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Background: We previously reported that increasing severity of watershed (WS) injury in neonatal magnetic resonance imaging (MRI) is associated with worse language outcomes in early childhood. In the present study, we investigated the relationship between neonatal injury patterns and cognitive profile in adolescents with neonatal encephalopathy., Methods: Term neonates with encephalopathy were prospectively enrolled and imaged using brain MRI from 1999 to 2008. Neonatal brain injury was scored according to the degree of injury in WS and basal ganglia/thalamus (BG/T) areas. The children underwent a neurocognitive assessment and follow-up brain MRI at the age of 10-16 years. The relationship between neonatal brain injury patterns and adolescent cognitive outcomes was assessed., Results: In a cohort of 16 children, neonatal MRI showed WS injury in 7, BG/T injury in 2, and normal imaging in 7. Children with WS injury had lower estimated overall cognitive ability than those with normal imaging. Increasing WS injury score was associated with decreasing estimated overall cognitive ability, Perceptual Reasoning Index, and digit span score., Conclusions: Children with the WS injury are at an increased risk of having problems in long-term intellectual ability. These cognitive outcomes may underlie early language difficulties seen in children with neonatal WS injury., Impact: Adolescents with a history of neonatal encephalopathy and watershed pattern of injury on neonatal brain magnetic resonance imaging (MRI) had lower overall cognitive ability, perceptual reasoning skills, and auditory working memory than those with normal neonatal imaging. Children with post-neonatal epilepsy and cerebral palsy had the worst cognitive outcomes. Watershed pattern of injury confers high long-term differences in intellectual ability., (© 2021. The Author(s).)

Objective: Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified., Methods: We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high-depth targeted DNA sequencing., Results: We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (SLC35A2) and mechanistic target of rapamycin kinase (MTOR) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen-activated protein kinase (MAPK) pathway genes (i.e., fibroblast growth factor receptor 1 [FGFR1], FGFR2, B-raf proto-oncogene, serine/threonine kinase [BRAF], and KRAS proto-oncogene, GTPase [KRAS]) was associated with low-grade epilepsy-associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes not yet associated with focal cortical dysplasia., Significance: These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes., (© 2022 International League Against Epilepsy.)

Background and Purpose: The aim of this study was to investigate the relevance of compartmentalized grey matter (GM) pathology and network reorganization in multiple sclerosis (MS) patients with concomitant epilepsy., Methods: From 3-T magnetic resonance imaging scans of 30 MS patients with epilepsy (MSE group; age 41 ± 15 years, 21 females, disease duration 8 ± 6 years, median Expanded Disability Status Scale [EDSS] score 3), 60 MS patients without epilepsy (MS group; age 41 ± 12 years, 35 females, disease duration 6 ± 4 years, EDSS score 2), and 60 healthy subjects (HS group; age 40 ± 13 years, 27 females) the regional volumes of GM lesions and of cortical, subcortical and hippocampal structures were quantified. Network topology and vulnerability were modelled within the graph theoretical framework. Receiver-operating characteristic (ROC) curve analysis was applied to assess the accuracy of GM pathology measures to discriminate between MSE and MS patients., Results: Higher lesion volumes within the hippocampus, mesiotemporal cortex and amygdala were detected in the MSE compared to the MS group (all p < 0.05). The MSE group had lower cortical volumes mainly in temporal and parietal areas compared to the MS and HS groups (all p < 0.05). Lower hippocampal tail and presubiculum volumes were identified in both the MSE and MS groups compared to the HS group (all p < 0.05). Network topology in the MSE group was characterized by higher transitivity and assortativity, and higher vulnerability compared to the MS and HS groups (all p < 0.05). Hippocampal lesion volume yielded the highest accuracy (area under the ROC curve 0.80 [0.67-0.91]) in discriminating between MSE and MS patients., Conclusions: High lesion load, altered integrity of mesiotemporal GM structures, and network reorganization are associated with a greater propensity for epilepsy occurrence in people with MS., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico-pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular-genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro-clinical-imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico-pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and "no definite FCD on histopathology" as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi-layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Pathology in the dentate gyrus, including sclerosis, is a hallmark of temporal lobe epilepsy, and reduced inhibition to dentate granule cells may contribute to epileptogenesis. The perisomatic-targeting axonal boutons of parvalbumin-expressing interneurons decrease in proportion with granule cells in temporal lobe epilepsy. In contrast, dendrite-targeting axonal boutons of somatostatin-expressing interneurons sprout exuberantly in temporal lobe epilepsy. A third major class of GABAergic interneurons expresses cannabinoid receptor type 1 (CB1) on their terminal boutons, but there is conflicting evidence as to whether these boutons are increased or decreased in temporal lobe epilepsy. Naturally occurring temporal lobe epilepsy in California sea lions, with unilateral or bilateral sclerosis, offers the benefit of neuroanatomy and neuropathology akin to humans, but with the advantage that the entirety of both hippocampi from control and epileptic brains can be studied. Stereological quantification in the dentate gyrus revealed that sclerotic hippocampi from epileptic sea lions had fewer CB1-labeled boutons than controls. However, the reduction in the number of granule cells was greater, resulting in increased CB1-labeled boutons per granule cell in sclerotic hippocampi at temporal levels. This suggests that although CB1-expressing boutons are decreased in sclerotic dentate gyri, surviving cells have enhanced innervation from these boutons in epileptic sea lions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pentylenetetrazole (PTZ)-induced kindling is an animal model for studying human temporal lobe epilepsy (TLE), which is characterized by alterations of hippocampal neurons and memory. Although the intranasal (IN) administration of oxytocin (OT) has limited efficiency, nanoparticles (NPs) are a promising candidate to deliver OT to the brain. However, there are very limited data on epilepsy research about oxytocin-loaded nanoparticles (NP-OTs). The aim of this study is to investigate the effects of IN administration of chronic NP-OTs on the hippocampus of PTZ-induced male epileptic rats in terms of seizure severity, memory, neurogenesis, and neuronal damage. Saline/OT/NP-OTs were administrated to both control (Ctrl) and PTZ groups intranasally. Consequently, saline and PTZ were injected, respectively, 25 times every 48 h. Then, seizure severity (score and latency) was calculated for the PTZ groups. A spatial working memory evaluation test (SWMET) was performed after the last injection. Hippocampus histopathology, neurogenesis, and apoptosis were demonstrated. Serum total antioxidant status (TAS) and total oxidant status (TOS) levels and the oxidative stress index (OSI) were measured. We showed that OTs and NP-OTs prevented the kindling development and had positive effects on seizure severity. SWMET-related behaviors were also recovered in the PTZ + NP-OT group. A significant increase of neurogenesis and decrease of apoptosis in the hippocampus of the PTZ + NP-OT group were observed, while OTs and NP-OTs had protective effects against PTZ-induced damage to hippocampal neurons. Our results indicate that the chronic administration of NP-OTs may have positive effects on hippocampal damage via increasing neurogenesis and decreasing apoptosis and seizure severity.

