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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.
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Imagen por Resonancia Magnética , Humanos , Femenino , Masculino , Imagen por Resonancia Magnética/métodos , Niño , Adolescente , Preescolar , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/cirugía , Malformaciones del Desarrollo Cortical/patología , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/cirugía , Epilepsia Refractaria/patología , Malformaciones del Desarrollo Cortical de Grupo I/diagnóstico por imagen , Malformaciones del Desarrollo Cortical de Grupo I/cirugía , Displasia Cortical FocalRESUMEN
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.
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Malformaciones del Desarrollo Cortical , Organoides , Proteínas Proto-Oncogénicas c-akt , Humanos , Organoides/metabolismo , Organoides/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/patología , Malformaciones del Desarrollo Cortical/metabolismo , Células Madre Embrionarias Humanas/metabolismo , Transducción de Señal/genética , Corteza Cerebral/patología , Corteza Cerebral/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Mutación , Neuronas/metabolismo , Neuronas/patología , Línea CelularRESUMEN
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.
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Discapacidad Intelectual , Proteínas de la Membrana , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Femenino , Masculino , Trastornos del Neurodesarrollo/genética , Alelos , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/patología , Niño , Preescolar , Diferenciación Celular/genética , Proteínas Supresoras de TumorRESUMEN
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.
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Epilepsia del Lóbulo Temporal , Hipocampo , Adulto , Humanos , Epilepsia , Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/patología , Hipocampo/patología , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical/diagnóstico , Malformaciones del Desarrollo Cortical/patología , Malformaciones del Desarrollo Cortical de Grupo I/diagnóstico , Malformaciones del Desarrollo Cortical de Grupo I/patologíaRESUMEN
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.
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Malformaciones del Desarrollo Cortical , Serina-Treonina Quinasas TOR , Humanos , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/patología , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Epilepsia Refractaria/patología , Epilepsia Refractaria/genética , Mutación , Corteza Cerebral/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Sustancia Blanca/patología , Sustancia Blanca/diagnóstico por imagen , Neuroimagen/métodosRESUMEN
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.
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Epilepsia Refractaria , Epilepsias Parciales , Epilepsia , Malformaciones del Desarrollo Cortical de Grupo I , Malformaciones del Desarrollo Cortical , Adulto , Humanos , Epilepsia Refractaria/genética , Epilepsia Refractaria/cirugía , Serina-Treonina Quinasas TOR , Epilepsias Parciales/genética , Epilepsias Parciales/diagnóstico , Convulsiones , Células Germinativas/patología , Malformaciones del Desarrollo Cortical/patologíaRESUMEN
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.
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Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Esclerosis del Hipocampo , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Epilepsia Refractaria/genética , Epilepsia Refractaria/etiología , Epilepsia Refractaria/patología , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/patología , Filaminas/genética , Variación Genética , Esclerosis del Hipocampo/genética , Esclerosis del Hipocampo/patología , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/complicaciones , Malformaciones del Desarrollo Cortical/patologíaRESUMEN
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.
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Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical , Humanos , Imagen por Resonancia Magnética/métodos , Femenino , Masculino , Adulto , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/patología , Adolescente , Adulto Joven , Epilepsias Parciales/diagnóstico por imagen , Epilepsias Parciales/patología , Persona de Mediana Edad , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/patología , Imagenología Tridimensional/métodos , Niño , Reacciones Falso Positivas , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Procesamiento de Imagen Asistido por Computador/métodos , Displasia Cortical FocalRESUMEN
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.
