Monocarboxylate transporter 1 is deficient on microvessels in the human epileptogenic hippocampus

Monocarboxylate transporter 1 (MCT1) facilitates the transport of important metabolic fuels (lactate, pyruvate and ketone bodies) and possibly also acidic drugs such as valproic acid across the blood-brain barrier. Because an impaired brain energy metabolism and resistance to antiepileptic drugs are common features of temporal lobe epilepsy (TLE), we sought to study the expression of MCT1 in the brain of patients with this disease. Immunohistochemistry and immunogold electron microscopy were used to assess the distribution of MCT1 in brain specimens from patients with TLE and concomitant hippocampal sclerosis (referred to as mesial TLE or MTLE (n=15)), patients with TLE and no hippocampal sclerosis (non-MTLE, n=13) and neurologically normal autopsy subjects (n=8). MCT1 was present on an extensive network of microvessels throughout the hippocampal formation in autopsy controls and to a lesser degree in non-MTLE. Patients with MTLE were markedly deficient in MCT1 on microvessels in several areas of the hippocampal formation, especially CA1, which exhibited a 37% to 48% loss of MCT1 on the plasma membrane of endothelial cells when compared with non-MTLE. These findings suggest that the uptake of blood-derived monocarboxylate fuels and possibly also acidic drugs, such as valproic acid, is perturbed in the epileptogenic hippocampus, particularly in MTLE. We hypothesize that the loss of MCT1 on brain microvessels is mechanistically involved in the pathophysiology of drug-resistant TLE, and propose that re-expression of MCT1 may represent a novel therapeutic approach for this disease.     

Distribution of regional gray matter abnormalities in a pediatric population with temporal lobe epilepsy and correlation with neuropsychological performance

OBJECTIVE: The goals of the work described here were to determine if hippocampal and extrahippocampal atrophy in children with temporal lobe epilepsy (TLE) follows a pattern similar to that in adult patients, and to assess the clinical and neuropsychological relevance of regional brain atrophy in pediatric TLE. METHODS: Children with symptomatic TLE (n=14: 9 with mesial TLE due to hippocampal atrophy and 5 with TLE due to neocortical lesions), healthy children (n=14), and 9 adults with mesial temporal lobe epilepsy (MTLE) were compared using voxel-based morphometry (VBM) of brain magnetic resonance imaging (MRI). The children underwent a comprehensive neuropsychological battery. RESULTS: Children with MTLE with unilateral hippocampal atrophy (n=9) exhibited a significant reduction in gray matter in the hippocampus ipsilateral to the seizure origin and significant atrophy in the ipsilateral cingulate gyrus and contralateral middle frontal lobe. Children with TLE (n=14) exhibited a significant reduction in the gray matter of the ipsilateral hippocampus and parahippocampal gyrus. There was a correlation between gray matter volume in children with TLE and scores on several neuropsychological tests. Atrophy in pediatric patients with MTLE was less extensive than that in adults, and involved the hippocampi and the frontal cortex. CONCLUSIONS: Similar to adult MTLE, pediatric MTLE is associated with hippocampal and extrahippocampal cell loss. However, children display less intense quantifiable gray matter atrophy, which affects predominantly frontal lobe areas. There was a significant association between volume of gray matter in medial temporal and frontal regions and scores on neuropsychological tests. In childhood, TLE and the concomitant cognitive/behavior disturbances are the result of a damaged neural network.     

Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy

Monocarboxylate transporter 1 (MCT1) facilitates the transport of monocarboxylate fuels (lactate, pyruvate and ketone bodies) and acidic drugs, such as valproic acid, across cell membranes. We recently reported that MCT1 is deficient on microvessels in the epileptogenic hippocampal formation in patients with medication-refractory temporal lobe epilepsy (TLE). To further define the role of MCT1 in the pathophysiology of TLE, we used immunohistochemistry and stereological analysis to localize and quantify the transporter in the hippocampal formation in three novel and highly relevant rat models of TLE and in nonepileptic control animals. One model utilizes methionine sulfoximine to induce brain glutamine synthetase deficiency and recurrent limbic seizures, while two models employ an episode of perforant pathway stimulation to cause epilepsy. MCT1 was lost on microvessels and upregulated on astrocytes in the hippocampal formation in all models of TLE. Notably, the loss of MCT1 on microvessels was not due to a reduction in microvessel density. The similarities in MCT1 expression among human subjects with TLE and several animal models of the disease strongly suggest a critical role of this molecule in the pathogenesis of TLE. We hypothesize that the downregulation of MCT1 may promote seizures via impaired uptake of ketone bodies and antiepileptic drugs by the epileptogenic brain. We also propose that the overexpression of MCT1 on astrocytes may lead to increased uptake or release of monocarboxylates by these cells, with important implications for brain metabolism and excitability. These hypotheses can now be rigorously tested in several animal models that replicate key features of human TLE.     

Increased expression of phosphate-activated glutaminase in hippocampal neurons in human mesial temporal lobe epilepsy

Patients with mesial temporal lobe epilepsy (MTLE) have increased basal concentrations of extracellular glutamate in the epileptogenic versus the non-epileptogenic hippocampus. Such elevated glutamate levels have been proposed to underlie the initiation and maintenance of recurrent seizures, and a key question is what causes the elevation of glutamate in MTLE. Here, we explore the possibility that neurons in the hippocampal formation contain higher levels of the glutamate synthesizing enzyme phosphate-activated glutaminase (PAG) in patients with MTLE versus patients with other forms of temporal lobe epilepsy (non-MTLE). Increased PAG immunoreactivity was recorded in subpopulations of surviving neurons in the MTLE hippocampal formation, particularly in CA1 and CA3 and in the polymorphic layer of the dentate gyrus. Immunogold analysis revealed that PAG was concentrated in mitochondria. Double-labeling experiments indicated a positive correlation between the mitochondrial contents of PAG protein and glutamate, as well as between PAG enzyme activity and PAG protein as determined by Western blots. These data suggest that the antibodies recognize an enzymatically active pool of PAG. Western blots and enzyme activity assays of hippocampal homogenates revealed no change in PAG between MTLE and non-MTLE, despite a greatly (>50%) reduced number of neurons in the MTLE hippocampal formation compared to non-MTLE. Thus, the MTLE hippocampal formation contains an increased concentration and activity of PAG per neuron compared to non-MTLE. This increase suggests an enhanced capacity for glutamate synthesis—a finding that might contribute to the disrupted glutamate homeostasis in MTLE. Tore Eid and Janniche Hammer contributed equally to this study.     

Surgical treatment for temporal lobe epilepsy in childhood]

We retrospectively analyzed 5 children (11-15 year) with intractable temporal lobe epilepsy (TLE) who underwent the anterior temporal lobectomy with hippocampectomy. Cases 1-3 had medial TLE (MTLE) with histologically verified hippocampal sclerosis, Case 4 had lateral TLE, and Case 5 had MTLE with old hemorrhagic lesion in the lateral temporal lobe. In Cases 3-5, chronic invasive electrocorticography recording using subdural electrodes was obtained, while in Cases 1 and 2, the epileptogenic region was defined by noninvasive preoperative evaluation. Postoperatively, Cases 1-3 became seizure free. All patients had psychosocial problems after the onset of their epilepsy, which was not improved even after the surgical control of epilepsy. Since most patients had morphological change and perfusional and metabolic disturbance outside the hippocampus at the time of surgery, earlier surgical consideration may be necessary.     

