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

BACKGROUND: This 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. METHODS: One 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). RESULTS: True 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. CONCLUSION: Patients 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.

Randomized controlled trial of 2.5-cm versus 3.5-cm mesial temporal resection in temporal lobe epilepsy--Part 1: intent-to-treat analysis.

BACKGROUND: Only one prospective randomized study on the extent of mesial resection in surgery for temporal lobe epilepsy (TLE) exists. This randomized controlled trial (RCT) examines whether 3.5-cm mesial resection is leading to a better seizure outcome than a 2.5-cm resection. METHODS: Three epilepsy surgery centers using similar MRI protocols, neuropsychological tests, and resection types for TLE surgery included 207 patients in a RCT with pre- and postoperative volumetrics. One hundred and four patients were randomized into a 2.5-cm resection group and 103 patients into a 3.5-cm resection group, i.e., an intended minimum resection length of 25 versus 35 mm for the hippocampus and parahippocampus. Primary outcome measure was seizure freedom Engel class I throughout the first year. The study was powered to detect a 20% difference in class I outcome. Seizure outcome was available for 207 patients, complete volumetric results for 179 patients. Outcome analysis was restricted to control of successful randomization and an intent-to-treat analysis of seizure outcome. RESULTS: The mean true resection volumes were significantly different for the 2.5-cm and 3.5-cm resection groups; thus, the randomization was successful. Median resection volume in the 2.5-cm group was 72.86% of initial volume and 83.44% in the 3.5-cm group. At 1 year, seizure outcome Engel class I was 74% in the 2.5-cm and 72.8% in the 3.5-cm resection group. CONCLUSIONS: The primary intent-to-treat analysis did not show a different seizure freedom rate for the more posteriorly reaching 3.5-cm resection group. It appears possible that not maximal volume resection but adequate volume resection leads to good seizure freedom.

The Wada test in Austrian, Dutch, German, and Swiss epilepsy centers from 2000 to 2005: a review of 1421 procedures.

Twenty-six Austrian, Dutch, German, and Swiss epilepsy centers were asked to report on use of the Wada test (intracarotid amobarbital procedure, IAP) from 2000 to 2005 and to give their opinion regarding its role in the presurgical diagnosis of epilepsy. Sixteen of the 23 centers providing information had performed 1421 Wada tests, predominantly the classic bilateral procedure (73%). A slight nonsignificant decrease over time in Wada test frequency, despite slightly increasing numbers of resective procedures, could be observed. Complication rates were relatively low (1.09%; 0.36% with permanent deficit). Test protocols were similar even though no universal standard protocol exists. Clinicians rated the Wada test as having good reliability and validity for language determination, whereas they questioned its reliability and validity for memory lateralization. Several noninvasive functional imaging techniques are already in use. However, clinicians currently do not want to rely solely on noninvasive functional imaging in all patients.

Assessment of a dose-response relationship of levetiracetam.

The aim of this study was to assess the relationship between levetiracetam dose and both efficacy and safety in adult patients with refractory partial epilepsy. Dose-response relationships for levetiracetam efficacy were evaluated using pooled data from three trials including adults with refractory partial epilepsy. Two were randomized, double-blind, placebo-controlled, parallel-group trials in which doses of 1000-3000 mg/day of levetiracetam were administered as adjunctive therapy. The third consisted of the two parts of a crossover randomized, double-blind study in which levetiracetam (1000 or 2000 mg/day) or placebo was added to ongoing therapy. Data from each part of the crossover trial were included as if it was an independent parallel-group study. A fourth randomized double-blind trial was added for the safety evaluation. It included data from adults receiving placebo or 2000 mg/day of levetiracetam as adjunctive therapy for refractory partial seizures. The combined analysis showed an increasing effect with increasing dose. The responder rates (> or = 50% reduction in seizures) for placebo and levetiracetam 1000, 2000, and 3000 mg/day were 13.1%, 28.5%, 34.3%, and 41.3%, respectively. The respective values for seizure freedom were 0.8%, 4.7%, 6.3%, and 8.6%. There was no evidence of a dose-response relationship with regard to adverse events, including those (asthenia, dizziness, somnolence) most commonly associated with this antiepileptic drug. Patients who do not become seizure-free at the lowest recommended levetiracetam dose (1000 mg/day) should be titrated to 2000 or 3000 mg/day to provide the greatest opportunity for efficacy with little or no increased risk for adverse events.

The density of dystopic neurons in the white matter of the gyrus frontalis inferior in epilepsies.