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Movimiento Celular , Modelos Animales de Enfermedad , Malformaciones del Desarrollo Cortical , N-Metilaspartato , Neuronas , Ratas Sprague-Dawley , Animales , Ratas , N-Metilaspartato/toxicidad , Femenino , Embarazo , Movimiento Celular/efectos de los fármacos , Neuronas/patología , Neuronas/efectos de los fármacos , Malformaciones del Desarrollo Cortical/inducido químicamente , Malformaciones del Desarrollo Cortical/patología , Animales Recién Nacidos , Acetato de Metilazoximetanol/toxicidad , Acetato de Metilazoximetanol/análogos & derivados , Corteza Cerebral/patología , Corteza Cerebral/efectos de los fármacos , Masculino , Imagen por Resonancia MagnéticaRESUMEN
INTRODUCTION: Rasmussen's encephalitis (RE) is a rare, predominantly pediatric epilepsy disorder of unknown etiology. It classically affects one of the cerebral hemispheres and histologically shows cortical chronic inflammation, gliosis, and neuronal loss. The etiopathogenesis of RE remains unknown, with genetic, infectious, and autoimmune factors all speculated to play a role. Although the histologic findings in RE are well described, few studies have investigated a large cohort of cases looking for the coexistence of RE with focal cortical dysplasia (FCD). DESIGN: The study is a retrospective review of RE patients who underwent surgical resection of brain tissue between 1979 and 2021. Relevant patient history was retrieved, and available histologic slides were reviewed. The histologic severity of RE was described according to the Pardo criteria. In cases where FCD was present, the observed patterns of FCD (namely Ia, Ib, IIa, IIb, etc.) were described using the International League Against Epilepsy (ILAE) classification. RESULTS: Thirty-eight resection specimens from 31 patients formed the study cohort. Seventeen patients (54.8 %) were male; average age at surgery was 8 years (range: 2-28 years). Twenty-seven resection specimens (71.1 %) from 23 patients (74 %) showed evidence of coexistent FCD. Most cases with FCD resembled the ILAE type Ib (n = 23) pattern. Cases of RE that did not show FCD were either Pardo stage 1 (n = 5) or 4 (n = 6), with all Pardo stage 2 and 3 cases demonstrating FCD. CONCLUSIONS: FCD was found in most patients with RE (74 %). The most observed pattern of FCD was ILAE Ib.
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Encefalitis , Epilepsia , Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Niño , Humanos , Masculino , Preescolar , Adolescente , Adulto Joven , Adulto , Femenino , Epilepsia/complicaciones , Epilepsia/patología , Encefalitis/complicaciones , Estudios Retrospectivos , Inflamación , Malformaciones del Desarrollo Cortical/complicaciones , Malformaciones del Desarrollo Cortical/patología , Malformaciones del Desarrollo Cortical/cirugía , Imagen por Resonancia MagnéticaRESUMEN
Focal cortical dysplasia (FCD) is a cortical malformation in brain development and is considered as one of the major causes of drug-resistant epilepsiesin children and adults. The pathogenesis of FCD is yet to be fully understood. Imaging markers such as MRI are currently the surgeons major obstacle due to the difficulty in delimiting the precise dysplasic area and a mosaic brain where there is epileptogenic tissue invisible to MRI. Also increased gene expression and activity may be responsible for the alterations in cell proliferation, migration, growth, and survival. Altered expressions were found, particularly in the PI3K/AKT/mTOR pathway. Surgery is still considered the most effective treatment option, due to drug-resistance, and up to 60 % of patients experience complete seizure control, varying according to the type and location of FCD. Both genetic and epigenetic factors may be involved in the pathogenesis of FCD, and there is no conclusive evidence whether these alterations are inherited or have an environmental origin.
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Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Adulto , Niño , Humanos , Fosfatidilinositol 3-Quinasas , Encéfalo/patología , Convulsiones/patología , Resultado del Tratamiento , Imagen por Resonancia Magnética/métodos , Biomarcadores , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/patología , Estudios RetrospectivosRESUMEN
OBJECTIVE: To evaluate whether ictal phase-amplitude coupling (PAC) between high-frequency activity and low-frequency activity could be used as a preoperative biomarker of Focal Cortical Dysplasia (FCD) subtypes. We hypothesize that FCD seizures present unique PAC characteristics that may be linked to their specific histopathological features. METHODS: We retrospectively examined 12 children with FCD and refractory epilepsy who underwent successful epilepsy surgery. We identified ictal onsets recorded with stereo-EEG. We estimated the strength of PAC between low-frequencies and high-frequencies for each seizure by means of modulation index. Generalized mixed effect models and receiver operating characteristic (ROC) curve analysis were used to test the association between ictal PAC and FCD subtypes. RESULTS: Ictal PAC was significantly higher in patients with FCD type II compared to type I, only on SOZ-electrodes (p < 0.005). No differences in ictal PAC were found on non-SOZ electrodes. Pre-ictal PAC registered on SOZ electrodes predicted FCD histopathology with a classification accuracy > 0.9 (p < 0.05). CONCLUSIONS: The correlations between histopathology and neurophysiology provide evidence for the contribution of ictal PAC as a preoperative biomarker of FCD subtypes. SIGNIFICANCE: Developed into a proper clinical application, such a technique may help improve clinical management and facilitate the prediction of surgical outcome in patients with FCD undergoing stereo-EEG monitoring.
