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Background: We aimed to analyze potentially prognostic factors which could have influence on postoperative seizure, neuropsychological and psychiatric outcome in a cohort of patients with mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis (HS) after selective amygdalohippocampectomy (SAHE) via transsylvian approach., Methods: Clinical variables of 171 patients with drug-resistant MTLE with HS (88 females) who underwent SAHE between 1994 and 2019 were evaluated using univariable and multivariable logistic regression models, to investigate which of the explanatory parameters can best predict the outcome., Results: At the last available follow-up visit 12.3 ± 6.3 years after surgery 114 patients (67.9%) were seizure-free. Left hemispheric MTLE was associated with worse postoperative seizure outcome at first year after surgery (OR = 0.54, p = 0.01), female sex-with seizure recurrence at years 2 (OR = 0.52, p = 0.01) and 5 (OR = 0.53, p = 0.025) and higher number of preoperative antiseizure medication trials-with seizure recurrence at year 2 (OR = 0.77, p = 0.0064), whereas patients without history of traumatic brain injury had better postoperative seizure outcome at first year (OR = 2.08, p = 0.0091). All predictors lost their predictive value in long-term course. HS types had no prognostic influence on outcome. Patients operated on right side performed better in verbal memory compared to left (VLMT 1-5 p < 0.001, VLMT 7 p = 0.001). Depression occurred less frequently in seizure-free patients compared to non-seizure-free patients (BDI-II Z = - 2.341, p = 0.019)., Conclusions: SAHE gives an improved chance of achieving good postoperative seizure, psychiatric and neuropsychological outcome in patients with in MTLE due to HS. Predictors of short-term outcome don't predict long-term outcome., (© 2024. The Author(s).)

Background and Purpose: Automated volumetry of the hippocampus is considered useful to assist the diagnosis of hippocampal sclerosis in temporal lobe epilepsy. However, voxel-based morphometry is rarely used for individual subjects because of high rates of false-positives. We investigated whether an approach with high dimensional warping to the template and nonparametric statistics would be useful to detect hippocampal atrophy in patients with hippocampal sclerosis., Materials and Methods: We performed single-subject voxel-based morphometry with nonparametric statistics within the framework of Statistical Parametric Mapping to compare MRI from 26 well-characterized patients with temporal lobe epilepsy individually against a group of 110 healthy controls. The following statistical threshold was used: P  < .05 corrected for multiple comparisons with family-wise error over the region of interest right and left hippocampus., Results: The sensitivity for the detection of atrophy related to hippocampal sclerosis was 0.92 (95% CI, 0.67-0.99) for the right hippocampus and 0.60 (0.31-0.83) for the left, and the specificity for volume changes was 0.98 (0.93-0.99). All clusters of decreased hippocampal volumes were correctly lateralized to the seizure focus. Hippocampal volume decrease was in accordance with neuronal cell loss on histology reports., Conclusions: Nonparametric voxel-based morphometry is sensitive and specific for hippocampal atrophy in patients with mesial temporal lobe epilepsy and may be useful in clinical practice., (© 2020 by American Journal of Neuroradiology.)

OBJECTIVE The aim of this study was to present long-term seizure outcome data in a consecutive series of patients with refractory mesial temporal lobe epilepsy primarily treated with transsylvian selective amygdalohippocampectomy (SAHE). METHODS The authors retrospectively analyzed prospectively collected data for all patients who had undergone resective surgery for medically refractory epilepsy at their institution between July 1994 and December 2014. Seizure outcome was assessed according to the International League Against Epilepsy (ILAE) and the Engel classifications. RESULTS The authors performed an SAHE in 158 patients (78 males, 80 females; 73 right side, 85 left side) with a mean age of 37.1 ± 10.0 years at surgery. Four patients lost to follow-up and 1 patient who committed suicide were excluded from analysis. The mean follow-up period was 9.7 years. At the last available follow-up (or before reoperation), 68 patients (44.4%) had achieved an outcome classified as ILAE Class 1a, 46 patients (30.1%) Class 1, 6 patients (3.9%) Class 2, 16 patients (10.4%) Class 3, 15 patients (9.8%) Class 4, and 2 patients (1.3%) Class 5. These outcomes correspond to Engel Class I in 78.4% of the patients, Engel Class II in 10.5%, Engel Class III in 8.5%, and Engel Class IV in 2.0%. Eleven patients underwent a second surgery (anterior temporal lobectomy) after a mean of 4.4 years from the SAHE (left side in 6 patients, right side in 5). Eight (72.7%) of these 11 patients achieved seizure freedom. The overall ILEA seizure outcome since (re)operation after a mean follow-up of 10.0 years was Class 1a in 72 patients (47.0%), Class 1 in 50 patients (32.6%), Class 2 in 7 patients (4.6%), Class 3 in 15 patients (9.8%), Class 4 in 8 patients (5.2%), and Class 5 in 1 patient (0.6%). These outcomes correspond to an Engel Class I outcome in 84.3% of the patients. CONCLUSIONS A satisfactory long-term seizure outcome following transsylvian SAHE was demonstrated in a selected group of patients with refractory temporal lobe epilepsy.

