[Focal cortical dysplasia: visual assessment of MRI and MR morphometry data]. / Fokal'naya kortikal'naya displaziya: sravnitel'nyi analiz vizual'noi otsenki dannykh magnitno-rezonansnoi tomografii i magnitno-rezonansnoi morfometrii.

OBJECTIVE: Assessing the diagnostic significance of MR morphometry in determining the localization of focal cortical dysplasias (FCD). MATERIAL AND METHODS: The study included 13 children after surgery for drug-resistant epilepsy caused by FCD type II and stable postoperative remission of seizures (Engel class IA, median follow-up 56 months). We analyzed the results of independent expert assessment of native MR data by three radiologists (HARNESS protocol) and MR morphometry data regarding accuracy of FCD localization. We considered 2 indicators, i.e. local cortical thickening and gray-white matter blurring. RESULTS: FCD detection rate was higher after MR morphometry compared to visual analysis of native MR data using the HARNESS protocol. MR morphometry also makes it possible to more often identify gray-white matter blurring as a sign often missed by radiologists (p<0.05). CONCLUSION: MR morphometry is an additional non-invasive method for assessing the localization of FCD.

A spectrum of AKT3 activating mutations cause focal malformations of cortical development (FMCDs) in cortical organoids.

Focal malformations of cortical development (FMCDs) are brain disorders mainly caused by hyperactive mTOR signaling due to both inactivating and activating mutations of genes in the PI3K-AKT-mTOR pathway. Among them, mosaic and somatic activating mutations of the mTOR pathway activators are more frequently linked to severe form of FMCDs. A human stem cell-based FMCDs model to study these activating mutations is still lacking. Herein, we genetically engineer human embryonic stem cell lines carrying these activating mutations to generate cortical organoids. Mosaic and somatic expression of AKT3 activating mutations in cortical organoids mimicking the disease presentation with overproliferation and the formation of dysmorphic neurons. In parallel comparison of various AKT3 activating mutations reveals that stronger mutation is associated with more severe neuronal migratory and overgrowth defects. Together, we have established a feasible human stem cell-based model for FMCDs that could help to better understand pathogenic mechanism and develop novel therapeutic strategy.

Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations.

CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.

[Advances of pathological research and classification in malformations of cortical development associated with refractory epilepsy].

With rapid development of genetic testing techniques, neuroimaging and neuroelectrophysiological technologies, our understanding of malformations of cortical development continues to be deepened and updated. In particular, mutations in genes related to the mammalian target of rapamycin (mTOR) signaling pathway have been successively discovered in focal cortical dysplasia (FCD). At the same time, the classification consensus on FCD issued by the International League Against Epilepsy (ILAE) in 2011 has encountered problems and challenges in diagnostic practice. Therefore, in 2022, ILAE proposed an updated version of the FCD classification based on the progress in molecular genetics over the past decade. The main addition to the classification system is "white matter lesions, " and it is also suggested to integrate histopathological, neuroimaging, and molecular testing results for multi-level integrated diagnosis to achieve reliable, clinically relevant, and therapeutic targeted final diagnosis.

A controversial question: Can morphometry and clinical history be enough to diagnose hippocampal dysplasia?

The presence of dysmorphic neurons with strong cytoplasmatic accumulation of heavy non-phosphorylated neurofilament is crucial for the diagnostics of focal cortical dysplasia type II (FCDII). While ILAE's classification describes neocortical dysplasias, some groups have reported patients with mesial t abnormal neurons in the hippocampus of mesial temporal lobe epilepsy. Here we report a patient with such abnormal neurons in the hippocampus and compared it with previous reports of hippocampal dysplasia. Finally, we discuss the need for diagnostic criteria of hippocampal dysplasia.

Early developmental changes in a rat model of malformations of cortical development: Abnormal neuronal migration and altered response to NMDA-induced excitotoxic injury.