It has been suspected for a long time that developmental disturbances of the brain could be a factor in the causation of epilepsies. The diagnostic term "microdysgenesis" indicates the morphological correlate for this hypothesis. An increase in the number of nerve cells in the white matter belongs to this microdysgenesis. Its diagnosis, judged purely qualitatively, is very uncertain and cannot be clearly be differentiated from normal findings. In this study, the nerve cell density in the white matter of the gyrus frontalis inferior was determined morphometrically. There was a significantly increased cell count in the group with primary generalized epilepsy compared to the control group. However, even in the group with traumatic epilepsy there still a significantly higher cell count than in the control group, although clearly lower than in the group with primary generalized epilepsy. The study supports the hypothesis that disturbed maturation could be an aetiological factor in 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.

[Magnetic resonance tomography (MRT) in temporal lobe lesions. Study of patients with psychomotor seizures]. / Magnetische Resonanztomographie (MRT) bei Temporallappenläsionen. Eine Untersuchung von Patienten mit psychomotorischen Anfällen.

A comparative study between magnetic resonance tomography (MRT) and CT was carried out in 16 patients with temporal lobe epilepsy. The MRT studies were performed on a 0.35 T Magnetom with T.1 modes in a coronal plane. MRT proved to the superior to CT. CT demonstrated a discreet temporal lobe lesion in three patients and MRT in four patients. In addition, unilateral atrophy of the temporal lobe was demonstrated by MRT in six cases; these could not be diagnosed by CT. The lack of artifacts near the skull base, the possibility of producing coronal sections and the excellent tissue differential of MRT provide the basis for improved diagnosis of lesions in the temporal lobes.

[Psychomotor epilepsy--a comparison of CT and MR in 100 patients]. / Psychomotorische Epilepsie--Vergleich von CT und MR bei 100 Patienten.

The value of CT and MR was studied in 100 patients with temporal lobe epilepsy. Axial CT scans were obtained before and after contrast injection. Coronary MR scans were carried out with T1-(SE 400/30, GE 315/14) and T2-weighted sequences (SE 1600/30 + 70). A circumscribed lesion was demonstrated in fifteen patients by CT and in 25 patients by MR. With the exception of a small area of calcification, all lesions seen on CT could also be recognized on MR. In four patients CT, MR and pathologic specimen could be compared following partial resection of temporal lobe. Localized glial reactions, which were not seen on CT, produced a signal difference on MR. Better sensitivity and improved demonstration of the temporal lobes makes MR the method of choice in the diagnosis of temporal lobe epilepsy.

Use of statistical parametric mapping of (18) F-FDG-PET in frontal lobe epilepsy.

AIM: Evaluation of the use of statistical parametrical mapping (SPM) of FDG-PET for seizure lateralization in frontal lobe epilepsy. PATIENTS: 38 patients with suspected frontal lobe epilepsy supported by clinical findings and video-EEG monitoring. METHOD: Statistical parametrical maps were generated by subtraction of individual scans from a control group, formed by 16 patients with negative neurological/psychiatric history and no abnormalities in the MR scan. The scans were also analyzed visually as well as semiquantitatively by manually drawn ROIs. RESULTS: SPM showed a better accordance to the results of surface EEG monitoring compared with visual scan analysis and ROI quantification. In comparison with intracranial EEG recordings, the best performance was achieved by combining the ROI based quantification with SPM analysis. CONCLUSION: These findings suggest that SPM analysis of FDG-PET data could be a useful as complementary tool in the evaluation of seizure focus lateralization in patients with supposed frontal lobe epilepsy.

Quantitative estimation of I-123-Iomazenil receptor binding in temporal lobe epilepsies using two SPECT acquisitions--comparison with the regional cerebral blood flow and a compartment model.

AIM: To compare published fractional rate constants of I-123-Iomazenil (IMZ) and C-11-Flumazenil (three-compartment/four-parameter model) with a I-123-Iomazenil receptor index calculated from two SPECT acquisitions and to compare the receptor index of the epileptogenic area with the contralateral side in patients with unilateral temporal lobe epilepsies. METHODS: 28 patients were studied. 13/28 patients had a drug-resistant unilateral temporal lobe epilepsy with a successful focus localisation performed by an extensive video/EEG monitoring. 15 other patients with clinically suspected focal epilepsy and a normal MRI and IMZ SPECT scanning were used as controls. SPECT scanning was performed in all patients 15 and 100 min after intravenous injection of 111 MBq IMZ and 10 min after application of 740 MBq Tc-99m-HMPAO. Quantification of the regional uptake was performed using ROI-technique and the specific and non-specific binding of IMZ was calculated. The receptor index was calculated by the difference of the specific binding from 15 to 100 min p.i. divided by the time interval. RESULTS: The receptor index showed a linear correlation with recently published fractional rate constants k3 (r = 0.69 and 0.67; p = 0.15) and a moderate correlation with the k4 constant (-0.53 and -0.43; p = 0.28) by the means of C-11-Flumazenil PET and I-123-Iomazenil SPECT studies, respectively. However, statistical significance was not reached due to the few data points available from the published reports. Furthermore, the IMZ receptor index was lower in the epileptogenic area of patients with unilateral temporal lobe epilepsies compared with their contralateral side (p = 0.02; Wilcoxon-test). The IMZ receptor index showed a weak correlation with the regional cerebral blood flow independent of the evaluated region (r < 0.4; p < 0.05). CONCLUSION: The IMZ receptor index indicated to be a simple routine approach to estimate the fractional rate constant k3 (r = 0.67). The lower value of the receptor index within the epileptogenic area might be due to a lower receptor density. However in further studies, IMZ might be a helpful tool to find out subtle changes of the receptor affinity due to its approximately 30-fold higher ligand-receptor affinity compared to C-11-Flumazenil.

