RESUMEN
The identification of the epileptogenic zone (EZ) boundaries is crucial for effective focal epilepsy surgery. We verify the value of a neurophysiological biomarker of focal ictogenesis, characterized by a low-voltage fast-activity ictal pattern (chirp) recorded with intracerebral electrodes during invasive presurgical monitoring (stereoelectroencephalography [SEEG]). The frequency content of SEEG signals was retrospectively analyzed with semiautomatic software in 176 consecutive patients with focal epilepsies that either were cryptogenic or presented with discordant anatomoelectroclinical findings. Fast activity seizure patterns with the spectrographic features of chirps were confirmed by computer-assisted analysis in 95.4% of patients who presented with heterogeneous etiologies and diverse lobar location of the EZ. Statistical analysis demonstrated (1) correlation between seizure outcome and concordance of sublobar regions included in the EZ defined by visual analysis and chirp-generating regions, (2) high concordance in contact-by contact analysis of 68 patients with Engel class Ia outcome, and (3) that discordance between chirp location and the visually outlined EZ correlated with worse seizure outcome. Seizure outcome analysis confirms the fast activity chirp pattern is a reproducible biomarker of the EZ in a heterogeneous group of patients undergoing SEEG.
Asunto(s)
Electroencefalografía , Epilepsias Parciales , Humanos , Femenino , Masculino , Adulto , Epilepsias Parciales/fisiopatología , Epilepsias Parciales/cirugía , Epilepsias Parciales/diagnóstico , Electroencefalografía/métodos , Estudios Retrospectivos , Adolescente , Persona de Mediana Edad , Adulto Joven , Niño , Electrodos Implantados , Preescolar , Electrocorticografía/métodosRESUMEN
OBJECTIVE: Encephaloceles (ENCs) may cause clinical complications, including drug-resistant epilepsy that can be cured with epilepsy surgery. METHODS: We describe clinical, diagnostic, and neuropathological findings of 12 patients with temporal ENC and epilepsy evaluated for surgery and compare them with a control group of 26 temporal lobe epilepsy (TLE) patients. RESULTS: Six patients had unilateral and 6 bilateral temporal ENCs. Compared to TLEs, ENCs showed i) later epilepsy onset, ii) higher prevalence of psychiatric comorbidities, iii) no history of febrile convulsions, and iv) ictal semiology differences. Seven patients had MRI signs of gliosis, and 9 of intracranial hypertension. Interictal EEG analysis in ENCs demonstrated significant differences with controls: prominent activity in the beta/gamma frequency bands in frontal regions, interictal short sequences of low-voltage fast activity, and less frequent and more localized interictal epileptiform discharges. Ictal EEG patterns analyzed in 9 ENCs showed delayed and slower contralateral spread compared to TLEs. All ENCs that underwent surgery (7 lobectomies and 1 lesionectomy) are in Engel class I. Neuropathological examination revealed 4 patterns: herniated brain fragments, focal layer I distortion, white matter septa extending into the cortex, and altered gyral profile. CONCLUSIONS AND SIGNIFICANCE: The described peculiarities might help clinicians to suspect the presence of largely underdiagnosed ENCs.
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Epilepsia del Lóbulo Temporal , Epilepsia , Humanos , Electroencefalografía/métodos , Encefalocele/complicaciones , Encefalocele/diagnóstico por imagen , Epilepsia/diagnóstico por imagen , Epilepsia/etiología , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/cirugía , Neuroimagen , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND AND OBJECTIVES: To report the progressive introduction of the exoscope (EX) from surface lesionectomy to antero-mesial temporal lobectomy (AMTL) in an epilepsy surgery practice. METHODS: We describe a population of ten consecutive patients undergoing EX surgery, with a minimum follow-up of 6 months, that was compared to a similar population of patients referred to operative microscopic surgery (OM). RESULTS: All surgeries were performed with the use of EX or OM alone. Transient neurological complications for surgery in eloquent regions were recorded in one patient for each population. Nine and seven patients undergoing, respectively, EX and OM surgery resulted in Engel class Ia (90% vs. 70%). The mean duration of EX and OM surgery resulted in 265.5 and 237.9 min, respectively, with a mean of 308.3 and 253.3 min for AMTL cases, respectively. CONCLUSIONS: This preliminary study revealed that ORBEYE EX can be safe and effective in different types of epilepsy surgeries. The transition from OM to EX is fast, even though it is slower for the more challenging mesial temporal structure removal. Ergonomic and operative team interaction is improved by the use of EX. Our data need to be confirmed by larger studies.