Malformations of cortical development (MCDs) are caused by abnormal neuronal migration processes during the fetal period and are a major cause of intractable epilepsy in infancy. However, the timing of hyperexcitability or epileptogenesis in MCDs remains unclear. To identify the early developmental changes in the brain of the MCD rat model, which exhibits increased seizure susceptibility during infancy (P12-15), we analyzed the pathological changes in the brains of MCD model rats during the neonatal period and tested NMDA-induced seizure susceptibility. Pregnant rats were injected with two doses of methylazoxymethanol acetate (MAM, 15 mg/kg, i.p.) to induce MCD, while controls were administered normal saline. The cortical development of the offspring was measured by performing magnetic resonance imaging (MRI) on postnatal days (P) 1, 5, and 8. At P8, some rats were sacrificed for immunofluorescence, Golgi staining, and Western analysis. In another set of rats, the number and latency to onset of spasms were monitored for 90 min after the NMDA (5 mg/kg i.p.) injection at P8. In MCD rats, in vivo MR imaging showed smaller brain volume and thinner cortex from day 1 after birth (p < 0.001). Golgi staining and immunofluorescence revealed abnormal neuronal migration, with a reduced number of neuronal cell populations and less dendritic arborization at P8. Furthermore, MCD rats exhibited a significant reduction in the expression of NMDA receptors and AMPAR4, along with an increase in AMPAR3 expression (p < 0.05). Although there was no difference in the latency to seizure onset between MCD rats and controls, the MCD rats survived significantly longer than the controls. These results provide insights into the early developmental changes in the cortex of a MCD rat model and suggest that delayed and abnormal neuronal development in the immature brain is associated with a blunted response to NMDA-induced excitotoxic injury. These developmental changes may be involved in the sudden onset of epilepsy in patients with MCD or prenatal brain injury.

Detection of somatic and germline pathogenic variants in adult cohort of drug-resistant focal epilepsies.

OBJECTIVE: This study investigates the prevalence of pathogenic variants in the mechanistic target of rapamycin (mTOR) pathway in surgical specimens of malformations of cortical development (MCDs) and cases with negative histology. The study also aims to evaluate the predictive value of genotype-histotype findings on the surgical outcome. METHODS: The study included patients with drug-resistant focal epilepsy who underwent epilepsy surgery. Cases were selected based on histopathological diagnosis, focusing on MCDs and negative findings. We included brain tissues both as formalin-fixed, paraffin-embedded (FFPE) or fresh frozen (FF) samples. Single-molecule molecular inversion probes (smMIPs) analysis was conducted, targeting the MTOR gene in FFPE samples and 10 genes within the mTOR pathway in FF samples. Correlations between genotype-histotype and surgical outcome were examined. RESULTS: We included 78 patients for whom we obtained 28 FFPE samples and 50 FF tissues. Seventeen pathogenic variants (22 %) were identified and validated, with 13 being somatic within the MTOR gene and 4 germlines (2 DEPDC5, 1 TSC1, 1 TSC2). Pathogenic variants in mTOR pathway genes were exclusively found in FCDII and TSC cases, with a significant association between FCD type IIb and MTOR genotype (P = 0.003). Patients carrying mutations had a slightly better surgical outcome than the overall cohort, however it results not significant. The FCDII diagnosed cases more frequently had normal neuropsychological test, a higher incidence of auras, fewer multiple seizure types, lower occurrence of seizures with awareness impairment, less ictal automatisms, fewer Stereo-EEG investigations, and a longer period long-life of seizure freedom before surgery. SIGNIFICANCE: This study confirms that somatic MTOR variants represent the primary genetic alteration detected in brain specimens from FCDII/TSC cases, while germline DEPDC5, TSC1/TSC2 variants are relatively rare. Systematic screening for these mutations in surgically treated patients' brain specimens can aid histopathological diagnoses and serve as a biomarker for positive surgical outcomes. Certain clinical features associated with pathogenic variants in mTOR pathway genes may suggest a genetic etiology in FCDII patients.

Combining magnetic resonance fingerprinting with voxel-based morphometric analysis to reduce false positives for focal cortical dysplasia detection.

OBJECTIVE: We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis. METHODS: We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level. RESULTS: MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients. SIGNIFICANCE: This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy.

Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.

Partial epilepsy: A pictorial review of 3 TESLA magnetic resonance imaging features

Epilepsy is a disease with serious consequences for patients and society. In many cases seizures are sufficiently disabling to justify surgical evaluation. In this context, Magnetic Resonance Imaging (MRI) is one of the most valuable tools for the preoperative localization of epileptogenic foci. Because these lesions show a large variety of presentations (including subtle imaging characteristics), their analysis requires careful and systematic interpretation of MRI data. Several studies have shown that 3 Tesla (T) MRI provides a better image quality than 1.5 T MRI regarding the detection and characterization of structural lesions, indicating that high-field-strength imaging should be considered for patients with intractable epilepsy who might benefit from surgery. Likewise, advanced MRI postprocessing and quantitative analysis techniques such as thickness and volume measurements of cortical gray matter have emerged and in the near future, these techniques will routinely enable more precise evaluations of such patients. Finally, the familiarity with radiologic findings of the potential epileptogenic substrates in association with combined use of higher field strengths (3 T, 7 T, and greater) and new quantitative analytical post-processing techniques will lead to improvements regarding the clinical imaging of these patients. We present a pictorial review of the major pathologies related to partial epilepsy, highlighting the key findings of 3 T MRI.

