Granule cell dispersion is associated with memory impairment in right mesial temporal lobe epilepsy

Purpose: We analyzed the association of granule cell dispersion (GCD) with memory performance, clinical data and surgical outcome in a series of patients with mesial temporal lobe epilepsy (MILE) and mesial temporal sclerosis (MTS).Method: Hippocampal specimens from 54 patients with MTLE (27 patients with right MILE and 27 with left MTLE) and unilateral MTS, who were separated into CCD and no-GCD groups and thirteen controls were studied. Quantitative neuropathological evaluation was performed using hippocampal sections stained with NeuN. Patients' neuropsychological measures, clinical data, type of MTS and surgical outcome were reviewed.Results: CCD occurred in 28 (51.9%) patients. No correlation between GCD and MTS pattern, clinical data or surgical outcome was found. the presence of GCD was correlated with worse visuospatial memory performance in right MTLE, but not with memory performance in left MTLE.Conclusion: GCD may be related to memory impairment in right MTLE-MTS patients. However, the role of GCD in memory function is not precisely defined. (c) 2012 British Epilepsy Association. Published by Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Instituto Nacional de Neurociencia Translacional (INNT), BrazilUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, Escola Paulista Med, Unidade Pesquisa & Tratamento Epilepsias, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, Escola Paulista Med, BR-04024002 São Paulo, BrazilSanta Casa São Paulo, Dept Pathol, São Paulo, BrazilAFIP, Dept Pathol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol & Neurosci, Escola Paulista Med, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, Escola Paulista Med, Unidade Pesquisa & Tratamento Epilepsias, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, Escola Paulista Med, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol & Neurosci, Escola Paulista Med, BR-04024002 São Paulo, BrazilWeb of Scienc

Caracterização dos subtipos de esclerose hipocampal e sua relação com os dados clínicos, neuropsicológicos e imaginológicos

Hippocampal sclerosis (HS) is the commonest histopathological finding in mesial temporal lobe epilepsy and neuropathological subtypes of HS are defined by the qualitative patterns of neuronal loss as assessed on NeuN immunohistochemistry. HS, however, may appear intermediate (Ind-HS) or difficult to classify. HS subtypes have been reported to predict memory deficits and seizure outcome following surgery. The purpose of this study was to verify if quantitative analysis using dendritic marker MAP2 would provide a more stringent classification of HS. Furthermore, analyse if HS subtypes, as well as alteration of hippocampal axonal networks, regenerative capacity and neurodegeneration correlated with MRI hippocampal volumes, accompanying memory deficits, and post-operative seizure outcome. This study was performed in two different centres in Brazil and England. The total number of patients selected was 154 (101 type 1 HS, 23 type 2, 2 type 3, 11 no-HS and 18 Ind-HS). Quantitative analysis was carried out on NeuN and MAP2 and a labelling index (LI) calculated for hippocampal subfields. Markers for hippocampal regenerative activity (MCM2, nestin, olig2, calbindin), degeneration (AT8/phosphorylated TAU), mossy-fibre pathway re-organization (ZnT3), and presence of basal dendrites on granule cells were also evaluated. Pathology measures were correlated with clinical, imaging, memory test scores, and post-operative outcomes, at one year following surgery. The mean MAP2 LI in CA4 in Ind-HS was statistically aligned with type 2 HS but not with NeuN labelling. Moderate and severe memory deficits were noted in all HS types. Memory deficits were correlated with multiple pathology factors including lower NeuN or MAP2 LI in CA4, CA1, dentate gyrus and subiculum, poor preservation of the mossy fibre pathway and fewer basal dendrites on granule cells. Smaller hippocampal volumes were associated with type 1 and 2 HS and with CA1, CA3, and CA4 neuronal density. Type 1 HS patients had better seizure control following surgery. Decline in memory at one year associated with AT8 labelling in the subiculum and dentate gyrus and the density of nestin-labelled cells in CA4, but not with HS subtype. We conclude that MAP2 is a useful adjunct in the classification of HS. The smaller hippocampal volumes on MRI indicate significant neuronal loss and HS pattern. HS subtype classification alone is not predictive of memory function, which was associated with multiple pathology factors including hippocampal axonal pathways, regenerative capacity and degenerative changes.A esclerose hipocampal (EH) é o substrato anatomopatológico mais comum na epilepsia do lobo temporal mesial e os padrões de EH podem ser determinados pela análise qualitativa da perda neuronal nos subcampos hipocampais aplicando a imuno-marcação com NeuN. Entretanto, alguns casos de EH podem apresentar-se intermediários (EH-ind) ou de difícil classificação. Os padrões de EH já foram relacionados aos déficits de memória e ao prognóstico pós-cirúrgico quanto ao controle de crises. O objetivo deste estudo foi verificar se a análise quantitativa da imuno-marcação dendrítica com MAP2 é capaz de auxiliar na classificação da EH. Adicionalmente, avaliar se os padrões de EH, bem como a reorganização axonal, capacidade regenerativa e neurodegenerativa se associam ao volume hipocampal na RM, aos déficits de memória e ao prognóstico pós-operatório. Este estudo foi desenvolvido em dois centros, no Brasil e Inglaterra. Ao todo foram selecionados 154 pacientes (101 com EH tipo 1, 23 EH tipo 2, 2 EH tipo 3, 11 sem EH e 18 com EH-ind). A análise quantitativa e determinação do índice de marcação (IM) foram realizadas para NeuN e MAP2. Marcadores de atividade regenerativa (MCM2, olig2, nestina, calbindina), degeneração (AT8), reorganização das fibras musgosas (ZnT3) e presença de dendritos basais foram analisados. Os dados histopatológicos foram relacionados aos dados clínicos, imaginológicos, neuropsicológicos e de controle de crises um ano após a cirurgia. O IM com MAP2 para os casos de EH-ind foi similar ao encontrado para a EH tipo 2. Déficits de memória moderado a grave foram reportados em todos os tipos de EH e foram correlacionados a múltiplos achados histopatológicos, incluindo: redução do IM com NeuN e MAP2 em CA4, CA1, giro dentado e subículo; menor preservação das fibras musgosas e presença de dendritos basais nas células granulares. Menores volumes hipocampais foram associados aos padrões de EH tipo 1 e 2 e à densidade neuronal de CA1, CA3 e CA4. Os pacientes com EH tipo 1 apresentaram melhor prognóstico pós-operatório quanto controle de crises. O declínio de memória após a cirurgia foi relacionado com a deposição de proteína TAU no subículo e giro dentado e com a densidade de células nestina-positivas em CA4, mas não com os subtipos de EH. Deste modo, o imuno-marcador MAP2 pode ser utilizado como adjunto na classificação dos casos indeterminados de EH. Além do mais, um menor volume hipocampal na RM sugere perda neuronal significativa e pode ser indicativo do padrão de EH. Entretanto, a classificação dos subtipos de EH não é preditiva da preservação da memória, que é associada a múltiplos achados histopatológicos incluindo as alterações nas vias axonais, na capacidade regenerativa e degenerativa do hipocampo.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016

