Heinz-Joachim Meencke

Stimulus and Potassium-Induced Epileptiform Activity in the Human Dentate Gyrus from Patients with and without Hippocampal Sclerosis

Hippocampal specimens resected to cure medically intractable temporal lobe epilepsy (TLE) provide a unique possibility to study functional consequences of morphological alterations. One intriguing alteration predominantly observed in cases of hippocampal sclerosis is an uncommon network of granule cells monosynaptically interconnected via aberrant supragranular mossy fibers. We investigated whether granule cell populations in slices from sclerotic and nonsclerotic hippocampi would develop ictaform activity when challenged by low-frequency hilar stimulation in the presence of elevated extracellular potassium concentration (10 and 12 mm) and whether the experimental activity differs according to the presence of aberrant mossy fibers. We found that ictaform activity could be evoked in slices from sclerotic and nonsclerotic hippocampi (27 of 40 slices, 14 of 20 patients; and 11 of 22 slices, 6 of 12 patients, respectively). However, the two patient groups differed with respect to the pattern of ictaform discharges and the potassium concentration mandatory for its induction. Seizure-like events were already induced with 10 mm K+. They exclusively occurred in slices from sclerotic hippocampi, of which 80% displayed stimulus-induced oscillatory population responses (250-300 Hz). In slices from nonsclerotic hippocampi, atypical negative field potential shifts were predominantly evoked with 12 mm K+. In both groups, the ictaform activity was sensitive to ionotropic glutamate receptor antagonists and lowering of [Ca2+]o. Our results show that, in granule cell populations of hippocampal slices from TLE patients, high K+-induced seizure-like activity and ictal spiking coincide with basic electrophysiological abnormalities, hippocampal sclerosis, and mossy fiber sprouting, suggesting that network reorganization could play a crucial role in determining type and threshold of such activity.

Effects of barium on stimulus-induced rises of [K+]o in human epileptic non-sclerotic and sclerotic hippocampal area CA1

In the hippocampus of patients with therapy‐refractory temporal lobe epilepsy, glial cells of area CA1 might be less able to take up potassium ions via barium‐sensitive inwardly rectifying and voltage‐independent potassium channels. Using ion‐selective microelectrodes we investigated the effects of barium on rises in [K+]o induced by repetitive alvear stimulation in slices from surgically removed hippocampi with and without Ammons horn sclerosis (AHS and non‐AHS). In non‐AHS tissue, barium augmented rises in [K+]o by 147% and prolonged the half time of recovery by 90%. The barium effect was reversible, concentration dependent, and persisted in the presence of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA), N‐methyl‐d‐aspartate (NMDA) and γ‐aminobutyric acid [GABA(A)] receptor antagonists. In AHS tissue, barium caused a decrease in the baseline level of [K+]o. In contrast to non‐AHS slices, in AHS slices with intact synaptic transmission, barium had no effect on the stimulus‐induced rises of [K+]o, and the half time of recovery from the rise was less prolonged (by 57%). Under conditions of blocked synaptic transmission, barium augmented stimulus‐induced rises in [K+]o, but only by 40%. In both tissues, barium significantly reduced negative slow‐field potentials following repetitive stimulation but did not alter the mean population spike amplitude. The findings suggest a significant contribution of glial barium‐sensitive K+‐channels to K+‐buffering in non‐AHS tissue and an impairment of glial barium‐sensitive K+‐uptake in AHS tissue.

Alterations of Neuronal Connectivity in Area CA1 of Hippocampal Slices from Temporal Lobe Epilepsy Patients and from Pilocarpine‐Treated Epileptic Rats

Summary: Purpose: Neuronal network reorganization might be involved in epileptogenesis in human and rat limbic epilepsy. Apart from aberrant mossy fiber sprouting, a more wide‐spread fiber rearrangement in the hippocampal formation might occur. Therefore, we studied sprouting in area CA1 because this region is most affected in human temporal lobe epilepsy.

Effects of barium on stimulus-induced changes in [K+]o and field potentials in dentate gyrus and area CA1 of human epileptic hippocampus

The effects of barium on stimulus-induced rises in [K+]o were studied in the dentate gyrus (DG) and area CA1 of human hippocampal slices. Rises in [K+]o elicited by repetitive stimulation of the hilus, stratum moleculare, alveus, or stratum radiatum were dependent on stimulus intensity and frequency. Barium augmented rises in [K+]o in the DG by about 120% but failed to do so in area CA1. In both DG and area CA1 barium had no effects on population spikes whereas stimulus-induced slow field potentials were reduced. Since barium interferes with K+ uptake and redistribution by blocking leak conductances and inwardly-rectifying currents in astrocytes, our findings suggest that glial cells in the sclerotic hippocampal area CA1 may contribute less to K+ regulation.

Impaired function of GABAB receptors in tissues from pharmacoresistant epilepsy patients

Purpose:  Effects of pre‐ and postsynaptic γ‐aminobutyric acid B (GABAB) receptor activation were characterized in human tissue from epilepsy surgery.

Verapamil attenuates the malignant treatment course in recurrent status epilepticus

In the scenario of refractory status epilepticus, the recommended approach of intensive care treatment is limited with respect to the available pharmacodynamic variability and its impeding, severe side effects. Alternative treatment options are therefore urgently needed. In the case described, a patient with nonlesional frontal lobe epilepsy had a high-frequency series of tonic seizures, which evolved into a malignant form of status epilepticus. Co-administration of verapamil, a potent multidrug transporter inhibitor, was followed by significant reduction in seizure frequency. We discuss the putative role of verapamil and the specific risk factors for this malignant treatment course.