Investigation of magnetic resonance imaging texture analysis as an aid tool for characterization of refractory epilepsies / Investigacao da analise de textura em imagem de ressonancia magnetica como auxilio para caracterizacao de epilepsias refratarias

Refractory epilepsies are syndromes for which therapies that employ two or more antiepileptic drugs, separately or in association, do not result in control of crisis. Patients may present focal cortical dysplasia or diffuse dysplasia and/or hippocampal atrophic alterations that may not be detectable by a simple visual analysis in magnetic resonance imaging. The aim of this study was to evaluate MRI texture in regions of interest located in the hippocampi, limbic association cortex and prefrontal cortex of 20 patients with refractory epilepsy and to compare them with the same areas in 20 healthy individuals, in order to find out if the texture parameters could be related to the presence of the disease. Of the 11 texture parameters calculated, three indicated the existence of statistically significant differences between the studied groups. Such findings suggest the possibility of this technique contributing to studies of refractory epilepsies.

Epilepsias refratárias compreendem síndromes para as quais as terapias que empregam duas ou mais drogas antiepilépticas, isoladamente ou em associação, não resultam no controle da frequência das crises. Portadores podem apresentar displasias corticais focais ou difusas e/ou alterações atróficas hipocampais que, em alguns casos, não são detectáveis por uma simples análise visual nas imagens de ressonância magnética. Nesse contexto, o objetivo deste estudo foi avaliar a textura de imagens de RM em regiões de interesse localizadas nos hipocampos, córtex de associação límbico e córtex pré-frontal de 20 pacientes com epilepsia refratária e compará-las às mesmas áreas de um grupo de 20 indivíduos sadios. Dos 11 parâmetros de textura calculados, três indicaram a existência de diferenças estatisticamente significantes entre os grupos estudados. Tais achados sugerem a possibilidade desta técnica contribuir para os estudos das epilepsias de difícil controle.

Cirugía de la epilepsia en niños con displasias corticales focales / Epilepsy surgery in children with focal cortical dysplasias

Introducción. Las displasias corticales focales (DCF) son la primera etiología de cirugía de la epilepsia pediátrica. La evaluación prequirúrgica en DCF a menudo es compleja, ya que son lesiones que pueden ser altamente epileptógenas y, a la vez, conservar función neurológica, y no visualizarse en la resonancia magnética. El éxito de la cirugía depende, en gran medida, de la adecuada identificación de la lesión y de la posibilidad de realizar una resección completa del tejido displá- sico. En este trabajo se revisa la bibliografía relacionada con el tema, en relación con la experiencia de los autores. Desarrollo. Se revisan algunos avances relacionados con la evaluación prequirúrgica y el abordaje neuroquirúrgico de la epilepsia en niños con DCF; se comentan los resultados de las series quirúrgicas en relación con las clasificaciones de DCF y los factores de pronóstico posquirúrgico; se describen algunos fenotipos anatomoelectroclínicos distintivos en niños con DCF y su abordaje quirúrgico; y se comentan brevemente los actuales retos y el futuro del tratamiento quirúrgico de la epilepsia en DCF. Conclusiones. El avance los métodos de diagnóstico prequirúrgico y de procedimientos quirúrgicos está permitiendo ofrecer un tratamiento exitoso en edades tempranas a pacientes con DCF previamente considerados ‘no lesionales’ y a pacientes con lesiones localizadas en la ‘corteza elocuente’. La identificación de fenotipos anatomoelectroclínicos de DCF permite establecer abordajes quirúrgicos y expectativas de pronóstico posquirúrgico adecuadas a cada situación, mejor en las DCF IIb transmantle y en las displasias de fondo de surco que en las DCF multilobares, en su mayoría DCF I (AU)