Quantitative analysis of benzodiazepine receptor in temporal lobe epilepsy: [(125)I]iomazenil autoradiographic study of surgically resected specimens

PURPOSE: To evaluate the changes of the inhibitory neurotransmitter receptor system related to epileptogenesis by measuring central benzodiazepine receptors (BZDRs) in surgically resected specimens of temporal lobe epilepsy by using [(125)I]iomazenil autoradiography. METHODS: Surgically resected specimens were obtained from 66 temporal lobe epilepsy patients [51 with mesial temporal lobe epilepsy (MTLE) and 15 with non-MTLE] receiving no BZDs and seven MTLE patients receiving BZDs. BZDR densities in brain sections were measured by using [(125)I]iomazenil autoradiography. Cell densities were measured from cresyl violet-stained sections. RESULTS: Compared with non-MTLE patients, non-BZD-treated MTLE patients showed remarkable reduction of BZDR density in the pyramidal cell region of cornu ammonis (CA) 1, CA3, and CA4, and a smaller but significant reduction in CA2 and the molecular and granule cell layers of dentate gyrus (mDG). In the MTLE group, the BZDR density in the mDG correlated with that in lateral cortex. Significant correlations between BZDR density and cell density were found in all hippocampal regions. A significant difference in BZDR density/cell-density ratio was observed in CA1 region between MTLE and non-MTLE. BZD-treated patients tended to have lower BZDR densities than did non-BZD-treated patients, although the differences did not reach significance. In all MTLE cases, [(123)I]iomazenil singlephoton emission computed tomography (SPECT) showed decreased BZDR binding in MTL. CONCLUSIONS: In MTLE, BZDR densities decreased parallel to reduction in cell density in most hippocampal subfields, but BZDR density appeared to decrease in excess of neuron loss in CA1. [(125)I]iomazenil SPECT might be useful for detecting in vivo changes of BZDR density.     

Relation of sorting impairment to hippocampal damage in temporal lobe epilepsy

One hundred and twelve patients with left (n=65) or right (n=47) temporal lobe epilepsy (TLE), associated with mesial or lateral temporal lobe lesion, were compared to 53 patients with left (n=30) or right (n=23) frontal lobe epilepsy (FLE), in order to explore the contributions of hippocampal lesions and of memory deficits to sorting impairment. Thirty-six healthy subjects of similar age and education were controls. The Modified Wisconsin Card Sorting Test (MWCST) was used to explore sorting ability. The two-syllable word span and consistent long-term retrieval from the selective reminding procedure for word-list learning were used to evaluate memory. Raven's Coloured Progressive Matrices and Attentive Matrices served to control for abstract reasoning and attention. Left FLE patients and TLE patients with left hippocampal sclerosis were significantly impaired on MWCST, short-term memory, and word learning. TLE patients with other left hippocampal lesions were also impaired on MWCST, although not significantly so. Analysis of individual scores showed that 42% of TLE patients with left hippocampal sclerosis, 14% of TLE patients with other hippocampal lesions, 63% of left FLE patients, and 30% of right FLE patients were impaired on the MWCST. In patients with left hippocampal sclerosis, MWCST score was associated with the learning score provided by the selective reminding procedure and Raven's Coloured Progressive Matrices score, whereas in FLE patients, MWCST score was associated with Attentive Matrices score. These results suggest that only some TLE patients, i.e. those with hippocampal damage, may be expected to be impaired on card sorting. The impaired sorting ability of these TLE patients may be due to involvement of the hippocampal function in forming associations or in registering new information.     

Pathophysiology of medial temporal lobe epilepsy: role of cerebral dysgenesis]

We studied the incidence of cerebral dysgenetic lesions(CD) in 39 operated patients with medial temporal lobe epilepsy(MTLE) who had hippocampal sclerosis. Four patients had CD, such as menigocele at the ipsilateral temporal fossa, schizencephaly in the ipsilateral peri-Rolandic area, focal cortical dysplasia in the ipsilateral inferior temporal gyrus and periventricular nodular heterotopia at the bilateral inferior horns of the lateral ventricle. Histological examinations of the resected lateral temporal lobes from 29 MTLE patients revealed the presence of microdysgenesis (microscopic cerebral dysgenesis) in 28 patients, including heterotopic white matter neuron(24 cases), molecular layer neuron(14), oligodendroglial cell cluster(11), dilated perivascular space(10). These findings suggest that the congenital factors, as well as hippocampal sclerosis, may be involved in the development of MTLE.     

