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Surgery for temporal lobe epilepsy refractory to medical treatment is a promising treatment option. After a short overview of historical developments in this field, we describe the present practice of presurgical evaluation and resection strategies as practiced at our institution and review the corresponding publications from other centers. We will be trying to outline major future developments for the surgical therapy of temporal lobe epilepsy based on present trends.

Purpose: Surgical treatment of refractory temporal lobe epilepsy (TLE) is promising for selected patients, but only little experience has been acquired in operating on older patients, especially with limited resections. We intend to delineate clinical and surgical factors influencing outcome in patients older than 50 years at operation and to compare the results with those of a younger patient cohort., Methods: Fifty-two patients older than 50 years were operated on for intractable mesial or combined mesiolateral TLE between 1991 and 2002. The mean age at operation was 55 years, and the mean duration of epilepsy was 33 years. Forty selective amygdalohippocampectomies (33 for hippocampal sclerosis, seven for removal of a mesiotemporal lesion), five lateral temporal lesionectomies plus amygdalohippocampectomy, and seven anterior temporal lobectomies were performed. Eleven (21%) patients had undergone invasive presurgical video-EEG monitoring. The mean follow-up period was 33 months. We compared the results with those of a younger cohort operated on in the same time period., Results: Thirty-seven older patients attained complete seizure control (71% class I), and 10 patients had only rare postoperative seizures (19% class II). Four patients improved >75% (8% class III), and one patient did not improve (2% class IV). The same rate of seizure control was attained by 11 patients older than 60 years at surgery. These results were not significantly different from those in a younger patient group. A trend toward better seizure control was noted in 16 patients with an epilepsy duration of <30 years (all class I or II), and in 20 patients with a seizure frequency of fewer than five seizures per month (all class I or II). No mortality resulted from a total of 65 diagnostic and therapeutic procedures. A 3.8% permanent neurologic morbidity (dysphasia and hemiparesis) was noted. Hemianopia occurred in three (5.9%) patients. Neuropsychological testing revealed low preoperative performances and some gradual further deterioration after surgery., Conclusions: Results of surgery for TLE with mainly limited resections are promising in patients older than 50 years and older 60 years, despite the long seizure history. As expected, the risk of complications is somewhat higher compared with that in a younger control group. The impact of low neuropsychological performance is a concern.

Purpose: The objective of this study was to correlate health-related quality of life (HRQOL) after surgery for mesial temporal lobe epilepsy, as revealed by a postoperative screening tool, to different modalities of seizure outcome classification (Engel, International League Against Epilepsy (ILAE))., Method: One hundred twenty-eight of one hundred forty consecutive patients returned a HRQOL questionnaire at a mean of 36 months after selective amygdalohippocampectomy. Patients answered in two ways: with an absolute estimation (values 1-4) and with a self-rated relative change (-1, 0, +1) after surgery., Results: Eighty patients were seizure- and aura-free (63.3% ILAE 1), 16 continued to have auras (12.5% ILAE 2), and 13 experienced 1-3 seizure days per year after surgery (10.2% ILAE 3). Ninety-two patients were classified seizure-free (71.9% Engel I), and 17 had two or fewer seizures per year (13.3% Engel II). Of 110 patients in ILAE 1-3, 100 (91%) stated good or even very good postoperative HRQOL, and 99 (90.0%) reported improvements in HRQOL. Only 9 of the remaining 18 (50%) reported good or very good HRQOL after surgery (P=0.01). Corresponding results were obtained with Engel classes I and II, suggesting a trend toward ILAE 1-3 and Engel I and II as overall satisfactory outcomes. A more detailed HRQOL assessment yielded lowest scores in the cognitive domain, and a significant correlation of self-rated changes in cognitive functioning with seizure control (P=0.01). Changes in physical capabilities and mood were significantly better with satisfactory seizure outcome (P=0.006 and P<0.001, respectively), whereas the social aspects were not significantly dependent on seizure outcome (P=0.06)., Conclusion: Correlation of HRQOL and seizure control suggested that ILAE 1-3 and Engel I and II most likely represent overall satisfactory outcome. Subdomain analyses revealed cognitive abilities as the most critical feature associated with seizure control, whereas social aspects remained mainly stable.

Purpose: Intellectual disabilities are often associated with bilateral or diffuse morphologic brain damage. The chances of becoming seizure free after focal surgery are therefore considered to be worse in patients with intellectual disabilities. The risk of postoperative cognitive deficits could increase because diffuse brain damage lowers the patient's ability to compensate for surgically induced deficits. Several studies in adult patients have indicated that IQ alone is not a good predictor of postoperative cognitive and seizure outcome. Our study evaluated this subject in children and adolescents., Methods: Pediatric patients with intellectual disabilities (IQ < or = 70), subaverage intelligence (IQ between 71 and 85), or average-range intelligence (IQ > 85) were matched according to several clinical and etiologic criteria to determine the influence of IQ (N = 66)., Results: No dependency of seizure outcome, postoperative cognitive development, and behavioral outcome on the IQ level was found. All groups slightly improved in attention while memory functions tended to decrease and executive functions were stable. School placement remained unchanged for the majority of patients. Between 67 and 78% were seizure free 1 year after surgery (Engel outcome class I)., Conclusions: IQ alone is not a good predictor of postoperative outcome in pediatric patients with epilepsy. As with patients of average-range intelligence, the decision to operate on patients with a low level of intelligence should depend on the results of the presurgical diagnostics. If the results of the neuropsychological examination indicate diffuse functional impairment, this should not hinder further steps, if all other findings are consistent.

Abnormalities in regional cerebral blood flow (rCBF) have been reported to characterize depressive episodes; they are at least partly reversed by antidepressant treatment. Treatment-specific as well as response-related changes in rCBF have been reported. We explored the changes in rCBF induced by vagus nerve stimulation (VNS), a recently proposed antidepressant strategy, by application of single photon emission-computed tomography with (99m)Tc-hexamethyl-propylene amine oxime in otherwise treatment-refractory patients. Both region-of-interest (ROI) and statistical parametric mapping (SPM) analytic approaches were used. Decreases of rCBF in the amygdala, left hippocampus, left subgenual cingulate cortex, left and right ventral anterior cingulum, right thalamus and brain stem were observed; the only increase of rCBF was found by SPM analysis in the middle frontal gyrus. This pattern shares features with changes of rCBF previously associated with the administration of selective serotonin reuptake inhibitors. Similarities to other brain-stimulation strategies in antidepressant treatment were less pronounced.

The present study aims at analyzing the modulation of two types of event-related potentials originating from the human medial temporal lobe, the rhinal AMTL-N400 and the hippocampal P600 by the processing of famous faces. Therefore, we used a face recognition paradigm in which subjects had to discriminate the faces of famous persons from the faces of non-famous persons. Eleven patients with unilateral medial temporal lobe epilepsy undergoing intrahippocampal depth electrode recording for presurgical evaluation participated in this study. Event-related potentials (ERP) were recorded while a sequence of famous and non-famous faces was presented to the patients. The presentation of each face was repeated. The faces evoked N400-like potentials (anterior medial temporal lobe N400, AMTL-N400) in the rhinal cortex and P600-like potentials in the hippocampus. ERPs elicited by famous faces were contrasted with ERPs elicited by non-famous faces. The first presentation of famous faces elicited an enhanced AMTL-N400 and an enhanced hippocampal P600 in comparison to the second presentations of the famous faces or the (first and second presentation of the) non-famous faces. This findings are discussed in terms of associative semantic memory processes and the retrieval of person-specific information from long-term memory stores triggered by the processing of famous faces.