GABAergic neurotransmission in the amygdala contributes to the regulation of emotional processes in anxiety, stress, reward, mnestic functions, addiction, and epilepsy. Species-specific differences in the distribution and composition of GABA A receptors may account for distinct effects and side-effects of GABAergic agents. However, data on the distribution and composition of GABA A receptors in the human amygdala are lacking. Here, the expression of GABA A receptor subunits α1, α2, α3, α5, β2, β2/3, and γ2 was studied in the human amygdala using immunohistochemistry. Hippocampi were evaluated as a reference structure. Neuronal counts and field fraction analyses were performed, and subcellular expression of GABA A receptor subunits was analyzed semiquantitatively. In the amygdala, field fraction analyses showed the highest α1 expression in the lateral nucleus (La), whereas α3 was prominent in intercalated nuclei (IC), and α5 and γ2 in the cortical nuclei, and amygdalo-hippocampal/parahippocampal-amygdala transition areas. In the hippocampus, α1 and α3 were accentuated in the dentate gyrus, CA1 region, and subiculum, whereas α5 expression was rather uniform. In both regions, α2 was homogenously distributed, and the two β subunits and γ2 showed faint immunostaining. The intensity of subunit expression also varied in the neuropil, neuronal somata, and/or cellular processes in the subregions. GABA A receptors containing subunit α1, showing the strongest expression in the La, and α3, with the strongest expression in the IC and subiculum, could be targets for treating amygdala-related disorders. Differences in GABA A receptor subunit expression between the human and rodent amygdala should be taken into consideration when developing subunit-selective drugs., (© 2017 Wiley Periodicals, Inc.)

Introduction: Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsy in adults. Because approximately half of these patients develop drug resistance, epilepsy surgery designed to remove the epileptogenic zone is an excellent option in selected patients. Histopathological analyses of hippocampal specimens in TLE patients revealed 4 types of Ammon's horn sclerosis, which are correlated with long-term epileptological outcome. The aim of this study was the correlation of noninvasive, high-resolution, morphological magnetic resonance imaging (MRI) at an ultra-high-field (7 T) of the hippocampus in TLE patients with histopathological findings., Methods: High-resolution, T2-weighted FSE MRI in 14 patients with drug-resistant temporal lobe epilepsy was performed on a 7 T Magnetom using a 32-channel coil. Four independent investigators assessed the delineation and semiquantitative evaluation of volume, signal intensity, internal architecture, and overall grading of the hippocampal subfields CA1-4, as well as the presence of the dentate granule cell layer (DGCL), on MRI scans. Results were compared with semiquantitative evaluation of neuronal loss and astrogliosis in the histological sections of the surgical specimens., Results: Seven-tesla MR examinations were evaluable in 13 cases. Volume loss and signal intensity, as well as overall grading, showed a strong correlation between MRI and histology in individual CA regions. Furthermore, sensitivity and specificity values up to 100% were found for the detection of pathology in the CA subfields. The prediction of Ammon's horn sclerosis type was correct in up to 12 of 13 cases, whereas the dentate gyrus could not be delineated on MRI., Discussion: High-resolution, ultra-high-field MRI is a promising tool for the detection of subtle changes in the hippocampus in patients with temporal lobe epilepsy. Large cohorts will be necessary to confirm the predictive value of 7 T MRI in the preoperative evaluation of TLE patients.