Clinical study on temporal lobe epilepsy in childhood caused by temporal lobe space-occupying lesions

We studied the clinicoelectrical and neuroimaging features of 11 patients with symptomatic temporal lobe epilepsy (TLE) caused by temporal lobe space occupying lesions (SOLs), and compared its characteristics with those of 19 mesial TLE (MTLE) patients. Brain MRI demonstrated SOLs in the mesiotemporal lobe in 9, and laterotemporal lobe in the remaining 2 patients. Ten of the 11 patients successfully underwent surgery, which revealed tumors in 7 and focal cortical dysplasia in 3 patients. Comparisons of the clinical features between those with SOTLE and MTLE showed that both conditions shared the same clinical seizure manifestations such as gastric uprising sensation or ictal fear and a favorable response to surgery. However, the patients with SOTLE had fewer febrile convulsion, and more frequent seizure recurrences as well as TLE EEG discharges and associations of the monophasic clinical course than those with MTLE. In addition, the MRI findings were characterized by unilateral hippocampal atrophy in MTLE and expanding or SOLs in the SOTLE group. Children with complex partial seizures of suspected temporal lobe origin should undergo extensive neuroimaging evaluation.     

Is Interictal Temporal Hypometabolism Related to Mesial Temporal Sclerosis? A Positron Emission Tomography/Magnetic Resonance Imaging Confrontation

Summary: The mechanism of interictal glucose hypometabolism remains unclear, but this abnormality occurs more frequently in temporal lobe epilepsy (TLE) than in other types of partial epilepsy. Therefore temporal hypometabolism has been suggested to reflect mesial temporal sclerosis (MTS). To investigate this, we selected 22 patients with refractory partial epilepsy of mesial temporal lobe origin (MTLE) who had hippocampal atrophy based on magnetic resonance imaging (MRI) volumetric analysis. We then analyzed the metabolic correlates of unilateral hippocampal atrophy. Thirteen temporal regions of interest (ROI) were defined on MRI scans for each individual and then applied to high-resolution FDG-positron emission tomography (PET) images obtained parallel to the long axis of the hippocampus. The most hypometabolic regions were the temporal pole and the hippocampal region. When we analyzed ensembles of temporal regions grouped into related networks, the temporolimbic network, which included the hippocampal region and the temporal pole, was abnormal in 95% of the patients at a 3-SD threshold. PET hypometabolism was highly correlated with the degree of hippocampal atrophy in this network, but not in other parts of the temporal lobe, which were less frequently hypometabolic. These data indicate that hypometabolism is a consequence of MTS in the temporolimbic region but not necessarily in the other parts of the temporal lobe. Our results also suggest that the combination of PET and MRI may facilitate the noninvasive diagnosis of MTLE.     

Sex differences in patients with mesial temporal lobe epilepsy

Possible sex differences in the pattern of interictalhypometabolism were investigated, and also seizure spread in patients with mesial temporal lobe epilepsy (n=48) and hippocampal sclerosis (MTLE). Male patients (n=21) more often had a frontal lobehypometabolism ipsilateral to the seizure onset (p<0.0001) and aspread of epileptiform activity to this region (p=0.001). By contrast,female patients more often exhibited hypometabolism (p=0.0052) and anictal spread to the contralateral temporal lobe (p=0.0097). Thesefindings suggest sex differences in spatial distribution of braindysfunction in MTLE, perhaps reflecting sexual dimorphism in regionalcerebral connectivity.

     

Surgery for temporal lobe epilepsy after cerebral malaria

The most common indication for epilepsy surgery is temporal lobe epilepsy (TLE) which usually is divided into two categories, mesial and lateral TLE. The commonest pathology underlying mesial temporal lobe epilepsy (MTLE) is mesial temporal sclerosis (MTS); we report on a 50-year-old male patient, who contracted cerebral malaria and developed MTLE shortly thereafter. Magnetic resonance imaging (MRI) showed MTS. Surgical treatment was an anteromedial temporal lobe resection with amygdalohippocampectomy. The patient is seizure free, 36 months after surgical treatment. This is the first report describing MTLE-onset subsequent to cerebral malaria and discussing the potential pathophysiological relationship between cerebral malaria and MTS.     