Thioredoxin, encoded by Txn1, is a critical antioxidant that protects against oxidative damage by regulating the dithiol/disulfide balance of interacting proteins. We recently discovered the Adem rat, an epileptic rat harboring the Txn1-F54L mutation, characterized by wild running and vacuolar degeneration in the midbrain. This study aimed to characterize the classification of epilepsy in Adem rats. We performed simultaneous video-electroencephalographic recordings, magnetic resonance imaging, neurotransmitter measurements using gas chromatography-mass spectrometry (GC-MS), and immunohistochemistry. Adem rats exhibited absence, tonic, and focal seizures. The type of epilepsy was classified as combined generalized and focal epilepsy. Neurotransmitters in the midbrain and cortex were measured at 3 weeks of age, when neuronal cell death occurs in the midbrain. The results of GC-MS ruled out the dominance of the excitatory system in the midbrain and cortex of Adem rats. Activation of astrocytes and microglia was more pronounced at 5 weeks of age, at which time epileptic seizures occurred frequently. The underlying pathology in Adem rats remains unknown. However, glial cell activation and inflammation may play a significant role in the occurrence of epilepsy., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

GNAO1 encephalopathy is an orphan genetic disease associated with early infantile epilepsy, impaired motor control, and severe developmental delay. The disorder is caused by mutations in the GNAO1 gene, leading to dysfunction of the encoded protein Gao1. There is no cure for this disease, and symptomatic therapy is ineffective. Phenotypic heterogeneity highlights the need for a personalized approach for treating patients with a specific clinical variant of GNAO1 and requires the study of the disease mechanism in animal and cell models. Towards this aim, we developed an approach for modeling GNAO1 encephalopathy and testing gene therapy drugs in primary neurons derived from healthy mice. We optimized the delivery of transgenes to Gαo1-expressing neurons using recombinant adeno-associated viruses (rAAV). We assessed the tropism of five neurotropic AAV serotypes (1, 2, 6, 9, DJ) for Gαo1-positive neurons from the whole mouse brain. The DJ serotype showed the highest potential as a reporter delivery vehicle, infecting up to 66% of Gαo1-expressing cells without overt cytotoxicity. We demonstrated that AAV-DJ also provides efficient delivery and expression of genetic constructs encoding normal and mutant Gαo1, as well as short hairpin RNA (shRNA) to suppress endogenous Gnao1 in murine neurons. Our results will further simplify the study of the pathological mechanism for clinical variants of GNAO1, as well as optimize the testing of gene therapy approaches for GNAO1 encephalopathy in cell models.

Epilepsy is one of the most common serious brain disorders, affecting about 1% of the population all over the world. Ginkgo biloba extract (GbE) and L-carnitine (LC) reportedly possess the antioxidative activity and neuroprotective potential. In this report, we investigated the possible protective and therapeutic effects of GbE and LC against pentylenetetrazol (PTZ)-induced epileptic seizures in rat hippocampus and hypothalamus. Adult male albino rats were equally divided into eight groups: control, GbE (100 mg/kg), LC (300 mg/kg), PTZ (40 mg/kg), protective groups (GbE + PTZ and LC + PTZ), and therapeutic groups (PTZ + GbE and PTZ + LC). The oxidative stress, antioxidant, and neurochemical parameters, viz., malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), acetylcholine esterase (AchE), dopamine (DA), norepinephrine (NE), and serotonin (5-HT), in the hippocampal and hypothalamic regions have been evaluated. PTZ injection leads to an increase in the seizure score, the levels of MDA and NO, and to a decrease in the activity of GSH, SOD, CAT, and GPx. Besides, monoamine neurotransmitters, DA, NE, and 5-HT, were depleted in PTZ-kindled rats. Furthermore, PTZ administration caused a significant elevation in the activity of AchE. Hippocampal and hypothalamic sections from PTZ-treated animals were characterized by severe histopathological alterations and, intensely, increased the ezrin immunolabeled astrocytes. Pre- and post-treatment of PTZ rats with GbE and LC suppressed the kindling acquisition process and remarkably alleviated all the aforementioned PTZ-induced effects. GbE and LC have potent protective and therapeutic effects against PTZ-induced kindling seizures via the amelioration of oxidative/antioxidative imbalance, neuromodulatory, and antiepileptic actions., (© 2022. The Author(s).)

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chronic subconvulsive activity in early life leads to sex-related autistic-like deficits in handling, object recognition, and social performance in pre-pubertal rats. Since autism and epilepsy are common neurodevelopmental disorders with high coincidence, we tested whether early-life chronic subconvulsive activity compared to convulsive activity alters handling, spatial memory, lateralization, coping strategy and the seizure threshold in a sex-dependent manner. A hypothesis is that convulsive seizures may alter sex differences induced by subconvulsive (SC) activity. Serial subconvulsive doses of kainic acid (KA) were administered postnatally (0.25-1 mg/kg) for 15 days to induce the chronic subconvulsive phenotype (SC group). Age-matched controls and a subset of SC pups were exposed to a convulsive dose of KA (KA and SC + KA groups; 7.5 mg/kg) or flurothyl vapors. In our open handling test, controls and the ASD groups escaped to a similar degree whereas after convulsive seizures, the pups exhibited freezing behavior; no escapes occurred. In the spontaneous alternating T-Maze control males and females entered the left arm with higher frequency. The SC males but not SC females entered left and right arms to a similar degree; alternation rates were reduced to chance revealing a sex difference. However, in KA and SC + KA groups, there was a sharp loss of spontaneous alternation rates. The rapid repetitive entries shifted to the right in both sexes possibly be due to hippocampal injury and changes in network activity induced by status epilepticus. In the forced swim test (FST), control and CS females were more active than corresponding males. After convulsions, immobility was reduced and vertical mobility was increased in SC and SC + KA males suggesting an elevated coping strategy compared to females. Onset and severity of KA induced status epilepticus was delayed in SC males and females possibly due to desensitization of KA receptors. Following flurothyl exposure, control males had faster onset of twitches and clonic seizures than control females which disappeared after the sub-convulsive pre-treatment. Data suggest that behavioral manifestations are more readily detectable between males and females when low levels of hyperexcitation are present chronically in early postnatal development but diminished after tonic-clonic convulsions persist. Therefore, therapeutic interventions may benefit patients if initiated upon the initial onset of sex-related autistic pathologies, particularly in males, which may reduce subsequent vulnerability to seizures., (Copyright © 2022. Published by Elsevier B.V.)