The dentate gyrus is believed to play an important pathophysiological role during experimentally induced kindling. In this study, we investigated whether an altered content of the calcium binding protein calbindin-D(28k) or an increased intrinsic excitability of hippocampal granule cells contribute to the induction of the kindling phenomenon. We determined the firing pattern of granule cells in hippocampal slices using perforated patch-clamp recordings in current clamp mode. The expression of calbindin-D(28k) and glutamic acid decarboxylase (GAD(67)) by granule cells was analyzed immunohistochemically. Rats developed secondarily generalized limbic seizures within approximately 11 days of twice-daily stimulation of the amygdala. As reported for other kindling paradigms, this protocol induced a clear up-regulation of GAD(67) in granule cells, indicating their involvement in the induced neuronal activity. However, when comparing kindled and control rats, we could not detect any differences in intrinsic excitability: Firing frequency, after-hyperpolarisations, action potentials, input resistance and membrane potentials were nearly identical between both groups. Furthermore, we did not observe any differences in the calbindin-D(28k) immunoreactivity between groups. In every slice, virtually all granule cells were found to be strongly calbindin-D(28k) positive, and there was no apparent reduction in the general level of calbindin-D(28k) expression. We conclude that changes in intrinsic membrane properties or in the calbindin-D(28k) content of granule cells are not necessary for the development of amygdala kindling.

Objectives: To evaluate the influence of clinical, investigational, surgical, and histopathological factors on postoperative seizure relief in patients with mesial temporal lobe epilepsy (MTLE) due to lesions other than ammonshornsclerosis (AHS)., Methods: Of 738 patients operated for TLE, 78 patients underwent limited resections for lesional MTLE (1990-2000). Seventy four patients with a follow up of more than one year were included. The preoperative clinical, neuropsychological, electroencephalogram, and neuroimaging characteristics were prospectively collected in a database. The histopathological material was re-examined., Results: The mean follow up was 49 months. Fifty eight patients were classified as seizure free (78.4% Class I), and six as almost seizure free (8.1% Class II), grouped together as satisfactory seizure control (64 patients, 86.5%). Five patients (6.8%) were categorised in Classes III and IV, respectively. These were grouped as unsatisfactory seizure control (10 patients, 13.5%). Surgical procedures were: 32 amygdalohippocampectomies (AH), 17 partial anterior AH, 15 AH plus polar resection, seven AH plus basal resection, and three AH plus extended temporal lesionectomy. There was no mortality and 2.7% mild permanent morbidity. Seizure relief did neither differ significantly with these approaches, nor with different classes of pathological findings (43 developmental tumours, 12 glial tumours, 10 dysplasias, and nine others). Even operation of dysplasias resulted in 80% satisfactory seizure control. Seizure onset during childhood proved to be a negative predictor for seizure relief (p = 0.020). MRI revealed 73 suspected lesions (98.6%), one dysembryoplastic neuroepithelial tumour was missed, in four cases no structural abnormalities could be confirmed with histopathological exam. Additionally, multifactorial regression revealed the factors "seizure onset after 10 years of age", "presence of complex partial seizures", "absence of a neurological deficit", and a "correlating neuropsychological deficit" as predictive for satisfactory seizure control., Conclusions: "Preoperative tailoring" resulting in limit resections has proven to be safe and to provide a very good chance for satisfactory seizure relief in patients with lesional MTLE.

Affection of the cerebral circulation following the extraaxial transsylvian approach has been reported. This study aims at the comparison of the risk for the development of vasospasm in the transparenchymal transcortical versus the transsylvian approach for selective amygdalohippocampectomy in patients with Ammon's horn sclerosis. n = 80 consecutive patients (13-58 years) were randomized and allotted to either the transsylvian (TS) or transcortical (TC) group. Bilateral middle cerebral arteries (MCA) and internal carotid arteries (ICA) were examined with transcranial Doppler pre-operatively, and from post-operative day 1 to 7. Blood flow velocities (BFV) were compared via ANOVA. Post-operatively, ipsilateral (= side of operative approach) mean BFV increased significantly in both groups with a mean ipsilateral increase of 79.2% in the TS group, and 48.8% in the TC group. This intergroup difference was also statistically significant. In addition, contralateral BFV increased significantly to a maximum mean of 26.3% in the TS group with no significant increase in the TC group. The results in the TS group are interpreted as vasospasm and not hyperemia - due to dissection of the sylvian vessels and the breakdown of blood within the basal cisterns. Factors such as the extent of visual field cuts and results from neuropsychological testing must be taken into account before drawing a conclusion leading to a fundamental change in surgical strategy.

Purpose: Selective amygdalohippocampectomy (SAH) is a surgical treatment option for patients with medically intractable mesial temporal lobe epilepsy. In contrast to standard anterior temporal lobectomy, resection of unaffected tissue is limited, although it achieves equal seizure outcomes in selected patients. In SAH, the mesial structures can be approached by different routes, the transsylvian approach and the transcortical approach. Advantages or disadvantages with respect to postoperative cognitive outcome are still a matter of debate., Methods: Eighty randomized patients were included in the analyses. In 41 patients, the transsylvian approach, and in 39 patients, the transcortical approach was performed. All patients received comprehensive neuropsychological testing of verbal and nonverbal memory, attention, and executive functions before and 6 months or 1 year after SAH., Results: Seventy-five percent of patients became completely seizure free with no difference depending on the chosen approach. Repeated measures multivariate analysis of variance (MANOVA) showed that cognitive outcomes after both approaches were essentially the same. The only exception was phonemic fluency, which was significantly improved after transcortical but not after transsylvian SAH., Conclusions: The results indicate that either surgical approach can be chosen independent of cognitive outcome criteria. Improvement in phonemic fluency after transcortical SAH may reflect selective normalization of cognitive function after epilepsy surgery, whereas frontal lobe manipulation might have hindered recovery of this function after transsylvian SAH., (Copyright 2004 International League Against Epilepsy)

Background and Purpose: Whether an epileptic lesion is detected with MR imaging depends on the quality of the images and the expertise of the reader. We analyzed the role of 1.5-T MR imaging in the presurgical evaluation of patients with drug-resistant epilepsy at one center., Methods: In a 2-year prospective study, 385 patients with drug-resistant epilepsy underwent standardized MR imaging at 1.5 T. We analyzed whether lesions were detected, whether they were precisely characterized by MR imaging, and whether lesion characterization allowed us to estimate seizure outcomes., Results: Lesions were found on MR images in 318 patients (83%). Following presurgical evaluation, 209 (66%) underwent surgery, and 109 (34%) did not. Freedom from seizures was achieved in 130 (70%) of 186 patients. Nine (14%) of 66 patients without an MR imaging lesion underwent surgery; histopathologic findings were unrevealing in seven patients, and five (56%) achieved freedom from seizures. Hippocampal sclerosis was the most common lesion (52%) and correctly characterized in 101 (97%) of 104 patients. Glioneuronal tumors (20%) were sometimes imprecisely characterized: Four nonenhancing gangliogliomas were mistaken for focal cortical dysplasias. Outcomes were not different between lesion groups. However, there were trends toward a favorable outcome for focal cortical dysplasias with balloon cells and an unfavorable outcome for gyral scars., Conclusion: MR imaging detection of lesions influences further presurgical workup, though lesion characterization does not allow us to predict seizure outcome. If MR imaging fails to depict a lesion and patients undergo surgery because of electrophysiologic findings, histopathologic findings are often unrevealing.