Asunto(s)
Epilepsia del Lóbulo Temporal , Epilepsia , Psicocirugía , Humanos , Epilepsia del Lóbulo Temporal/cirugía , Resultado del Tratamiento , Epilepsia/cirugía , Lobectomía Temporal Anterior , Estudios RetrospectivosRESUMEN
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.
Asunto(s)
Epilepsia , Malformaciones del Desarrollo Cortical de Grupo I , Malformaciones del Desarrollo Cortical , Consenso , Epilepsia/diagnóstico , Epilepsia/patología , Humanos , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/genética , Malformaciones del Desarrollo Cortical de Grupo I/diagnóstico , Neuroimagen , Estudios RetrospectivosRESUMEN
Neuronal dendritic arborizations and dendritic spines are crucial for a normal synaptic transmission and may be critically involved in the pathophysiology of epilepsy. Alterations in dendritic morphology and spine loss mainly in hippocampal neurons have been reported both in epilepsy animal models and in human brain tissues from patients with epilepsy. However, it is still unclear whether these dendritic abnormalities relate to the cause of epilepsy or are generated by seizure recurrence. We investigated fine neuronal structures at the level of dendritic and spine organization using Golgi impregnation, and analysed synaptic networks with immunohistochemical markers of glutamatergic (vGLUT1) and GABAergic (vGAT) axon terminals in human cerebral cortices derived from epilepsy surgery. Specimens were obtained from 28 patients with different neuropathologically defined aetiologies: type Ia and type II focal cortical dysplasia, cryptogenic (no lesion) and temporal lobe epilepsy with hippocampal sclerosis. Autoptic tissues were used for comparison. Three-dimensional reconstructions of Golgi-impregnated neurons revealed severe dendritic reshaping and spine alteration in the core of the type II focal cortical dysplasia. Dysmorphic neurons showed increased dendritic complexity, reduction of dendritic spines and occasional filopodia-like protrusions emerging from the soma. Surprisingly, the intermingled normal-looking pyramidal neurons also showed severe spine loss and simplified dendritic arborization. No changes were observed outside the dysplasia (perilesional tissue) or in neocortical postsurgical tissue obtained in the other patient groups. Immunoreactivities of vGLUT1 and vGAT showed synaptic reorganization in the core of type II dysplasia characterized by the presence of abnormal perisomatic baskets around dysmorphic neurons, in particular those with filopodia-like protrusions, and changes in vGLUT1/vGAT expression. Ultrastructural data in type II dysplasia highlighted the presence of altered neuropil engulfed by glial processes. Our data indicate that the fine morphological aspect of neurons and dendritic spines are normal in epileptogenic neocortex, with the exception of type II dysplastic lesions. The findings suggest that the mechanisms leading to this severe form of cortical malformation interfere with the normal dendritic arborization and synaptic network organization. The data argue against the concept that long-lasting epilepsy and seizure recurrence per se unavoidably produce a dendritic pathology.
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Corteza Cerebral/ultraestructura , Dendritas/ultraestructura , Espinas Dendríticas/ultraestructura , Epilepsia/patología , Sinapsis/ultraestructura , Adolescente , Adulto , Corteza Cerebral/metabolismo , Preescolar , Humanos , Lactante , Microscopía Electrónica , Persona de Mediana Edad , Sinapsis/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismo , Adulto JovenRESUMEN
Loss of myelin and altered oligodendrocyte distribution in the cerebral cortex are commonly observed both in postsurgical tissue derived from different focal epilepsies (such as focal cortical dysplasias and tuberous sclerosis) and in animal models of focal epilepsy. Moreover, seizures are a frequent symptom in demyelinating diseases, such as multiple sclerosis, and in animal models of demyelination and oligodendrocyte dysfunction. Finally, the excessive activity reported in demyelinated axons may promote hyperexcitability. We hypothesize that the extracellular potassium rise generated during epileptiform activity may be amplified by the presence of axons without appropriate myelin coating and by alterations in oligodendrocyte function. This process could facilitate the triggering of recurrent spontaneous seizures in areas of altered myelination and could result in further demyelination, thus promoting epileptogenesis.
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Axones/patología , Enfermedades Desmielinizantes/complicaciones , Convulsiones/etiología , Animales , Enfermedades Desmielinizantes/patología , Epilepsia/etiología , Humanos , Modelos Biológicos , Vaina de Mielina/fisiologíaRESUMEN
OBJECTIVE: Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme. METHODS: Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients. RESULTS: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa = .65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases. SIGNIFICANCE: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype-phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype-phenotype diagnosis in the near future.
