RESUMO
Low-grade neuroepithelial tumors are major causes of drug-resistant focal epilepsy. Clinically, these tumors are defined as low-grade epilepsy-associated neuroepithelial tumors (LEATs). The BRAF V600E mutation is frequently observed in LEAT and linked to poor seizure outcomes. However, its molecular role in epileptogenicity remains elusive. To understand the molecular mechanism underlying the epileptogenicity in LEAT with the BRAF V600E genetic mutation (BRAF V600E-LEAT), we conducted RNA sequencing (RNA-seq) analysis using surgical specimens of BRAF V600E-LEAT obtained and stored at a single institute. We obtained 21 BRAF V600E-LEAT specimens and 4 control specimens, including 24 from Japanese patients and 1 from a patient of Central Asian origin, along with comprehensive clinical data. We submitted the transcriptome dataset of 21 BRAF V600E-LEAT plus 4 controls, as well as detailed clinical information, to a public database. Preliminary bioinformatics analysis using this dataset identified 2134 differentially expressed genes between BRAF V600E-LEAT and control. Additionally, gene set enrichment analysis provided novel insights into the association between estrogen response-related pathways and the epileptogenicity of BRAF V600E-LEAT patients. Our datasets and findings will contribute toward the understanding of the pathology of epilepsy caused by LEAT and the identification of new therapeutic targets.
Assuntos
Neoplasias Encefálicas , Epilepsia , Neoplasias Neuroepiteliomatosas , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Epilepsia/genética , Epilepsia/complicações , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/metabolismo , Neoplasias Neuroepiteliomatosas/patologia , Transcriptoma , MutaçãoRESUMO
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia associated with retinal degeneration. The disease is rare in Japan, and this is the first full description of clinicopathological findings in a Japanese autopsy case of genetically confirmed SCA7 having 49 cytosine-adenine-guanine (CAG) trinucleotide repeats in the ataxin 7 gene. A 34-year-old Japanese man with no family history of clinically apparent neurodegenerative diseases presented with gait disturbance, gradually followed by truncal instability with progressive visual loss by the age of 42 years. He became wheelchair-dependent by 51 years old, neurologically exhibiting cerebellar ataxia, slow eye movement, slurred and scanning speech, lower limb spasticity, hyperreflexia, action-related slowly torsional dystonic movements in the trunk and limbs, diminished vibratory sensation in the lower limbs, auditory impairment, and macular degeneration. Brain magnetic resonance imaging revealed atrophy of the brainstem and cerebellum. He died of pneumonia at age 60 with a 26-year clinical duration of disease. Postmortem neuropathological examination revealed pronounced atrophy of the spinal cord, brainstem, cerebellum, external globus pallidus (GP), and subthalamic nucleus, microscopically showing neuronal cell loss and fibrillary astrogliosis with polyglutamine-immunoreactive neuronal nuclei and/or neuronal nuclear inclusions (NNIs). Degeneration was also accentuated in the oculomotor system, auditory and visual pathways, upper and lower motor neurons, and somatosensory system, including the spinal dorsal root ganglia. There was a weak negative correlation between the frequency of nuclear polyglutamine-positive neurons and the extent of neuronal cell loss. Clinicopathological features in the present case suggest that neurological symptoms, such as oculomotor, auditory, visual, and sensory impairments, are attributable to degeneration in their respective projection systems affected by SCA7 pathomechanisms and that dystonic movement is related to more significant degeneration in the external than internal GP.
