Dataset Information

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy.

ABSTRACT: Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2-interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from patients with intractable temporal lobe epilepsy. A short period of status epilepticus in rats that damaged the hippocampus activated FKHR/FKHRL-1 and induced a significant increase in expression of Bim. Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro. Inhibition of Akt increased the FKHR/Bim response and DNA fragmentation within the normally resistant cortex. Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures. We conclude that Bim expression may be a critical determinant of whether seizures damage the brain, and that its control may be neuroprotective in status epilepticus and epilepsy.

SUBMITTER: Shinoda S

PROVIDER: S-EPMC379318 | biostudies-literature | 2004 Apr

REPOSITORIES: biostudies-literature

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Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy.

Shinoda Sachiko S Schindler Clara K CK Meller Robert R So Norman K NK Araki Tomohiro T Yamamoto Akitaka A Lan Jing-Quan JQ Taki Waro W Simon Roger P RP Henshall David C DC

The Journal of clinical investigation 20040401 7

Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2-interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from p ...[more]

PMID: 15057313

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Project description:BackgroundMedial temporal lobe epilepsy (MTLE) is associated with limbic atrophy involving the hippocampus, peri-hippocampal and extra-temporal structures. While MTLE is related to static structural limbic compromise, it is unknown whether the limbic system undergoes dynamic regional perfusion network alterations during seizures. In this study, we aimed to investigate state specific (i.e. ictal versus interictal) perfusional limbic networks in patients with MTLE.MethodsWe studied clinical information and single photon emission computed tomography (SPECT) images obtained with intravenous infusion of the radioactive tracer Technetium- Tc 99 m Hexamethylpropyleneamine Oxime (Tc-99 m HMPAO) during ictal and interictal state confirmed by video-electroencephalography (VEEG) in 20 patients with unilateral MTLE (12 left and 8 right MTLE). Pair-wise voxel-based analyses were used to define global changes in tracer between states. Regional tracer uptake was calculated and state specific adjacency matrices were constructed based on regional correlation of uptake across subjects. Graph theoretical measures were applied to investigate global and regional state specific network reconfigurations.ResultsA significant increase in tracer uptake was observed during the ictal state in the medial temporal region, cerebellum, thalamus, insula and putamen. From network analyses, we observed a relative decreased correlation between the epileptogenic temporal region and remaining cortex during the interictal state, followed by a surge of cross-correlated perfusion in epileptogenic temporal-limbic structures during a seizure, corresponding to local network integration.ConclusionsThese results suggest that MTLE is associated with a state specific perfusion and possibly functional organization consisting of a surge of limbic cross-correlated tracer uptake during a seizure, with a relative disconnection of the epileptogenic temporal lobe in the interictal period. This pattern of state specific shift in metabolic networks in MTLE may improve the understanding of epileptogenesis and neuropsychological impairments associated with MTLE.

Project description:ObjectiveTo provide a multi-atlas framework for automated hippocampus segmentation in temporal lobe epilepsy (TLE) and clinically validate the results with respect to surgical lateralization and post-surgical outcome.MethodsWe retrospectively identified 47 TLE patients who underwent surgical resection and 12 healthy controls. T1-weighted 3?T MRI scans were acquired for all subjects, and patients were identified by a neuroradiologist with regards to lateralization and degree of hippocampal sclerosis (HS). Automated segmentation was implemented through the Joint Label Fusion/Corrective Learning (JLF/CL) method. Gold standard lateralization was determined from the surgically resected side in Engel I (seizure-free) patients at the two-year timepoint. ROC curves were used to identify appropriate thresholds for hippocampal asymmetry ratios, which were then used to analyze JLF/CL lateralization.ResultsThe optimal template atlas based on subject images with varying appearances, from normal-appearing to severe HS, was demonstrated to be composed entirely of normal-appearing subjects, with good agreement between automated and manual segmentations. In applying this atlas to 26 surgically resected seizure-free patients at a two-year timepoint, JLF/CL lateralized seizure onset 92% of the time. In comparison, neuroradiology reads lateralized 65% of patients, but correctly lateralized seizure onset in these patients 100% of the time. When compared to lateralized neuroradiology reads, JLF/CL was in agreement and correctly lateralized all 17 patients. When compared to nonlateralized radiology reads, JLF/CL correctly lateralized 78% of the nine patients.SignificanceWhile a neuroradiologist's interpretation of MR imaging is a key, albeit imperfect, diagnostic tool for seizure localization in medically-refractory TLE patients, automated hippocampal segmentation may provide more efficient and accurate epileptic foci localization. These promising findings demonstrate the clinical utility of automated segmentation in the TLE MR imaging pipeline prior to surgical resection, and suggest that further investigation into JLF/CL-assisted MRI reading could improve clinical outcomes. Our JLF/CL software is publicly available at https://www.nitrc.org/projects/ashs/.

Project description:ObjectivePatients with temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) have diffuse subtle gray matter (GM) atrophy detectable by MRI quantification analyses. However, it is not clear whether the etiology and seizure frequency are associated with this atrophy. We aimed to evaluate the occurrence of GM atrophy and the influence of seizure frequency in patients with TLE and either normal MRI (TLE-NL) or MRI signs of HS (TLE-HS).MethodsWe evaluated a group of 172 consecutive patients with unilateral TLE-HS or TLE-NL as defined by hippocampal volumetry and signal quantification (122 TLE-HS and 50 TLE-NL) plus a group of 82 healthy individuals. Voxel-based morphometry was performed with VBM8/SPM8 in 3T MRIs. Patients with up to three complex partial seizures and no generalized tonic-clonic seizures in the previous year were considered to have infrequent seizures. Those who did not fulfill these criteria were considered to have frequent seizures.ResultsPatients with TLE-HS had more pronounced GM atrophy, including the ipsilateral mesial temporal structures, temporal lobe, bilateral thalami and pre/post-central gyri. Patients with TLE-NL had more subtle GM atrophy, including the ipsilateral orbitofrontal cortex, bilateral thalami and pre/post-central gyri. Both TLE-HS and TLE-NL showed increased GM volume in the contralateral pons. TLE-HS patients with frequent seizures had more pronounced GM atrophy in extra-temporal regions than TLE-HS with infrequent seizures. Patients with TLE-NL and infrequent seizures had no detectable GM atrophy. In both TLE-HS and TLE-NL, the duration of epilepsy correlated with GM atrophy in extra-hippocampal regions.ConclusionAlthough a diffuse network GM atrophy occurs in both TLE-HS and TLE-NL, this is strikingly more evident in TLE-HS and in patients with frequent seizures. These findings suggest that neocortical atrophy in TLE is related to the ongoing seizures and epilepsy duration, while thalamic atrophy is more probably related to the original epileptogenic process.

Dataset Information

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy.

Publications

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy.

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