex developmental alterations occurring in both the SBH and the overlying cortex concur to creating pathogenic circuits prone to generate seizures. Our study also suggests that early and targeted interventions could potentially influence the course of these altered developmental trajectories, and favorably modify epileptogenesis in malformations of cortical development., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The piriform cortex (PC) is part of the olfactory system, principally receiving input from the lateral olfactory tract and projecting to downstream components of the olfactory network, including the amygdala. Based on preclinical studies, PC is vulnerable to injury and can be easily kindled as an onset site for seizures. While the role of PC in human epilepsy has been studied indirectly and the subject of speculation, cases of demonstrated PC seizure onset from direct intracranial recording are rare. We present a pediatric patient with drug-resistant focal reflex epilepsy and right mesial temporal sclerosis with habitual seizures triggered by coconut aroma. The patient underwent stereoelectroencephalography with implantation of olfactory cortices including PC, through which we identified PC seizure onset, mapped high-frequency activity associated with presentation of olfactory stimuli and performance on cognitive tasks, and reproduced habitual seizures via cortical stimulation of PC. Coconut odor did not trigger seizures in our work with the patient. Surgical workup resulted in resection of the patient's right amygdala, PC, and mesial temporal pole, following which she has been seizure free for 20 months without functional decline in cognition or smell. Histological findings from resected tissue showed astrogliosis and subpial gliosis.

Somatic variants are a major cause of human disease, including neurological disorders like focal epilepsies, but can be challenging to study due to their mosaicism in bulk tissue biopsies. Coupling single-cell genotype and transcriptomic data has potential to provide insight into the role somatic variants play in disease etiology, such as by determining what cell types are affected or how the mutations affect gene expression. Here, we asked whether commonly used single-nucleus 3'- or 5'-RNA-sequencing assays can be used to derive single-nucleus genotype data for a priori known variants that are located near to either end of a transcript. To that end, we compared performance of commercially available single-nuclei 3'- and 5'- gene expression kits using resected brain samples from three pediatric patients with focal epilepsy. We quantified the ability to detect genetic variants in single-nucleus datasets depending on distance from the transcript end. Finally, we demonstrated the ability to identify affected cell types in a patient with a RHEB somatic variant causing an epilepsy-associated cortical malformation. Our results demonstrate that single-nuclei 3' or 5'-RNA-sequencing data can be used to identify known somatic variants in single-nuclei when they are expressed within proximity to a transcript end., (© 2023. The Author(s).)

Fetal alcohol spectrum disorders (FASD) are spectrum of neurodevelopmental conditions associated with prenatal alcohol exposure. The FASD manifests mostly with facial dysmorphism, prenatal and postnatal growth retardation, and selected birth defects (including central nervous system defects). Unrecognized and untreated FASD leads to severe disability in adulthood. The diagnosis of FASD is based on clinical criteria and neither biomarkers nor imaging tests can be used in order to confirm the diagnosis. The quantitative electroencephalography (QEEG) is a type of EEG analysis, which involves the use of mathematical algorithms, and which has brought new possibilities of EEG signal evaluation, among the other things-the analysis of a specific frequency band. The main objective of this study was to identify characteristic patterns in QEEG among individuals affected with FASD. This study was of a pilot prospective study character with experimental group consisting of patients with newly diagnosed FASD and of the control group consisting of children with gastroenterological issues. The EEG recordings of both groups were obtained, than analyzed using a commercial QEEG module. As a results we were able to establish the dominance of the alpha rhythm over the beta rhythm in FASD-participants compared to those from the control group, mostly in frontal and temporal regions. Second important finding is an increased theta/beta ratio among patients with FASD. These findings are consistent with the current knowledge on the pathological processes resulting from the prenatal alcohol exposure. The obtained results and conclusions were promising, however, further research is necessary (and planned) in order to validate the use of QEEG tools in FASD diagnostics., (© 2023. The Author(s).)

Objective: This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics., Methods: Frozen brain tissue (ages = 2-19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p < .05) and label-free quantitative mass spectrometry (false discovery rate < 5%) in the three groups., Results: WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA-DRB1, HLA-DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10 -6 , z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10 -13 , z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10 -13 , z = 5.61). Proteomics detected fewer altered targets., Significance: In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow-up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression., (© 2022 International League Against Epilepsy.)