Asunto(s)
Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/patología , Adolescente , Adulto , Edad de Inicio , Diversidad de Anticuerpos , Encéfalo/patología , Niño , Preescolar , Técnica Delphi , Femenino , Genotipo , Humanos , Inmunohistoquímica , Lactante , Imagen por Resonancia Magnética , Masculino , Malformaciones del Desarrollo Cortical/cirugía , Persona de Mediana Edad , Mutación/genética , Procedimientos Neuroquirúrgicos , Variaciones Dependientes del Observador , Fenotipo , Convulsiones/etiología , Adulto JovenRESUMEN
Epilepsy is a pathologic condition with high prevalence and devastating consequences for the patient and its entourage. Means for accurate diagnosis of type, patient monitoring for predicting seizures and follow up, and efficacious treatment are desperately needed. To improve this adverse outcome, miRNAs and the chaperone system (CS) are promising targets to understand pathogenic mechanisms and for developing theranostics applications. miRNAs implicated in conditions known or suspected to favor seizures such as neuroinflammation, to promote epileptic tolerance and neuronal survival, to regulate seizures, and others showing variations in expression levels related to seizures are promising candidates as useful biomarkers for diagnosis and patient monitoring, and as targets for developing novel therapies. Components of the CS are also promising as biomarkers and as therapeutic targets, since they participate in epileptogenic pathways and in cytoprotective mechanisms in various epileptogenic brain areas, even if what they do and how is not yet clear. The data in this review should help in the identification of molecular targets among the discussed miRNAs and CS components for research aiming at understanding epileptogenic mechanisms and, subsequently, develop means for predicting/preventing seizures and treating the disease.
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Epilepsia/metabolismo , Proteínas de Choque Térmico/metabolismo , MicroARNs/metabolismo , Animales , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Epilepsia/patología , Proteínas de Choque Térmico/genética , Humanos , MicroARNs/genéticaRESUMEN
Immune changes occur in experimental and clinical epilepsy. Here, we tested the hypothesis that during epileptogenesis and spontaneous recurrent seizures (SRS) an impairment of the endogenous anti-inflammatory pathway glucocorticoid receptor (GR)-annexin A1 (ANXA1) occurs. By administrating exogenous ANXA1, we studied whether pharmacological potentiation of the anti-inflammatory response modifies seizure activity and pathophysiology. We used an in vivo model of temporal lobe epilepsy based on intrahippocampal kainic acid (KA) injection. Video-electroencephalography, molecular biology analyses on brain and peripheral blood samples, and pharmacological investigations were performed in this model. Human epileptic cortices presenting type II focal cortical dysplasia (IIa and b), hippocampi with or without hippocampal sclerosis (HS), and available controls were used to study ANXA1 expression. A decrease of phosphorylated (phospho-) GR and phospho-GR/tot-GR protein expression occurred in the hippocampus during epileptogenesis. Downstream to GR, the anti-inflammatory protein ANXA1 remained at baseline levels while inflammation installed and endured. In peripheral blood, ANXA1 and corticosterone levels showed no significant modifications during disease progression except for an early and transient increase poststatus epilepticus. These results indicate inadequate ANXA1 engagement over time and in these experimental conditions. By analyzing human brain specimens, we found that where significant inflammation exists, the pattern of ANXA1 immunoreactivity was abnormal because the typical perivascular ANXA1 immunoreactivity was reduced. We next asked whether potentiation of the endogenous anti-inflammatory mechanism by ANXA1 administration modifies the disease pathophysiology. Although with varying efficacy, administration of exogenous ANXA1 somewhat reduced the time spent in seizure activity as compared to saline. These results indicate that the anti-inflammatory GR-ANXA1 pathway is defective during experimental seizure progression. The prospect of pharmacologically restoring or potentiating this endogenous anti-inflammatory mechanism as an add-on therapeutic strategy for specific forms of epilepsy is proposed.-Zub, E., Canet, G., Garbelli, R., Blaquiere, M., Rossini, L., Pastori, C., Sheikh, M., Reutelingsperger, C., Klement, W., de Bock, F., Audinat, E., Givalois, L., Solito, E., Marchi, N. The GR-ANXA1 pathway is a pathological player and a candidate target in epilepsy.