Assuntos
Ataxia Cerebelar , Ataxias Espinocerebelares , Masculino , Humanos , Pessoa de Meia-Idade , Adulto , Movimentos Oculares , Autopsia , Ataxia Cerebelar/patologia , Vias Visuais/patologia , População do Leste Asiático , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Corpos de Inclusão Intranuclear/patologia , Atrofia/patologiaRESUMO
A 23-year-old male was aware of pain around his left hip joint and visited a nearby orthopedic clinic. Swelling of the right testis was pointed out, and a testicular tumor was suspected. He was referred to the urology department of a local hospital. Blood analysis showed an increase of α-fetoprotein (AFP) (3,620 ng/ml). Computed tomographic (CT) -scan revealed a left iliac bone metastasis and morbid fracture. Right radical inguinal orchiectomy was performed. The pathological examination revealed mixed germ cell tumor (embryonic carcinoma and immature teratoma: 70%, seminoma: 30%). The diagnosis was non-seminomatous germ cell tumor, stage IIIc, and poor risk on the International Germ Cell Consensus Classification. After one cycle of a bleomycin, etoposide and cisplatinum (BEP) regimen, he was referred to our hospital. After a total of 4 cycles of BEP, AFP was normalized. Denosumab was also administered monthly. The CT-scan showed a reduction of bone metastasis and recovery of ossification. Bone biopsy did not show viable tumor cells. Because extirpation of the remaining mass would require resection of the left part of the pelvic bone with significant functional loss of the left limb, we performed close follow-up after an additional 2 courses of the etoposide and cisplatin regimen. The patient is currently alive without recurrence at 45 months after the last systemic chemotherapy.
Assuntos
Neoplasias Ósseas , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Masculino , Humanos , Adulto Jovem , Adulto , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/patologia , Etoposídeo/uso terapêutico , alfa-Fetoproteínas/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/cirurgia , Bleomicina/uso terapêutico , Orquiectomia , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológicoRESUMO
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.
Assuntos
Epilepsia , Malformações do Desenvolvimento Cortical do Grupo I , Malformações do Desenvolvimento Cortical , Consenso , Epilepsia/diagnóstico , Epilepsia/patologia , Humanos , Imageamento por Ressonância Magnética , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical do Grupo I/diagnóstico , Neuroimagem , Estudos RetrospectivosRESUMO
The definite diagnosis of central nervous system vasculitis requires pathological verification by biopsy or surgical resection of the lesion, which may not always be feasible. A 74-year-old woman with a history of allergic rhinitis, but not asthma, presented with slowly progressive left hemiparesis. Magnetic resonance imaging of the head revealed a heterogeneously enhancing mass involving the right internal capsule and corona radiata. Histological examination of the resected specimen revealed eosinophil-rich non-granulomatous small vessel vasculitis with no neutrophil infiltration or foci of microbial infection. Epstein-Barr virus in situ hybridization was negative, and polymerase chain reaction tests for both T-cell receptor gamma and immunoglobulin heavy-chain variable region genes did not show rearrangements, excluding the possibility of lymphoma and lymphoproliferative disorders. Blood hypereosinophilia and elevated erythrocyte sedimentation rate were observed; however, anti-neutrophil cytoplasmic antibodies were not detected. A biopsy of the erythema in the hips and thighs revealed perivasculitis with eosinophilic infiltration within the dermis. Chest computed tomography revealed multiple small nodules in the lungs. Her symptoms, aside from hemiparesis, disappeared after corticosteroid administration. The clinicopathological features were similar to eosinophilic granulomatosis with polyangiitis but did not meet its current classification criteria and definition. This patient is the first reported case of idiopathic eosinophilic vasculitis or idiopathic hypereosinophilic syndrome-associated vasculitis affecting the small vessels in the brain. Further clinicopathological studies enrolling similar cases are necessary to establish the disease concept and unravel the underlying pathogenesis.
Assuntos
Cérebro , Síndrome de Churg-Strauss , Infecções por Vírus Epstein-Barr , Granulomatose com Poliangiite , Síndrome Hipereosinofílica , Idoso , Síndrome de Churg-Strauss/diagnóstico , Eosinófilos , Feminino , Granulomatose com Poliangiite/diagnóstico , Herpesvirus Humano 4 , Humanos , Síndrome Hipereosinofílica/complicações , ParesiaRESUMO
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.
