Corpora amylacea in the neocortex in patients with temporal lobe epilepsy and focal cortical dysplasia.

INTRODUCTION: Corpora amylacea (CoA) are present in about 60% of atrophic hippocampi resected from patients with drug resistant temporal lobe epilepsy (DRTLE). They have also been described in the lateral temporal neocortex, although less frequently. OBJECTIVE: The objective is to measure the presence, distribution and density of CoA in the lateral temporal lobes of patients with DRTLE and focal cortical dysplasia (FCD), also examining how CoA density may be linked to demographic and clinical traits. METHODS: Resected tissue from 35 patients was analysed. CoA density was assessed with a semi-quantitative scale according to the criteria established by Cherian et al. RESULTS: Presence of CoA in the neocortex of 9 patients was associated with hippocampal sclerosis (FCD type iiia, 7 cases), disembryoplastic neuroepithelial tumour (FCD type iiib, 1 case), and cavernous angioma (FCD type iiic, 1 case). The meningeal surface (MS) was involved in all cases, and 8 cases displayed CoA in the cerebral parenchyma (white matter) and around blood vessels. CoA density on the MS showed a negative correlation with age at seizure onset (r = -0.828, P<.05) and a positive correlation with disease duration (r = 0.678, P<.05) but not with postoperative clinical outcome. CONCLUSIONS: Patients with DRTLE and a primary lesion (hippocampal sclerosis, tumour, vascular malformation) associated with mild FCD were shown to have CoA deposits in the neocortex. No association was found between presence of CoA and clinical outcome one year after surgery.

Muerte neuronal en la neocorteza de pacientes con epilepsia del lóbulo temporal resistente a fármacos / Neuronal death in the neocortex of drug resistant temporal lobe epilepsy patients

Introducción. La participación de mecanismos de muerteapoptótica en la epilepsia del lóbulo temporal resistente afármacos (ELTRF) es un aspecto muy discutido en la actualidad.Investigamos si existe pérdida neuronal y la inmunodeteccióna diferentes marcadores de muerte en tejido neocorticalen ocho pacientes con ELTRF y como tejido controlse evaluaron cinco neocortezas de sujetos fallecidos porcausas no neurológicas, pareados en edad y sexo.Métodos. La evaluación de la pérdida neuronal se realizópor medio de un estudio estereológico y por técnica inmunohistoquímicacon el marcador sinaptofisina. Se evaluóla inmunopositividad a diferentes marcadores apoptóticos(anexina V, caspasa 3 y 8, bcl-2 y p53), así como la detecciónde fragmentación del ácido desoxirribonucleico (ADN) (TUNEL),y se realizó en todos los casos un doble marcaje con sinaptofisina.Los resultados fueron evaluados por microscopiaconfocal y analizados por el programa Zeiss LSM 5 ImageBrowser, 2.80.1113 (Alemania).Resultados. Se observó una disminución estadísticamentesignificativa del número total de células (p<0,05), asícomo de las células sinaptofisina+ (p<0,01) en la neocorteza(capa IV) de los pacientes con ELTRF al ser comparadoscon el tejido control. No mostraron diferencias significativaslos marcadores apoptóticos bcl-2, p53, caspasa 3 y 8 paraninguna de las capas de neocorteza, mientras que sí resultóestadísticamente aumentado el número de células TUNEL+(p<0,05) y anexina V+ (p<0,05) en la capa IV neocortical delos pacientes.Conclusiones. Este grupo de evidencias hablan a favorde la existencia en la capa IV de neocorteza de una afectaciónen el número neuronal que se puede asociar a un procesode muerte apoptótica por una vía no dependiente de caspasas,sin que pueda ser descartada la muerte por necrosis (AU)