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Epilepsia , Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Niño , Humanos , Estudios Retrospectivos , Epilepsia/cirugía , Convulsiones , Biomarcadores , Malformaciones del Desarrollo Cortical/diagnóstico , Malformaciones del Desarrollo Cortical/cirugía , Malformaciones del Desarrollo Cortical/patología , Electroencefalografía , Imagen por Resonancia MagnéticaRESUMEN
Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.
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Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Humanos , Reproducibilidad de los Resultados , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/patología , Encéfalo/patología , Imagen por Resonancia Magnética/métodosRESUMEN
The cerebral cortex represents a laminar structure of precisely spatially organized neurons in horizontal layers and vertical columns. Neurogenesis, neuronal migration and neuronal wiring are tightly regulated and coordinated procedures that result in the accurate formation of the human cerebral cortex. Abnormal fetal corticogenesis results in several types of migration and gyration anomalies, known as malformations of cortical development, which have long been a topic of investigation. According to the stage of cortical development that is affected, with diverse genetic and non-genetic etiologies, these malformations can cause abnormal head size, abnormal brain surface and abnormal cortical layering with various degrees of neurodevelopmental delay and epilepsy. The pathogenesis of these malformations is multifactorial and includes genetic mutations or environmental insults, acquired either in utero at varying stages of brain development or during the perinatal period after corticogenesis. In this article, we focus on cortical malformations detected on fetal MRI. We present the main antenatal findings that should raise suspicion for malformations of cortical development, together with findings that might be missed on prenatal imaging and describe the correlations between fetal and postnatal MRI.
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Epilepsia , Malformaciones del Desarrollo Cortical , Embarazo , Humanos , Femenino , Encéfalo/diagnóstico por imagen , Encéfalo/anomalías , Imagen por Resonancia Magnética/métodos , Feto/patología , Malformaciones del Desarrollo Cortical/complicaciones , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical/patologíaRESUMEN
Dendritic spines are the postsynaptic sites for most excitatory glutamatergic synapses. We previously demonstrated a severe spine loss and synaptic reorganization in human neocortices presenting Type II focal cortical dysplasia (FCD), a developmental malformation and frequent cause of drug-resistant focal epilepsy. We extend the findings, investigating the potential role of complement components C1q and C3 in synaptic pruning imbalance. Data from Type II FCD were compared with those obtained in focal epilepsies with different etiologies. Neocortical tissues were collected from 20 subjects, mainly adults with a mean age at surgery of 31 years, admitted to epilepsy surgery with a neuropathological diagnosis of: cryptogenic, temporal lobe epilepsy with hippocampal sclerosis, and Type IIa/b FCD. Dendritic spine density quantitation, evaluated in a previous paper using Golgi impregnation, was available in a subgroup. Immunohistochemistry, in situ hybridization, electron microscopy, and organotypic cultures were utilized to study complement/microglial activation patterns. FCD Type II samples presenting dendritic spine loss were characterized by an activation of the classical complement pathway and microglial reactivity. In the same samples, a close relationship between microglial cells and dendritic segments/synapses was found. These features were consistently observed in Type IIb FCD and in 1 of 3 Type IIa cases. In other patient groups and in perilesional areas outside the dysplasia, not presenting spine loss, these features were not observed. In vitro treatment with complement proteins of organotypic slices of cortical tissue with no sign of FCD induced a reduction in dendritic spine density. These data suggest that dysregulation of the complement system plays a role in microglia-mediated spine loss. This mechanism, known to be involved in the removal of redundant synapses during development, is likely reactivated in Type II FCD, particularly in Type IIb; local treatment with anticomplement drugs could in principle modify the course of disease in these patients.