Histone deacetylases (HDACs) have been described to have both neurotoxic and neuroprotective roles, and partly, depend on its sub-cellular distribution. HDAC inhibitors have a long history of use in the treatment of various neurological disorders including epilepsy. Key role of HDACs in GABAergic neurotransmission, synaptogenesis, synaptic plasticity and memory formation was demonstrated whereas very less is known about their role in drug-resistant epilepsy pathologies. The present study was aimed to investigate the changes in the expression of HDACs, activity and its sub-cellular distribution in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. For this study, surgically resected hippocampal tissue specimens of 28 MTLE-HS patients and 20 hippocampus from post-mortem cases were obtained. Real-time PCR was done to analyse the mRNA expression. HDAC activity and the protein levels of HDACs in cytoplasm as well as nucleus were measured spectrophotometrically. Further, sub-cellular localization of HDACs was characterized by immunofluorescence. Significant upregulation of HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC10 and HDAC11 mRNA were observed in MTLE-HS. Alterations in the mRNA expression of glutamate and gamma-aminobutyric acid (GABA) receptor subunits have been also demonstrated. We observed significant increase of HDAC activity and nuclear level of HDAC1, HDAC2, HDAC5 and HDAC11 in the hippocampal samples obtained from patients with MTLE-HS. Moreover, we found altered cytoplasmic level of HDAC4, HDAC6 and HDAC10 in the hippocampal sample obtained from patients with MTLE-HS. Alterations in the level of HDACs could potentially be part of a dynamic transcription regulation associated with MTLE-HS. Changes in cytoplasmic level of HDAC4, 6 and 10 suggest that cytoplasmic substrates may play a crucial role in the pathophysiology of MTLE-HS. Knowledge regarding expression pattern and sub-cellular distribution of HDACs may help to devise specific HDACi therapy for epilepsy., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: Loss-of-function KCNMA1 variants cause Liang-Wang syndrome (MIM #618729), a newly identified multiple malformation syndrome with a broad spectrum of developmental and neurological phenotypes. However, the full spectrum of clinical features and underlying pathogenic mechanisms need full elucidation., Methods: Exome sequencing was used to identify pathogenic variants. Patch-clamp recordings were performed to access the effects of KCNMA1 variants on BK channels. Total and membrane protein expression levels of BK channels were characterized using Western blotting., Results: We report identification and functional characterization of two new de novo loss-of-function KCNMA1 variants p.(A172T) and p.(A314T) with characteristics of Liang-Wang syndrome. Variant p.(A172T) is associated with developmental delay, cognitive impairment and ataxia. Mechanistically, p.(A172T) abolishes BK potassium current, inhibits Mg 2+ -dependent gating, but shifts conductance-voltage (G-V) curves to more positive potentials when complexed with WT channels. Variant p.(A314T) is associated with developmental delay, intellectual disability, cognitive impairment, mild ataxia and generalized epilepsy; suppresses BK current amplitude; and shifts G-V curves to more positive potentials when expressed with WT channels. In addition, two new patients with previously reported gain-of-function variants p.(N536H) and p.(N995S) are found to show epilepsy and paroxysmal dyskinesia as reported previously, but also exhibit additional symptoms of cognitive impairment and dysmorphic features. Furthermore, variants p.(A314T) and p.(N536H) reduced total and membrane levels of BK proteins., Conclusion: Our findings identified two new loss-of-function mutations of KCNMA1 associated with Liang-Wang syndrome, expanded the spectrum of clinical features associated with gain-of-function KCNMA1 variants and emphasized the overlapping features shared by gain-of-function and loss-of-function mutations., (© 2022 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Objective: Although previous imaging studies have reported cerebellar gray matter loss in patients with familial cortical myoclonic tremor with epilepsy (FCMTE), the corresponding white matter alterations remain unknown. We investigated white matter structural changes in FCMTE1 and compared them with clinical and electrophysiological features., Methods: We enrolled 36 patients carrying heterozygous pathogenic intronic pentanucleotide insertions in the SAMD12 gene and 52 age- and sex-matched healthy controls. Diffusion tensor imaging-derived metrics, including fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were calculated along with white matter voxel-based morphometry (VBM) analysis. We also examined correlations between magnetic resonance metrics and clinical and electrophysiological features., Results: We detected widespread white matter reductions in MD, RD, and AD values in FCMTE1 patients, including in the commissural, projection, and association fibers. VBM analysis revealed that increases in white matter volume predominantly occurred in the right cerebellum and sagittal stratum. MD, RD, AD, and VBM analysis clearly indicated changes in the sagittal stratum. We found a positive correlation between VBM values in the right cerebellum and somatosensory-evoked potential P25-N33 amplitude. Decreased MD and AD values in the right sagittal stratum were detected in patients with versus without photophobia., Significance: FCMTE is a network disorder involving a wide range of cortical and subcortical structures, including the cerebellum, thalamus, thalamocortical connections, and corticocortical connections. The right sagittal stratum is closely related with visual symptoms, especially photophobia. Our findings indicate that cerebellum and cortical hyperexcitability are closely linked, and emphasize the important role of the cerebellum in the pathophysiological mechanisms of cortical tremor., (© 2022 International League Against Epilepsy.)

Outcomes of treating low-grade epilepsy-associated tumors (LEATs) in the temporal lobe with MRI-guided laser interstitial thermal therapy (MRgLITT) remain poorly characterized. This study aimed to compare the safety and effectiveness of treating temporal lobe LEATs with MRgLITT versus open resection in a consecutive single-institution series. We reviewed all adult patients with epilepsy that underwent surgery for temporal lobe LEATs at our institution between 2002 and 2019, during which time we switched from open surgery to MRgLITT. Surgical outcome was categorized by Engel classification at >12mo follow-up and Kaplan-Meir analysis of seizure freedom. We recorded hospital length of stay, adverse events, and available neuropsychological results. Of 14 total patients, 7 underwent 9 open resections, 6 patients underwent MRgLITT alone, and 1 patient underwent an open resection followed by MRgLITT. Baseline group demographics differed and were notable for preoperative duration of epilepsy of 9.0 years (range 1-36) for open resection versus 14.0 years (range 2-34) for MRgLITT. Median length of stay was one day shorter for MRgLITT compared to open resection (p=<.0001). There were no major adverse events in the series, but there were fewer minor adverse events following MRgLITT. At 12mo follow-up, 50% (5/10) of patients undergoing open resection and 57% (4/7) of patients undergoing MRgLITT were free of disabling seizures (Engel I). When comparing patients who underwent similar procedures in the dominant temporal lobe, patients undergoing MRgLITT had fewer and milder material-specific neuropsychological declines than patients undergoing open resections. In this small series, MRgLITT was comparably safe and effective relative to open resection of temporal lobe LEATs., Competing Interests: Declaration of competing interests Dr. Willie has received research support from and/or has served as a paid consultant for Medtronic (consulting and research support), Neuropace (consulting and research support), ClearPoint/MRI Interventions (consulting), and AiM Medical (consulting). Dr. Gross has received research support from and/or has served as a paid consultant for Abbott (consulting and research support), Boston Scientific (consulting and research support), SanBio (consulting and research support), Voyager Therapeutics (consulting and research support), Medtronic (consulting and research support), Neuropace (consulting and research support), and Zimmer Biomet (consulting). Dr. Drane has received research support from Medtronic, Inc. The remaining authors have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Epilepsy is a common chronic neurological disorder related to genetic factors. Base on the non-integrating episomal vector technique, a human induced pluripotent stem cell (iPSC) line, termed as LZUSHI001-A, was generated from peripheral blood mononuclear cells (PBMCs) of a 11-year-old male patient with Epilepsy, who had a heterozygous (c.2042G>A, p.R681Q) mutation in the DGKG gene. LZUSHI001-A offers a useful resource to investigate pathogenic mechanisms in epilepsy, as well as a cell-based model for drug development to treat epilepsy., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Low-grade epilepsy-associated neuroepithelial tumor (LEAT) is highly responsive to surgery in general. The appropriate surgical strategy remains controversial in temporal LEAT. The aim of this study is to analyze the surgical seizure outcome of temporal LEAT, focusing on the aspects of surgical strategy., Methods: Sixty-one patients from a single epilepsy center with temporal LEAT underwent surgery. The surgical strategy was according to the multidisciplinary presurgical evaluation. Electrocorticogram (ECoG)-assisted resection was utilized. Surgical extent including lesionectomy and extended resection was described in detail. Seizure outcome was classified as satisfactory (Engel class I) and unsatisfactory (Engel classes II-IV)., Results: After a median follow-up of 36.0 (30.0) months, 83.6% of patients achieved satisfactory outcome, including 72.1% with Engel class Ia. There was 39.3% (24/61) of patients with antiepileptic drug (AED) withdrawal. Use of ECoG (χ2 = 0.000, P > 0.1), preresection spike (χ2 = 0.000, P = 0.763), or spike residue (P = 0.545) was not correlated with the seizure outcome. For lateral temporal LEAT, outcome from lesionectomy was comparable to extended resection (χ2 = 0.499, P > 0.1). For mesial temporal LEAT, 94.7% (18/19) of patients who underwent additional hippocampectomy were satisfactory, whereas only 25% (1/4) of patients who underwent lesionectomy were satisfactory (P = 0.009)., Conclusion: Surgical treatment was highly effective for temporal LEAT. ECoG may not influence the seizure outcome. For lateral temporal LEAT, lesionectomy with or without cortectomy was sufficient in most patients. For mesial temporal LEAT, extended resection was recommended., (© 2021. The Author(s).)