Granule cell dispersion is not a predictor of surgical outcome in temporal lobe epilepsy with mesial temporal sclerosis

The aim of this retrospective study of a series of patients with mesial temporal lobe epilepsy (MTLE) and mesial temporal sclerosis (MTS) was to analyze the association of granule cell dispersion (GCD) with surgical prognosis, patterns of MTS and clinical data. Hippocampal specimens from 66 patients with MTLE and unilateral MTS and from 13 controls were studied. Quantitative neuropathological evaluation was performed on NeuN-stained hippocampal sections. Patients' clinical data, types of MTS and surgical outcome were reviewed. GCD occurred in 45.5% of cases and was not correlated with clinical variable. More severe neuronal loss was observed in patients with GCD. Except for MTS Type 2 observed only in four no-GCD patients groups did not differ with respect to the types of MTS. Surgical outcome was similar in both groups. in conclusion, GCD was associated with the degree of hippocampal cell loss, but was not a predictor of surgical outcome.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Instituto Nacional de Neurociencia Translacional (INNT), BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Neurol & Neurosurg, São Paulo, BrazilSanta Casa São Paulo, Dept Pathol, São Paulo, BrazilAFIP, Dept Pathol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Neurol & Neurosci, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Neurol & Neurosurg, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Neurol & Neurosci, São Paulo, BrazilWeb of Scienc

Hippocampal atrophy on MRI is predictive of histopathological patterns and surgical prognosis in mesial temporal lobe epilepsy with hippocampal sclerosis