Objective: Hippocampal Sclerosis (HS) is widely recognized as a significant underlying cause of drug-resistant temporal lobe epilepsy (TLE) in adults. In contrast, HS is a rare finding in pediatric surgical series, and a higher incidence of HS associated with cortical dysplasia (i.e. FCD type IIIa according to the new ILAE classification) than in adult series has been reported. Data about the electro-clinical characteristics of this subgroup are scarce., Methods: We studied 15 children and adolescents with drug-resistant TLE and HS who had anterior temporal lobe resection at our center with regard to electroclinical characteristics, MRI features and histopathology. Children in whom histopathology was consistent with Focal Cortical Dysplasia (FCD) type IIIa (n = 7) were compared with those who had HS only (n = 8)., Results: Clinical characteristics associated with this highly selective subset of patients with FCD type IIIa were: the presence of febrile seizures during infancy, a shorter duration of active epilepsy and a lower age at epilepsy surgery. In addition, there were non-significant trends towards more extended abnormalities on both EEG and neuroimaging. We were, however, not able to find group differences with respect to neuropathologic subtyping of the HS., Conclusion: We present the first detailed description and comprehensive data analysis of children with FCD type IIIa. According to our results, this patient group seems to show a distinct clinical phenotype., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Retrospective data analysis was performed in a sample of 45 consecutive patients who underwent epilepsy surgery for medically refractory mTLE-HS. Beck Depression Inventory (BDI) was used preoperatively to detect actual depressive symptoms and label patients into those "with depressive symptoms" or "without depressive symptoms". Postoperative seizure outcome one, two, and three years after surgery was classified into "complete seizure freedom" versus "presence of auras and/or seizures". Postoperative seizure outcomes were compared in patients with and without depressive symptoms, and no significant difference of postoperative seizure outcome was found. However, there was a non-significant trend for patients with preoperative depressive symptoms to experience a postoperative running down phenomenon more frequently than nondepressed patients. Depressive symptoms, identified by the BDI, do not seem to have a predictive value for postoperative seizure outcome in this highly selected patient population with mTLE-HS, but may be positive predictors for experiencing a postoperative running down phenomenon., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Temporal lobe epilepsy (TLE) is characterized by distinct neuropathological findings, such as hippocampal sclerosis and reactive astrogliosis. Recently, MRI studies have revealed the presence of white matter pathology in brains of epilepsy patients. The purpose of this study is to evaluate the involvement of oligodendroglia in the epileptogenic process. Using TPPP/p25 as a marker for mature oligodendroglia, we evaluated the hippocampus in 26 surgical specimens from patients with TLE and 9 autopsy controls without neuropathological alterations for changes in oligodendroglial cell densities (mm2) in hippocampal, entorhinal, and temporal white matter, and the amount of perineuronal oligodendrocytes in CA1 subregion. Oligodendrocyte cell densities were significantly elevated in epilepsy patients compared to controls in all four examined white matter subregions. In addition, in the CA1 sector, the percentage of neurons showing more than one perineuronal oligodendrocyte was significantly higher in epilepsy patients. In conclusion, our study expands the glial reactions beyond astrogliosis and shows that prominent oligodendroglial response is a consistent pathological feature characteristic for TLE.

Recently, expression of glutamate decarboxylase-67 (GAD67), a key enzyme of GABA synthesis, was detected in the otherwise glutamatergic mossy fibers of the rat hippocampus. Synthesis of the enzyme was markedly enhanced after experimentally induced status epilepticus. Here, we investigated the expression of GAD67 protein and mRNA in 44 hippocampal specimens from patients with mesial temporal lobe epilepsy (TLE) using double immunofluorescence histochemistry, immunoblotting, and in situ hybridization. Both in specimens with (n = 37) and without (n = 7) hippocampal sclerosis, GAD67 was highly coexpressed with dynorphin in terminal areas of mossy fibers, including the dentate hilus and the stratum lucidum of sector CA3. In the cases with Ammon's horn sclerosis, also the inner molecular layer of the dentate gyrus contained strong staining for GAD67 immunoreactivity, indicating labeling of mossy fiber terminals that specifically sprout into this area. Double immunofluorescence revealed the colocalization of GAD67 immunoreactivity with the mossy fiber marker dynorphin. The extent of colabeling correlated with the number of seizures experienced by the patients. Furthermore, GAD67 mRNA was found in granule cells of the dentate gyrus. Levels, both of GAD67 mRNA and of GAD67 immunoreactivity were similar in sclerotic and nonsclerotic specimens and appeared to be increased compared to post mortem controls. Provided that the strong expression of GAD67 results in synthesis of GABA in hippocampal mossy fibers this may represent a self-protecting mechanism in TLE. In addition GAD67 expression also may result in conversion of excessive intracellular glutamate to nontoxic GABA within mossy fiber terminals., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Selective amygdalohippocampectomy (SAHE) yields 60-80% of patients with medically refractory mesial temporal lobe epilepsy seizure-free and seems to be equally effective compared to the more extended temporal lobe resections. The resection of the entire entorhinal cortex (EC) is of crucial importance to warrant complete seizure control for those patients. Thus, evidence of residual EC could be a predictor of a potentially successful reoperation in patients with recurrent seizures after SAHE. We performed an analysis of preoperative and postoperative magnetic resonance imaging (MRI) in patients who underwent a reoperation after an unsuccessful transsylvian SAHE to assess the presence of residual EC before reoperation and to determine whether certain anatomical variants may dispose patients to incomplete resection of EC., Materials and Methods: Ten patients who underwent reoperation after SAHE for the recurrence of medically refractory seizures were studied. MRI after SAHE was assessed for the presence of residual EC using T2-weighted and inversion recovery sequences perpendicularly to the main axis of the hippocampus. The results were compared with a control group of ten patients who became seizure-free after SAHE. In the nine patients of the study group, the sulcal anatomy of the basal temporal lobe was graphically outlined and analysed on MRI scans performed before SAHE to characterise the sulcal boundaries of the EC., Findings: Residual EC was found in nine of ten patients and was absent in the control group. After reoperation (median follow-up of 36.5 months), eight out of ten patients were completely seizure-free. In seven out of nine patients, a discontinuous course of the lateral sulcal boundaries of the EC was determined., Conclusions: Careful analysis of MRI verified residual mesiotemporal structures in the majority of patients who became seizure-free after reoperation. Certain temporobasal sulcal patterns might dispose for a higher risk of incomplete resection of the EC. The study confirms that reoperation is an effective treatment modality for patients with recurrent seizures after transsylvian SAHE.