The identification of abnormal electrographic activity is important in a wide range of neurological disorders, including epilepsy for localizing epileptogenic tissue. However, this identification may be challenging during non-seizure (interictal) periods, especially if abnormalities are subtle compared to the repertoire of possible healthy brain dynamics. Here, we investigate if such interictal abnormalities become more salient by quantitatively accounting for the range of healthy brain dynamics in a location-specific manner. To this end, we constructed a normative map of brain dynamics, in terms of relative band power, from interictal intracranial recordings from 234 participants (21 598 electrode contacts). We then compared interictal recordings from 62 patients with epilepsy to the normative map to identify abnormal regions. We proposed that if the most abnormal regions were spared by surgery, then patients would be more likely to experience continued seizures postoperatively. We first confirmed that the spatial variations of band power in the normative map across brain regions were consistent with healthy variations reported in the literature. Second, when accounting for the normative variations, regions that were spared by surgery were more abnormal than those resected only in patients with persistent postoperative seizures (t = -3.6, P = 0.0003), confirming our hypothesis. Third, we found that this effect discriminated patient outcomes (area under curve 0.75 P = 0.0003). Normative mapping is a well-established practice in neuroscientific research. Our study suggests that this approach is feasible to detect interictal abnormalities in intracranial EEG, and of potential clinical value to identify pathological tissue in epilepsy. Finally, we make our normative intracranial map publicly available to facilitate future investigations in epilepsy and beyond., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.)

In drug-resistant temporal lobe epilepsy, precise predictions of drug response, surgical outcome and cognitive dysfunction at an individual level remain challenging. A possible explanation may lie in the dominant 'one-size-fits-all' group-level analytical approaches that does not allow parsing interindividual variations along the disease spectrum. Conversely, analysing inter-patient heterogeneity is increasingly recognized as a step towards person-centred care. Here, we used unsupervised machine learning to estimate latent relations (or disease factors) from 3 T multimodal MRI features [cortical thickness, hippocampal volume, fluid-attenuated inversion recovery (FLAIR), T1/FLAIR, diffusion parameters] representing whole-brain patterns of structural pathology in 82 patients with temporal lobe epilepsy. We assessed the specificity of our approach against age- and sex-matched healthy individuals and a cohort of frontal lobe epilepsy patients with histologically verified focal cortical dysplasia. We identified four latent disease factors variably co-expressed within each patient and characterized by ipsilateral hippocampal microstructural alterations, loss of myelin and atrophy (Factor 1), bilateral paralimbic and hippocampal gliosis (Factor 2), bilateral neocortical atrophy (Factor 3) and bilateral white matter microstructural alterations (Factor 4). Bootstrap analysis and parameter variations supported high stability and robustness of these factors. Moreover, they were not expressed in healthy controls and only negligibly in disease controls, supporting specificity. Supervised classifiers trained on latent disease factors could predict patient-specific drug response in 76 ± 3% and postsurgical seizure outcome in 88 ± 2%, outperforming classifiers that did not operate on latent factor information. Latent factor models predicted inter-patient variability in cognitive dysfunction (verbal IQ: r = 0.40 ± 0.03; memory: r = 0.35 ± 0.03; sequential motor tapping: r = 0.36 ± 0.04), again outperforming baseline learners. Data-driven analysis of disease factors provides a novel appraisal of the continuum of interindividual variability, which is probably determined by multiple interacting pathological processes. Incorporating interindividual variability is likely to improve clinical prognostics., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Knowledge about the activity of single neurons is essential in understanding the mechanisms of synchrony generation, and particularly interesting if related to pathological conditions. The generation of interictal spikes-the hypersynchronous events between seizures-is linked to hyperexcitability and to bursting behaviour of neurons in animal models. To explore its cellular mechanisms in humans we investigated the activity of clustered single neurons in a human in vitro model generating both physiological and epileptiform synchronous events. We show that non-epileptic synchronous events resulted from the finely balanced firing of excitatory and inhibitory cells, which was shifted towards an enhanced excitability in epileptic tissue. In contrast, interictal-like spikes were characterised by an asymmetric overall neuronal discharge initiated by excitatory neurons with the presumptive leading role of bursting pyramidal cells, and possibly terminated by inhibitory interneurons. We found that the overall burstiness of human neocortical neurons is not necessarily related to epilepsy, but the bursting behaviour of excitatory cells comprising both intrinsic and synaptically driven bursting is clearly linked to the generation of epileptiform synchrony., (© 2022. The Author(s).)

MRI is a cornerstone in presurgical evaluation of epilepsy. Despite guidelines, clinical practice varies. In light of the E-PILEPSY pilot reference network, we conducted a systematic review and meta-analysis on the diagnostic value of MRI in the presurgical evaluation of epilepsy patients. We included original research articles on diagnostic value of higher MRI field strength and guideline-recommended and additional MRI sequences in detecting an epileptogenic lesion in adult or paediatric epilepsy surgery candidates. Lesion detection rate was used as a metric in meta-analysis. Eighteen studies were included for MRI field strength and 25 for MRI sequences, none were free from bias. In patients with normal MRI at lower-field strength, 3T improved lesion detection rate by 18% and 7T by 23%. Field strengths higher than 1.5T did not have higher lesion detection rates in patients with hippocampal sclerosis (HS). The lesion detection rate of epilepsy-specific MRI protocols was 83% for temporal lobe epilepsy (TLE) patients. Dedicated MRI protocols and evaluation by an experienced epilepsy neuroradiologist increased lesion detection. For HS, 3DT1, T2, and FLAIR each had a lesion detection rate at around 90%. Apparent diffusion coefficient indices had a lateralizing value of 33% for TLE. DTI fractional anisotropy and mean diffusivity had a localizing value of 8% and 34%. A dedicated MRI protocol and expert evaluation benefits lesion detection rate in epilepsy surgery candidates. If patients remain MRI negative, imaging at higher-field strength may reveal lesions. In HS, apparent diffusion coefficient indices may aid lateralization and localization more than increasing field strength. DTI can add further diagnostic information. For other additional sequences, the quality and number of studies is insufficient to draw solid conclusions. Our findings may be used as evidence base for developing new high-quality MRI studies and clinical guidelines.