Asunto(s)
Anexina A1/metabolismo , Epilepsia , Receptores de Glucocorticoides/metabolismo , Animales , Anexina A1/genética , Recuento de Células Sanguíneas , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Corticosterona/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Hipocampo , Humanos , Inflamación/metabolismo , Inflamación/patología , Ácido Kaínico/administración & dosificación , Ácido Kaínico/farmacología , Ratones , Ratones Endogámicos C57BL , Receptores de Glucocorticoides/genéticaRESUMEN
OBJECTIVE: Activity-dependent changes have been reported in animal models and in human epileptic specimens and could potentially be used as tissue biomarkers to evaluate the propensity of a tissue to generate seizure activity. In this context, cAMP-response element binding protein (CREB) activation was specifically reported in human epileptic foci and related mainly to interictal spike activity. To get further insights into CREB activation in human epilepsy, we analyzed pCREB expression on brain tissue samples from patients who underwent surgery for drug-resistant focal epilepsy, correlating this expression with intracranial stereo-electroencephalography (SEEG) recording in a subgroup. METHODS: Neocortical specimens from patients with neuropathological diagnosis of no lesion (cryptogenic), malformations of cortical development,mainly type II focal cortical dysplasia (FCD), and hippocampi with and without hippocampal sclerosis have been analyzed by immunohistochemistry. Peritumoral cortex from non-epileptic patients and autoptic samples were used as controls, whereas rat brains were used to test possible loss of pCREB antigenicity due to fixation procedures and postmortem delay. RESULTS: pCREB was consistently expressed in layer II neuronal nuclei in regions with normal cortical lamination both in epileptic and non-epileptic surgical tissues. In patients with SEEG recordings, this anatomical pattern was unrelated to the presence of interictal spike activity. Conversely, in the core of type II FCD, as well as in other developmental malformations, pCREB was scattered without any laminar specificity. Furthermore, quantitative data did not reveal significant differences between epileptic and non-epileptic tissues, except for an increased immunoreactivity in the core of type IIB FCD lesion related mainly to reactive glial and balloon cells. SIGNIFICANCE: The present data argue against the reliability of pCREB immunohistochemistry as a marker of epileptic focus but underscores its layer-related expression, suggesting a potential application in the study of malformations of cortical development, a wide range of diseases arising from perturbations of normal brain development.
Asunto(s)
Encéfalo/metabolismo , Encéfalo/cirugía , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/biosíntesis , Epilepsia Refractaria/metabolismo , Epilepsia Refractaria/cirugía , Adolescente , Adulto , Anciano , Animales , Encéfalo/patología , Preescolar , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Epilepsia Refractaria/genética , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Ratas , Ratas Sprague-Dawley , Técnicas EstereotáxicasRESUMEN
OBJECTIVE: Drebrins are crucial for synaptic function and dendritic spine development, remodeling, and maintenance. In temporal lobe epilepsy (TLE) patients, a significant hippocampal synaptic reorganization occurs, and synaptic reorganization has been associated with hippocampal hyperexcitability. This study aimed to evaluate, in TLE patients, the hippocampal expression of drebrin using immunohistochemistry with DAS2 or M2F6 antibodies that recognize adult (drebrin A) or adult and embryonic (pan-drebrin) isoforms, respectively. METHODS: Hippocampal sections from drug-resistant TLE patients with hippocampal sclerosis (HS; TLE, n = 33), of whom 31 presented with type 1 HS and two with type 2 HS, and autopsy control cases (n = 20) were assayed by immunohistochemistry and evaluated for neuron density, and drebrin A and pan-drebrin expression. Double-labeling immunofluorescences were performed to localize drebrin A-positive spines in dendrites (MAP2), and to evaluate whether drebrin colocalizes with inhibitory (GAD65) and excitatory (VGlut1) presynaptic markers. RESULTS: Compared to controls, TLE patients had increased pan-drebrin in all hippocampal subfields and increased drebrin A-immunopositive area in all hippocampal subfields but CA1. Drebrin-positive spine density followed the same pattern as total drebrin quantification. Confocal microscopy indicated juxtaposition of drebrin-positive spines with VGlut1-positive puncta, but not with GAD65-positive puncta. Drebrin expression in the dentate gyrus of TLE cases was associated negatively with seizure frequency and positively with verbal memory. TLE patients with lower drebrin-immunopositive area in inner molecular layer (IML) than in outer molecular layer (OML) had a lower seizure frequency than those with higher or comparable drebrin-immunopositive area in IML compared with OML. SIGNIFICANCE: Our results suggest that changes in drebrin-positive spines and drebrin expression in the dentate gyrus of TLE patients are associated with lower seizure frequency, more preserved verbal memory, and a better postsurgical outcome.