This 15-year-old girl had subacute onset of secondary generalized seizures, confusion, and subsequent memory decline. MRI showed bilateral hippocampal swelling progressing to unilateral mesial temporal sclerosis (MTS) within 12 months. Epilepsy surgery was performed, and laboratory data were consistent with non-paraneoplastic limbic encephalitis. 18 months after epilepsy surgery, the patient is seizure-free with stable cognitive functions.

Objectives: Hippocampal abnormalities may coexist with malformations of cortical development (MCD). This cross-sectional MRI study aimed at categorizing hippocampal abnormalities in a large group of MCD and comparing MCD patients with (group W) and without (group W/O) hippocampal abnormalities., Methods: Hippocampal anatomy, rotation, size, internal structure, and MRI signal alterations were assessed visually by 3 independent raters in patients with MCD and epilepsy. Four types of hippocampal abnormalities were examined in 220 patients (116 women, mean age 31 +/- 16.6, range 2-76 years): partially infolded/hypoplastic hippocampus (HH), hippocampal sclerosis (HS), malrotated hippocampus (MH), and enlarged hippocampus (EH). The commonest MCD in the cohort were focal cortical dysplasia (27%), polymicrogyria (PMG) (21%), developmental tumors (15%), and periventricular nodular heterotopia (PNH) (14%)., Results: Hippocampal abnormalities were seen in 69/220 (31%) patients: HH in 34/69 (49%); HS in 18/69 (26%); MH in 15/69 (22%); and EH in 2/69 (3%). PNH (21/30 [70%]) and PMG (22/47 [47%]) were most commonly associated with hippocampal abnormalities. Compared to the W/O group, patients in the W group had a higher rate of learning disability (W 41/69 [59%] vs W/O 56/151 [37%]; p = 0.003) and delayed developmental milestones (W 36/69 [52%] vs W/O 53/151 [35%]; p = 0.025); groups did not differ otherwise with regard to clinical presentation. HH was associated with symptomatic generalized epilepsies (11/34 [32%]) and high rate of learning disability (27/34 [79%]), neurologic deficits (25/34 [73%]), and delayed developmental milestones (23/34 [68%])., Conclusions: About a third of patients with malformations of cortical development had hippocampal abnormalities. Patients with hypoplastic hippocampus had the most severe clinical phenotype.

Purpose: To study long-term postoperative course and identify predictors for postoperative seizure control in patients with medically intractable temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS), diagnosed by magnetic resonance imaging (MRI), and ascertained histopathologically. To compare patients becoming seizure-free (i.e., cured from epilepsy) and patients experiencing prolonged seizure-free periods interposed with recurring seizures., Methods: One hundred thirty-five patients (74 women) underwent complete evaluation for epilepsy surgery. The predictive value of duration of epilepsy, age at onset, age at surgery, gender, febrile convulsion history, ictal dystonic posturing, unilateral interictal electroencephalography (EEG) discharges (IED), preoperative secondarily generalized tonic-clonic seizures (SGTCS), and preoperative seizure frequency for short- and long-term postoperative seizure control were evaluated with two classification systems: Classification 1 (seizure-freedom with or without auras during 12-months before observation points) and the stringent classification 2 [International League Against Epilepsy (ILAE) Ia; absolute absence of seizures and auras after operation]., Results: Unilateral IED at year 1 and 2 (p = 0.037 and p = 0.034), male gender and low seizure frequency at year 2 (p = 0.013 and p = 0.046) were significant predictors for seizure freedom using classification 1. All variables (except male gender at year 2; p = 0.035) lost their predictive power, applying classification 2. The proportion of seizure-free patients remained stable between 70% to 79% with classification 1, but decreased from 64.4% at year 1 to 45.8% at year 5 with classification 2., Discussion: Positive predictors of short-term outcome do not predict long-term outcome in patients with TLE associated with HS. Absolute freedom of seizures and auras cannot be predicted by conventional preoperative variables.