Cortical lesions close to the central region may be difficult to localize on orthogonal MRI slices, especially when space-occupying lesions distort the brain surface relief and obscure anatomical landmarks. The purpose of this study was to evaluate, whether localization can be improved with planar brain surface (Mercator or "pancake") reformations. Three independent MRI readers localized superficial brain lesions of 30 patients on orthogonal MRI slices and on planar brain surface views reformatted from a sagittal 3D T(1)-weighted gradient echo sequence. On orthogonal MRI slices 46% of lesions were considered easy to localize, 37% difficult and 17% could not be localized. Corresponding values for planar brain surface views were 82%, 16% and 2%, respectively. Evaluation of orthogonal MRI slices took 190 min compared to 100 min for planar brain surface views. Thus, planar brain surface reformations are a helpful and time-saving means to localize superficial brain lesions.

Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are suggested to be important neurosteroids. We investigated steroid sulfatase (STS) in human temporal lobe biopsies in the context of possible cerebral DHEA(S) de novo biosynthesis. Formation of DHEA(S) in mature human brain tissue has not yet been studied. 17 alpha-Hydroxylase/C17-20-lyase and hydroxysteroid sulfotransferase catalyze the formation of DHEA from pregnenolone and the subsequent sulfoconjugation, respectively. Neither their mRNA nor activity were detected, indicating that DHEA(S) are not produced within the human temporal lobe. Conversely, strong activity and mRNA expression of DHEAS desulfating STS was found, twice as high in cerebral neocortex than in subcortical white matter. Cerebral STS resembled the characteristics of the known placental enzyme. Immunohistochemistry revealed STS in adult cortical neurons as well as in fetal and adult Cajal-Retzius cells. Organic anion transporting proteins OATP-A, -B, -D, and -E showed high mRNA expression levels with distinct patterns in cerebral neocortex and subcortical white matter. Although it is not clear whether they are expressed at the blood-brain barrier and facilitate an influx rather than an efflux, they might well be involved in the transport of steroid sulfates from the blood. Therefore, we hypothesize that DHEAS and/or other sulfated 3beta-hydroxysteroids might enter the human temporal lobe from the circulation where they would be readily converted via neuronal STS activity.

Objective: Resection strategies for the treatment of temporal lobe epilepsy (TLE) are a matter of discussion. Few data on the significance of resection type are available for pediatric patients with TLE., Methods: Data for a series of 89 children who were surgically treated for TLE were analyzed. A first cohort of patients were mainly surgically treated with anterior temporal lobectomies. For a second cohort, resections were preoperatively "tailored" to the lesion and presumed epileptogenic area., Results: The follow-up period was 46 months (range, 14-118 mo). Seventy-seven patients (87%) attained satisfactory seizure control (82% Engel Class I and 5% Class II). For 12 patients (13%), seizure control was unsatisfactory (8% Class III and 5% Class IV). Anterior temporal lobectomies resulted in 94% satisfactory seizure control (33 patients), whereas the success rates were only 74% (20 patients) for amygdalohippocampectomy (AH) (P = 0.023) and 77% (13 patients) for lesionectomy plus hippocampectomy (not significant). All patients who underwent purely lateral temporal lesionectomies became seizure-free (14 patients). Logistic regression revealed the factors of AH (P = 0.021) and left-side surgery (P = 0.017) as significant predictors of unsatisfactory seizure control. Satisfactory seizure control was not dependent on the histopathological diagnoses. There was a low rate of verbal memory deterioration after left-side operations. Neuropsychological deterioration was rare after right temporal resections. Attentional and contralateral functions improved after surgery., Conclusion: Surgery for the treatment of juvenile TLE is successful and safe, but the resection type may influence outcomes. Results after AHs were disappointing, probably because of difficulties in precise localization of the epileptogenic focus among children. Neuropsychological results demonstrated minimal rates of deterioration and significant improvements in contralateral functions. Surgical treatment of juvenile TLE should be encouraged, but the use of especially left AH should possibly be restricted.

Background: Highly selective epilepsy surgery in temporal lobe epilepsy is intended to achieve seizure freedom at a lower cognitive risk than standard en bloc resections, but bears the risk of collateral cortical damage resulting from the surgical approach., Objective: To investigate cortical damage associated with selective amygdalo-hippocampectomy (SAH)., Methods: 34 epileptic patients were evaluated. They were randomly assigned to SAH using either a sylvian (9 left/10 right) or a transcortical surgical approach (5 left/10 right). Postoperative MRI signal intensity changes adjacent to the approach were correlated with performance changes in serial word and design list learning., Results: Losses in verbal learning and recognition memory were positively related to signal intensity changes, independent of the side of the resection, the surgical approach, or the extent of the mesial resection. Losses in consolidation/retrieval (memory) were greater after left sided surgery. Losses in design learning were related to right sided surgery and signal intensity changes. Seizure outcome (85% seizure-free) did not differ depending on the side or type of surgery., Conclusions: Collateral damage to cortical tissues adjacent to the surgical approach contributes to postoperative verbal and figural memory outcome after SAH. Controlling for collateral damage may clarify the controversial memory outcomes after SAH reported by different surgical centres.

Objectives: To assess the significance of symptomatic hemorrhagic complications occurring after different temporal resections for temporal lobe epilepsy (TLE) and to compare this data to findings with postoperative hematomas after temporal surgery for mostly glial or metastatic tumors., Patients and Methods: Patient charts were retrospectively reviewed for 442 patients who underwent surgery for refractory TLE between 1995 and 2000. Procedures were 247 transsylvian amygdalohippocampectomies (AH), 40 transcortical AH, 57 anterior temporal lobectomies (ATL), 23 lesionectomies plus AH, and 75 lesionectomies without AH. All patients with delayed awakening or new neurological deficits due to hemorrhages were included in the study. An identical procedure was performed to detect symptomatic hemorrhages after 208 procedures for temporal tumor resection during the same time period., Results: Symptomatic postoperative hemorrhages were found in 17 patients (3.8 %) undergoing epilepsy surgery, while the incidence was 3.0 % in a group with space-occupying temporal tumors (six patients). Hemorrhages showed a characteristic distribution after epilepsy surgery: in eight patients they were located remote from the site of surgery in the upper cerebellar vermis and foliae. Five typical hemorrhages associated with dysphasia were found in the left frontal operculum, only three patients had hematomas in the resection cavity, and one was located epidurally. Two patients had more than one location of hemorrhage. Transsylvian AH and ATL had a similar risk for postoperative hemorrhage, whereas none was found after lateral lesionectomies or transcortical AH. Intraoperative manipulations were associated with opercular hemorrhages; the only predisposing factor for resection site hematomas was older age, whereas cerebellar hemorrhages were associated with cerebrospinal fluid (CSF) loss during AH and ATL. There was no mortality in the TLE group, and 0.75 % permanent mild deficits. Seizure outcome did not differ from the rest of the group (82.5 % satisfactory seizure control). In contrast, all intraaxial hematomas after tumor surgery (N = 4, incidence 1.9 %) were located in or adjacent to the resection cavity. Prognosis was much worse with parenchymal hemorrhages after tumor surgery: three of four patients died, one survived with a severe hemiparesis, only two patients with extraaxial hematomas (incidence 1 %) had a complete recovery. The 3 % incidence of symptomatic hemorrhages was only insignificantly lower compared to the TLE group, patients with tumor surgery were older than TLE patients (49 versus 33 years), and in five of six patients only incomplete tumor resection was achieved., Conclusion: Although associated with a low permanent morbidity, features of postoperative hemorrhages after TLE surgery are characteristically different to complications after surgery for other indications, which has to be kept in mind for patient counseling and obtaining informed consent.