Introduction. Focal cortical dysplasias (FCD) are the first cause of surgery in paediatric epilepsy surgery. The pre-surgical assessment in FCD is often complex, since they are lesions that can be highly epileptogenic and at the same time can preserve neurological functioning and may not be displayed in magnetic resonance imaging. The success of the operation largely depends on the proper identification of the lesion and the possibility of performing a complete resection of the dysplastic tissue. In this work we review the literature related with this topic, in relation to the authors’ experience. Development. The study reviews some of the advances made as regards the pre-surgical assessment and the neurosurgical management of epilepsy in children with FCD; results from the surgical series regarding the classifications of FCD and the post-surgical prognostic factors are commented on; some anatomo-clinical phenotypes that are distinctive in children with FCD and their surgical management are described; and current challenges and the future of the surgical treatment of epilepsy in FCD are also briefly discussed. Conclusions. The advances being made in the methods of pre-surgical diagnosis and surgical procedures are making it possible to offer successful treatment at earlier ages in patients with FCD who were previously considered ‘non-lesional’ and in patients with localised lesions in the ‘eloquent cortex’. The identification of anatomo-electro-clinical phenotypes of FCD makes it possible to establish surgical approaches and post-surgical prognostic expectations that are well suited to each situation, which are better in the transmantle-type FCD IIb and in bottom-of-sulcus dysplasias than in multilobe FCD, which are mostly FCD I (AU)

Surgical and postmortem pathology studies: contribution for the investigation of temporal lobe epilepsy / Patologia cirúrgica e post mortem: contribuição para a investigação da epilepsia do lobo temporal

Pathology studies in epilepsy patients bring useful information for comprehending the physiopathology of various forms of epilepsy, as well as aspects related to response to treatment and long-term prognosis. These studies are usually restricted to surgical specimens obtained from patients with refractory focal epilepsies. Therefore, most of them pertain to temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS) and malformations of cortical development (MCD), thus providing information of a selected group of patients and restricted regions of the brain. Postmortem whole brain studies are rarely performed in epilepsy patients, however they may provide extensive information on brain pathology, allowing the analysis of areas beyond the putative epileptogenic zone. In this article, we reviewed pathology studies performed in epilepsy patients with emphasis on neuropathological findings in TLE with MTS and MCD. Furthermore, we reviewed data from postmortem studies and discussed the importance of performing these studies in epilepsy populations.

Estudos de patologia em pacientes com epilepsia trazem informações úteis para compreender a fisiopatologia de várias formas de epilepsia, bem como aspectos relacionados ao tratamento e ao prognóstico a longo prazo. Esses estudos são usualmente restritos a espécimes cirúrgicos obtidos de pacientes com epilepsias focais refratárias. Portanto, a maioria diz respeito à epilepsia do lobo temporal (ELT) com esclerose mesial temporal (EMT) e às malformações do desenvolvimento cortical (MDC). Desse modo, fornecem informações sobre um grupo selecionado de pacientes e sobre regiões restritas do cérebro. Raramente são realizados estudos post mortem do cérebro inteiro em pacientes com epilepsia; entretanto, eles podem prover informações relevantes sobre patologia cerebral, permitindo a análise de áreas além da zona epileptogênica putativa. Neste artigo, foram revisados estudos de patologia feitos em pacientes com epilepsia, com ênfase nos achados neuropatológicos em ELT com EMT e MDC. Foram revisados, ainda, dados de estudos post mortem e discutiu-se a importância da realização desses estudos em populações de pessoas com epilepsia.

Magnetoencephalography in Pediatric Lesional Epilepsy Surgery

This study was performed to assess the usefulness of magnetoencephalography (MEG) as a presurgical evaluation modality in Korean pediatric patients with lesional localization-related epilepsy. The medical records and MEG findings of 13 pediatric patients (6 boys and 7 girls) with localization-related epilepsy, who underwent epilepsy surgery at Seoul National University Children's Hospital, were retrospectively reviewed. The hemispheric concordance rate was 100% (13/13 patients). The lobar or regional concordance rate was 77% (10/13 patients). In most cases, the MEG spike sources were clustered in the proximity of the lesion, either at one side of the margin (nine patients) or around the lesion (one patient); clustered spike sources were distant from the lesion in one patient. Among the patients with clustered spike sources near the lesion, further extensions (three patients) and distal scatters (three patients) were also observed. MEG spike sources were well lateralized and localized even in two patients without focal epileptiform discharges in the interictal scalp electroencephalography. Ten patients (77%) achieved Engel class I postsurgical seizure outcome. It is suggested that MEG is a safe and useful presurgical evaluation modality in pediatric patients with lesion localization-related epilepsy.

Recent progress in epilepsy in neuropathology / 法医学杂志

Epilepsy is a common cerebral disease, and may cause sudden death. Although electric activity study of epileptic brain had been emphasized in the past, the neuropathological study of epilepsy has become a main focus in clinical and forensic medicine recently. This article reviews the recent progress in neuropathology of epilepsy including developmental disorder, abnormal tumoral proliferation, hippocampal sclerosis, dual pathological alteration, and mossy fiber sprouting. Its significance in forensic medicine, particularly for the diagnosis of sudden unexpected death in epilepsy, is discussed.