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Epilepsia Refractaria , Epilepsia , Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Adulto , Humanos , Espinas Dendríticas/patología , Vía Clásica del Complemento , Malformaciones del Desarrollo Cortical/patología , Epilepsia/patología , Epilepsia Refractaria/patologíaRESUMEN
BACKGROUND: Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) show persistent neuroinflammation, which promotes epileptogenesis and epilepsy progression, suggesting that endogenous resolution of inflammation is inadequate to relieve neuronal network hyperexcitability. To explore the potential roles of formyl peptide receptor 2 (FPR2), which is a key regulator of inflammation resolution, in epilepsy caused by FCDIIb and TSC, we examined the expression and cellular distribution of FPR2. METHOD: The expression of FPR2 and nuclear factor-κB (NF-κB) signaling pathway was examined by real-time PCR, western blots, and analyzed via one-way analysis of variance. The distribution of FPR2 was detected using immunostaining. The expression of resolvin D1 (RvD1, the endogenous ligand of FPR2) was observed via enzyme-linked immunosorbent assay. Pearson's correlation test was used to evaluate the correlation between the expression levels of FPR2 and RvD1 and the clinical variants. RESULTS: The expression of FPR2 was significantly lower in FCDIIb (p = .0146) and TSC (p = .0006) cortical lesions than in controls, as was the expression of RvD1 (FCDIIb: p = .00431; TSC: p = .0439). Weak FPR2 immunoreactivity was observed in dysmorphic neurons (DNs), balloon cells (BCs), and giant cells (GCs) in FCDIIb and TSC tissues. Moreover, FPR2 was mainly distributed in dysplastic neurons; it was sparse in microglia and nearly absent in astrocytes. The NF-κB pathway was significantly activated in patients with FCDIIb and TSC, and the protein level of NF-κB was negatively correlated with the protein level of FPR2 (FCDIIb: p = .00395; TSC: p = .0399). In addition, the protein level of FPR2 was negatively correlated with seizure frequency in FCDIIb (p = .0434) and TSC (p = .0351) patients. CONCLUSION: In summary, these results showed that the expression and specific distribution of FPR2 may be involved in epilepsy caused by FCDIIb and TSC, indicating that downregulation of FPR2 mediated the dysfunction of neuroinflammation resolution in FCDIIb and TSC.
Asunto(s)
Epilepsia , Malformaciones del Desarrollo Cortical , Esclerosis Tuberosa , Humanos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Epilepsia/genética , Epilepsia/metabolismo , Inflamación/patología , Malformaciones del Desarrollo Cortical/metabolismo , Malformaciones del Desarrollo Cortical/patología , FN-kappa B/metabolismo , Receptores de Formil Péptido/genética , Receptores de Formil Péptido/metabolismo , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/metabolismoRESUMEN
OBJETIVE: Analyze pre-surgical evaluation modalities, surgical failures, long-term results of surgery and neurocognitive outcome in children with Low-grade Epilepsy Associated brain Tumors (LEAT). METHODS: Retrospective observational study of 37 children who underwent epilepsy surgery, with a minimum follow-up of 12 months. At time of surgery, pharmaco-sensitivity (Group 1; n = 8) and drug-resistance (Group 2; n = 29), were considered. RESULTS: Age range of seizure onset was 5 months-14 years (mean 5.73years) and age at surgery was 2.2-18.7years (mean 10.7years). Gangliogliomas (35.1%) or DNTs (29.7%), combined or not to a focal cortical dysplasia (FCD), were the most frequent. Extended lesionectomy 16 children (43.2%) were the most frequently used surgical approach in both groups. At one year of follow-up, 36 children (97.2%) were classified as Engel I. Within the age-range studied, duration of epilepsy and time to surgery appeared to have no impact on clinical and neurocognitive outcome in both groups. It is noteworthy, however, that antiseizure medications (ASMs) were withdrawn in 100% of the pharmacosensitive group vs 34.5% of the drug-resistant group (p = 0.002). In children with a pharmaco-sensitive epilepsy, neurocognitive evaluation showed significant improvement in the verbal comprehension index (p = 0.029). CONCLUSIONS: Epilepsy-surgery is a safe therapeutic option for LEATs including for children with seizures controlled by ASMs. Presence of associated lesions is not rare. Comprehensive pre-surgical evaluation increases the chances for control of the seizures, the early discontinuation of medications and favours neurocognitive development.