Asunto(s)
Epilepsia Refractaria/metabolismo , Epilepsia del Lóbulo Temporal/metabolismo , Hipocampo/metabolismo , Neuropéptidos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Lobectomía Temporal Anterior , Región CA1 Hipocampal/metabolismo , Región CA2 Hipocampal/metabolismo , Región CA3 Hipocampal/metabolismo , Estudios de Casos y Controles , Dendritas/metabolismo , Dendritas/patología , Giro Dentado/metabolismo , Epilepsia Refractaria/patología , Epilepsia Refractaria/cirugía , Epilepsia del Lóbulo Temporal/patología , Epilepsia del Lóbulo Temporal/cirugía , Femenino , Glutamato Descarboxilasa/metabolismo , Hipocampo/patología , Hipocampo/cirugía , Humanos , Inmunohistoquímica , Masculino , Microscopía Confocal , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Plasticidad Neuronal , Esclerosis , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
OBJECTIVE: The microscopic review of hematoxylin-eosin-stained images of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex remains challenging. Both entities are distinct subtypes of human malformations of cortical development that share histopathological features consisting of neuronal dyslamination with dysmorphic neurons and balloon cells. We trained a convolutional neural network (CNN) to classify both entities and visualize the results. Additionally, we propose a new Web-based deep learning application as proof of concept of how deep learning could enter the pathologic routine. METHODS: A digital processing pipeline was developed for a series of 56 cases of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex to obtain 4000 regions of interest and 200 000 subsamples with different zoom and rotation angles to train a neural network. Guided gradient-weighted class activation maps (Guided Grad-CAMs) were generated to visualize morphological features used by the CNN to distinguish both entities. RESULTS: Our best-performing network achieved 91% accuracy and 0.88 area under the receiver operating characteristic curve at the tile level for an unseen test set. Novel histopathologic patterns were found through the visualized Guided Grad-CAMs. These patterns were assembled into a classification score to augment decision-making in routine histopathology workup. This score was successfully validated by 11 expert neuropathologists and 12 nonexperts, boosting nonexperts to expert level performance. SIGNIFICANCE: Our newly developed Web application combines the visualization of whole slide images with the possibility of deep learning-aided classification between focal cortical dysplasia IIb and tuberous sclerosis complex. This approach will help to introduce deep learning applications and visualization for the histopathologic diagnosis of rare and difficult-to-classify brain lesions.
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Corteza Cerebral/patología , Aprendizaje Profundo , Epilepsia/patología , Malformaciones del Desarrollo Cortical de Grupo I/patología , Neuronas/patología , Esclerosis Tuberosa/patología , Algoritmos , Área Bajo la Curva , Diagnóstico por Computador , Epilepsia/diagnóstico , Humanos , Internet , Malformaciones del Desarrollo Cortical de Grupo I/diagnóstico , Redes Neurales de la Computación , Neuropatología , Prueba de Estudio Conceptual , Curva ROC , Reproducibilidad de los Resultados , Esclerosis Tuberosa/diagnósticoRESUMEN
BACKGROUND: Cerebrovascular dysfunction and inflammation occur in epilepsy. Here we asked whether pericytes, a pivotal cellular component of brain capillaries, undergo pathological modifications during experimental epileptogenesis and in human epilepsy. We evaluated whether pro-inflammatory cytokines, present in the brain during seizures, contribute to pericyte morphological modifications. METHODS: In vivo, unilateral intra-hippocampal kainic acid (KA) injections were performed in NG2DsRed/C57BL6 mice to induce status epilepticus (SE), epileptogenesis, and spontaneous recurrent seizures (SRS). NG2DsRed mice were used to visualize pericytes during seizure progression. The effect triggered by recombinant IL-1ß, TNFα, or IL-6 on pericytes was evaluated in NG2DsRed hippocampal slices and in human-derived cell culture. Human brain specimens obtained from temporal lobe epilepsy (TLE) with or without sclerosis (HS) and focal cortical dysplasia (FCD-IIb) were evaluated for pericyte-microglial cerebrovascular assembly. RESULTS: A disarray of NG2DsRed+ pericyte soma and ramifications was found 72â¯h post-SE and 1â¯week post-SE (epileptogenesis) in the hippocampus. Pericyte modifications topographically overlapped with IBA1+ microglia clustering around the capillaries with cases of pericytes lodged within the microglial cells. Microglial clustering around the NG2DsRed pericytes lingered at SRS. Pericyte proliferation (Ki67+) occurred 72â¯h post-SE and during epileptogenesis and returned towards control levels at SRS. Human epileptic brain tissues showed pericyte-microglia assemblies with IBA1/HLA microglial cells outlining the capillary wall in TLE-HS and FCD-IIb specimens. Inflammatory mediators contributed to pericyte modifications, in particular IL-1ß elicited pericyte morphological changes and pericyte-microglia clustering in NG2DsRed hippocampal slices. Modifications also occurred when pro-inflammatory cytokines were added to an in vitro culture of pericytes. CONCLUSIONS: These results indicate the occurrence of pericytosis during seizures and introduce a pericyte-microglial mediated mechanism of blood-brain barrier dysfunction in epilepsy.