Mesial temporal lobe epilepsy (MTLE), the most common form of epilepsy, is characterised by cytoarchitectural abnormalities including neuronal cell loss and reactive gliosis in hippocampus. Determination of aberrant cytoskeleton protein expression by proteomics techniques may help to understand pathomechanism that is still elusive. We searched for differential expression of hippocampal proteins by an analytical method based on two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry unambiguously identifying 77 proteins analysed in eight control and eight MTLE hippocampi. Proteins were quantified and we observed 18 proteins that were altered in MTLE. Cytoskeleton proteins tubulin alpha-1 chain, beta-tubulin, profilin II, neuronal tropomodulin were significantly reduced and one actin spot was missing, whereas ezrin and vinculin were significantly increased in MTLE. Proteins of several classes as e.g. antioxidant proteins (peroxiredoxins 3 and 6), chaperons (T-complex protein 1-alpha, stress-induced-phosphoprotein 1), signaling protein MAP kinase kinase 1, synaptosomal proteins (synaptotagmin I, alpha-synuclein), NAD-dependent deacetylase sirtuin-2 and 26S protease regulatory subunit 7 protein, neuronal-specific septin 3 were altered in MTLE. Taken together, the findings may represent or lead to cytoskeletal impairment; aberrant antioxidant proteins, chaperons, MAP kinase kinase 1 and NAD-dependent deacetylase sirtuin-2 may have been involved in pathogenetic mechanisms and altered synaptosomal protein expression possibly reflects synaptic impairment in MTLE.

Temporal lobe epilepsy (TLE) is characterized by hippocampal sclerosis together with profound losses and phenotypic changes of different classes of interneurons, including those expressing somatostatin (SRIF). To understand the functional significance of the plasticity of SRIF transmission in TLE, unraveling the status of SRIF receptors is, however, a prerequisite. To address this issue, we characterized expression and distribution of the major SRIF receptor, the sst2 subtype, in hippocampal tissue resected in patients with TLE using complementary neuroanatomic approaches. In patients with hippocampal sclerosis, the number of cells expressing sst2 receptor mRNA as well as sst2 receptor-binding sites and immunoreactivity decreased significantly in the CA1-3, reflecting neuronal loss. By contrast, in the dentate gyrus, sst2 receptor mRNA expression was strongly increased in the granule cell layer, and sst2 receptor-binding sites and immunoreactivity was preserved in the inner but decreased significantly in the outer molecular layer. In this latter region, pronounced changes in SRIF terminal fields were observed. Decreased receptor density in the distal dendrites of granule cells is likely to reflect downregulation of sst2 receptors in response to physiopathologic release of SRIF. Because sst2 receptors have anticonvulsant and antiepileptogenic properties, this phenomenon may contribute to the etiology of TLE seizures.

Apolipoprotein A-I (apo A-I), a major component of high density lipoproteins, has been shown to be involved in lipid metabolism, cholesterol homeostasis and degeneration/regeneration of brain tissues and was proposed as a useful marker for the extent and severity of CNS injury. We searched for aberrant protein expression in hippocampus from patients with mesial temporal lobe epilepsy (MTLE) by an analytical method based on two-dimensional gel electrophoresis coupled with mass spectrometry (MALDI-TOF/TOF) and unambiguously identified 2 spots as apolipoprotein A-I forms in brain of MTLE patients with 7.5-fold increased levels (controls: 0.046 +/- 0.046; MTLE patients: 0.343 +/- 0.154, mean +/- SD, P = 0.003). Western blot analysis confirmed increased apo A-I levels in MTLE. Immunohistochemistry detected staining for apo A-I extracellularly in perivasal brain parenchyma, neuropil and areas with increased glial fibrillary acidic protein (GFAP) expression as well as some pyramidal neurons and subpial astrocytes. These findings indicate that the increase of apo A-I in MTLE was possibly not reflecting a pathogenetic role but was rather due to extravasates, bleedings or increase of microvascular endothelial cells known to synthesize apo A-I. Care has to be taken when protein expressional findings are to be interpreted in the presence of plasma proteins, including apo A-I, thus clearly representing a confounding factor.