Aims: We aimed to investigate putative neuroprotective effects of nesfatin-1 on oxidative brain injury and memory dysfunction induced by a single epileptic seizure and to compare these effects with those of antiepileptic phenytoin., Main Methods: Wistar albino rats were randomly divided into a control group and pentylenetetrazole (PTZ)-seizure groups pretreated intraperitoneally (ip) with saline or nesfatin-1 (NES-1; 0.3, 1 or 3 μg/kg/day) or phenytoin (PHE; 40 mg/kg/day) or PHE + NES-1 (0.3 μg/kg/day) at 30 min before the single-dose PTZ injection (45 mg/kg; ip). All treatments were repeated at the 24th and 48th h of the provoked epileptic seizure. Passive-avoidance test was performed to assess memory function. The rats were decapitated at the 72nd hour of seizures and brain tissues were analyzed for histopathological changes and for measuring levels of malondialdehyde, glutathione, myeloperoxidase activity and reactive oxygen/nitrogen species., Key Findings: In parallel to the effects of phenytoin, NES-1 reduced seizure score, elevated antioxidant glutathione content, depressed generation of nitric oxide and protected against seizure-induced neuronal damage. Additionally, increased malondialdehyde levels and elevated glial fibrillary acidic protein immunoreactivity in the cortex and hippocampus were decreased and memory dysfunction was improved by NES-1. However, NES-1 had no impact on myeloperoxidase activity or production of reactive oxygen species in the brain., Significance: The findings of the present study demonstrate that nesfatin-1 treatment provides neuroprotection against seizure-induced oxidative damage and memory dysfunction by inhibiting reactive nitrogen species and upregulating antioxidant capacity, indicating its potential in alleviating memory deficits and increasing the effectiveness of conventional anti-convulsant therapies., (Copyright © 2022. Published by Elsevier Inc.)

Purpose of the Review: Neurocysticercosis (NCC) has been well recognized as a leading cause of epilepsy. More recently, studies of other parasitic diseases such as cerebral malaria (CM) and onchocerciasis are yielding novel insights into the pathogenesis of parasite-associated epilepsy. We compare the clinical and electrophysiological findings in epilepsy associated with these highly prevalent parasites and discuss the mechanisms involved in epileptogenesis., Recent Findings: Electrophysiological and imaging biomarkers continue to emerge, and individuals who are at-risk of developing parasite-associated epilepsies are being identified with greater reliability. While both Taenia solium and Plasmodium falciparum directly affect the brain parenchyma, Onchocerca volvulus is not known to invade the central nervous system. Thus, the causal association between O. volvulus and epilepsy remains controversial. Both NCC and CM have a well-defined acute phase when the parasites directly or indirectly invade the brain parenchyma and lead to local inflammatory changes. This is followed by a chronic phase marked by recurrent seizures. However, these stages of epileptogenic process have not been identified in the case of O. volvulus., (© 2022. The Author(s).)

Objectives: We compared the proteomic signatures of the hippocampal lesion induced in three different animal models of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS): the systemic pilocarpine model (PILO), the intracerebroventricular kainic acid model (KA), and the perforant pathway stimulation model (PPS)., Methods: We used shotgun proteomics to analyze the proteomes and find enriched biological pathways of the dorsal and ventral dentate gyrus (DG) isolated from the hippocampi of the three animal models. We also compared the proteomes obtained in the animal models to that from the DG of patients with pharmacoresistant MTLE+HS., Results: We found that each animal model presents specific profiles of proteomic changes. The PILO model showed responses predominantly related to neuronal excitatory imbalance. The KA model revealed alterations mainly in synaptic activity. The PPS model displayed abnormalities in metabolism and oxidative stress. We also identified common biological pathways enriched in all three models, such as inflammation and immune response, which were also observed in tissue from patients. However, none of the models could recapitulate the profile of molecular changes observed in tissue from patients., Significance: Our results indicate that each model has its own set of biological responses leading to epilepsy. Thus, it seems that only using a combination of the three models may one replicate more closely the mechanisms underlying MTLE+HS as seen in patients., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Developmental and Epileptic Encephalopathy (DEE) is a group of disorders affecting children at early stages of infancy, which is characterized by frequent seizures, epileptiform activity on EEG, and developmental delayor regression. Developmental and epileptic encephalopathy-30 (DEE30) is a severe neurologic disorder characterized by onset of refractory seizures soon after birth or in the first months of life. Which was recently found to be caused by heterozygous mutations in the salt-inducible kinase SIK1. In this study, we investigated a patient with early onset epilepsy. DNA sequencing of the whole coding region revealed a de novel heterozygous nucleotide substitution (c.880G > A) causing a missense mutation (p.A294T). This mutation was classified as variant of unknown significance (VUS) by American College of Medical Genetics and Genomics (ACMG). To further investigate the pathogenicity and pathogenesis of this mutation, we established a human neuroblastoma cell line (SH-SY5Y) stably-expressing wild type SIK1 and A294T mutant, and compared the transcriptome and metabolomics profiles. We presented a pediatric patient suffering from infantile onset epilepsy. Early EEG showed a boundary dysfunction of activity and MRI scan of the brain was normal. The patient responded well to single anti-epileptic drug treatment. Whole-exome sequencing found a missense mutation of SIK1 gene (c.880G > A chr21: 43,420,326 p. A294T). Dysregulated transcriptome and metabolome in cell models expressing WT and MUT SIK1 confirmed the pathogenicity of the mutation. Specifically, we found MEF2C target genes, certain epilepsy causing genes and metabolites are dysregulated by SIK1 mutation. We found MEF2C target genes, certain epilepsy causing genes and metabolites are dysregulated by SIK1 mutation. Our finding further expanded the disease spectrum and provided novel mechanistic insights of DEE30., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

PCDH19 clustering epilepsy (PCDH19-CE) is a genetic disease characterized by a heterogeneous phenotypic spectrum ranging from focal epilepsy with rare seizures and normal cognitive development to severe drug-resistant epilepsy associated with intellectual disability and autism. Unfortunately, little is known about the pathogenic mechanism underlying this disease and an effective treatment is lacking. Studies with zebrafish and murine models have provided insights on the function of PCDH19 during brain development and how its altered function causes the disease, but these models fail to reproduce the human phenotype. Induced pluripotent stem cell (iPSC) technology has provided a complementary experimental approach for investigating the pathogenic mechanisms implicated in PCDH19-CE during neurogenesis and studying the pathology in a more physiological three-dimensional (3D) environment through the development of brain organoids. We report on recent progress in the development of human brain organoids with a particular focus on how this 3D model may shed light on the pathomechanisms implicated in PCDH19-CE.

Glucose, the primary substrate for ATP synthesis, is catabolized during glycolysis to generate ATP and precursors for the synthesis of other vital biomolecules. Opportunistic viruses and cancer cells often hijack this metabolic machinery to obtain energy and components needed for their replication and proliferation. One way to halt such energy-dependent processes is by interfering with the glycolytic pathway. 2-Deoxy-d-glucose (2-DG) is a synthetic glucose analogue that can inhibit key enzymes in the glycolytic pathway. The efficacy of 2-DG has been reported across an array of diseases and disorders, thereby demonstrating its broad therapeutic potential. Recent approval of 2-DG in India as a therapeutic approach for the management of the COVID-19 pandemic has brought renewed attention to this molecule. The purpose of this perspective is to present updated therapeutic avenues as well as a variety of chemical synthetic strategies for this medically useful sugar derivative, 2-DG.