Hippocampal sclerosis: MR prediction of seizure intractability

PURPOSE: Patients with refractory temporal lobe epilepsy (refractory TLE) often have hippocampal sclerosis (HS). However, some HS patients have less-severe, drug-responsive epilepsy (mild TLE). We investigated the pattern of MR changes in these two HS groups. METHODS: We acquired a 3D volumetric sequence, T(2) relaxation times (T2) and proton MR spectroscopy (MRS) in 41 HS patients (24 refractory TLE, 17 mild TLE) and 60 controls. Hippocampal volumes were measured bilaterally. T2 was measured in the hippocampus, amygdala, thalamus, in the white matter of the anterior temporal lobe (ATL), and in the frontal lobe. The temporal lobe MRS established concentrations of N-acetylaspartate (NAA), choline, creatine, myoinositol and glutamine/glutamate. RESULTS: The degree of hippocampal volume loss and hippocampal T2 increase was not different between the two HS groups. However, in refractory TLE, the T2 signal in the ipsilateral ATL was increased, and the ipsilateral NAA concentration was reduced (p < or = 0.05). CONCLUSIONS: In this group of HS patients, the degree of HS was not related to the clinical course, possibly reflecting the common cause of epilepsy. In contrast, refractory TLE patients had pronounced white matter changes and metabolite disturbance in the ipsilateral temporal lobe. These abnormalities may indicate the refractory nature of the epilepsy.     

The significance of corpora amylacea in mesial temporal lobe epilepsy

Temporal lobe epilepsy (TLE) associated with mesial temporal sclerosis (MTS), mesial TLE (MTLE), is the commonest medically refractory adult epilepsy syndrome. Corpora amylacea (CoA) have been shown to be a marker of MTS. We compared 9 patients with MTS who had dense deposition of CoA in their hippocampi with 25 patients with MTS who did not have CoA. The patients with CoA were significantly older and they showed a trend towards having a significantly longer duration of epilepsy. The postoperative seizure outcome at 2 years was not different in the 2 groups. Our results could indicate the progressive nature of the pathology of MTS, probably indicating excitotoxic damage due to recurrent seizures, but they need to be verified by clinicopathological correlation among a larger number of patients with MTLE.     

Distribution of regional gray matter abnormalities in a pediatric population with temporal lobe epilepsy and correlation with neuropsychological performance

ObjectiveThe goals of the work described here were to determine if hippocampal and extrahippocampal atrophy in children with temporal lobe epilepsy (TLE) follows a pattern similar to that in adult patients, and to assess the clinical and neuropsychological relevance of regional brain atrophy in pediatric TLE.MethodsChildren with symptomatic TLE (n = 14: 9 with mesial TLE due to hippocampal atrophy and 5 with TLE due to neocortical lesions), healthy children (n = 14), and 9 adults with mesial temporal lobe epilepsy (MTLE) were compared using voxel-based morphometry (VBM) of brain magnetic resonance imaging (MRI). The children underwent a comprehensive neuropsychological battery.ResultsChildren with MTLE with unilateral hippocampal atrophy (n = 9) exhibited a significant reduction in gray matter in the hippocampus ipsilateral to the seizure origin and significant atrophy in the ipsilateral cingulate gyrus and contralateral middle frontal lobe. Children with TLE (n = 14) exhibited a significant reduction in the gray matter of the ipsilateral hippocampus and parahippocampal gyrus. There was a correlation between gray matter volume in children with TLE and scores on several neuropsychological tests. Atrophy in pediatric patients with MTLE was less extensive than that in adults, and involved the hippocampi and the frontal cortex.ConclusionsSimilar to adult MTLE, pediatric MTLE is associated with hippocampal and extrahippocampal cell loss. However, children display less intense quantifiable gray matter atrophy, which affects predominantly frontal lobe areas. There was a significant association between volume of gray matter in medial temporal and frontal regions and scores on neuropsychological tests. In childhood, TLE and the concomitant cognitive/behavior disturbances are the result of a damaged neural network.     