Estrogens play a crucial role in multiple functions of the brain and the proper balance of inactive estrone and active estradiol-17beta might be very important for their cerebral effects. The interconversion of estrone and estradiol-17beta in target tissues is known to be catalysed by a number of human 17beta-hydroxysteroid dehydrogenase (17beta-HSD) isoforms. The present study shows that enzyme catalysed interconversion of estrone and estradiol-17beta occurs in the human temporal lobe. The oxidative cerebral pathway preferred estradiol-17beta to Delta(5)-androstenediol and testosterone, whereas the reductive pathway preferred dehydroepiandrosterone (DHEA) to Delta(4)-androstenedione and estrone. An allosteric Hill kinetic for NAD-dependent oxidation of estradiol-17beta was observed, whereas a typical Michaelis-Menten kinetic was shown for NADPH-dependent reduction of estrone. Investigations of the interconversion of estrogens in cerebral neocortex (CX) and subcortical white matter (SC) preparations of brain tissue from 12 women and 10 men revealed no sex-differences, but provide striking evidence for the presence of at least one oxidative membrane-associated 17beta-HSD and one cytosolic enzyme that catalyses both the reductive and the oxidative pathway. Membrane-associated oxidation of estradiol-17beta was shown to be significantly higher in CX than in SC (P<0.05), whereas the cytosolic enzyme activities were significantly higher in SC than in CX (P<0.0005). Finally, real-time RT-PCR analyses revealed that besides 17beta-HSD types 4 and 5 also the isozymes type 7, 8, 10 and 11 show substantial expression in the human temporal lobe. The characteristics of the isozymes lead us to the conclusion that cytosolic 17beta-HSD type 5 is the best candidate for the observed cytosolic enzyme activities, whereas the data gave no clear answer to the question, which enzyme is responsible for the membrane-associated oxidation of estradiol-17beta. In conclusion, the study strongly suggests that different cell types and different isozymes are involved in the cerebral interconversion of estrogens, which might play a pivotal role in maintaining the functions of the central nervous system.

In the human central nervous system, progesterone is rapidly metabolised to 5 alpha-dihydroprogesterone which subsequently is further reduced to allopregnanolone (AP). These conversions are catalysed by 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD). Although different isoforms of both enzymes have been identified in the brain, our knowledge of their expression in the human brain remains limited. The aim of the present study was to investigate the mRNA expression of 5 alpha-reductase 1 as well as 3 alpha-HSD 1, 2, 3 and 20 alpha-HSD in brain tissue from patients with pharmacoresistant temporal lobe epilepsy (TLE). Specimens were derived from either the hippocampus or the temporal lobe cortex and from the tumor-free approach corridor tissue of patients with brain tumors. Quantification of different mRNAs was achieved by real time PCR. In addition, we provide data on simultaneous evaluation of serum AP concentrations. We could demonstrate that 3 alpha-HSD 1 was not expressed in the hippocampus and temporal lobe of patients with TLE. In the hippocampus and temporal lobe, the expression levels of 3 alpha-HSD 2 were about 20% of that in liver tissue, those of 3 alpha-HSD 3 about 7% and those of 20 alpha-HSD about 2%, respectively. In patients with TLE, expression of 3 alpha-HSD 2 was significantly higher in the hippocampus than in temporal lobe cortex tissue (P<0.006). AP concentrations did not correlate significantly with the mRNA expression levels of 5 alpha-reductase 1, 3 alpha-HSD 2 and 3 and 20 alpha-HSD in any of the patient groups under investigation. In conclusion, the present study demonstrates mRNA expression of 5 alpha-reductase 1 and 3 alpha-HSD 2 and 3 and 20 alpha-HSD in the hippocampus and temporal lobe of epileptic patients. These findings provide further molecular biological evidence for the formation and metabolism of neuroactive steroids in the human brain.

Activation of presynaptic metabotropic glutamate receptors (mGluRs) leads to a powerful inhibition of glutamate release from many synaptic terminals throughout the CNS. mGluRs as autoreceptors are believed to provide a negative feedback system that prevents potentially toxic accumulation of glutamate in the extracellular space during synchronous synaptic activity such as epileptic seizures. In this study we analyzed the function of presynaptic mGluR8 on terminals of the lateral perforant pathway in the pilocarpine model of limbic epilepsy. Field excitatory postsynaptic potentials (fEPSPs) recorded in hippocampal slices of rats that developed spontaneous recurrent seizures after pilocarpine-induced status epilepticus (SRS group) showed a significantly reduced sensitivity to Group III mGluR agonists and severe mossy fiber sprouting. The Group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 10 microM) depressed fEPSPs in the SRS group only by 26 +/- 21% compared to 50 +/- 18% in untreated rats. Similarly, the mGluR8 preferring agonist (R,S)-4-phosphonophenylglycine (PPG, 5 microM) was significantly less effective in slices from SRS rats (43 +/- 4% vs. 83 +/- 5%). Concentration-response curves for L-AP4 revealed that the EC(50) values were not different between the control and SRS group (13 +/- 7 microM vs. 9 +/- 9 microM), while the maximal depressing effect was significantly reduced. The remaining depressing effect of L-AP4 in the SRS group could be blocked by the Group III specific antagonists (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) and alpha-methyl-L-AP4 (MAP4). Rats that did not develop SRS following pilocarpine-induced status epilepticus were indistinguishable from control rats: fEPSPs were highly sensitive to L-AP4 and there was no mossy fiber sprouting. The results show that pilocarpine-induced status epilepticus can lead to a downregulation of mGluR8 and suggest that the condition of SRS is associated with a deteriorated autoregulation of glutamate release., (Copyright 2003 Wiley-Liss, Inc.)

Objective: To describe the outcome of surgery in patients with drug resistant epilepsy and a histopathological diagnosis of focal cortical dysplasia., Methods and Subjects: Analysis of histories and presurgical and follow up data was carried out in 53 patients with a histological diagnosis of focal cortical dysplasia. Their mean age was 24.0 years (range 5 to 46), and they included 14 children and adolescents. Mean age at seizure onset was 12.4 years (0.4 to 36) and mean seizure duration was 11.6 years (1 to 45)., Results: The presurgical detection rate of focal cortical dysplasia with magnetic resonance imaging (MRI) was 96%. There were 24 temporal and 29 extratemporal resections; additional multiple subpial transections were done in 12 cases to prevent spread of seizure discharges. There was a 6% rate of complications with permanent neurological deficit, but no deaths. All resected specimens were classified by neuropathological criteria as focal cortical dysplasia. Balloon cells were seen in most cases of extratemporal focal cortical dysplasia. After a mean follow up of 50 months, 38 patients (72%) were seizure-free, two (4%) had less than two seizures a year, nine (17%) had a reduction of seizure frequency of more than 75%, and four (8%) had no improvement. Seizure outcome was similar after temporal and extratemporal surgery. The patients in need of multilobar surgery had the poorest outcome., Conclusions: Circumscribed lesionectomy of focal dysplastic lesions provides seizure relief in patients with chronic drug resistant temporal and extratemporal epilepsy. There was a trend for the best seizure outcome to be in patients with early presurgical evaluation and early surgery, and in whom lesions were identified on the preoperative MRI studies.