Introduction. Participation of apoptotic death mechanisms in drug resistant temporal lobe epilepsy (DRTLE) is currently under great debate. We have investigated if there is neuronal loss and the immunodetection to differentmarkers in neocortical tissue death in eigth patients with DRTLE. The neocortexes of five patients deceased due to non-neurological causes, paired in age and gender were evaluated as control tissue. Methods. The evaluation of neuronal loss was made by means of a stereological study and with immunohisto chemical techniques with the synaptophysin marker. Immunopositivity to different apoptotic markers (annexin V, caspase 3 and 8, bcl-2 and p53) and detection of deoxyribonucleic acid (DNA) fragmentation (TUNEL) wereanalyzed and double labeling with synaptophysin was performed in every case. The results were evaluated with confocal microscope and analyzed with the Zeiss LSM 5 Image Browser Program, 2.80.1113 (Germany). Results. A statistically significant decrease in the total number of cells (p < 0.05) and the synaptophysin cells+ (p<0.01) in the neocortex (layer IV) of the patients with DRTLE when compared with the control tissue was found. No significant differences were found in the apoptotic markers bcl-2, p53, caspase 3 and 8 for any of the neocortex layers while there was a statistically significantincrease in the number of TUNEL cells+ (p<0.05) and annexin V+ (p<0.05) in the neocortical layer IV of the patients. Conclusions. This group of evidence speaks in favor of the existence of an effect on the neuronal number in the neocortex layer IV that may be associated with non caspase dependent apoptotic death process, without beingable to rule out death by necrosis

[Pathological neocortical findings in patients with medication-resistant medial temporal lobe epilepsy submitted to surgery]. / Hallazgos patológicos neocorticales en pacientes con epilepsia del lóbulo temporal medial farmacorresistente sometidos a cirugía.

INTRODUCTION: The dual pathology consisting of hippocampal sclerosis plus focal cortical dysplasia (FCD) is often reported in patients with medication-resistant medial temporal lobe epilepsy (MTLE). AIMS: To determine the histopathological changes that take place in the neocortex of patients with medication-resistant MTLE submitted to surgery and to evaluate the relation between the histopathological changes, pathological background and the clinical course of patients who had received surgical treatment. MATERIALS AND METHODS: Tissue obtained by en bloc resection from the neocortex of 18 patients with MTLE refractory to medical treatment was processed histologically and a tailored temporal lobectomy was performed with electrocorticography. RESULTS: Dual pathology was diagnosed in 13 patients (72.2%). Imaging studies confirmed the existence of mesial sclerosis of the temporal in 100% of cases and there was no evidence of neocortical lesions. Histologically, 46.15% and 38.46% of the patients were diagnosed as belonging to FCD type 1a and FCD type 1b, respectively. Only one patient presented FCD type 2a. A statistically significant relation was found between the presence of dual pathology and the existence of an early precipitating injury (p = 0.04). One year after surgery, 72.7% (8/11) patients with dual pathology were classified as belonging to Engel class I. CONCLUSIONS: In patients with MTLE there are microscopic FCD-type alterations in the neocortex. There is an association between these alterations and the existence of an initial precipitating injury. Complete resection of the epileptogenic area, which is guaranteed by the lobectomy tailored by electrocorticography, allows patients to enjoy a favourable post-surgical progression one year after surgery.

[Neuronal death in the neocortex of drug resistant temporal lobe epilepsy patients]. / Muerte neuronal en la neocorteza de pacientes con epilepsia del lóbulo temporal resistente a fármacos.