Assuntos
Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/patologia , Adolescente , Adulto , Idade de Início , Diversidade de Anticorpos , Encéfalo/patologia , Criança , Pré-Escolar , Técnica Delphi , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Lactente , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/cirurgia , Pessoa de Meia-Idade , Mutação/genética , Procedimentos Neurocirúrgicos , Variações Dependentes do Observador , Fenótipo , Convulsões/etiologia , Adulto JovemRESUMO
End folium sclerosis or hippocampal sclerosis (HS) type 3 is often associated with another coexisting epileptogenic lesion (dual pathology); however, the pathogenesis of HS type 3 remains elusive. A 46-year-old man presented with medically intractable focal aware seizures and focal impaired awareness seizures (FIAS) with occasional focal to bilateral tonic-clonic seizures (FBTCS) two years after surgical treatment with extensive cranial reconstruction for a brain abscess in the right temporal lobe associated with intracranial extension of ipsilateral cholesteatoma. Head magnetic resonance imaging (MRI) at age 49 revealed atrophy of the right cerebral hemisphere including the hippocampus and amygdala. The patient's first epilepsy surgery was a lateral temporal lobectomy, in which the mesial temporal structures were preserved because no epileptiform discharge was detected on the intraoperative electrocorticogram. However, FIAS with FBTCS started 15 months after the operation. The second surgery, amygdalohippocampectomy, at age 52, resulted in the patient being seizure-free again for one year before seizures of the right lateral temporal origin recurred. He underwent a third surgery, resection of the Heschl's and supramarginal gyri, at age 53, but he continued to have drug-resistant epilepsy over two years after that. Histopathological examination revealed dual pathology consisting of glial scar in the lateral temporal lobe and ipsilateral HS type 3 with an unusually severe lesion in the subiculum. No significant inflammatory change was observed. The clinicopathological features in the present case indicate that HS developed secondarily in the context of neocortical epilepsy due to glial scar, suggesting a role of repetitive abnormal electrical input from neocortical epileptogenic lesions into the hippocampus finally via the perforant pathway in the pathogenesis of HS type 3. Severe hippocampal atrophy on preoperative MRI together with its silent electrocorticogram recording at initial epilepsy surgery may represent clinically pre-epileptogenic HS in a seizure-free "silent or latent period" before completion of hippocampal epileptogenesis to the extent that clinical epileptic seizures occur.
Assuntos
Abscesso Encefálico/diagnóstico por imagem , Epilepsia do Lobo Temporal/diagnóstico por imagem , Gliose/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Neocórtex/diagnóstico por imagem , Abscesso Encefálico/complicações , Abscesso Encefálico/cirurgia , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/cirurgia , Gliose/etiologia , Gliose/cirurgia , Hipocampo/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Neocórtex/cirurgia , EscleroseRESUMO
Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disorder caused by mutations in either TSC1 on chromosome 16 or TSC2 on chromosome 9, clinically characterized mainly by facial angiofibroma, epilepsy, and intellectual disability. Cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytoma are characteristic central nervous system lesions among 11 major features in the current clinical diagnostic criteria for TSC. We encountered an unusual case of genetically confirmed TSC1 presenting with symptomatic West syndrome due to an isolated cortical dysplasia in the left occipital lobe of a six-month-old male infant who did not meet the clinical diagnostic criteria for TSC. The patient underwent left occipital lesionectomy at age 11 months and has been seizure-free for nearly six years since then. Histological examination of the resection specimen revealed cortical neuronal dyslamination with abundant dysmorphic neurons and ballooned cells, consistent with focal cortical dysplasia (FCD) type IIb. However, the lesion was also accompanied by unusual features, including marked calcifications, dense fibrillary gliosis containing abundant Rosenthal fibers, CD34-positive glial cells with abundant long processes confined to the dysplastic cortex, and multiple nodular lesions occupying the underlying white matter, consisting exclusively of ballooned cell and/or balloon-like astrocytes with focal calcifications. Genetic testing for TSC1 and TSC2 using the patient's peripheral blood revealed a germline heterozygous mutation in exon 7 (NM_000368.5: c.526dupT, p.Tyr176fs) in TSC1. Isolated FCD with unusual features such as calcification, dense fibrillary gliosis, Rosenthal fibers and/or subependymal nodule-like lesions in the white matter may indicate the possibility of a cortical tuber even without a clinical diagnosis of TSC. Identification of such histopathological findings has significant implications for early and accurate diagnosis and treatment of TSC, and is likely to serve as an important supplementary feature for the current clinical diagnostic criteria for TSC.