Dehydroepiandrosterone and its sulphate are important factors for vitality, development and functions of the CNS. They were found to be subjects to a series of enzyme-mediated conversions within the rodent CNS. In the present study, we were able to demonstrate for the first time that membrane-associated dehydroepiandrosterone 7alpha-hydroxylase activity occurs within the human brain. The cytochrome P450 enzyme demonstrated a sharp pH optimum between 7.5 and 8.0 and a mean KM value of 5.4 micro m, corresponding with the presence of the oxysterol 7alpha-hydroxylase CYP7B1. Real-time RT-PCR analysis verified high levels of CYP7B1 mRNA expression in the human CNS. The additionally observed conversion of dehydroepiandrosterone via cytosolic 17beta-hydroxysteroid dehydrogenase activity could be ascribed to the activity of an enzyme with a broad pH optimum and an undetectably high KM value. Subsequent experiments with cerebral neocortex and subcortical white matter specimens revealed that 7alpha-hydroxylase activity is significantly higher in the cerebral neocortex than in the subcortical white matter (p < 0.0005), whereas in the subcortical white matter, 17beta-hydroxysteroid dehydrogenase activity is significantly higher than in the cerebral neocortex (p < 0.0005). No sex differences were observed. In conclusion, the high levels of CYP7B1 mRNA in brain tissue as well as in a variety of other tissues in combination with the ubiquitous presence of 7alpha-hydroxylase activity in the human temporal lobe led us to assume a neuroprotective function of the enzyme such as regulation of the immune response or counteracting the deleterious effects of neurotoxic glucocorticoids, rather than a distinct brain specific function such as neurostimulation or neuromodulation.

Rat or human neocortical synaptosomes were used to study the role of voltage-gated Ca(2+) channels and the Na(+)/Ca(2+) exchanger in (45)Ca(2+) influx into nerve terminals. K(+) depolarization-induced (45)Ca(2+) influx through voltage-gated Ca(2+) channels into rat or human synaptosomes was completely blocked by mibefradil 30 microM or Cd(2+) 100 microM but was not affected by tetrodotoxin 1 microM. It was reduced by omega-agatoxin IVA 0.2 microM by 68% in synaptosomes of either species, whereas omega-conotoxin GVIA 0.1 microM and nifedipine 1 microM had no effect. Veratridine-induced (45)Ca(2+) entry into rat neocortical synaptosomes was completely blocked by mibefradil 30 microM, reduced by 80% by Cd(2+) 100 microM, by 90% by tetrodotoxin 1 microM and by 53% by omega-agatoxin IVA 0.2 microM but not by omega-conotoxin GVIA 0.1 microM or nifedipine 1 microM. Na(+)/Ca(2+) exchanger-mediated (45)Ca(2+) uptake into rat neocortical synaptosomes evoked by replacement of Na(+) by choline(+) in the incubation buffer was reduced by KB-R7943 (3-50 microM), an inhibitor of the Na(+)/Ca(2+) exchanger, in a concentration-dependent manner (maximal inhibition by 46% at 50 microM; IC(23%)=7.1 microM). Mibefradil also inhibited the Na(+)/Ca(2+) exchanger-mediated Ca(2+) uptake, although at 3.7 times lower potency (IC(23%)=26 microM). It is concluded that in rat and human neocortical nerve terminals Ca(2+) entry is mediated under physiological conditions by P/Q-type, but not by N- or L-type Ca(2+) channels or the Na(+)/Ca(2+) exchanger. If the cytosolic Na(+) concentration is increased, Ca(2+) is also taken up via the Na(+)/Ca(2+) exchanger. In addition to the ability of mibefradil to block all voltage-operated Ca(2+) channels, this drug is a low potency inhibitor of the Na(+)/Ca(2+) exchanger.

Object: It is unknown whether different resection strategies for temporal lobe epilepsy (TLE) produce alterations in seizure control or neuropsychological performance., Methods: A series of 321 patients who underwent surgery for TLE between 1989 and 1997 was submitted to a uni- and multifactorial analysis of clinical, electrophysiological, neuroimaging, neuropsychological, and surgical factors to determine independent predictors of outcome. Until 1993, most patients with TLE underwent standard anterior temporal lobectomy (ATL); beginning in 1993, surgical procedures were increasingly restricted to lesions detected on magnetic resonance (MR) imaging and the presumed epileptogenic foci: for example, amygdalohippocampectomy (AH) or lesionectomy/corticectomy began to be used more often. The mean follow-up duration in this study was 38 months. Two hundred twenty-seven patients were classified as seizure free (70.7%), and 36 patients had rare and nondisabling seizures (11.2%); these groups were summarized as having good seizure control (81.9%). Twenty-four patients attained more than 75% improvement (7.5%), and no worthwhile improvement was seen in 34 cases (10.6%); these groups were summarized as having unsatisfactory seizure control (18.1%). On unifactorial analysis the following preoperative factors were associated with good seizure control (p < 0.05): single and concordant lateralizing focus on electroencephalography studies, low seizure frequency, absence of status epilepticus, concordant lateralizing memory deficit, clear abnormality on MR images, suspected ganglioglioma or dysembryoplastic neuroepithelial tumor (DNT), and absence of dysplasia on MR images. Stepwise logistic regression revealed a model containing five factors that were predictive for good seizure control (p < 0.1): 1) clear abnormality on MR images; 2) absence of status epilepticus; 3) MR imaging-confirmed ganglioglioma or DNT; 4) concordant lateralizing memory deficit; and 5) absence of dysplasia on MR images. Seizure outcome was mainly correlated with diagnosis and clinical factors. No significant differences were found regarding different resection types performed for comparable tumors. Neuropsychological testing revealed better postoperative results after limited resections compared with standard ATL, especially with regard to attention level, verbal memory, and calculated total neuropsychological performance., Conclusions: Different strategies for surgical approaches in TLE result in equally good outcomes. Seizure outcome is mainly dependent on the diagnosis and clinical factors, whereas the neuropsychological results are more beneficial after resections limited to an epileptogenic lesion and focus.

Outcome studies concerning memory after pediatric temporal lobe surgery in the treatment of epilepsy are rare and have not yielded consistent results. In the present study, 55 children and adolescents with temporal lobe epilepsy (TLE; 26 left, 29 right, 6-17 years) performed a verbal memory test before and 3 as well as 12 months after different types of temporal lobe resections (anterior lobectomy, amygdalo-hippocampectomy (AH), lesionectomy (LX)). Groups did not significantly differ before surgery. Three months after surgery, the left resected group showed a decline in learning and delayed recall, and performed significantly lower than the right resected group. Recoveries were evident 1 year after surgery. The postoperative memory declines were associated with a left-sided resection and a higher preoperative performance. Comparisons on the different resection types suggest a special risk in patients undergoing a left-sided AH. In summary, our results indicate a functional association of verbal memory functions with the left temporal lobe similar to findings in adult patients. Declines after left-sided temporal resections seem to be reversible at least for part of the children, perhaps due to the greater plasticity of the immature brain.

Hybrid clamp protocols, in which a discontinuous single electrode voltage clamp (dSEVC) amplifier is switched from current to voltage clamp during the recording, are frequently used to investigate conductance changes after high frequency trains of action potentials. This technique is advantageous because it combines physiological stimulation of the cell with the possibility of analyzing the consecutive conductance changes quantitatively. In this study an improved hybrid clamp protocol, called dynamic hybrid clamp, is developed that enables the experimenter to study tail currents after single action potentials. The protocol employs real time action potential detection to assure precise timing of the mode switch and utilizes an external sample and hold amplifier to avoid voltage steps during the switch to voltage clamp. With the use of whole-cell patch clamp recordings and high switching frequencies (> or =25 kHz), dSEVC can easily be started with a minimal delay (<1.5 ms) after single action potentials and tail currents underlying afterhyperpolarisations (AHPs) and afterdepolarisations ensuing single spikes are clearly resolved. The dynamic hybrid clamp should also be useful for analysis of spontaneously occurring events such as intrinsic or population bursts.