Objective: Epilepsy surgery has shown efficacy in children. We aimed to assess long-term seizure outcome in children who underwent epilepsy surgery and determine predictive factors for seizure freedom., Methods: This is a retrospective study of 196 children who underwent epilepsy surgery between 1994 and 2015 and had a minimum postoperative follow-up of 5 years., Results: The median age at the time of surgery was 9.5 (0.08-19.8) years; 110 (56.1%) had temporal, 62 (31.6%) had extratemporal resections, and 24 (12.2%) had hemispheric surgery. The duration of postsurgical follow-up was between 5 and 20 years (mean±SD: 7 ± 3.2). Overall, 129 of 196 (65.8%) patients had Engel class I outcome at final visit. Among patients who underwent temporal, extratemporal and hemispheric surgery; 84 of 110 (76.4%), 34 of 62 (54.8%), and 11 of 24 (45.8%) patients had complete seizure freedom, respectively (p: 0.016). Patients with tumors had the best outcome, with 83.1% seizure freedom. The number of preoperative antiseizure medications (OR 3.19, 95% CI 1.07-9.48), the absence of postoperative focal epileptiform discharges (OR 8.98, 95% CI 4.07-19.79) were independent predictors of seizure freedom. Across two decades, the age at surgery was decreased (p: 0.003), overall seizure freedom (61.8% vs 68%) did not differ. In the past decade, a higher proportion of malformations of cortical development was operated (14.7% vs 35.9%, p: 0.007)., Significance: Our findings showed favorable long-term seizure outcome in children who underwent epilepsy surgery. The results are encouraging for developing centers with limited resources to establish pediatric epilepsy programs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

TRAPPC4-related neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (MIM# 618741) is a recently described TRAPPopathy with clinical findings of developmental delay, seizures, postnatal microcephaly, spasticity, facial dysmorphism, and cerebral and cerebellar atrophy. Muscle involvement, a frequent finding in TRAPPopathies, was observed in one individual with TRAPPC4-related disorder previously. Only a single variant, an in-frame deletion in one family has been reported outside a recurrent disease-causing variant. We report three individuals from two Indian families harboring novel bi-allelic missense variants c.191T>C and c.278C>T (NM&#95;016146.6) in TRAPPC4 with classic clinical presentation in one and milder and later onset in the other family. We provide further evidence for muscle involvement and review the detailed phenotypic findings in individuals reported with this disorder till date., (© 2021 John Wiley & Sons Ltd/University College London.)

Objectives: Epileptic patients suffer from seizure recurrence after surgery due to the challenging localization. Improvement of the noninvasive imaging-based approach for a better definition of the abnormalities would be helpful for a better outcome., Methods: The quantitative anisotropy (QA) of diffusion spectrum imaging (DSI) is a quantitative scalar of evaluating the water diffusivity. Herein, we investigated the association between neuronal diameters or density acquired in literature and QA of DSI as well as the seizure localization in temporal lobe epilepsy. Thirty healthy controls (HCs) and 30 patients with hippocampal sclerosis (HS) were retrospectively analyzed. QA values were calculated and interactively compared between the areas with different neuronal diameter/density acquired from literature in the HCP-1021 template. Diagnostic tests were performed on Z-transformed asymmetry indices (AIs) of QA (which exclude physical asymmetry) among HS patients to evaluate its clinical value., Results: The QA values in HCs conformed with different pyramidal cell distributions ranged from giant to small; corresponding groups were the motor-sensory, associative, and limbic groups, respectively. Additionally, the QA value was correlated with the neuronal diameter/density in cortical layer IIIc (correlation coefficient with diameter: 0.529, p = 0.035; density: -0.678, p = 0.011). Decreases in cingulum hippocampal segments (Chs) were consistently observed on the sclerosed side in patients. The area under the curve of the Z-transformed AI in Chs to the lateralization of HS was 0.957 (sensitivity: 0.909, specificity: 0.895)., Interpretation: QA based on DSI is likely to be useful to provide information to reflect the neuronal diameter/density and further facilitate localization of epileptic tissues., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Epilepsy is a serious hazard to human health. Minimally invasive surgery is an extremely effective treatment to refractory epilepsy currently if the location of epileptic foci is given. However, it is challenging to locate the epileptic foci since a multitude of patients are MRI-negative. It is well known that DKI (diffusion kurtosis imaging) can analyze the pathological changes of local tissues and other regions of epileptic foci at the molecular level. In this article, we propose a new localization way for epileptic foci based on machine-learning method with kurtosis tensor in DKI., Methods: We recruited 59 children with hippocampus epilepsy and 70 age- and sex-matched normal controls; their T1-weighted images and DKI were collected simultaneously. Then, the hippocampus in DKI is segmented based on a mask as a local brain region, and DKE is utilized to estimate the kurtosis tensor of each subject's hippocampus. Finally, the kurtosis tensor is fed into SVM (support vector machine) to identify epilepsy., Results: The classifier produced 95.24% accuracy for patient versus normal controls, which is higher than that obtained with FA (fractional anisotropy) and MK (mean kurtosis). Experimental results show that the kurtosis tensor is a kind of remarkable feature to identify epilepsy, which indicates that DKI images can act as an important biomarker for epilepsy from the view of clinical diagnosis., Conclusion: Although the classification task for epileptic patients and normal controls discussed in this article did not directly achieve the location of epileptic foci and only identified epilepsy on certain brain region, the epileptic foci can be located with the results of identifying results on other brain regions., (© 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Honoured as the second genome in humans, the gut microbiota is involved in a constellation of physiological and pathological processes, including those related to the central nervous system. The communication between the gut microbiota and the brain is realized by a complex bidirectional connection, known as the "microbiota-gut-brain axis", via neuroendocrine, immunological, and direct neural mechanisms. Recent studies indicate that gut dysfunction/dysbiosis is presumably involved in the pathogenesis of and susceptibility to epilepsy. In addition, the reconstruction of the intestinal microbiome through, for example, faecal microbiota transplantation, probiotic intervention, and a ketogenic diet, has exhibited beneficial effects on drug-resistant epilepsy. The purposes of this review are to provide a brief overview of the microbiota-gut-brain axis and to synthesize what is known about the involvement of the gut microbiota in the pathogenesis and treatment of epilepsy, to bring new insight into the pathophysiology of epilepsy and to present a preliminary discussion of novel therapeutic options for epilepsy based on the gut microbiota., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Increasing evidence corroborates the fundamental role of neuroinflammation in the development of epilepsy. Proinflammatory cytokines (PICs) are crucial contributors to the inflammatory reactions in the brain. It is evidenced that epileptic seizures are associated with elevated levels of PICs, particularly interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), which underscores the impact of neuroinflammation and PICs on hyperexcitability of the brain and epileptogenesis. Since the pathophysiology of epilepsy is unknown, determining the possible roles of PICs in epileptogenesis could facilitate unraveling the pathophysiology of epilepsy. About one-third of epileptic patients are drug-resistant, and existing treatments only resolve symptoms and do not inhibit epileptogenesis; thus, treatment of epilepsy is still challenging. Accordingly, understanding the function of PICs in epilepsy could provide us with promising targets for the treatment of epilepsy, especially drug-resistant type. In this review, we outline the role of neuroinflammation and its primary mediators, including IL-1β, IL-1α, IL-6, IL-17, IL-18, TNF-α, and interferon-γ (IFN-γ) in the pathophysiology of epilepsy. Furthermore, we discuss the potential therapeutic targeting of PICs and cytokine receptors in the treatment of epilepsy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

EIF2S3 pathogenic variants have been shown to cause MEHMO syndrome - a rare X-linked intellectual disability syndrome. In most cases, DNA diagnostics of MEHMO syndrome is performed using exome sequencing. We describe two cousins with profound intellectual disability, severe microcephaly, microgenitalism, hypoglycemia, epileptic seizures, and hypertrichosis, whose clinical symptoms allowed us to suspect MEHMO syndrome. To confirm this diagnosis, we designed an mRNA analysis for the EIF2S3 gene. It is a cost-effective method to detect coding sequence variants in multi-exonic genes, as well as splicing defects and allelic imbalance. Our mRNA sequence analysis revealed a novel EIF2S3 variant c.820C>G in both cousins. We also found the same variant in female family members in the heterozygous state. To investigate the pathogenicity of the c.820C>G variant, we performed expression analysis, which showed that the DDIT3 transcript level was significantly increased in the patient relative to the controls. We, thus, demonstrate that mRNA analysis is an efficient tool for performing genetic testing in patients with distinct phenotypic features., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

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.)