Assuntos
Epilepsia/diagnóstico por imagem , Malformações do Desenvolvimento Cortical do Grupo I/diagnóstico por imagem , Espasmos Infantis/diagnóstico por imagem , Esclerose Tuberosa/diagnóstico por imagem , Criança , Epilepsia/complicações , Epilepsia/terapia , Humanos , Lactente , Masculino , Malformações do Desenvolvimento Cortical do Grupo I/complicações , Malformações do Desenvolvimento Cortical do Grupo I/terapia , Espasmos Infantis/etiologia , Espasmos Infantis/terapia , Esclerose Tuberosa/complicaçõesRESUMO
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.
Assuntos
Córtex Cerebral/patologia , Aprendizado Profundo , Epilepsia/patologia , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Neurônios/patologia , Esclerose Tuberosa/patologia , Algoritmos , Área Sob a Curva , Diagnóstico por Computador , Epilepsia/diagnóstico , Humanos , Internet , Malformações do Desenvolvimento Cortical do Grupo I/diagnóstico , Redes Neurais de Computação , Neuropatologia , Estudo de Prova de Conceito , Curva ROC , Reprodutibilidade dos Testes , Esclerose Tuberosa/diagnósticoRESUMO
Hypoglycemic coma causes neuronal death in the cerebral neocortex; however, its unclear pathogenesis prevents the establishment of preventive measures. Inflammation plays a pivotal role in neuronal damage in the hypoglycemic state; however, the dynamics of glial cell activation or cytokine expression remain unknown. Here, we aimed to elucidate the spatiotemporal morphological changes of microglia and time-course cytokine expression profiles in the rat cerebral cortex after hypoglycemic coma. We performed histopathological and immunohistochemical (Iba1, neuronal nuclei, glial fibrillary acidic protein) analyses in the cingulate cortex and four areas of the neocortex: hindlimb area (HL), parietal cortex area 1 (Par1), parietal cortex area 2 (Par2), and perirhinal cortex (PRh). We measured tumor necrosis factor alpha (TNFα) and interleukin-6 messenger RNA (mRNA) expression by real-time reverse transcriptase-polymerase chain reaction. Necrotic neurons appeared in the neocortex as early as 3 h after hypoglycemic coma, while they were absent in the cingulate cortex. Neuronal nuclei-immunopositive neurons in the HL, Par2, and PRh were significantly less abundant than in the control at day 1. In Iba1 immunostaining, large rod-shaped cells were detected at 3-6 h after hypoglycemia, and commonly observed in the HL, Par2, and PRh. After 6 h, rod-shaped cells were rarely observed; instead, there was a prominent infiltration of hypertrophic and ameboid-shaped cells until day 7. The mRNA expression of TNFα was significantly higher than the control at 3-6 h after hypoglycemia in the neocortex, while it was significantly higher only at 3 h in the cingulate cortex. Our results indicate that early and transient appearance of rod-shaped microglia and persisting high TNFα expression levels characterize inflammatory responses to hypoglycemic neuronal damage in the cerebral neocortex, which might contribute to neuronal necrosis in response to transient hypoglycemic coma.