Metabotropic glutamate receptors (mGluRs) control excitatory neurotransmission as inhibitory autoreceptors at many synapses throughout the CNS. Since pharmacological activation of mGluRs potently depresses excitatory transmission, anticonvulsive effects were found in a number of experimental epilepsies. However, although native rodent mGluRs and heterologously expressed human mGluRs have so far been investigated in great detail, our knowledge about native human mGluRs in situ is limited. Here we used acute human hippocampal slices prepared from hippocampi surgically removed for the treatment of temporal lobe epilepsy in order to investigate the modulation of glutamatergic transmission by human mGluRs at the perforant path-granule cell synapse. The broad spectrum mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) profoundly and reversibly reduced field EPSPs (fEPSPs) with an EC(50) of 30+/-7.4 microM. Paired-pulse depression of fEPSPs was converted into strong facilitation. The inhibition of fEPSPs by ACPD was mimicked by the specific group II mGluR agonist (2S, 2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), while the specific group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) was ineffective. The effect of ACPD was blocked by group II antagonist (2S,3S,4S)-2methyl-2-(carboxycyclopropyl)glycine (MCCG) but was not changed by coapplication of the specific group III antagonist (S)2 amino2methyl4phosphonobutanoic acid (MAP4). ACPD reduced pharmacologically isolated intracellular EPSPs in granule cells to the same extent as fEPSPs, whereas a specific group III agonist had no effect on EPSPs. Whole-cell recordings from morphologically identified granule cells revealed that DCG-IV significantly reduced the frequency of miniature EPSCs (mEPSCs) in granule cells while the mean amplitude of mEPSCs was not affected. We conclude that in human dentate gyrus mGluR2/3 can almost completely depress glutamate release by a presynaptic mechanism which acts downstream of presynaptic voltage gated calcium-entry and most likely involves a direct modulation of the release machinery.

We investigated the neuropsychological performance of children with frontal lobe epilepsy (FLE, n = 12) before and 1 year after surgery. Children with temporal lobe epilepsy (TLE, n = 12) were included as control group. Preoperatively, children with FLE had a significantly higher IQ than children with TLE, but were significantly more often impaired in manual motor coordination. Postoperatively, both groups improved in attention, short-term and long-term memory, and manual coordination, although the latter was not significant. Neuropsychological outcome in FLE patients was not better in seizure-free patients than in patients with continuing seizures. To avoid deterioration in language functions of patients in whom surgery involved left area 44, correspondence of results in cortical stimulation and intracarotid amytal test may be essential. All in all, our data indicate a favorable cognitive outcome in children 1 year after frontal lobe surgery.

Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.

Summary: Epilepsy surgery has been established as a successful treatment in patients with drug-resistant focal epilepsies. Different standardized surgical approaches were developed for resective or functional treatment. Successful surgical treatment, however, necessitates a careful presurgical evaluation. Although there are international standards for non invasive and invasive presurgical procedures most centers differ in their diagnostic strategy. This article gives a survey of the Bonn Epilepsy surgery program within which more than 1300 patients have been treated. After the method of patient selection different we describe tools of non invasive and invasive evaluation. This article serves only as a description of current practice in one center with a relatively large volume of cases. It presents just one opinion of a specific group within a wide spectrum of possible algorithms for presurgical evaluation that have briefly been outlined for 33 centers in Engels book [4].

Objective: To describe the technical steps, advantages, and limitations of a quicker, minimal-exposure, functional hemispherectomy procedure developed from a hemispherical deafferentation technique previously described., Methods: The surgical approach using the transsylvian/transsulcal passage to the ventricular system, with the anatomic orientation points and key features for planning of the small trepanation, is described. Through a linear incision, a craniotomy (4 x 4 to 4 x 5 cm) is placed over the sylvian fissure. Transsylvian exposure of the circular sulcus allows transcortical exposure of the entire ventricular system, from the frontal horn to the temporal horn encircling the insular cortex. The frontobasal and mesial white matter is disconnected via the intraventricular approach, with a callosotomy. An amygdalohippocampectomy completes the dissection. The experience with 20 patients who were treated using the transsylvian keyhole hemispherectomy technique is summarized., Results: The operation time was significantly shorter (mean, 3.6 h) than with the Rasmussen technique (mean, 6.3 h) and 25% shorter than with the transcortical perisylvian technique (mean, 4.9 h). The proportion of patients requiring blood replacements was lower (15 versus 58%), as was the mean amount of transfused blood. The mean follow-up period was 46 months; 88% of patients were in Engel Outcome Class I, 6% in Class III, and 6% in Class IV., Conclusion: The transsylvian keyhole procedure has been demonstrated to further reduce operation time and the need for blood replacement. It is most easily performed in cases with enlarged ventricles or perinatal ischemic cysts and is not recommended for hemimegalencephaly. The immediate seizure relief was satisfying. This minimal-exposure approach seems to be a satisfying alternative among possible functional hemispherectomy procedures.

Objects: In the adult population surgical treatment is generally less favorable for refractory frontal lobe epilepsy (FLE) than for temporal lobe epilepsy (TLE). Predictive factors and outcome of FLE surgery had not previously been described for the pediatric and adolescent population. Therefore, 32 children and adolescents who underwent FLE surgery were analyzed in this study., Methods: Medical records were reviewed for demographic data, presurgical evaluation procedures, surgical procedures, pathological findings and follow-up., Results: Mean age at operation was 10.8 years, with seizure onset at 4.6 years. Excellent outcomes were observed in 21 of the 32 patients following evaluation a mean of 34.5 months after surgery. Nineteen of 22 patients became seizure free after tailored resections, versus 2 out of 10 after lobectomy. Transient neurological and surgical complications occurred in 4 patients. Focal neoplastic lesions detectable by MRI were associated with a favorable outcome., Conclusions: As seen in adult FLE series, the detection of a resectable ictal neoplastic lesion on preoperative MRI is associated with an excellent outcome comparable to that of TLE surgery.

21-hydroxylase converts progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone to 11-deoxycortisol, the substrates which are required for the production of the main adrenal steroids, corticosterone, aldosterone, and cortisol. As 21-hydroxylase activity has been detected in rodent and fetal human brain, we studied whether and to what extent 21-hydroxylase mRNA is expressed in hippocampal tissue specimens from patients undergoing epilepsy surgery (n=42). 21-hydroxylase mRNA was detected in the hippocampus with an expression 10 000 times lower than in adrenal gland tissue. There was no significant difference in expression levels between women (9.5+/-2.7 arbitrary units (aU); mean+/-SEM) and men (8.0+/-2.2 aU); however, mRNA concentrations in the hippocampus of children (n=4, 1.8+/-0.5 aU) were considerably lower than in adults (n=38, 8.6+/-1.7 aU). The expression of 21-hydroxylase mRNA in the hippocampus suggests that this human brain area has the enzymatic capability to convert progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone to 11-deoxycortisol.

Objectives: To clarify whether different causative events (trauma, stroke, intracranial surgery), time of intervention, and treatment mode influence outcome, patients with fixed and dilated pupils (FDPs) in a prospective neurosurgical series were evaluated., Methods: Ninety nine consecutive patients who presented with or developed one or two FDPs, were split into three groups according to the respective aetiology: 46 patients had a trauma, 41 patients a stroke (subarachnoid or intracerebral haemorrhage), and 12 patients had undergone previous elective intracranial surgery. Appropriate therapy was performed depending on the CT findings. Outcome was classified according to the Glasgow outcome scale (GOS)., Results: Overall mortality was 75%. In 15% outcome was unfavourable (GOS 2 and 3), and in 10% favourable (GOS 4, 5) at 24 month follow up. No differences in outcome were found between trauma, stroke, and postelective surgery groups. Unilaterally FDP was associated with a better chance of survival (46% v 13%; p<0.01). Age did not correlate with survival, but younger survivors had a significantly better outcome. Patients in whom an intracranial mass was removed surgically had a 42% survival rate, compared with 8% with conservative treatment (p<0.01). Patients with a shorter delay from FDPs to intervention had a better chance of recovery after trauma and previous intracranial surgery (p<0.05). No patient survived better than a vegetative state, if previous FDPs did not become reactive shortly after therapy. If both pupils became reactive on therapy, the chance of survival was 62%. Of these survivors 42% had a favourable outcome., Conclusion: Bilateral restoration of pupillary reactivity shortly after therapy is crucial for survival. Surgical evacuation of an intracranial mass, unilateral FDPs, early intervention, and younger age are related to better chances of survival or recovery. The prognosis of patients with FDPs after trauma, stroke, and previous elective intracranial surgery is similar.

