Impact of hippocampal subfield histopathology in episodic memory impairment in mesial temporal lobe epilepsy and hippocampal sclerosis.

OBJECTIVE: The objective of the study was to analyze preoperative visual and verbal episodic memories in a homogeneous series of patients with mesial temporal lobe epilepsy (MTLE) and unilateral hippocampal sclerosis (HS) submitted to corticoamygdalohippocampectomy and its association with neuronal cell density of each hippocampal subfield. METHODS: The hippocampi of 72 right-handed patients were collected and prepared for histopathological examination. Hippocampal sclerosis patterns were determined, and neuronal cell density was calculated. Preoperatively, two verbal and two visual memory tests (immediate and delayed recalls) were applied, and patients were divided into two groups, left and right MTLE (36/36). RESULTS: There were no statistical differences between groups regarding demographic and clinical data. Cornu Ammonis 4 (CA4) neuronal density was significantly lower in the right hippocampus compared with the left (p=0.048). The groups with HS presented different memory performance - the right HS were worse in visual memory test [Complex Rey Figure, immediate (p=0.001) and delayed (p=0.009)], but better in one verbal task [RAVLT delayed (p=0.005)]. Multiple regression analysis suggested that the verbal memory performance of the group with left HS was explained by CA1 neuronal density since both tasks were significantly influenced by CA1 [Logical Memory immediate recall (p=0.050) and Logical Memory and RAVLT delayed recalls (p=0.004 and p=0.001, respectively)]. For patients with right HS, both CA1 subfield integrity (p=0.006) and epilepsy duration (p=0.012) explained Complex Rey Figure immediate recall performance. Ultimately, epilepsy duration also explained the performance in the Complex Rey Figure delayed recall (p<0.001). SIGNIFICANCE: Cornu Ammonis 1 (CA1) hippocampal subfield was related to immediate and delayed recalls of verbal memory tests in left HS, while CA1 and epilepsy duration were associated with visual memory performance in patients with right HS.

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.

Granule cell dispersion is associated with hippocampal neuronal cell loss, initial precipitating injury, and other clinical features in mesial temporal lobe epilepsy and hippocampal sclerosis.

PURPOSE: To characterize a 10-year series of patients with mesial temporal lobe epilepsy (MTLE) and unilateral hippocampal sclerosis (HS) and determine the histopathological characteristic of the association between granule cell dispersion (GCD) and hippocampal neuronal loss. METHODS: The study included 108 MTLE/HS patients. Histopathological analyses were performed in NeuN-stained hippocampal sections for HS pattern, neuronal density, dentate gyrus (DG) pathology, and granule cell layer width. Statistical tests investigated the association between DG pathologies and HS patterns, as well as the correlation of DG width with total hippocampal and subfield-specific neuronal densities. RESULTS: Fifty-six patients (51.9%) presented right HS. All the four ILAE HS patterns were represented (90 Type 1, 11 Type 2, 2 Type 3, and 5 no-HS). Sixty-seven patients (62.0%) presented GCD, 39 (36.1%) normal DG, and 2 (1.9%) narrow DG. GCD was associated with initial precipitating injury, higher numbers of monthly focal seizures and lifetime bilateral tonic-clonic seizures, longer epilepsy duration, and older age at surgery. GCD was prevalent in all HS patterns, except for Type 2 (81.8% normal versus 18.2% GCD, p = 0.005). GCD was associated with total hippocampal and subfield-specific neuronal loss, except for CA1. DG width correlated with total hippocampal (r = -0.201, p = 0.037) and CA4 neuronal densities (r = -0.299, p = 0.002). Patients with HS Type 1 had better surgical outcomes, with 51 (61.4%) seizure-free in the first year post-surgery. CONCLUSIONS: This study confirmed that seizure control in MTLE/HS patients submitted to surgical treatment is comparable worldwide. Moreover, histopathological analyses showed an association between GCD and hippocampal neuronal loss, especially in the CA4 subfield.

Do Hippocampal Neurons Really Count for Comorbid Depression in Patients With Mesial Temporal Lobe Epilepsy and Hippocampal Sclerosis? A Histopathological Study.

Depression is the most frequent psychiatric comorbidity seen in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis (HS). Moreover, the HS is the most frequent pathological hallmark in MTLE-HS. Although there is a well-documented hippocampal volumetric reduction in imaging studies of patients with major depressive disorder, in epilepsy with comorbid depression, the true role of the hippocampus is not entirely understood. This study aimed to verify if patients with unilateral MTLE-HS and the co-occurrence of depression have differences in neuronal density of the hippocampal sectors CA1-CA4. For this purpose, we used a histopathological approach. This was a pioneering study with patients having both clinical disorders. However, we found no difference in hippocampal neuronal density when depression co-occurs in patients with epilepsy. In this series, CA1 had the lowest counting in both groups, and HS ILAE Type 1 was the most prevalent. More studies using histological assessments are needed to clarify the physiopathology of depression in MTLE-HS.