Assuntos
Córtex Cerebral/patologia , Citocinas/biossíntese , Hipoglicemia/complicações , Neuroglia/patologia , Neurônios/patologia , Animais , Córtex Cerebral/metabolismo , Hipoglicemiantes/toxicidade , Insulina/toxicidade , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Although increased production of prostaglandin E2 (PGE2) has been implicated in tissue damage in several pathological settings, the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE2 synthesis, in dopaminergic neurodegeneration remains unclear. Here we show that mPGES-1 is up-regulated in the dopaminergic neurons of the substantia nigra of postmortem brain tissue from PD patients and in neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. The expression of mPGES-1 was also up-regulated in cultured dopaminergic neurons stimulated with 6-OHDA. The genetic deletion of mPGES-1 not only abolished 6-OHDA-induced PGE2 production but also inhibited 6-OHDA-induced dopaminergic neurodegeneration both in vitro and in vivo. Nigrostriatal projections, striatal dopamine content, and neurological functions were significantly impaired by 6-OHDA administration in wild-type (WT) mice, but not in mPGES-1 knockout (KO) mice. Furthermore, in cultured primary mesencephalic neurons, addition of PGE2 to compensate for the deficiency of 6-OHDA-induced PGE2 production in mPGES-1 KO neurons recovered 6-OHDA toxicity to almost the same extent as that seen in WT neurons. These results suggest that induction of mPGES-1 enhances 6-OHDA-induced dopaminergic neuronal death through excessive PGE2 production. Thus, mPGES-1 may be a valuable therapeutic target for treatment of PD.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Prostaglandina-E Sintases/metabolismo , Substância Negra/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Oxidopamina/administração & dosagem , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Cultura Primária de Células , Prostaglandina-E Sintases/genéticaRESUMO
Epileptic seizure has been reported to enhance adult neurogenesis and induce aberrant synaptic reorganization in the human dentate gyrus in the hippocampal formation. However, adult neurogenesis in the extrahippocampal regions has not been well studied. To investigate seizure-enhanced neurogenesis in the extrahippocampal regions, we performed histological and immunohistochemical as well as western blot analyses on the cerebrum of Sprague-Dawley rats (n = 51, male, 7 weeks old, body weight 250-300 g) treated with intraperitoneal injection of kainic acid (KA, 10 mg/kg) to induce status epilepticus (SE) (n = 36) or normal saline solution (n = 15) followed by 5'-bromo-2-deoxyuridine (BrdU) injection to label newborn cells. Even though severe neuronal damage was found in the piriform cortex of rats having SE, immunohistochemistry for double cortin (DCX) revealed an increase in the number of immature neurons in the piriform cortex. Double immunofluorescence staining demonstrated that DCX-positive cells in the piriform cortex were positive for both BrdU and neuronal nuclear antigen. Immunohistochemistry and western blotting revealed increased expressions of synaptophysin and postsynaptic density protein 95 in the piriform cortex of rat having SE. These results suggested the enhanced neurogenesis and possible synaptic reorganization in the piriform cortex of the KA-treated rat.
Assuntos
Neurogênese , Plasticidade Neuronal , Córtex Piriforme/patologia , Estado Epiléptico/patologia , Animais , Proteína 4 Homóloga a Disks-Large/metabolismo , Proteína Duplacortina , Quinases Semelhantes a Duplacortina , Filamentos Intermediários/efeitos dos fármacos , Ácido Caínico , Masculino , Neurônios/citologia , Neurônios/patologia , Córtex Piriforme/citologia , Córtex Piriforme/fisiopatologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/fisiopatologia , Sinaptofisina/metabolismoRESUMO
Fragility of atheromatous plaque in the internal carotid artery can be a risk of brain infarction. The activation of macrophages by oxidative stress and the vulnerability of vascular endothelial cells have been reported to participate in the fragility of atheromatous plaque. Therefore, from the view point of prevention of brain infarction, we investigated the pathological factors which may influence the stabilization of atheromatous plaque. Patients undertaking carotid endoarterectomy (CEA) were continuously screened. Then, 21 samples were obtained from the atheromatous plaques of CEA patients. The expression of connexin (Cx) which composes a gap junction, an intercellular communication organ, was immunohistochemicaly observed. The expression of CD36, an oxidized low-density lipoprotein receptor, was assessed as a marker of oxidative stress. As a result, asymptomatic plaques which were assumed the stable plaques expressed Cx43 along with CD36 expression. In contrast, in the symptomatic plaques, the expression of Cx43 was few and there was almost no coexpression with CD36. The distribution of Cx37 expression was not different between asymptomatic and symptomatic plaques. The expressions of CD36, Cx37 and Cx43 showed no relation to the previous treatment with statins. In conclusion, Cx43 might contribute to the stabilization of atheromatous plaque which is affected by oxidative stress.