An enzyme-mediated metabolism of androgens and estrogens including 17beta-HSD activity in the brain of vertebrates was discovered approximately 30 years ago. Mainly 5alpha-reductase and aromatase have been studied in detail. Recently we could demonstrate reductive and oxidative 17beta-HSD activity as well as considerable mRNA expression of the 17beta-HSD types 3 and 4 in the human brain. In the present study, we report on 17beta-HSD type 5 mRNA expression in brain tissue of women and men. Data analysis did not reveal sex specific differences, but we determined a significantly higher mRNA concentration in the subcortical white matter (SC) than in the cerebral cortex (CX). Investigation of reductive 17beta-HSD in vitro activity with 2 microM androstenedione as the substrate revealed no sex specific differences. Testosterone formation was significantly higher in SC than in CX. Moreover, enzyme activity was significantly higher in brain tissue of adults compared to that of children.

The effects of corticosteroids in the brain are mediated through the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). We used a sensitive competitive RT-PCR assay to quantify the amounts of GR and MR mRNA in human brain tissue specimens from patients with focal epilepsies. GR and MR mRNAs were expressed at approximately the same levels in the temporal lobe, frontal lobe, and hippocampus as compared to tissues with high glucocorticoid/mineralocorticoid receptor expression (liver/kidney). GR and MR mRNA concentrations in the temporal lobe increased markedly during childhood and reached adult levels at puberty. GR and MR mRNA expression was significantly higher in the temporal lobe and frontal lobe cortex of women than in those of men. In women, MR and GR mRNA concentrations were markedly lower in hippocampal tissue than in frontal and temporal lobe cortex tissue. In conclusion, our data demonstrate sex- and site-dependent expression of corticosteroid receptor mRNA in the human brain.

The androgen receptor (AR) plays a central role in mediating androgen action. Since the hippocampus is a target of steroid modulation, we studied the expression of AR mRNAs in hippocampal tissue specimens from patients undergoing epilepsy surgery (n=42). AR mRNA expression was in the same order of magnitude than in prostate tissue, known for its high expression of AR. AR mRNA concentrations showed no significant difference in AR mRNA expression between men (49.3+/-8.0 arbitrary units (aU); mean+/-SEM) and women (54.3+/-11.2 aU) and no sex-specific hippocampal lateralization pattern was observed. No relationship could be detected between duration of epilepsy, individual seizure frequency, age of the patients and the expression levels of AR. The high expression of AR in the hippocampus suggests that this human brain area is an important target for androgen action.

Metabotropic glutamate receptors (mGluRs) provide a powerful control of synaptic transmission in the hippocampus and may serve as a target for drug development in human temporal lobe epilepsies. Agonists and antagonists at these receptors influence the development and propagation of seizures in some animal models of epilepsy. Experimental seizures can change the level of expression of mGluRs in the rat hippocampus. In the human dentate gyrus of patients suffering from temporal lobe epilepsy (TLE), group III mGluR mediated inhibition of synaptic transmission is almost lost in the sub-group with Ammon's horn sclerosis. We tested the modulation of synaptic transmission by the group III mGluR specific agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) in the dentate gyrus outer molecular layer in control and amygdala-kindled rats, a common model for TLE. Extracellular field potential recordings upon subthreshold stimulation of lateral perforant path fibers were measured simultaneously in the outer molecular layer and granule cell layer. Analysis of 'paired-pulse' characteristics in the absence and presence of L-AP4 and group III mGluR mediated inhibition of synaptic transmission in the lateral perforant path revealed no significant alterations in fully kindled rats. Since there is no evidence of altered L-AP4 responses, a loss of group III mGluR function, particularly that of subtype mGluR8, seems not necessary for the kindling epilepsy., (Copyright 1999 Elsevier Science B.V.)

Human temporal lobe epilepsy is characterized by strong synaptic reorganization that leads to abnormal recurrent excitatory synaptic connections among hippocampal neurons. In addition, electrophysiological studies show that synaptic activity of the main afferent input to the hippocampus, the perforant path, is prolonged and amplified by changes in postsynaptic glutamate receptors. The current view is that these morphological and physiological abnormalities contribute significantly to the hyperexcitability seen in the hippocampus of temporal lobe epilepsy. Recently, it was found that presynaptic inhibitory metabotropic glutamate receptors are an important negative feedback mechanism that controls synaptic release of glutamate in the hippocampus. In this study, we assessed the functionality of this feedback system by investigating the metabotropic glutamate receptor mediated depression of excitatory synaptic transmission in surgically removed hippocampi from patients with marked synaptic reorganization (Ammon's horn sclerosis group) and from patients without detectable reorganization (lesion group). We report here that this control of synaptic transmission is lost in hippocampi from the Ammon's horn sclerosis group whereas this control is preserved in hippocampi from the lesion group. The data presented here suggest that the loss of feedback inhibition mediated by metabotropic glutamate receptors could be a further, previously not recognized, mechanism in the pathophysiology of temporal lobe epilepsy.

We investigated the electrophysiology of morphologically identified human granule cells with conventional current-clamp recordings. Slices were prepared from 14 human epileptic sclerotic hippocampi. Granule cells appeared to have a diverse electrophysiology. Each cell was distinguished by the shape of the afterhyperpolarization following single action potentials. Two types could be discerned: type I afterhyperpolarizations were monophasic and brief (typically 10-40 ms), whilst type II afterhyperpolarizations were biphasic and long (typically 50-100 ms). The two types also differed in their repetitive firing behaviour and action potential morphology: type I cells had significantly weaker spike frequency adaptation, lower action potential amplitude and smaller action potential upstroke/downstroke ratio. Thus, the firing pattern of type I cells resembled that of rodent dentate interneurons. In contrast, the corresponding parameters of type II cells were comparable to rodent dentate granule cells. Despite the distinct firing patterns, membrane properties were not different. The two types of cells also differed in their synaptic responses to stimulation of the perforant path. At strong suprathreshold stimulation intensity, type I cells always generated multiple action potentials, whereas type II cells usually spiked once only. Slow inhibitory postsynaptic potentials were not detected in type I neurons, but were easily identified in type II neurons. Extracellular recordings of perforant path-evoked field potentials in the cell layer confirmed that the majority of granule cells showed multiple discharges even when we recorded simultaneously from a type II cell that generated one action potential only. The morphology of both types of cells was characteristic of what has been described for primate dentate granule cells. Based on comparisons with previous studies on rodent and human granule cells, we tentatively hypothesize that: (i) the majority of granule cells from sclerotic hippocampus display an hyperexcitable epileptogenic electrophysiology; (ii) there is a subset of granule cells whose electrophysiology is preserved and is more comparable to granule cells from non-epileptic hippocampus.