Different patterns of epileptiform-like activity are generated in the sclerotic hippocampus from patients with drug-resistant temporal lobe epilepsy.

Human hippocampal slice preparations from patients with temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) are excellent material for the characterization of epileptiform-like activity. However, it is still unknown if hippocampal regions as cornu Ammonis (CA) 1, CA3 and CA4, generate population epileptiform-like activity. Here, we investigated epileptiform activities of the subiculum, CA1, CA2, CA3, CA4 (induced by elevation of extracellular potassium concentration) and the dentate gyrus (induced with hilar stimulation and elevation of potassium concentration) from sclerotic hippocampi of patients with drug-resistant TLE. Five types of epileptiform-like activity were observed: interictal-like events; periodic ictal spiking; seizure-like events; spreading depression-like events; tonic seizure-like events and no activity. Different susceptibilities to generate epileptiform activity among hippocampal regions were observed; the dentate gyrus was the most susceptible region followed by the subiculum, CA4, CA1, CA2 and CA3. The incidence of epileptiform activity pattern was associated with specific regions of the hippocampal formation. Moreover, it was observed that each region of the hippocampal formation exhibits frequency-specific ranges in each subfield of the sclerotic human tissue. In conclusion, this study demonstrates that epileptiform-like activity may be induced in different regions of the hippocampal formation, including regions that are severely affected by neuronal loss.

The impact of epilepsy duration in a series of patients with mesial temporal lobe epilepsy due to unilateral hippocampal sclerosis.

PURPOSE: To evaluate if the duration of epilepsy influences MRI volumes of the hippocampus, amygdala, parahippocampal gyrus, entorhinal cortex and temporal pole of both hemispheres and epileptogenic hippocampus neuronal cell density and dentate gyrus granular cells distribution in patients with refractory mesial temporal lobe epilepsy due to hippocampal sclerosis (MTLE/HS). METHODS: Seventy-seven patients with refractory MTLE/HS submitted to surgery were included. Histopathological analysis included: (1) quantitative: hippocampal subfields and total estimated hippocampal cell density (HCD), thickness of the dentate gyrus - normal, thinning or dispersion; (2) qualitative: type of HS and granule cells pathology in the dentate gyrus (normal, neuronal cell loss, dispersion and bilamination). Automated MRI-derived measurements from bilateral temporal structures (hippocampus, amygdala, parahippocampal gyrus, temporal pole, entorhinal cortex) were obtained for 58 subjects. Histopathological and imaging findings were compared with data from specimens obtained in autopsies of age-matched individuals and living controls, respectively, and the data were adjusted for the age at epilepsy onset and the frequency of focal impaired awareness seizures/month. RESULTS: Forty-two (54.5%) patients presented right HS. The greater the duration of epilepsy, the smaller the total estimated HCD (p = 0.025; r = -0.259). Patients with a normal distribution of the granular cells had a shorter epilepsy duration than those with dispersion (p = 0.018) or thinning (p = 0.031). A reduced ipsilateral hippocampal volume (r = -0.551, p = 0.017) and a smaller hippocampal asymmetry index (r = -0.414, p = 0.002) were correlated to a longer epilepsy duration. The estimated HCD was correlated to the volume of the ipsilateral hippocampus (r = 0.420, p = 0.001). CONCLUSION: Our study showed an increasing atrophy of the ipsilateral hippocampus in patients with a longer epilepsy duration. Our data suggest that this reduction in hippocampal volume is related to neuronal loss. Besides that, we also showed an increased probability of exhibiting an abnormal distribution of the granular cells in the dentate gyrus in patients with longer epilepsy duration.

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 1.5T 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.

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.

Temporal lobe epilepsy with mesial temporal sclerosis: hippocampal neuronal loss as a predictor of surgical outcome.

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.

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 (MTLE) and mesial temporal sclerosis (MTS). METHOD: Hippocampal specimens from 54 patients with MTLE (27 patients with right MTLE and 27 with left MTLE) and unilateral MTS, who were separated into GCD 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: GCD 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.

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

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

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

Temporal lobe epilepsy with mesial temporal sclerosis: hippocampal neuronal loss as a predictor of surgical outcome / 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.