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

Background: Tuberous sclerosis complex (TSC) patients may have different specific neuropsychological deficits related to the location of the tubers. Autism spectrum disorders (ASD) are common in TSC patients but the relationship between these diagnoses has not been formally explored. In this study we sought to examine brain Magnetic Resonance Imaging (MRI) findings in TSC patients with ASD., Methods: We evaluated 34 TSC patients on the basis of DSM-V diagnostic criteria for ASD, Wechsler Intelligence Scale for Children (WISC-R), psychiatrist's examination and also structured parent interviews. The number and localization of the tubers, postcontrast signal characteristics of the tubers, SWI findings, DWI findings on brain MRI were recorded. Demographic features, epilepsy histories, number of antiseizure medications, cognitive status were eveluated also. Patients were divided into two groups: ASD group, which represented group 1 and group 2 consisting of patients without any ASD symptoms., Results: In our study, the mean number of tuber count was 21.8 in patients with ASD patients (Group 1, n = 13) and 12.4 in other TSC patients without ASD (Group 2, n = 21). Rate of tubers in prefrontal cortex/whole tubers (0.51) in patients with ASD was determined to be higher in group 1 (p = 0.003). Also a significant difference was detected between generalize epileptiform activities on EEG and the rate of DRE (p = 0.002; p = 0.001) between groups. Cognitive disturbances and infantile spasm history were similar between groups. TSC2 mutations have been identified in 29 (86%) patients., Conclusion: The mean of total tuber count and the rate of the location in the prefrontal cortex were determined to be higher in TSC patients with ASD. Specific areas on brain MRI may help understanding the development of ASD in TSC patients., Competing Interests: Conflicts of interest There is no any conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Temporal lobe epilepsy is the fourth most common neurological disorder, with about 40% of patients not responding to pharmacological treatment. Increased cellular loss is linked to disease severity and pathological phenotypes such as heightened seizure propensity. While the hippocampus is the target of therapeutic interventions, the impact of the disease at the cellular level remains unclear. Here, we show that hippocampal granule cells change with disease progression as measured in living, resected hippocampal tissue excised from patients with epilepsy. We show that granule cells increase excitability and shorten response latency while also enlarging in cellular volume and spine density. Single-nucleus RNA sequencing combined with simulations ascribes the changes to three conductances: BK, Cav2.2, and Kir2.1. In a network model, we show that these changes related to disease progression bring the circuit into a more excitable state, while reversing them produces a less excitable, "early-disease-like" state., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Low-grade neuroepithelial tumors (LNETs) represent an important group of central nervous system neoplasms, some of which may be associated to epilepsy. The concept of long-term epilepsy-associated tumors (LEATs) includes a heterogenous group of low-grade, cortically based tumors, associated to drug-resistant epilepsy, often requiring surgical treatment. LEATs entities can sometimes be poorly discriminated by histological features, precluding a confident classification in the absence of additional diagnostic tools. This study aimed to provide an updated review on the genomic findings and DNA methylation profiling advances in LNETs, including histological entities of LEATs. A comprehensive search strategy was conducted on PubMed, Embase, and Web of Science Core Collection. High-quality peer-reviewed original manuscripts and review articles with full-text in English, published between 2003 and 2022, were included. Results were screened based on titles and abstracts to determine suitability for inclusion, and when addressed the topic of the review was screened by full-text reading. Data extraction was performed through a qualitative content analysis approach. Most LNETs appear to be driven mainly by a single genomic abnormality and respective affected signaling pathway, including BRAF p.V600E mutations in ganglioglioma, FGFR1 abnormalities in dysembryoplastic neuroepithelial tumor, MYB alterations in angiocentric glioma, BRAF fusions in pilocytic astrocytoma, PRKCA fusions in papillary glioneuronal tumor, between others. However, these molecular alterations are not exclusive, with some overlap amongst different tumor histologies. Also, clustering analysis of DNA methylation profiles allowed the identification of biologically similar molecular groups that sometimes transcend conventional histopathological classification. The exciting developments on the molecular basis of these tumors reinforce the importance of an integrative histopathological and (epi)genetic classification, which can be translated into precision medicine approaches., (© 2022 Japanese Society of Neuropathology.)