Introduction. Participation of apoptotic death mechanisms in drug resistant temporal lobe epilepsy (DRTLE) is currently under great debate. We have investigated if there is neuronal loss and the immunodetection to different markers in neocortical tissue death in eigth patients with DRTLE. The neocortexes of five patients deceased due to non-neurological causes, paired in age and gender were evaluated as control tissue. Methods. The evaluation of neuronal loss was made by means of a stereological study and with immunohistochemical techniques with the synaptophysin marker. Immunopositivity to different apoptotic markers (annexin V, caspase 3 and 8, bcl-2 and p53) and detection of deoxyribonucleic acid (DNA) fragmentation (TUNEL) were analyzed and double labeling with synaptophysin was performed in every case. The results were evaluated with confocal microscope and analyzed with the Zeiss LSM 5 Image Browser Program, 2.80.1113 (Germany). Results. A statistically significant decrease in the total number of cells (p < 0.05) and the synaptophysin cells+ (p<0.01) in the neocortex (layer IV) of the patients with DRTLE when compared with the control tissue was found. No significant differences were found in the apoptotic markers bcl-2, p53, caspase 3 and 8 for any of the neocortex layers while there was a statistically significant increase in the number of TUNEL cells+ (p<0.05) and annexin V+ (p<0.05) in the neocortical layer IV of the patients. Conclusions. This group of evidence speaks in favor of the existence of an effect on the neuronal number in the neocortex layer IV that may be associated with noncaspase dependent apoptotic death process, without being able to rule out death by necrosis. Key words: Drug resistant temporal lobe epilepsy. Apoptosis. Necrosis. Neuronal loss. Neurología 2008;23(9):555-565.

Hallazgos patológicos neocorticales en pacientes con epilepsia del lóbulo temporal medial farmacorresistente sometidos a cirugía / Pathological neocortical findings in patients with medication-resistant medial temporal lobe epilepsy submitted to surgery

La patología dual compuesta por esclerosis hipocampal y displasia cortical focal (DCF) se describecon frecuencia en pacientes con epilepsia del lóbulo temporal medial (ELTM) farmacorresistente. Objetivos. Determinar los cambios histopatológicos en la neocorteza de pacientes con ELTM farmacorresistente sometidos a cirugía y evaluar la relación entre los cambios histopatológicos, los antecedentes patológicos y la evolución clínica en los pacientes operados. Materialesy métodos. Se procesó histológicamente el tejido resecado en bloque (neocorteza) de 18 pacientes con ELTM refractaria a tratamiento médico, y se les realizó lobectomía temporal ajustada por electrocorticografía. Resultados. Se diagnóstico patología dual en 13 pacientes (72,2%). Los estudios imagenológicos confirmaron en el 100% de los casos la esclerosis mesialdel temporal y no existieron evidencias de lesión neocortical. Histológicamente, el 46,15% y el 38,46% de los pacientes fueron diagnosticados como DCF tipo 1a y DCF tipo 1b, respectivamente. Sólo un paciente presentó DCF tipo 2a. Se demostró una relación estadísticamente significativa entre la presencia de patología dual y la existencia de una daño precipitante inicial (p = 0,04). El 72,7% (8/11) de los pacientes con patología dual un año después de la cirugía se clasificó en la clase Ide Engel. Conclusiones. En los pacientes con ELTM existen alteraciones microscópicas en la neocorteza del tipo DCF. Estas alteraciones se asocian a la existencia de un daño precipitante inicial. La resección completa de la zona epileptogénica, garantizadapor la lobectomía ajustada por electrocorticografía, permite una buena evolución posquirúrgica un año después de la cirugía

The dual pathology consisting of hippocampal sclerosis plus focal cortical dysplasia (FCD) is oftenreported in patients with medication-resistant medial temporal lobe epilepsy (MTLE). Aims. To determine the histopathological changes that take place in the neocortex of patients with medication-resistant MTLE submitted to surgery and to evaluate the relation between the histopathological changes, pathological background and the clinical course of patients whohad received surgical treatment. Materials and methods. Tissue obtained by en bloc resection from the neocortex of 18 patients with MTLE refractory to medical treatment was processed histologically and a tailored temporal lobectomy was performed with electrocorticography. Results. Dual pathology was diagnosed in 13 patients (72.2%). Imaging studies confirmed the existenceof mesial sclerosis of the temporal in 100% of cases and there was no evidence of neocortical lesions. Histologically, 46.15% and 38.46% of the patients were diagnosed as belonging to FCD type 1a and FCD type 1b, respectively. Only one patient presented FCD type 2a. A statistically significant relation was found between the presence of dual pathology and the existenceof an early precipitating injury (p = 0.04). One year after surgery, 72.7% (8/11) patients with dual pathology were classified as belonging to Engel class I. Conclusions. In patients with MTLE there are microscopic FCD-type alterations in the neocortex.There is an association between these alterations and the existence of an initial precipitating injury. Complete resection of the epileptogenic area, which is guaranteed by the lobectomy tailored by electrocorticography, allows patients to enjoy a favourable post-surgical progression one year after surgery