A series of enzyme alterations has been shown to be associated with several forms of epilepsy, in mesial temporal lobe epilepsy (MTLE), however, information is limited. It was therefore the aim of the study to determine brain enzyme protein expression using a proteomic screening approach. Hippocampi of controls and patients with drug-resistant MTLE were used for evaluation of protein expression. We applied two-dimensional electrophoresis (2-DE) with mass spectrometrical identification and immunoblotting. 2-DE revealed a remarkably decreased spot identified as cytosolic acyl-CoA thioester hydrolase (BACH; EC 3.1.2.2) in patients with MTLE. Western blotting showed absence of bands at 37 kDa in MTLEs using an antibody against mouse BACH and at 140 kDa in MTLEs using anti-rat BACH. This study demonstrates that BACHs were deranged in hippocampus of MTLE patients. This finding may well contribute to the understanding of the still elusive pathomechanisms involved in MTLE.

Although the syndrome of mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis has been elaborated in recent years, pathogenesis and pathomechanisms are still elusive. Performing protein hunting in hippocampus of patients with MTLE we detected derangement of collapsin response mediated protein-2 (CRMP-2). Hippocampal tissue from controls and MTLEs was taken and two-dimensional gel electrophoresis with subsequent MALDI-MS-characterisation was applied. The proteomic approach identified 13 spots unambiguously assigned to CRMP-2. Three spots at molecular weight 55 kDa showed a significant decrease in MTLE and other 3 spots at 65 kDa showed deranged in MTLE. Immunoblotting revealed two bands at 65 and 55 kDa in the control group whereas the 55 kDa band was extremely low expressed in MTLE. CRMP-2 is required to induce axonal outgrowth and maintaining neuronal polarity in hippocampal neurons and the significant decrease of this protein may represent or underlie impaired neuronal plasticity, neurodegeneration, wiring of the brain in MTLE and may explain abnormal migration. Therefore, the decrease of CRMP-2 may well contribute to the understanding of the still unclear pathomechanisms involved in MTLE.

Mesial temporal lobe epilepsy (TLE) is associated with pronounced anatomical and biochemical changes in the hippocampal formation including extensive neurodegeneration, reorganization of mossy fibres and sprouting of interneurons. Although the anatomical features and some of the physiological consequences of hippocampal remodeling have been well documented, the molecular mechanisms underlying the profound and orientated outgrowth of hippocampal neurons in TLE are not yet understood. The reticulon protein Nogo-A has been associated with an inhibitory action on axon growth and plasticity. Using immunohistochemistry and in situ hybridization, we investigated the expression of Nogo-A in specimens obtained at surgery from patients with TLE compared with those obtained from autopsy controls. In control specimens, Nogo-A immunoreactivity and mRNA were mainly confined to oligodendrocytes. Only approximately 40% of the specimens revealed low expression of Nogo-A mRNA in neurons. In contrast, in TLE patients with and without Ammon's horn sclerosis, Nogo-A mRNA and immunoreactivity were markedly up-regulated in most neurons (3.6- and 4.4-fold increases in Nogo-A mRNA in granule cells of sclerotic and nonsclerotic specimens) and their processes throughout the hippocampal formation. Similar elevations in Nogo-A mRNA and protein levels were determined by quantitative RT-PCR and Western blotting. Since Nogo-A expression was also up-regulated in specimens without hippocampal sclerosis, it may be induced by seizures prior to progressing neurodegeneration.

The hippocampus is an important brain region playing a central role in short-term memory formation. Information on protein expression in human hippocampus is limited and we therefore decided to generate a protein map of this pivotal brain structure thus providing protein building blocks and an analytical tool. Two-dimensional electrophoresis with in-gel digestion of protein spots followed by mass spectrometrical identification coupled to the Mascot search program was applied. Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) or in special cases MALDI-TOF/TOF was used in order to warrant unambiguous identification. 266 protein spots representing 165 different proteins and 101 probable isoforms or post-translational modifications were identified. The identified proteins were categorized into several protein groups as metabolic, cytoskeleton, antioxidant, chaperone, signaling, transcriptional, proteolytic, synaptosomal and neuronal, hypothetical and miscellaneous structures. This human hippocampus protein map provides an analytical tool for hydrophilic and even relatively small-molecular-weight proteins and contributes to the knowledge on protein building blocks thus forming the basis for protein-chemical work in this brain area in health and disease.

Malfunctioning of the GABA-ergic system has been postulated as a possible cause of epilepsy. We investigated changes in the mRNA expression of the GABA(B) receptor subtypes GABA(B)-R1 and GABA(B)-R2 and of GABA(B) receptor binding in the hippocampus of patients with temporal lobe epilepsy (TLE) compared with post-mortem controls. In patients with Ammon's horn sclerosis, significant decreases in [3H]CG54626A binding were observed in subfields CA1 and CA3 of the hippocampus proper and the dentate hilus. On the other hand, both GABA(B) receptor mRNAs and receptor binding were enhanced after correction for neuronal loss in dentate granule cells and in the molecular layer, respectively, and the subiculum of patients with and without hippocampal sclerosis. These increases were even more pronounced when correcting the values for cell losses in the respective areas and indicated also increased expression of GABA(B)-R in the dentate hilus. Increased expression of both subtypes of GABA(B) receptors indicates augmented presynaptic inhibition of glutamate release as a possible protective mechanism in TLE.