An accidental high dose of intraventricular mezlocillin was given during antibiotic treatment for pneumonia in a patient admitted because of severe traumatic brain injury and occlusive hydrocephalus. Because of serial epileptic seizures not responsive to antiepileptic drug treatment, CSF exchange was performed. The CSF was drained through a ventricular catheter, while mock CSF was infused into the lumbar subarachnoid space. The patient soon recovered to her clinical status previous to intraventricular mezlocillin application. Side effects of CSF exchange were not seen. Under continued antiepileptic medication no more seizures occurred. It is concluded that high doses of intraventricular mezlocillin have proconvulsive effects. In this patient CSF exchange was a suitable means of preventing putatively permanent impairment of brain function caused by serial epileptic seizures due to intraventricular mezlocillin application.

Metabotropic glutamate receptors (mGluRs) have emerged as an interesting family of eight different receptor subtypes that can be divided into three groups according to their pharmacology and sequence similarity. In the present study, the specific mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depressed field excitatory postsynaptic potentials (fEPSPs) in the rat dentate gyrus evoked by perforant path stimulation in a concentration-dependent, rapid and reversible manner (EC50: L-AP4 5.9 +/- 1.6 microM, (1S,3R)-ACPD 80 +/- 34 microM). In a 'paired-pulse' stimulation protocol, the first fEPSP showed a stronger reduction, resulting in 'paired-pulse' facilitation. The effects of L-AP4 but not of (1S,3R)-ACPD could be antagonized by the group III mGluR antagonists (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG). Moreover, (1S,3R)-ACPD was still potently depressing fEPSPs after preperfusion of near saturating concentrations of L-AP4. Together, the results suggest that both substances act on different mGluRs. The effects of (1S,3R)-ACPD could not be further differentiated by selective group I or group II mGluR agonists. Although (2S,1'S,2'S)-2-carboxycyclopropylglycine (L-CCG-I) blocked fEPSPs at concentrations >> 1 microM, these effects, as well as L-AP4 effects, were potently antagonized by MAP4. This suggests that mGluR8 might be responsible for the actions of L-AP4 and L-CCG-I. The two different mGluRs showed a distinct distribution when fEPSPs were recorded simultaneously in the outer and middle molecular layer (OML/MML): The L-AP4 sensitive receptor, possibly mGluR8, seems to be located in the OML while (1S,3R)-ACPD showed its main effect in the MML.

1. Properties of voltage- and Ca(2+)-dependent K+ currents were investigated in thirty-four dentate granule cells acutely isolated from the resected hippocampus of eleven patients with therapy-refractory temporal lobe epilepsy (TLE). 2. When intracellular Ca2+ was strongly buffered with 11.5 mM EGTA-1 mM Ca2+ in the recording pipette, K+ currents (IK) with a slow activation and biexponential time-dependent decay could be elicited, which showed a threshold for activation around -30 mV. 3. A contribution of Ca(2+)-dependent K+ currents became apparent with intracellular solution containing 1 mM BAPTA-0.1 mM Ca2+. Superfusion of low-Ca2+ extracellular solution blocked 43% of outward currents in this recording configuration. Outward current components could also be blocked by substituting 5 mM Ba2+ for extracellular Ca2+ (78%), or by application of 100 microM Cd2+ (25%). 4. The Ca(2+)-dependent K+ currents could be pharmacologically subdivided into two components. One component was sensitive to 500 microM tetraethylammmonium (TEA; 41%) and 10 nM charybdotoxin (CTX; 47.2%). The blocking effects of 10 nM CTX and 500 microM TEA were not additive, suggesting that both agents block the same conductance. A second, smaller outward current component was blocked by 50 nM apamin (13%). 5. A transient A-type K+ current could be observed in six neurones and showed a fast monoexponential time-dependent inactivation with a steady-state voltage dependence that was distinct from that of IK. The A-type current was blocked by 4-aminopyridine (4-AP) but not by TEA or low-Ca2+ solution. 6. We conclude that outward currents in human hippocampal dentate granule cells can be separated into at least four types by their kinetic and pharmacological properties. These include at least one voltage-dependent current similar to those observed in mammalian hippocampal neurones, and two Ca(2+)-dependent K+ currents that most probably correspond to SK- and BK-type currents. A classical A-type current could be detected in some patients with Ammon's horn sclerosis (AHS) but not in patients with lesion-associated TLE.

Purpose: Properties of potassium outward currents were investigated in human hippocampal dentate gyrus granule cells from 11 hippocampal specimens obtained from patients with temporal lobe epilepsy (TLE) during resective surgery., Methods: Dentate granule cells were isolated enzymatically and outward currents analyzed by using the whole-cell configuration of the patch-clamp method. Hippocampal specimens were classified neuropathologically with respect to severe segmental cell loss, gliosis, and axonal sprouting (Ammon's horn sclerosis, AHS), or the presence of a focal lesion in the adjacent temporal lobe., Results: A delayed rectifier outward current (IK), but not an A-type potassium current (IA) or inwardly rectifying potassium currents, was observed in all cells. The average current density of IK, the time-dependent decay of IK, and the resting membrane characteristics were not significantly different between patients with and without AHS. The voltage of half-maximal activation V1/2(act) was 5.4 +/- 1.8 mV in AHS compared with -2.9 +/- 1.8 mV in lesion-associated epilepsy (NS). In contrast, V1/2(inact) was shifted in a hyperpolarizing direction in AHS (-67.7 +/- 0.6 mV) compared with that in hippocampi not showing AHS (-47.7 +/- 2.6 mV; p = 0.0017)., Conclusions: The altered steady-state voltage-dependence of IK may result in abnormal excitability of dentate granule cells in AHS and exert a marked influence on input-output properties of the dentate gyrus.

The functional consequences of lesions of the entorhinal cortex of rats were studied by analysing laminar distributions of stimulus induced field potentials in the dentate gyrus with a subsequent current source density analysis. Stimulation of the inner molecular layer elicits large excitatory postsynaptic potentials with small if any population spikes in the stratum granulare both in normal and lesioned animals. In lesioned animals middle molecular layer stimulation causes large excitatory sinks in the stratum moleculare without generation of population spikes in stratum granulare, while the same stimulation in slices from normal animals readily induces population spikes. The current source density analysis revealed a shift of current sinks induced by stimulation of either the inner or the middle molecular layer to common site. The N-methyl-D-aspartate receptor contribution to the current sink and source was found to be more prominent after middle molecular layer stimulation in comparison to inner molecular layers stimulation in the control group, while such a distinction could not be made in the lesioned group. Activation of mossy fibers did not reveal any significant differences between normal and lesioned animals. Following entorhinal cortex lesion sprouting of remaining afferents (e.g. commissural fibers) into the termination zones of the degenerated perforant path has been reported suggesting a compensatory replacement of excitatory synaptic input. However, persistent transneuronal dendritic alterations of neurons in the dentate gyrus have been observed which might result in altered dentate gyrus function. Our findings suggest that the reorganization process after entorhinal cortex lesion does not lead to full functional compensation of the lost perforant path input, resulting in an altered balance between excitation and inhibition.

We tested in rat hippocampal slices whether kindling causes sprouting of mossy fibers thereby augmenting excitatory coupling and epileptogenicity. Field potentials (fp's) evoked by orthodromic stimulation of the medial perforant path (MPP) and antidromic stimulation of mossy fibers in slices from control, amygdala kindled (AK) and beta-carboline (FG 7142) kindled rats were recorded in the dentate gyrus granule cell layer. Orthodromic paired pulse inhibition was increased in both groups of kindled animals. In contrast, neither in normal medium nor under additional application of the GABAA receptor antagonist bicuculline nor in Mg(2+)-free artificial cerebrospinal fluid (ACSF) there was evidence for an excitatory field EPSP component upon stimulation of mossy fibers in any of the investigated groups. The results indicate that functional mossy fiber sprouting does not occur as an obligatory step in the induction of kindling epilepsy.