Purpose: To correlate hippocampal volumes obtained from brain structural imaging with histopathological patterns of hippocampal sclerosis (HS), in order to predict surgical outcome. Methods: Patients with mesial temporal lobe epilepsy (MTLE) with HS were selected. Clinical data were assessed pre-operatively and surgical outcome in the first year post surgery. One block of mid hippocampal body was selected for HS classification according to ILAE criteria. NeuN-immunoreactive cell bodies were counted within hippocampal subfields, in four randomly visual fields, and cell densities were transformed into z-score values. FreeSurfer processing of 1.5 T brain structural images was used for subcortical and cortical volumetric estimation of the ipsilateral hippocampus. Univariate analysis of variance and Pearson's correlation test were applied for statistical analyses. Results: Sixty-two cases (31 female, 32 right HS) were included. ILAE type 1 HS was identified in 48 patients, type 2 in eight, type 3 in two, and four had no-HS. Better results regarding seizure control, i.e. ILAE 1, were achieved by patients with type 1 HS (58.3%). Patients with types 1 and 2 had smaller hippocampal volumes compared to those with no-HS (p<0.001 and p=0.004, respectively). Positive correlation was encountered between hippocampal volumes and CA1, CA3, CA4, and total estimated neuronal densities. CA2 was the only sector which did not correlate its neuronal density with hippocampal volume (p = 0.390). Conclusion: This is the first study correlating hippocampal volume on MRI submitted to FreeSurfer processing with ILAE patterns of HS and neuronal loss within each hippocampal subfield, a fundamental finding to anticipate surgical prognosis for patients with drug-resistant MTLE and HS. (C) 2016 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Fed Sao Paulo UNIFESP, Dept Neurol & Neurosurg, Clin Neurol Sect, Rua Pedro Toledo 650,1 Andar, BR-04039002 Sao Paulo, SP, BrazilFac Ciencias Med Santa Casa Sao Paulo, Dept Pathol Sci, Rua Dr Cesareo Mottak Jr,61 Vila Buarque, BR-01221020 Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Neurosurg Sect, Dept Neurol & Neurosurg, Rua Napoleao Barros 715,6 Andar Vila Clementino, BR-04024002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Diagnost Imaging Sect, Dept Diagnost Imaging, Rua Napoleao Barros 800 Vila Clementino, BR-04024002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Neurosci Sect, Dept Neurol & Neurosurg, Rua Pedro Toledo 669,2 Andar Vila Clementino, BR-04039032 Sao Paulo, SP, BrazilClinical Neurology Sector, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 650 – Vila Clementino, CEP 04039-002, São Paulo, SP, BrazilNeurosurgery Sector, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 715, 6° andar – Vila Clementino, CEP 04024-002, São Paulo, SP, BrazilDiagnostic Imaging Sector, Department of Diagnostic Imaging, Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 800 – Vila Clementino, CEP 04024-002, São Paulo, SP, BrazilNeuroscience Sector, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669, 2° andar – Vila Clementino, CEP 04039-032, São Paulo, SP, BrazilWeb of Scienc

Epilepsia do lobo temporal com esclerose mesial temporal: o padrão da perda neuronal hipocampal como preditor do prognóstico cirúrgico

OBJECTIVE: To analyze retrospectively a series of patients with temporal lobe epilepsy (TLE) and mesial temporal sclerosis (MTS), and the association of patterns of hippocampal sclerosis with clinical data and surgical prognosis. METHOD: Sixty-six patients with medically refractory TLE with unilateral MTS after anterior temporal lobectomy were included. Quantitative neuropathological evaluation was performed on NeuN-stained hippocampal sections. Patient's clinical data and surgical outcome were reviewed. RESULTS: Occurrence of initial precipitating insult (IPI), as well as better postoperative seizure control (i.e. Engel class 1), were associated with classical and severe patterns of hippocampal sclerosis (MTS type 1a and 1b, respectively). CONCLUSION: Quantitative evaluation of hippocampal neuronal loss patterns predicts surgical outcome in patients with TLE-MTS.OBJETIVO: Analisar retrospectivamente uma série de pacientes com epilepsia do lobo temporal (ELT) e esclerose mesial temporal (EMT), bem como correlacionar os padrões de esclerose hipocampal com os dados clínicos e o prognóstico cirúrgico. MÉTODOS: Foram incluídos neste estudo 66 pacientes com ELT refratária a tratamento medicamentoso e com EMT unilateral submetidos à lobectomia temporal anterior. A análise neuropatológica quantitativa foi realizada em seções hipocampais imunomarcadas com NeuN. Dados clínicos e resultados do acompanhamento pós-cirúrgico foram revisados. RESULTADOS: Ocorrência de evento precipitante inicial e melhor controle de crises após a cirurgia (i.e. classe 1 de Engel) foram associados aos padrões clássico (EMT tipo 1a) e severo (EMT tipo 1b) de esclerose hipocampal. CONCLUSÃO: A análise quantitativa do padrão de perda neuronal do hipocampo é capaz de predizer o prognóstico cirúrgico em pacientes com ELT-EMT

Surgical and postmortem pathology studies: contribution for the investigation of temporal lobe epilepsy

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