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Circulación Cerebrovascular/fisiología , Progresión de la Enfermedad , Mediadores de Inflamación/metabolismo , Microglía/metabolismo , Pericitos/metabolismo , Convulsiones/metabolismo , Adolescente , Adulto , Animales , Barrera Hematoencefálica/química , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/fisiopatología , Células Cultivadas , Niño , Preescolar , Femenino , Hipocampo/irrigación sanguínea , Hipocampo/química , Hipocampo/metabolismo , Hipocampo/fisiopatología , Humanos , Lactante , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/química , Pericitos/química , Convulsiones/fisiopatologíaRESUMEN
OBJECTIVE: The contribution of recurring seizures to the progression of epileptogenesis is debated. Seizure-induced brain damage is not conclusively demonstrated either in humans or in animal models of epilepsy. We evaluated the expression of brain injury biomarkers on postsurgical brain tissue obtained from 20 patients with frequent seizures and a long history of drug-resistant focal epilepsy. METHODS: The expression patterns of specific glial, neuronal, and inflammatory molecules were evaluated by immunohistochemistry in the core of type II focal cortical dysplasias (FCD-II), at the FCD boundary (perilesion), and in the adjacent normal-appearing area included in the epileptogenic region. We also analyzed surgical specimens from cryptogenic patients not presenting structural alterations at imaging. RESULTS: Astroglial and microglial activation, reduced neuronal density, perivascular CD3-positive T-lymphocyte clustering, and fibrinogen extravasation were demonstrated in the core of FCD-II lesions. No pathological immunoreactivity was observed outside the FCD-II or in cryptogenetic specimens, where the occurrence of interictal and ictal epileptiform activity was confirmed by either stereo-electroencephalography or intraoperative electrocorticography. INTERPRETATION: Recurrent seizures do not induce the expression of brain damage markers in nonlesional epileptogenic cortex studied in postsurgical tissue from cryptogenic and FCD patients. This evidence argues against the hypothesis that epileptiform activity per se contributes to focal brain injury, at least in the neocortical epilepsies considered here. Ann Neurol 2017;82:331-341.
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Encéfalo/metabolismo , Epilepsias Parciales/metabolismo , Epilepsia/metabolismo , Malformaciones del Desarrollo Cortical de Grupo I/metabolismo , Convulsiones/metabolismo , Adolescente , Adulto , Encéfalo/patología , Niño , Preescolar , Epilepsias Parciales/patología , Epilepsia/patología , Femenino , Humanos , Lactante , Masculino , Malformaciones del Desarrollo Cortical de Grupo I/patología , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/metabolismo , Neuronas/patología , Convulsiones/patología , Adulto JovenRESUMEN
OBJECTIVE: In the present report, the correlations between ex vivo high-resolution imaging and specific histological and ultrastructural patterns in type II focal cortical dysplasia (FCD) have been studied to explain the differences in the magnetic resonance imaging (MRI) detection of dysplasia and to contribute to the presurgical imaging evaluation of this pathology. METHODS: Surgical specimens from 13 patients with FCD IIa/b were submitted to 7T MRI scanning, and then analyzed histologically and ultrastructurally to compare the results with the MRI findings. Region of interest (ROI)-based measures on T2-weighted images (T2wi) were quantitatively evaluated in the lesion and in adjacent perilesional gray and white matter. RESULTS: Matched histological sections and 7T T2wi showed that the core of the lesion was characterized by patchy aggregates of abnormal cells and fiber disorganization related to inhomogeneity of intracortical signal intensity. The quantitative approach on T2wi can help to distinguish the lesions and perilesional areas even in a clinical MRI-negative case. The ultrastructural study showed that the strong signal hyperintensity in the white matter of FCD IIb was related to a dysmyelination process associated with severe fiber loss and abnormal cells. Less severe histopathological features were found in FCD IIa, thus reflecting their less evident MRI alterations. INTERPRETATION: We suggest that white matter abnormalities in type IIb FCD are due to defects of the myelination processes and maturation, impaired by the presence of balloon cells. To reveal the presence and the border of type II cortical dysplasia on MRI, a quantitative ROI-based analysis (coefficient of variation) is also proposed.