It has been postulated that dysfunction of the GABA-ergic transmission is causatively related to the development of epilepsy. Animal models of temporal lobe epilepsy (TLE) revealed considerable changes in the expression of GABA(A) receptor subunits in the hippocampus. Using immunocytochemistry, we investigated the expression of GABA(A) receptor subunits alpha1, alpha3, beta1-3, and gamma2 in hippocampal specimens obtained at surgery from TLE patients with and without hippocampal sclerosis and in autopsy controls. Consistent with the severe neurodegeneration in the CA1 sector, significant decreases in alpha1-, alpha3-, beta3-, and gamma2-subunit immunoreactivity (IR) were detected in sclerotic but not in nonsclerosic specimens. In contrast, pronounced increases in IR of all 3 beta-subunits were observed in most sectors of the hippocampal formation both in sclerotic and nonsclerotic specimens, being especially pronounced in the dentate molecular layer and in the subiculum where subunit alpha3- and gamma2-IR were also elevated. Using in situ hybridization for subunits beta2 and beta3, increased expression of the respective mRNAs was detected in dentate granule cells of patients with and without hippocampal sclerosis. Beta-subunits are important constituents of the GABA(A) receptor and contribute to the binding site of GABA. Our data indicate pronounced adaptive changes in the expression of these GABA(A) receptor subunits related to seizure activity and indicate altered assembly of GABA(A) receptors in TLE.

Object: The concept of selective amygdalohippocampectomy is based on pathophysiological insights into the epileptogenicity of the hippocampal region and the definition of the clinical syndrome of mesial temporal lobe epilepsy (TLE). High-resolution magnetic resonance (MR) imaging allows correlation of the site of histologically conspicuous tissue with anatomical structure. The highly variable sulcal pattern of the basal temporal lobe, however, definitely complicates the morphometric analysis of histomorphologically defined subdivisions of the hippocampal region. The goal of this study was to define individual variations in the sulcal anatomy on the basis of preoperative MR images obtained in patients suffering from TLE., Methods: The authors analyzed coronal MR images obtained in 50 patients for the presence of and intrinsic relationships among the rhinal, collateral, and occipitotemporal sulci. The surface relief of consecutive sections of 100 temporal lobes was graphically outlined and the resulting maps were used for visual analysis. The sulci were characterized by measurement of their depth, distance to the temporal horn, and laterality. The anatomical measurements and frequencies of sulcal patterns were assessed for statistical correlation with patients' histories and the lateralization of the seizure focus., Conclusions: Statistical assessment shows that patient sex is a significant factor in sulcal patterns. Anatomical measurements are significantly decreased on the side of the seizure origin, which relates to loss of white matter, a known morphological abnormality associated with TLE. Magnetic resonance imaging allows for accurate preoperative knowledge of individual sulcal patterns and facilitates intraoperative orientation to anatomical landmarks.

Voltage-dependent calcium channels, the initial components in the calcium signalling cascade, are increasingly being recognised as relevant factors in the pathology of epilepsy. To further characterise their role in temporal lobe epilepsy associated with Ammon's horn sclerosis, we investigated the immunohistochemical distribution of five different voltage-dependent calcium channel alpha(1) subunits (alpha(1A), alpha(1B), alpha(1C), alpha(1D), alpha(1E)) in 14 hippocampal specimens of patients with Ammon's horn sclerosis in comparison with eight autopsy control cases. In epilepsy specimens an increased immunoreactivity was observed for alpha(1A), alpha(1B), alpha(1D) and alpha(1E) in the neuropil of the dentate gyrus molecular layer. Dentate gyrus granule cells and residual CA3 pyramidal neurones showed enhanced immunoreactivity for alpha(1A), while labelling of these neurones was decreased for alpha(1C). Astrocytes in Ammon's horn sclerosis specimens were strongly immunoreactive for the alpha(1C) subunit contrasting with an absent astrocytic alpha(1C) labelling in controls. Our results suggest that the expression of calcium channels in neurones and glial cells is dynamically regulated in temporal lobe epilepsy, supporting the relevance of calcium signalling pathways for this disease.