Assuntos
Estenose das Carótidas/metabolismo , Estenose das Carótidas/patologia , Conexina 43/metabolismo , Conexinas/metabolismo , Placa Aterosclerótica/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antígenos CD36/metabolismo , Estenose das Carótidas/complicações , Feminino , Humanos , Inflamação/complicações , Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Placa Aterosclerótica/complicações , Proteína alfa-4 de Junções ComunicantesRESUMO
Epilepsy surgery is an effective treatment in many patients with drug-resistant focal epilepsies. An early decision for surgical therapy is facilitated by a magnetic resonance imaging (MRI)-visible brain lesion congruent with the electrophysiologically abnormal brain region. Recent advances in the pathologic diagnosis and classification of epileptogenic brain lesions are helpful for clinical correlation, outcome stratification, and patient management. However, application of international consensus classification systems to common epileptic pathologies (e.g., focal cortical dysplasia [FCD] and hippocampal sclerosis [HS]) necessitates standardized protocols for neuropathologic workup of epilepsy surgery specimens. To this end, the Task Force of Neuropathology from the International League Against Epilepsy (ILAE) Commission on Diagnostic Methods developed a consensus standard operational procedure for tissue inspection, distribution, and processing. The aims are to provide a systematic framework for histopathologic workup, meeting minimal standards and maximizing current and future opportunities for morphofunctional correlations and molecular studies for both clinical care and research. Whenever feasible, anatomically intact surgical specimens are desirable to enable systematic analysis in selective hippocampectomies, temporal lobe resections, and lesional or nonlesional neocortical samples. Correct orientation of sample and the sample's relation to neurophysiologically aberrant sites requires good communication between pathology and neurosurgical teams. Systematic tissue sampling of 5-mm slabs along a defined anatomic axis and application of a limited immunohistochemical panel will ensure a reliable differential diagnosis of main pathologies encountered in epilepsy surgery.
Assuntos
Comitês Consultivos/normas , Encéfalo/cirurgia , Consenso , Epilepsia/diagnóstico , Epilepsia/cirurgia , Internacionalidade , Guias de Prática Clínica como Assunto/normas , Relatório de Pesquisa/normas , Encéfalo/patologia , Epilepsia/epidemiologia , Hemisferectomia/métodos , Hemisferectomia/normas , Hipocampo/patologia , Humanos , Malformações do Desenvolvimento Cortical/diagnóstico , Malformações do Desenvolvimento Cortical/epidemiologia , Malformações do Desenvolvimento Cortical/cirurgia , Psicocirurgia/métodos , Psicocirurgia/normas , Técnicas Estereotáxicas/normas , Lobo Temporal/patologiaRESUMO
Recurrent seizures without interictal resumption (status epilepticus) have been reported to induce neuronal death in the midline thalamic region that has functional roles in memory and decision-making; however, the pathogenesis underlying status epilepticus-induced thalamic neuronal death is yet to be determined. We performed histological and immunohistochemical studies as well as cerebral blood flow measurement using 4.7 tesla magnetic resonance imaging spectrometer on midline thalamic region in Sprague-Dawley rats (n = 75, male, 7 weeks after birth, body weight 250-300 g) treated with intraperitoneal injection of kainic acid (10 mg/kg) to induce status epilepticus (n = 55) or normal saline solution (n = 20). Histological study using paraffin-embedded specimens revealed neuronal death showing ischemic-like changes and Fluoro-Jade C positivity with calcium deposition in the midline thalamic region of epileptic rats. The distribution of neuronal death was associated with focal loss of immunoreactivity for excitatory amino acid transporter 2 (EAAT2), stronger immunoreaction for glutamate and increase in number of Iba-1-positive microglial cells showing swollen cytoplasm and long processes. Double immunofluorescence study demonstrated co-expression of interleukin-1 beta (IL-1ß) and inducible nitric oxide synthase (iNOS) within microglial cells, and loss of EAAT2 immunoreactivity in reactive astrocytes. These microglial alterations and astrocytic EAAT2 downregulation were also observed in tissue without obvious neuronal death in kainic acid-treated rats. These results suggest the possible role of glutamate excitotoxicity in neuronal death in the midline thalamic region following kainic acid-induced status epilepticus due to astrocytic EAAT2 downregulation following microglial activation showing upregulation of IL-1ß and iNOS.