Microdysgenesis in mesial temporal lobe epilepsy: a clinicopathological study

The interrelationship of mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis, and febrile convulsions still remains an enigma. Additional microscopical cortical dysplasia or microdysgenesis has been suggested as pre-existent susceptibility factor rendering the affected brain vulnerable to the development of MTLE after initial precipitating injuries such as febrile convulsions. Twenty-four MTLE cases with histopathologically definite hippocampal sclerosis were examined for clearly defined features of microdysgenesis and further signs of neocortical dysplasia. Although unequivocal signs of dysplasia were absent, 29.2% of cases showed cortical neuronal clustering, 25.0% showed perivascular clustering, and 20.8% showed increased white matter neurons. The features of microdysgenesis studied here were not linked with each other and were not related to initial precipitating injuries, positive family history, or any other clinical parameter. Their suggested fundamental role as dysplastic factor within development of hippocampal sclerosis and MTLE is not confirmed.     

Correlation of Hippocampal Neuronal Density and FDG-PET in Mesial Temporal Lobe Epilepsy

Summary: Purpose: Interictal [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) reveals regional hypometabolism in 60–80% of patients with mesial temporal lobe epilepsy (MTLE). The extent of hypometabolism generally extends beyond the epileptogenic zone. The pathophysiology underlying this widespread change is unknown. This study evaluated the relation between hippocampal neuronal loss and hypometabolism in patients with MTLE.
Methods: Forty-three patients with MTLE after anterior temporal lobectomy were included. Pathology demonstrated mesial temporal sclerosis (n = 41) or endfolium sclerosis (n = 2). Interictal FDG-PET scans were graded by visual analysis on a scale ranging from normal (grade 1) to severe (grade 5) hypometabolism. Neuronal counting was performed in the subiculum, hippocampal subfields, and dentate granular cell layer (DG). Neuronal density of patients was compared with that of seven autopsy controls. Data were compared by using Student's t tests and Kruskal-Wallis one-way analysis of variance (ANOVA).
Results: Significant neuronal loss in CA1 through CA4 and DG was found in patients compared with controls. Neuronal density in the subiculum, CA1, CA4, and DG did not correlate with severity of hypometabolism. However, patients with abnormal FDG-PET had higher neuronal density in CA2 and CA3 versus patients with normal studies.
Conclusions: This study supports a previous observation that degree of FDG-PET hypometabolism does not parallel severity of hippocampal neuronal loss in MTLE.     

Temporal lobe epilepsy with sensory aura: interictal glucose hypometabolism

Patients with mesial temporal lobe epilepsy (mTLE) exhibit marked depressions of the regional cerebral glucose metabolism (rCMRGlu) in the mesiotemporal region. We hypothesised that patients with temporal lobe epilepsy (TLE) who have a bilateral somatosensory or acoustic ( = temporolateral/SII-) aura can be differentiated from mTLE by rCMRGlu depressions primarily involving temporo-perisylvian locations. We therefore used this ictal semiology as a clinical criterion to define a subgroup of such patients and measured the rCMRGlu in 16 patients with TLE as evident from interictal and ictal EEG-video monitoring. Clinically, they presented with medically refractory complex partial seizures and were subjected to presurgical evaluation. The pattern of the interictal rCMRGlu in the TLE patients was different from that observed in patients with mTLE and showed significant depressions ipsilateral to the epileptic focus in mesial temporal and lateral temporal regions but spared the thalamus. The neocortical metabolic depressions were spatially more extended in right than in left TLE patients. Magnetic resonance images (MRI) were either normal (n = 5) or revealed unilateral or bilateral hippocampal atrophy/sclerosis (n = 7), or temporal or extratemporal focal cortical dysplasia (n = 4). The selected TLE patients presented here comprise a heterogeneous group showing most pronounced metabolic depressions in the lateral temporal cortex. Thus, our data suggest that non-invasive metabolic imaging can assist in identifying the neocortical symptomatogenic zone in putative temporo-perisylvian lobe epilepsy.