Chromogranins are polypeptides which are widely expressed in the central nervous system. They are stored in dense core vesicles of nerve terminals, from where they are released upon stimulation. Using immunocytochemistry, we investigated the distribution of chromogranin A, chromogranin B, secretoneurin, and, for comparison, dynorphin in hippocampal specimens removed at routine surgery from patients with drug-resistant mesial temporal lobe epilepsy and in autopsy tissues from nonneurologically deceased subjects. In post mortem controls (n = 21), immunoreactivity for all 4 peptides (most prominently for chromogranin B and dynorphin) was observed in the terminal field of mossy fibers. For chromogranins, staining was observed also in sectors CA1 to CA3 and in the subiculum. Chromogranin B immunoreactivity was found in the inner molecular layer of the dentate gyrus, the area of terminating associational-commissural fibers. Secretoneurin and dynorphin immunoreactivity labeled the outer molecular layer and the stratum lacunosum moleculare of sectors CA1 to CA3, where projections from the entorhinal cortex terminate. In specimens with Ammon's horn sclerosis (n = 25), staining for all 3 chromogranins and for dynorphin was reduced in the hilus of the dentate gyrus. Instead, intense staining was observed in the inner molecular layer, presumably delineating terminals of sprouted mossy fibers. Specimens obtained from temporal lobe epilepsy patients without Ammon's horn sclerosis (n = 4) lacked this pronounced rearrangement of mossy fibers. In the stratum lacunosum moleculare of sector CA1, secretoneurin and dynorphin immunoreactivity was reduced in sclerotic, but not in nonsclerotic, specimens, paralleling the partial loss of fibers arising from the entorhinal cortex. Instead, presumably sprouted secretoneurin-immunoreactive fibers were found in the outer dentate molecular layer in sclerotic specimens. These changes in staining patterns for chromogranins and dynorphin mark profound plastic and functional rearrangement of hippocampal circuitry in temporal lobe epilepsy.

Marked expression of neuropeptide Y (NPY) and its Y2 receptors in hippocampal mossy fibers has been reported in animal models of epilepsy. Because NPY can suppress glutamate release by activating presynaptic Y2 receptors, these changes have been proposed as an endogenous protective mechanism. Therefore, we investigated whether similar changes in the NPY system may also take place in human epilepsy. We investigated Y1 and Y2 receptor binding and NPY immunoreactivity in hippocampal specimens that were obtained at surgery from patients with temporal lobe epilepsy and in autopsy controls. Significant increases in Y2 receptor binding (by 43-48%) were observed in the dentate hilus, sectors CA1 to CA3, and subiculum of specimens with, but not in those without, hippocampal sclerosis. On the other hand, Y1 receptor binding was significantly reduced (by 62%) in the dentate molecular layer of sclerotic specimens. In the same patients, the total lengths of NPY immunoreactive (NPY-IR) fibers was markedly increased (by 115-958%) in the dentate molecular layer and hilus, in the stratum lucidum of CA3, and throughout sectors CA1 to CA3 and the subiculum, as compared with autopsies. In nonsclerotic specimens, increases in lengths of NPY-IR fibers were more moderate and statistically not significant. NPY mRNA was increased threefold in hilar interneurons of sclerotic and nonsclerotic specimens. It is suggested that abundant sprouting of NPY fibers, concomitant upregulation of Y2 receptors, and downregulation of Y1 receptors in the hippocampus of patients with Ammon's horn sclerosis may be endogenous anticonvulsant mechanisms.

Purpose: Chromogranins are neuropeptide precursors stored in large dense core vesicles. Because physiological functions have been postulated for peptides originating from chromogranins, we investigated the distribution of chromogranins A and B and secretoneurin (a peptide derived from secretogranin II) in the control and epileptic hippocampus of humans and rats., Methods: Chromogranin immunoreactivity (IR) was investigated in paraformaldehyde-fixed hippocampal specimens from 24 temporal lobe epilepsy patients with intractable seizures, postmortem from 15 patients deceased from nonneurological disorders, in rats 30 days after kainate-induced limbic seizures, and in control rats., Results: In control rats and in humans, chromogranin A and B IR and secretoneurin IR were present in mossy fibers. In addition, chromogranin B IR was found in granule cells, and chromogranin A IR was found in granule and CA2 pyramidal cells in the human hippocampus. In both species, chromogranin B and secretoneurin were unevenly distributed in the molecular layer of the dentate gyrus. The most intriguing change seen in human temporal lobe epilepsy specimens and in the kainic acid model of the rat was the prominent staining of the inner molecular layer, indicating storage of chromogranins A and B and secretoneurin in terminals of reorganized mossy fibers, from which they may be released upon nerve stimulation., Conclusion: Chromogranins A and B and secretoneurin are valid markers for hippocampal neurons and delineate epilepsy-induced reorganization of mossy fibers.