Assuntos
Transportador 2 de Aminoácido Excitatório/metabolismo , Núcleos da Linha Média do Tálamo/metabolismo , Núcleos da Linha Média do Tálamo/patologia , Neurônios/fisiologia , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Animais , Astrócitos/metabolismo , Morte Celular , Regulação para Baixo , Ácido Caínico , Espectroscopia de Ressonância Magnética , Masculino , Microglia/metabolismo , Núcleos da Linha Média do Tálamo/irrigação sanguínea , Neurônios/citologia , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamenteRESUMO
Trisomy 18 or Edwards syndrome is known to exhibit various developmental abnormalities in the central nervous system. We report dominant uncrossed pyramidal tract in trisomy 18 syndrome, based on the postmortem neuropathologic study of eight consecutive autopsied fetuses and infants with trisomy 18 ranging in age from 16 to 39 weeks of gestation, including six males and two females, along with autopsy cases of a stillborn triploid infant with 69XXX and two stillborn infants without chromosomal or neurodevelopmental abnormalities. Five out of eight cases with trisomy 18 showed a larger proportion of uncrossed than crossed pyramidal tract. All of these cases were male, and the anterior corticospinal tract on one side was constantly larger than the contralateral lateral corticospinal tract in the spinal cord on both sides, while the pyramidal tract was hypoplastic in female cases with trisomy 18 and a case with 69XXX. Abnormal pyramidal decussation has been found in cases with posterior fossa malformations such as occipital encephaloceles, Dandy-Walker malformation, Joubert syndrome and Möbius syndrome, but has not been described in cases with trisomy 18. Our data, together with the previous reports describing uncrossed aberrant ipsilateral pyramidal tract in patients with congenital mirror movements caused by DCC gene mutation in chromosome 18, and hypolasia and hyperplasia of the pyramidal tract in X-linked recessive disorders caused by L1CAM and Kal1 gene mutations, respectively, suggest a role of trisomy 18 in association with X-chromosome in the abnormal development of the pyramidal tract.
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Feto/anormalidades , Feto/patologia , Tratos Piramidais/anormalidades , Tratos Piramidais/patologia , Natimorto , Trissomia/patologia , Cromossomos Humanos Par 18 , Feminino , Doenças Fetais/patologia , Humanos , Recém-Nascido , Masculino , Síndrome da Trissomía do Cromossomo 18RESUMO
Distal anterior inferior cerebellar artery(AICA)aneurysms are rare, so its pathogenesis and treatment remain controversial. Here, we report the unique pathogenesis of a ruptured aneurysm in this area that was based on anomalous components as well as partial dissection of the arterial wall. A 61-year-old woman presented to our hospital with sudden headache and nausea. On admission, neurological examination revealed slight consciousness disturbance. Computed tomography(CT)of the head showed a clotted subarachnoid hemorrhage(SAH)that was dominant in the right cerebellopontine and prepontine cistern. Three-dimensional CT angiography detected an irregular fusiform aneurysm 4.5×3.2mm in size in the distal portion of the AICA. The patient underwent trapping without distal vascular reconstruction by the lateral suboccipital approach. After surgery, she experienced right hearing disturbance and ipsilateral facial palsy that were considered to be caused by vasogenic edema at the cerebellar peduncle that resulted from the initial SAH damage. Pathology revealed an aneurysmal wall with anomalous components and arterial dissection in the arterial wall. To our knowledge, only one article has reported the histological findings of a distal AICA aneurysm. Based on the pathology of this case, these findings may suggest a useful treatment strategy for this rare aneurysm.