Aims: We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low-grade epilepsy-associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma-like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours., Methods: Centralised pathological examination was performed as well as targeted molecular analysis of v-Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done., Results: We first reclassified our cohort into three groups: ganglioglioma (GG, n = 14), dysembryoplastic neuroepithelial tumours (DNTs, n = 19) and glioneuronal tumours/paediatric-type low-grade glioma (LGG) not otherwise specified (GNT/PLGG NOS, n = 39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or neurotrophic tyrosine kinase receptor type 2 [NTRK2] in 9/25 cases. DNA methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed two clusters: Cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG-DNT methylation class (MC), with haematopoietic progenitor cell antigen (CD34) negativity and FGRF1 alterations; Cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG-GG MC MC, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low-grade neuroepithelial tumour of the young belonged to Cluster 2, whereas diffuse LGG mitogen-activated protein kinase (MAPK) pathway-altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma-like component., Conclusions: Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma-like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinicopathological relevance of the four types recognised by the WHO CNS5 within this spectrum of tumours is questionable., (© 2021 British Neuropathological Society.)

Epilepsy is a disease that affects millions of people around the globe and has a multifactorial cause. Inflammation is a process that can be involved in the development of seizures. Thus, the present study proposed the design and synthesis of new candidates for antiepileptic drugs that would also control the inflammatory process. Nine new derivatives of the substituted thiazophthalimide hybrid core were obtained with satisfactory purity ≥99% and yields between 27% and 87%. All compounds showed cell viability values greater than 90% in the culture of PBMC cells from healthy volunteers and, therefore, were not considered cytotoxic. These compounds modulated proinflammatory cytokines IFN-y and IL-17A and can mitigate inflammation. Acute toxicity studies of compound 7i in an animal model indicated that the compound has low toxicity and an LD50 greater than 2 g/kg in healthy adult rats. The same compound did not show positive results for anticonvulsant activity through the PTZ test. However, 7i demonstrates the interaction with the target GABA-A receptor in silico, indicating a possible activity as an agonist of that receptor. Thus, further studies are needed to investigate the anticonvulsant activity, in particular, using models in which the inflammatory process triggers epileptic seizures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aluminium is known to accumulate in neuropathological hallmarks. However, such has only tentatively been suggested in Biondi ring tangles. Owing to their intracellular and filamentous structure rich in β-pleated sheets, Biondi ring tangles might attract the adventitious binding of aluminium in regions of the blood-cerebrospinal fluid barrier. The study's objective was to establish whether aluminium co-localises with Biondi ring tangles in the brains of Parkinson's disease donors versus a donor that went on to develop late-onset epilepsy. Herein, we have performed immunohistochemistry for phosphorylated tau, complemented with aluminium-specific fluorescence microscopy in the choroid plexus of Parkinson's disease donors and in a donor that developed late-onset epilepsy. Aluminium co-localises with lipid-rich Biondi ring tangles in the choroid plexus. While Biondi ring tangles are not composed of phosphorylated tau, the latter is identified in nuclei of choroidal cells where aluminium and Biondi ring tangles are co-located. Although Biondi ring tangles are considered artefacts in imaging studies using positron emission tomography, their ability to bind aluminium and then release it upon their subsequent rupture and escape from choroidal cells may allow for a mechanism that may propagate for aluminium toxicity in vivo., (© 2022. The Author(s).)

Polyamines are organic polycations ubiquitously present in living cells. Polyamines are involved in many cellular processes, and their content in mammalian cells is tightly controlled. Among their function, these molecules modulate the activity of several ion channels. Spermine oxidase, specifically oxidized spermine, is a neuromodulator of several types of ion channel and ionotropic glutamate receptors, and its deregulated activity has been linked to several brain pathologies, including epilepsy. The Dach-SMOX mouse line was generated using a Cre/loxP-based recombination approach to study the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain. This mouse genetic model overexpresses spermine oxidase in the neocortex and is a chronic model of excitotoxic/oxidative injury and neuron vulnerability to oxidative stress and excitotoxic, since its phenotype revealed to be more susceptible to different acute oxidative insults. In this review, the molecular mechanisms underlined the Dach-SMOX phenotype, linked to reactive astrocytosis, neuron loss, chronic oxidative and excitotoxic stress, and susceptibility to seizures have been discussed in detail. The Dach-SMOX mouse model overexpressing SMOX may help in shedding lights on the susceptibility to epileptic seizures, possibly helping to understand the mechanisms underlying epileptogenesis in vulnerable individuals and contributing to provide new molecular mechanism targets to search for novel antiepileptic drugs.

Epilepsy is a severe neurological disease characterized by spontaneous recurrent seizures (SRS). A complex pathophysiological process referred to as epileptogenesis transforms a normal brain into an epileptic one. Prevention of epileptogenesis is a subject of intensive research. Currently, there are no clinically approved drugs that can act as preventive medication. Our previous studies have revealed highly promising antiepileptogenic properties of a compound-myo-inositol (MI) and the present research broadens previous results and demonstrates the long-term disease-modifying effect of this drug, as well as the amelioration of cognitive comorbidities. For the first time, we show that long-term treatment with MI: (i) decreases the frequency and duration of electrographic SRS in the hippocampus; (ii) has an ameliorating effect on spatial learning and memory deficit associated with epileptogenesis, and (iii) attenuates cell loss in the hippocampus. MI treatment also alters the expression of the glial fibrillary acidic protein, LRRC8A subunit of volume-regulated anion channels, and protein tyrosine phosphatase receptor type R, all expected to counteract the epileptogenesis. All these effects are still present even 4 weeks after MI treatment ceased. This suggests that MI may exert multiple actions on various epileptogenesis-associated changes in the brain and, therefore, could be considered as a candidate target for prevention of epileptogenesis.

Background and Objectives: To identify white matter fiber tracts that exhibit structural abnormality in patients with bottom-of-sulcus dysplasia (BOSD) and investigate their association with seizure activity., Methods: Whole-brain fixel-based analysis of diffusion MRI data was performed to identify white matter fiber tracts with significant reductions in fiber density and cross-section in patients with BOSD (n = 20) when compared to healthy control participants (n = 40). Results from whole-brain analysis were used to investigate the association of fiber tract abnormality with seizure frequency and epilepsy duration., Results: Despite the focal nature of the dysplasia, patients with BOSD showed widespread abnormality in white matter fiber tracts, including the bilateral corticospinal, corticothalamic, and cerebellothalamic tracts, superior longitudinal fasciculi, corpus callosum (body), and the forceps major. This pattern of bilateral connectivity reduction was not related to the laterality of the lesion. Exploratory post hoc analyses showed that high seizure frequency was associated with greater reduction in fiber density at the forceps major, bilateral corticospinal, and cerebellothalamic tracts., Discussion: We demonstrate evidence of a bilaterally distributed, specific white matter network that is vulnerable to disruption in BOSD. The degree of tract abnormality is partly related to seizure activity, but additional contributors such as the genetic background and effects of treatment or environment have not been excluded., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Gap junctions (GJs) are intercellular junctions that allow the direct transfer of ions and small molecules between neighboring cells, and GJs between astrocytes play an important role in the development of various pathologies of the brain, including regulation of the pathological neuronal synchronization underlying epileptic seizures. Recently, we found that a pathological change is observed in astrocytes during the ictal and interictal phases of 4-aminopyridin (4-AP)-elicited epileptic activity in vitro, which was correlated with neuronal synchronization and extracellular epileptic electrical activity. This finding raises the question: Does this signal depend on GJs between astrocytes? In this study we investigated the effect of the GJ blocker, carbenoxolone (CBX), on epileptic activity in vitro and in vivo. Based on the results obtained, we came to the conclusion that the astrocytic syncytium formed by GJ-associated astrocytes, which is responsible for the regulation of potassium, affects the formation of epileptic activity in astrocytes in vitro and epileptic seizure onset. This effect is probably an important, but not the only, mechanism by which CBX suppresses epileptic activity. It is likely that the mechanisms of selective inhibition of GJs between astrocytes will show important translational benefits in anti-epileptic therapies.