Levetiracetam in Focal Epilepsy and Hepatic Porphyria: A Case Report

Summary:  We report a patient with focal epilepsy and latent hereditary coproporphyria who had exacerbation of clinical symptoms of porphyria under treatment with valproate and primidone and was then treated with levetiracetam without exacerbation of clinically latent porphyria.

Randomized controlled trial of 2.5-cm versus 3.5-cm mesial temporal resection—part 2: volumetric resection extent and subgroup analyses

BackgroundThis paper is addressing outcome differences in interesting subgroups from a previous randomized controlled trial of the extent of mesial temporal lobe resection (TLR) for drug-resistant epilepsy, by looking at effects of randomization, intended resection group, center, and true resection extent on seizure outcome.MethodsOne hundred and seventy-nine cases with volumetrically assessed resection extent were used. Analyses of the extent of resection and subgroups and within subgroups for the two treatment arms will be performed, looking for confounding factors and using statistical methods (chi-square test, logistic regression analysis, and two-factorial ANOVA).ResultsTrue resection extent varied considerably. Outcome comparison for right versus left resections, subgroups with mesial temporal sclerosis (MTS), or largest and smallest resections revealed no remarkable difference, compared to overall class I outcome. The intent-to-treat analyses within these subgroups revealed differences for class I outcome, albeit lacking in significance, except for better TLR outcome. Small true resection volume differences or randomization into the two resection groups could not explain the outcome differences between the selective amygdalohippocampectomy (SAH) and TLR subgroups. Logistic regression analysis showed an interaction between intended resection length and surgery type, confirming the impression of different impacts of the intended resection length under the two surgery types. The outcome difference between SAH and TLR was more likely explained by a center effect. In a two-factorial ANOVA for resected hippocampal volume, Engel outcome class I, and resection type, the outcome was not found to be correlated with true resection volume. A multifactorial logistic regression showed a mild interaction between the resection type with center on the Engel outcome class, extent of resection, and surgery type interacted, as did the extent of resection and center.ConclusionPatients with quite similar extent of resection can be seizure free or non-seizure free. In this cohort, seizure freedom rates fell again when the extent of mesial resection was maximized. Differences in class I outcome for SAH and TLR were not due to erroneous randomization, true resection extent, or presence of MTS, but were influenced by a center effect. Subgroup analyses did not help to provide arguments to favor one surgery type over the other.

Drug Resistance in Cortical and Hippocampal Slices from Resected Tissue of Epilepsy Patients: No Significant Impact of P-Glycoprotein and Multidrug Resistance-Associated Proteins

Drug resistant patients undergoing epilepsy surgery have a good chance to become sensitive to anticonvulsant medication, suggesting that the resected brain tissue is responsible for drug resistance. Here, we address the question whether P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs) expressed in the resected tissue contribute to drug resistance in vitro. Effects of anti-epileptic drugs [carbamazepine (CBZ), sodium valproate, phenytoin] and two unspecific inhibitors of Pgp and MRPs [verapamil (VPM) and probenecid (PBN)] on seizure-like events (SLEs) induced in slices from 35 hippocampal and 35 temporal cortex specimens of altogether 51 patients (161 slices) were studied. Although in slice preparations the blood brain barrier is not functional, we found that SLEs predominantly persisted in the presence of anticonvulsant drugs (90%) and also in the presence of VPM and PBN (86%). Following subsequent co-administration of anti-epileptic drugs and drug transport inhibitors, SLEs continued in 63% of 143 slices. Drug sensitivity in slices was recognized either as transition to recurrent epileptiform transients (30%) or as suppression (7%), particularly by perfusion with CBZ in PBN containing solutions (43, 9%). Summarizing responses to co-administration from more than one slice per patient revealed that suppression of seizure-like activity in all slices was only observed in 7% of patients. Patients whose tissue was completely or partially sensitive (65%) presented with higher seizure frequencies than those with resistant tissue (35%). However, corresponding subgroups of patients do not differ with respect to expression rates of drug transporters. Our results imply that parenchymal MRPs and Pgp are not responsible for drug resistance in resected tissue.

Perioperative fluctuations of lamotrigine serum levels in patients undergoing epilepsy surgery

UNLABELLED Some patients undergoing epilepsy surgery suffer from early postoperative seizures which may have a negative impact on later outcome. Factors contributing to these seizures have not to date been examined systematically. We hypothesized that reduction of postoperative serum levels of antiepileptic drugs (AED) may be one risk factor for early postoperative seizures. METHODS We retrospectively reviewed medical records from 20 patients treated with lamotrigine (LTG) who underwent epilepsy surgery between January 1997 and February 2004. Demographic data, anaesthesiological and surgical procedures, co-medication, and pre- as well as one or more postoperative LTG serum levels were evaluated. RESULTS We found a significant decrease in LTG serum levels, amounting to more than 20% (mean 46%, range 21.9-69.1%), in 16 of 20 patients (80%). Six patients (30%) suffered from seizures in the first 2 weeks after surgery. In three patients, postoperative seizures occurred isochronically with the LTG serum level nadir. The magnitude of the reduction in serum levels was not influenced by age, sex, duration of the operation, the type of anaesthetic drugs or the postoperative co-medication. DISCUSSION Reductions in LTG serum levels are a relevant contributing factor for early postoperative seizures. Postoperative alteration of the gastrointestinal motility and transient time leading to delayed absorption and reduced bioavailability of AED may be a major risk factor. Therefore, close monitoring of postoperative LTG serum levels is necessary and should lead to a temporary dose augmentation and/or anticonvulsant co-medication with benzodiazepines in case of a pronounced reduction of serum levels.