Asunto(s)
Neoplasias Encefálicas , Epilepsia , Malformaciones del Desarrollo Cortical , Niño , Humanos , Lactante , Epilepsia/etiología , Epilepsia/cirugía , Epilepsia/patología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Convulsiones/etiología , Convulsiones/cirugía , Encéfalo/patología , Malformaciones del Desarrollo Cortical/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: To analyze structural characteristics of malformations of cortical development (MCD) at 7T and 3T MRI. METHODS: Twenty-five patients were examined with a 7T MRI-scanner in addition to 3T examinations performed for epilepsy evaluation. 7T sequences included a 3D-T1-weighted (T1w) MPRAGE, 3D-T2w FLAIR, and heavily T2w axial and coronal high-resolution (0.5 × 0.5 × 0.75-1.0 mm3) 2D-TSE sequences. Images were reviewed for 7T MRI imaging characteristics of MCD, visibility and frequency of identified lesions on 7T and on 3T (original reports and second reading). RESULTS: In 25 patients 112 lesions were identified (57 gray matter (GM) heterotopia, 37 focal cortical dysplasia (FCD), and 18 other MCD). Imaging characteristics of the 37 FCD were cortical thickening (n = 11); GM-WM border blurring (n = 30); GM signal intensity changes (n = 18); juxtacortical WM signal intensity changes (n = 18); and transmantle WM signal intensity changes (n = 11). None of the 7T MRI sequences was sufficient to detect all types of lesions. Heterotopia were in general isointense to normal GM. Structural associations between 36 heterotopia and overlaying cortex were observed, composed either of a direct connection, vessel-like structures, or GM-like bridges. FCD were mentioned in 30% (11 of 37) of the original reports at 3T, and in 57% (21 of 37) after second reading. FCD connections to subcortical heterotopia were clinically not reported at all. CONCLUSION: 7T MRI revealed subtle connections between heterotopia and previous unidentified pathology in overlaying cortex. These findings may be significant for the understanding of the anatomical seizure origin and propagation pathways.
Asunto(s)
Epilepsias Parciales , Epilepsia , Malformaciones del Desarrollo Cortical , Epilepsias Parciales/diagnóstico por imagen , Epilepsias Parciales/patología , Epilepsia/diagnóstico por imagen , Epilepsia/patología , Humanos , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/patologíaRESUMEN
INTRODUCTION: Focal cortical dysplasia (FCD) is a most common cause of intractable focal epilepsy in children. Surgery is considered as a radical option for such patients with the prerequisite of lesion detection. Magnetic resonance imaging (MRI) plays a significant role in detection of FCDs in epilepsy patients; however, the detection of FCDs even in epilepsy dedicated MRI sequence shows relatively low positive rate. Last year, Middlebrooks et al introduced the novel three-dimensional Edge-Enhancing Gradient Echo (3D-EDGE) MRI sequence and using this sequence successfully identified five cases of FCDs which indicates its potential role in those epilepsy patients who may have FCDs. CASE PRESENTATION: We present a 14-year-old, right-handed, male patient who has suffered from drug-resistant epilepsy over the past 3 years. It was unable to localize the lesion of the seizure, even using the series of epilepsy dedicated MRI sequences. Inspired by the previous report, the lesion of the seizure was successfully targeted by 3D-EDGE sequence. Combined with intraoperative navigation and precisely removed the lesion. He was uneventfully recovered with no signs of cerebral dysfunction and no seizure recurrence 8 months after surgery. CONCLUSION: The 3D-EDGE sequences show a higher sensitivity for FCD detection in epilepsy patients compared with a series of epilepsy-dedicated MRI protocols. We confirmed that the study by Middlebrooks et al is of great clinical value. If the findings on routine MRI sequences or even epilepsy-dedicated MRI sequences were reported as negative, however, the semiology, video-electroencephalography, and fluorodeoxyglucose-positron emission tomography results suggest a local abnormality, and the results are concordant with each other, a 3D-EDGE sequence may be a good option.