Assuntos
Aneurisma Roto/cirurgia , Artéria Basilar/cirurgia , Aneurisma Intracraniano/cirurgia , Hemorragia Subaracnóidea/etiologia , Aneurisma Roto/complicações , Aneurisma Roto/diagnóstico , Angiografia Cerebral/métodos , Feminino , Humanos , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/diagnóstico , Pessoa de Meia-Idade , Hemorragia Subaracnóidea/diagnóstico , Resultado do TratamentoRESUMO
OBJECTIVE: Aging is considered to cause atherosclerotic changes in the carotid artery, but few studies have evaluated this relationship. In this study, we used carotid plaques removed from patients with carotid artery stenosis and investigated how aging contributes to carotid plaque morphology and symptoms. MATERIALS AND METHODS: A total of 60 patients(55 men, 5 women; mean age, 70.5 years; range, 53-85 years) treated at our hospital between January 2009 and April 2012 were enrolled in this study. All patients underwent carotid endarterectomy; their carotid plaques were stained with hematoxylin-eosin and/or Elastica-Masson stain and examined by a pathologist. Using these data, the carotid systolic velocity and plaque morphology were analyzed considering the age by decade as well as the symptomatology. RESULTS: Of the 60 patients, 29 were symptomatic(transient ischemic attack (TIA) in 8 patients; infarction in 20;and amaurosis in 1). Symptoms were less common as patient age increased. The incidence of TIA also tended to decrease with an increase in age, although the opposite trend was seen with infarction. In plaque morphology, the presence of active plaque, macrophage, inflammatory infiltration, and capillary angiogenesis decreased as age increased, while the presence of degenerative plaques, decrease in smooth muscle cell number, and calcification inversely increased. Active, degenerative, and combined (active/degenerative) lesions are statistically unrelated to symptoms as well as systolic velocity (cm/sec) at the carotid stenosis. The rates of hemorrhagic lesions were similar among decades, but the lesion statistically contributed to increasing symptoms (p=0.0045) and increasing systolic velocity (p=0.031). CONCLUSION: Increasing age contributes to morphological changes in carotid plaques and symptoms. When hemorrhagic lesions are suspected in carotid plaques, patients will be symptomatic and may require surgery.
Assuntos
Estenose das Carótidas/patologia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Estenose das Carótidas/complicações , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We present neuropathological findings in three autopsy brains from patients diagnosed clinically with idiopathic normal pressure hydrocephalus (iNPH) in Japan; still, specific findings of iNPH remain unclear. Comorbid atherosclerosis and hypertensive microvascular diseases, including arterio- and arteriolosclerosis and ischemic changes in the brain parenchyma, are frequently (65%) observed in autopsy brain tissue from patients with iNPH, which has drawn attention to the clinicopathological similarities and differences between iNPH and Binswanger's disease. Additionally, Aß protein deposition and phosphorylated tau-positive neurofibrillary tangles and neuropil threads are observed in cerebral cortical biopsy specimens obtained during intracranial pressure monitoring or shunt surgery among a subset of patients with iNPH. These findings are as frequent as those reported in autopsy data of the age-matched general population. Alterations in aquaporin-4 expression in the cerebral cortex have also been reported, suggestive of a possible association with altered volume or composition of the interstitial fluid in the microenvironment, particularly in the vicinity of capillaries, or glymphatic system dysfunction and consequent altered interstitial fluid drainage. Greater understanding of the normal anatomical structures and pathways involved in cerebrospinal fluid circulation, particularly in absorption and drainage, in the craniospinal region is essential for better clarity regarding iNPH neuropathology.
Assuntos
Hidrocefalia de Pressão Normal , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/complicações , Hidrocefalia de Pressão Normal/cirurgia , Encéfalo/patologia , Córtex Cerebral , Neuropatologia , AutopsiaRESUMO
Introduction: Low-grade epilepsy-associated tumors are the second most common histopathological diagnoses in cases of drug-resistant focal epilepsy. However, the connection between neuroimaging features and genetic alterations in these tumors is unclear, prompting an investigation into genotype-relevant neuroimaging characteristics. Methods: This study retrospectively analyzed neuroimaging and surgical specimens from 46 epilepsy patients with low-grade epilepsy-associated neuroepithelial tumors that had genetic mutations identified through panel sequencing to investigate their relationship to genotypes. Results: Three distinct neuroimaging groups were established: Group 1 had indistinct borders and iso T1-weighted and slightly high or high T2-weighted signal intensities without a diffuse mass effect, associated with 93.8% sensitivity and 100% specificity to BRAF V600E mutations; Group 2 exhibited sharp borders and very or slightly low T1-weighted and very high T2-weighted signal intensities with a diffuse mass effect and 100% sensitivity and specificity for FGFR1 mutations; and Group 3 displayed various characteristics. Histopathological diagnoses including diffuse low-grade glioma and ganglioglioma showed no clear association with genotypes. Notably, postoperative seizure-free rates were higher in Group 1 tumors (BRAF V600E) than in Group 2 tumors (FGFR1). Discussion: These findings suggest that tumor genotype may be predicted by neuroimaging before surgery, providing insights for personalized treatment approaches.