[Video-EEG evaluation complemented by spectral and EEG source analysis in patients with medication-resistant medial temporal lobe epilepsy]. / Evaluación videoelectroencefalográfica complementada con análisis espectral y de las fuentes generadoras del electroencefalograma en pacientes con epilepsia del lóbulo temporal medial resistente a los fármacos.

AIM: To evaluate the value of prolonged video-electroencephalographic (video-EEG) monitoring complemented with spectral and EEG source analysis in identifying the epileptogenic area in patients with medial temporal lobe epilepsy who are candidates for non-lesional resective surgery. PATIENTS AND METHODS: The electrographic patterns during the onset of seizures were evaluated in over 667 seizures from 41 patients with a clinical diagnosis of medication-resistant partial epilepsy. Analyses were performed using Harmonie software and variable resolution electrical tomography (VARETA). RESULTS: Video-EEG was used to determine that 53.6% of the patients evaluated suffered complex partial seizures of a temporal origin; these were characterised by having an average frequency of 5.56 +/- 1.56 Hz, while the non-temporal seizures displayed a frequency within the range 9.17 +/- 3.32 Hz. The topographic location of the dominant ictal frequency during the period of maximum spectral energy in patients with temporal lobe epilepsy enabled us to draw a distinction between a group of patients with mesial seizures and those with non-mesial seizures that exceeded the number that was determined by visual inspection of the EEG, that is, 78.9 versus 47.3%, respectively. There was a 100% coincidence between the area where the seizures began as defined by surface EEG complemented with spectral analysis, the generator of this activity as defined by VARETA and the epileptogenic region. CONCLUSIONS: The localising information provided by video-EEG complemented with spectral and EEG source analysis allows for non-invasive location of the epileptogenic region in patients with medial temporal lobe epilepsy even when structural imaging studies show an absence or bilaterality of abnormalities.

Evaluación videoelectroencefalográfica complementada con análisis espectral y de las fuentes generadoras del electroencefalograma en pacientes con epilepsia del lóbulo temporal medial resistente a los fármacos / Video-EEG evaluation complemented by spectral and EEG source analysis in patients with medication-resistant medal temporal lobe epilepsy

Objetivo. Evaluar la contribución de la monitorización prolongada videoelectroencefalográfica (video-EEG) complementada con análisis espectral y de las fuentes generadoras del electroencefalograma (EEG) en la identificación de la zona epileptogénica de pacientes con epilepsia del lóbulo temporal medial candidatos a cirugía resectiva no lesional. Pacientes y métodos. Se evaluaron los patrones electrográficos del inicio ictal en más de 667 crisis correspondientes a 41 pacientes con diagnóstico clínico de epilepsia parcial resistente a fármacos. Para el análisis se utilizaron el software Harmonie y la tomografía eléctrica de resolución variable (VARETA). Resultados. Mediante video-EEG se determinó que el 53,6% de los pacientes evaluados presentaba crisis parciales complejas de origen temporal; éstas se caracterizaron por una frecuencia media de 5,56 ± 1,56 Hz, mientras que las no temporales presentaron una frecuencia en el rango de 9,17 ± 3,32 Hz. La localización topográfica de la frecuencia ictal dominante durante el período de energía espectral máxima en los pacientes con epilepsia del lóbulo temporal permitió distinguir a un grupo de pacientes con crisis mesiales y otros no mesiales que superaron el número determinado por la inspección visual del EEG: un 78,9 frente a un 47,3%, respectivamente. Se evidenció una coincidencia del 100% entre la zona de inicio ictal definida por EEG de superficie complementada con análisis espectral, el generador de esta actividad definido por VARETA y la zona epileptogénica. Conclusiones. La información localizadora aportada por el video-EEG complementada con el análisis espectral y de las fuentes del EEG permite localizar de forma no invasiva la zona epileptogénica en pacientes con epilepsia del lóbulo temporal medial aun cuando los estudios imaginológicos estructurales evidencian ausencia o bilateralidad de anomalías