Asunto(s)
Epilepsia/cirugía , Imagen por Resonancia Magnética/métodos , Malformaciones del Desarrollo Cortical de Grupo I/patología , Sustancia Blanca/patología , Adolescente , Adulto , Niño , Preescolar , Epilepsia/patología , Humanos , Lactante , Imagen por Resonancia Magnética/instrumentación , Persona de Mediana Edad , Sustancia Blanca/ultraestructura , Adulto JovenRESUMEN
OBJECTIVE: Several studies have reported that inhibitory networks are altered in dysplastic tissue obtained from epilepsy surgery specimens. A consistent decrease in the number of inhibitory interneuronal subpopulation that expresses parvalbumin (PV) was reported in postsurgical tissue from patients with focal cortical dysplasia (FCD). We tested if the decrease in PV protein expression observed in epileptic tissue corresponds to a parallel impairment in the γ-aminobutyric acid (GABA)ergic compartment. METHODS: We analyzed postsurgical tissue from 30 surgically treated patients who underwent surgery for intractable epilepsy including 26 patients with FCD (types I, II, and III) and 4 patients without any microscopic visible lesion (cryptogenic) as controls. Serial sections were processed using in situ hybridization with GAD-65 and GAD-67 probes and immunocytochemistry with antibody against PV. The density of inhibitory PV-immunoreactive interneurons in relation to GABAergic cells was estimated in controls and in all different pathologic groups by using a two- and three-dimensional (2D and 3D) cell-counting technique. Field fraction and line profile analyses were added to estimate immunostaining proportion and distribution of PV signal generated in gray matter. RESULTS: A reduction of PV-positive cells and PV-immunoreactivity was observed exclusively in FCD type I/III specimens compared with cryptogenic tissue from control patients with a poor postsurgical outcome. In FCD type II, a profound rearrangement in the cortical distribution of PV immunoreactivity was observed, without a quantitative reduction of the number of neurons and terminals. In situ hybridization did not reveal significant variations of GAD expression in any FCD subtype. SIGNIFICANCE: Our study suggests a preservation of inhibitory networks in FCD postsurgical tissue, demonstrated by a substantial normal count of GABAergic neurons. A selective PV expression impairment is demonstrated in FCD type I and III and an abnormal, but not reduced, distribution of PV cells and terminals is confirmed in type II FCD. Possible functional consequences are discussed.
Asunto(s)
Encéfalo/metabolismo , Epilepsia/patología , Malformaciones del Desarrollo Cortical/patología , Parvalbúminas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Adolescente , Adulto , Encéfalo/patología , Recuento de Células , Preescolar , Epilepsia/etiología , Femenino , Glutamato Descarboxilasa/metabolismo , Humanos , Interneuronas/metabolismo , Masculino , Malformaciones del Desarrollo Cortical/clasificación , Malformaciones del Desarrollo Cortical/complicaciones , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: Hippocampal sclerosis (HS) is the most frequent neuropathologic finding in patients undergoing surgery for intractable temporal lobe epilepsy (TLE). The International League Against Epilepsy (ILAE) has recently proposed a new classification of HS based on specific patterns of cell loss. The aim of this study was to investigate the relationships between HS types, their etiologic factors, and the short- and long-term postsurgical outcomes of patients undergoing surgery because of drug-resistant TLE with HS. METHODS: Two hundred thirteen patients with a neuropathologic diagnosis of HS and a minimum follow-up of 2 years were divided on the basis of their ILAE HS type and further classified into: (1) isolated HS, (2) HS associated with focal cortical dysplasia (FCD IIIa), or (3) HS associated with other lesions. Their clinical and neuropathologic data were correlated with their Engel class postsurgical outcomes. RESULTS: The main findings were the following: (1) HS type 1 was associated with a longer duration of epilepsy; (2) >80% of the patients had an Engel class I short- and long-term outcomes, regardless of HS type and associated pathology; (3) short- and long-term postsurgical outcomes were less satisfactory in the patients who were completely seizure-free (Engel class Ia), and patients with HS type 2 had better long-term seizure outcomes than those with type 1; (4) the concomitant presence of FCD contributed to a worse outcome, regardless of HS type; and (5) a shorter duration of epilepsy significantly correlated with an Engel class Ia outcome. SIGNIFICANCE: These data suggest that HS type and associated pathologies may predict the risk of recurrence, but other variables such as the duration of epilepsy need to be considered. A common neuropathologic classification system may help to identify preoperative predictive factors and improve the selection of patients who may benefit from epilepsy surgery.