Epilepsy is one of the most common diseases of the central nervous system, impacting nearly 50 million people around the world. Heterogeneous in nature, epilepsy presents in children and adults alike. Currently, surgery is one treatment approach that can completely cure epilepsy. However, not all individuals are eligible for surgical procedures or have successful outcomes. In addition to surgical approaches, antiepileptic drugs (AEDs) have also allowed individuals with epilepsy to achieve freedom from seizures. Others have found treatment through nonpharmacologic approaches such as vagus nerve stimulation, or responsive neurostimulation. Difficulty in accessing samples of human brain tissue along with advances in sequencing technology have driven researchers to investigate sampling liquid biopsies in blood, serum, plasma, and cerebrospinal fluid within the context of epilepsy. Liquid biopsies provide minimal or non-invasive sample collection approaches and can be assayed relatively easily across multiple time points, unlike tissue-based sampling. Various efforts have investigated circulating nucleic acids from these samples including microRNAs, cell-free DNA, transfer RNAs, and long non-coding RNAs. Here, we review nucleic acid-based liquid biopsies in epilepsy to improve understanding of etiology, diagnosis, prediction, and therapeutic monitoring., (© 2021. The Author(s).)

Neuropathological examination of the temporal lobe provides a better understanding and management of a wide spectrum of diseases. We focused on inflammatory diseases, epilepsy, and neurodegenerative diseases, and highlighted how the temporal lobe is particularly involved in those conditions. Although all these diseases are not specific or restricted to the temporal lobe, the temporal lobe is a key structure to understand their pathophysiology. The main histological lesions, immunohistochemical markers, and molecular alterations relevant for the neuropathological diagnostic reasoning are presented in relation to epidemiology, clinical presentation, and radiological findings. The inflammatory diseases section addressed infectious encephalitides and auto-immune encephalitides. The epilepsy section addressed (i) susceptibility of the temporal lobe to epileptogenesis, (ii) epilepsy-associated hippocampal sclerosis, (iii) malformations of cortical development, (iv) changes secondary to epilepsy, (v) long-term epilepsy-associated tumors, (vi) vascular malformations, and (vii) the absence of histological lesion in some epilepsy surgery samples. The neurodegenerative diseases section addressed (i) Alzheimer's disease, (ii) the spectrum of frontotemporal lobar degeneration, (iii) limbic-predominant age-related TDP-43 encephalopathy, and (iv) α-synucleinopathies. Finally, inflammatory diseases, epilepsy, and neurodegenerative diseases are considered as interdependent as some pathophysiological processes cross the boundaries of this classification., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Adults with large multilobar lesions of temporal, parietal and occipital lobes of the dominant hemisphere suffering from drug-resistant epilepsy were considered inoperable for a long time., Objective: To demonstrate favorable postoperative outcome in a patient with massive periventricular heterotopia of the left temporal and occipital lobes complicated by drug-resistant epilepsy., Material and Methods: We analyzed localization of the brain malformation (massive periventricular heterotopia) and its relationship with surrounding structures in a 38-year-old patient considering preoperative MRI, functional MRI and MR tractography data. Quality of modified posterior quadrant disconnection was assessed within a day and 6 months after surgery in accordance with MRI data. Transcranial stimulation, direct cortical and subcortical monopolar stimulation were used for intraoperative monitoring of corticospinal tract. We also assessed neurological status and linguistic testing data before surgery, 4 days and 6 months after surgery., Results: Modified posterior disconnection of temporal, parietal and occipital lobes was performed. Intraoperative neurophysiological cortical mapping (asleep-awake-sedation protocol) verified localization of Wernicke's area. There was an expected right-sided homonymous hemianopsia in postoperative period without speech disorders. Postoperative outcome Engel grade 1A under anticonvulsant therapy was obtained., Conclusion: The authors report successful surgical treatment of massive malformation of the left temporal, parietal and occipital lobes and literature review devoted to this issue.

Objective: The goal of this review is to summarize data concerning radiological and histological diagnosis of epileptogenic tumors, as well as to discuss their surgical treatment., Material and Methods: PubMed literature database was searched for relevant articles, we also used our own clinical experience., Results: Benign glioneuronal tumors are the second most common cause of drug resistant epilepsy in adults after hippocampal sclerosis. Exceptionally slow growth (more than 2 years), localization in the brain cortex, presence of differentiated neuronal tissue in tumoral body and long history of epilepsy are the key features of these tumors called LEAT (long-term epilepsy-associated tumors). Management of LEAT requires epileptological as well as neurooncological approach. The epileptogenic zone commonly spreads beyond the tumor borders and simple lesionectomy alone may not be sufficient for achieving seizure freedom., Conclusion: LEAT typically exhibit low proliferative activity, however they should be thoroughly differentiated from more aggressive glial tumors; while this task is sometimes quite challenging, it's achievable by means of histological and immunohistochemical examination.

Purpose: The purpose of this study was to demonstrate the prognostic value of afterdischarges(ADs) on surgical outcome by comparing the disparate properties in epilepsy patients with different surgical outcomes METHODS: 27 lesional epilepsy patients were retrospectively analyzed. The brain region covered by subdural electrodes in each patient was dichotomized into the area of the brain lobe(s) where the MRI lesion is located (region ML) and other brain areas (region nML). The occurrence of ADs and ADs evolving into clinical seizure, ADs threshold and ADs duration in region ML and nML were compared between seizure-free (SF) and non-seizure-free (nSF) patients., Results: A total of 2535 contacts were analyzed, and the total occurrence of ADs was 18.6% (471/2535). The overall occurrence of ADs in region ML (24.8%) was significantly higher than that in region nML (10.3%) (P < 0.001). In region ML, compared with SF patients, nSF patients had a lower occurrence of ADs (19.2% vs. 31.2%, P < 0.001), a higher occurrence of ADs evolves into clinical seizure (8.7% vs. 2.4%, P = 0.006), a higher ADs threshold (12.8 ± 4.1 mA vs. 11.0 ± 3.7 mA, P < 0.001) and a shorter ADs duration (15.3 ± 14.2 s vs. 20.6 ± 17.0 s, P < 0.001). However, in region nML, there was no significant difference in properties of ADs between SF and nSF patients., Conclusion: Higher occurrence of ADs in region ML might predict a good outcome, whereas higher occurrence of ADs evolving into clinical seizure, higher ADs threshold and shorter ADs duration might predict an unfavorable surgical outcome. ADs might help predict surgical outcomes in epilepsy patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)