Aim. To evaluate the value of prolonged video-electroencephalographic (video-EEG) monitoring complemented with spectral and EEG source analysis in identifying the epileptogenic area in patients with medial temporal lobe epilepsy who are candidates for non-lesional resective surgery. Patients and methods. The electrographic patterns during the onset of seizures were evaluated in over 667 seizures from 41 patients with a clinical diagnosis of medication-resistant partial epilepsy. Analyses were performed using Harmonie software and variable resolution electrical tomography (VARETA). Results. Video- EEG was used to determine that 53.6% of the patients evaluated suffered complex partial seizures of a temporal origin; these were characterised by having an average frequency of 5.56 ± 1.56 Hz, while the non-temporal seizures displayed a frequency within the range 9.17 ± 3.32 Hz. The topographic location of the dominant ictal frequency during the period of maximum spectral energy in patients with temporal lobe epilepsy enabled us to draw a distinction between a group of patients with mesial seizures and those with non-mesial seizures that exceeded the number that was determined by visual inspection of the EEG, that is, 78.9 versus 47.3%, respectively. There was a 100% coincidence between the area where the seizures began as defined by surface EEG complemented with spectral analysis, the generator of this activity as defined by VARETA and the epileptogenic region. Conclusions. The localising information provided by video-EEG complemented with spectral and EEG source analysis allows for non-invasive location of the epileptogenic region in patients with medial temporal lobe epilepsy even when structural imaging studies show an absence or bilaterality of abnormalities

Réplica. Alteraciones inmunológicas en pacientes epilépticos asociadas a la localización del foco epileptogénico / Reply. Immunological disorders in epileptic patients are associated to the epileptogenic focus localization

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[Immunological disorders in epileptic patients are associated to the epileptogenic focus localization]. / Alteraciones inmunológicas en pacientes epilépticos asociadas a la localización del foco epileptogénico.

OBJECTIVE: Clinical and experimental data support the role of immune mechanisms in the pathogeny of epilepsy. The purpose of this work was to study the immunological aspects in 30 epileptic patients with complex partial crisis resistant to antiepileptic drugs. PATIENTS AND METHODS: The patients were evaluated by EEG-Video and they were grouped attending to epileptogenic focus localization in: temporals (n = 16), lateralized (n = 6) and extratemporals (n = 4). We also studied a group with psychogenic epilepsy (n = 4), this group was diagnosed after EEG-video evaluation. The following immunological evaluations has been carried out: levels of serum immunoglobulins (IgG, IgM e IgA) by radial immunodiffusion test and lymphocytic subpopulations using immunocytochemical methods. We measured the percent of T and B lymphocytes (CD3 and CD20), helper/inductor lymphocyte T (CD4), suppressor/cytotoxic (CD8), interleukine-2 receptor (CD25) and human leukocyte antigen (HLA-DR). RESULTS: The results show a significant increase of CD8+ lymphocytes (p < 0.05) and in the activation markers (CD25+ and HLA-DR+ cells). The evaluation of immunological parameters applied to different group of epileptogenic focus localization shown that the increase of CD8+ lymphocytes is limited to temporal and lateralized patients (p < 0.01). The patients with extratemporal localization of focus and the psychogenic cases shown normal values for the evaluated immunological lymphocyte markers. We did not find a deficit in the humoral immunological aspects. CONCLUSIONS: Taking into account that patients diagnosed as psychogenic received an antiepileptic drug treatment identical to that of the other group, the observed immunological changes might be related with the patogeny of certain epilepsy variants associated with the focus localization and not with the medication.