Asunto(s)
Epilepsia Refractaria/cirugía , Epilepsia del Lóbulo Temporal/cirugía , Hipocampo/patología , Malformaciones del Desarrollo Cortical/patología , Adulto , Epilepsia Refractaria/patología , Epilepsia del Lóbulo Temporal/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Malformaciones del Desarrollo Cortical/complicaciones , Procedimientos Neuroquirúrgicos , Estudios Retrospectivos , Esclerosis/complicaciones , Resultado del Tratamiento , Adulto JovenRESUMEN
Rasmussen encephalitis (RE) is a progressive inflammatory disorder characterized by brain hemiatrophy, unilateral focal deficits, and drug-refractory focal epilepsy. Epilepsia partialis continua (EPC) is a hallmark of the disease. Several immunomodulatory treatments may slow but not halt the disease progression. The treatment of choice still relies on surgical hemispheric disconnection, which is burdened by heavy neurologic morbidity. More limited cortical resections, although more tolerable, are usually considered to be, at best, only transiently effective in RE. Hemispheric disconnections may be not feasible when neurologic functions are preserved and the dominant hemisphere is affected. Adult patients with a milder RE course that preserves neurologic function for a long period are particularly at risk of developing severe deficits after surgery. In this study we present the histories of two patients with adult-onset RE who have undergone selective cortical resections to control EPC, avoiding, at the same time, the severe postsurgical deficits that may be induced by hemispheric disconnective surgery. The good result obtained on EPC has been stable over a prolonged period; however, this result was not paralleled by the stop of neurologic progression in one of the two cases. A PowerPoint slide summarizing this article is available for download in the Supporting Information section http://dx.doi.org/10.1111/epi.12596/supinfo.
Asunto(s)
Corteza Cerebral/cirugía , Encefalitis/cirugía , Adulto , Atrofia , Corteza Cerebral/patología , Decorticación Cerebral , Progresión de la Enfermedad , Electroencefalografía , Encefalitis/diagnóstico , Encefalitis/patología , Epilepsia Parcial Continua/diagnóstico , Epilepsia Parcial Continua/patología , Epilepsia Parcial Continua/cirugía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Complicaciones Posoperatorias/diagnósticoRESUMEN
OBJECTIVE: Hippocampal sclerosis (HS) is the major structural brain lesion in patients with temporal lobe epilepsy (TLE). However, its internal anatomic structure remains difficult to recognize at 1.5 or 3 Tesla (T) magnetic resonance imaging (MRI), which allows neither identification of specific pathology patterns nor their proposed value to predict postsurgical outcome, cognitive impairment, or underlying etiologies. We aimed to identify specific HS subtypes in resected surgical TLE samples on 7T MRI by juxtaposition with corresponding histologic sections. METHODS: Fifteen nonsclerotic and 18 sclerotic hippocampi were studied ex vivo using an experimental 7T MRI scanner. T2 -weighted images (T2wi) and diffusion tensor imaging (DTI) data were acquired and validated using a systematic histologic analysis of same specimens along the anterior-posterior axis of the hippocampus. RESULTS: In nonsclerotic hippocampi, differences in MR intensity could be assigned to seven clearly recognizable layers and anatomic boundaries as confirmed by histology. All hippocampal subfields could be visualized also in the hippocampal head with three-dimensional imaging and angulated coronal planes. Only four discernible layers were identified in specimens with histopathologically confirmed HS. All sclerotic hippocampi showed a significant atrophy and increased signal intensity along the pyramidal cell layer. Changes in DTI parameters such as an increased mean diffusivity, allowed to distinguish International League Against Epilepsy (ILAE) HS type 1 from type 2. Whereas the increase in T2wi signal intensities could not be attributed to a distinct specific histopathologic substrate, that is, decreased neuronal or increased glial cell densities, intrahippocampal projections and fiber tracts were distorted in HS specimens suggesting a complex disorganization of the cellular composition, fiber networks, as well as its extracellular matrix. SIGNIFICANCE: Our data further advocate high-resolution MRI as a helpful and promising diagnostic tool for the investigation of hippocampal pathology along the anterior-posterior extent in TLE, as well as in other neurologic and neurodegenerative disorders.