Introduction and Objective: Epilepsy is one of the most common brain diseases during childhood and adolescence. Atrophy in different brain areas is possible during epilepsy. This study aimed to verify whether cerebellar volume differences could be detected by volume analysis using magnetic resonance imaging (MRI) in children with epilepsy., Method: In this retrospective study, 41 children (3.1-18.8 years) with epilepsy of unknown etiology were included (duration of epilepsy 1.9 ± 3 years). A cranial MRI with a volumetric 3-dimensional, T 1 -weighted sequence was used for volume analysis. The MRIs of 26 patients with headache (5.3-17.1 years) were analyzed for comparison. A volume analysis of the cerebellum was performed using region-based morphometry. Total cerebellar volume, total white and gray matter volume, and 48 regional lobules (L), separated into white and gray matter, were calculated. Cerebellar volumes are presented in relative ratios as the volume fraction of cerebellar volume to total intracranial volume: CV/TIV., Results: The ratio of overall white matter volume was significantly lower in the case group (23.93 × 10 -3 , P  = .039). A significantly lower ratio of regional white matter volume was detected in LV right ( P  = .031) and left ( P  = .014), in LVIIIB right ( P  = .011) and left ( P  = .019), and in LVIIIA left ( P  = .009)., Conclusion: Our results emphasize that volume analysis of the total cerebellar volume alone is insufficient to characterize cerebellar differences in children with epilepsy. Rather, in specific cerebellar region volume analysis using region-based morphometry, children with epilepsy showed significantly lower regional volumes of lobules, which are important for sensorimotor function (LV, LVIII) and higher cognitive function (crus I).

Objetive: Analyze pre-surgical evaluation modalities, surgical failures, long-term results of surgery and neurocognitive outcome in children with Low-grade Epilepsy Associated brain Tumors (LEAT)., Methods: Retrospective observational study of 37 children who underwent epilepsy surgery, with a minimum follow-up of 12 months. At time of surgery, pharmaco-sensitivity (Group 1; n = 8) and drug-resistance (Group 2; n = 29), were considered., Results: Age range of seizure onset was 5 months-14 years (mean 5.73years) and age at surgery was 2.2-18.7years (mean 10.7years). Gangliogliomas (35.1%) or DNTs (29.7%), combined or not to a focal cortical dysplasia (FCD), were the most frequent. Extended lesionectomy 16 children (43.2%) were the most frequently used surgical approach in both groups. At one year of follow-up, 36 children (97.2%) were classified as Engel I. Within the age-range studied, duration of epilepsy and time to surgery appeared to have no impact on clinical and neurocognitive outcome in both groups. It is noteworthy, however, that antiseizure medications (ASMs) were withdrawn in 100% of the pharmacosensitive group vs 34.5% of the drug-resistant group (p = 0.002). In children with a pharmaco-sensitive epilepsy, neurocognitive evaluation showed significant improvement in the verbal comprehension index (p = 0.029)., Conclusions: Epilepsy-surgery is a safe therapeutic option for LEATs including for children with seizures controlled by ASMs. Presence of associated lesions is not rare. Comprehensive pre-surgical evaluation increases the chances for control of the seizures, the early discontinuation of medications and favours neurocognitive development., 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., (© 2022 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Purpose: Self-limited epilepsy with centrotemporal spikes (SLECTS) is a pediatric benign epilepsy but often accompanied by subsequent (in adulthood) functional changes such as language, which are thought to have distinct areas of hemispheric lateralization and functional differentiation. This study aimed to explore hemispheric specialization measured by resting-state functional magnetic resonance imaging (rs-fMRI) functional connectivity in drug-naïve and drug-receiving SLECTS., Methods: Hemispheric specialization was quantified in three groups of children, including 21 drug-naïve patients (DNP) with SLECTS, 34 drug-receiving patients (DRP) with SLECTS and 36 demographically matched typical development (TD)., Results: Compared with the TD group, both the DNP and DRP groups exhibited significantly higher specialization in the left superior temporal gyrus, right parahippocampus, left putamen, and right caudate. The DNP group exhibited significantly higher hemispheric specialization in the right precentral gyrus and right inferior temporal gyrus, while the DRP group demonstrated significantly higher hemispheric specialization in the left postcentral gyrus and right hippocampus than the TD group. Furthermore, bilateral cerebellum&#95;6 showed opposing hemispheric specialization trends in the two patient groups. Further meta-analytical mapping demonstrated that hemispheric specialization-related differential brain regions are primarily involved in language processing., Conclusion: Our findings showed that children with SLECTS had altered hemispheric specialization, mainly in language processing regions, suggesting both abnormal intrahemispheric segregation and interhemispheric integration in these children., 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 © 2022 Elsevier Inc. All rights reserved.)