Improving diagnostic procedure and treatment in patients with non-epileptic seizures (NES).

The purpose of this study was to examine the incidence of patients with NES vs. NES and concomitant epilepsy in an epilepsy centre and to present a diagnostic algorithm. We collected and reviewed the data of 322 patients consecutively referred to the adult ward of our epilepsy centre in 1 year. The results of our study reveal that 44 (14%) of all patients referred had NES. Of these, nine proved to have concomitant epilepsy. Of 44 patients with NES, 20 were treated with AED on admission. In 14 cases this unnecessary antiepileptic drug treatment was stopped. In six remaining patients with NES and concomitant epilepsy, the total number of AEDs could be reduced until discharge. The maximum duration of AED treatment among patients with NES only, had been longer than 360 months (median 72 months). Much has been written about whether the diagnosis of psychogenic non-epileptic events is overused. According to our experience however, the fact that many patients with so-called 'pharmacoresistant epilepsy', suspected NES or other diagnoses are referred to a centre of excellence much too late, proves to be the key problem in diagnosis and treatment of NES. We conclude that early admission of so-called 'pharmacoresistant epilepsy' to an epilepsy centre, establishing a standard work-up and clarifying the medical terminology will improve diagnosis and lead to adequate therapy of NES as well as prevent unnecessary drug treatment.

Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy.

OBJECTIVE: We report the results of a prospective study of the efficacy and tolerability of levetiracetam, a new antiepileptic drug with a unique mechanism of action, in comparison with controlled-release carbamazepine as first treatment in newly diagnosed epilepsy. METHODS: Adults with > or =2 partial or generalized tonic-clonic seizures in the previous year were randomly assigned to levetiracetam (500 mg twice daily, n = 288) or controlled-release carbamazepine (200 mg twice daily, n = 291) in a multicenter, double-blind, noninferiority, parallel-group trial. If a seizure occurred within 26 weeks of stabilization, dosage was increased incrementally to a maximum of levetiracetam 1,500 mg twice daily or carbamazepine 600 mg twice daily. Patients achieving the primary endpoint (6-month seizure freedom) continued on treatment for a further 6-month maintenance period. RESULTS: At per-protocol analysis, 73.0% (56.6%) of patients randomized to levetiracetam and 72.8% (58.5%) receiving controlled-release carbamazepine were seizure free at the last evaluated dose (adjusted absolute difference 0.2%, 95% CI -7.8% to 8.2%) for > or =6 months (1 year). Of all patients achieving 6-month (1-year) remission, 80.1% (86.0%) in the levetiracetam group and 85.4% (89.3%) in the carbamazepine group did so at the lowest dose level. Withdrawal rates for adverse events were 14.4% with levetiracetam and 19.2% with carbamazepine. CONCLUSIONS: Levetiracetam and controlled-release carbamazepine produced equivalent seizure freedom rates in newly diagnosed epilepsy at optimal dosing in a setting mimicking clinical practice. This trial has confirmed in a randomized, double-blind setting previously uncontrolled observations that most people with epilepsy will respond to their first-ever antiepileptic drug at low dosage.

Neuron density in the molecular layer of the frontal cortex in primary generalized epilepsy.

Developmental disturbance of the brain as a factor in the causation of epilepsies has been suspected for a long time. An increase of nerve cells in the stratum moleculare, which is qualitatively observed in primary generalized epilepsy, is thought to be an indicator for slight maldevelopment. In this morphometric study, the neuron density of layer I in the frontal lobe in primary generalized epilepsy is measured. Compared with age-matched controls, the neuron density in primary generalized epilepsy is significantly increased. Thus, neuron density could be a significant index for the disturbance of regional maturation of the cortex.

Neuropathological findings in primary generalized epilepsy: a study of eight cases.

On neuropathological investigation of eight cases with primary generalized epilepsy, none showed elective parenchymal necrosis, which is regarded (qualitatively and topologically) as characteristic of epilepsy in classical neuropathology. In seven of the eight cases, however, marked microdysgenesis with varying regional distribution was found. These maturation disturbances are to be interpreted as pathological and refute the currently held view that there is no evidence of pathological brain damage in primary generalized epilepsy.

Morphological aspects of aetiology and the course of infantile spasms (West-syndrome).

The present study using the results of the postmortem examination of twenty-four children, who had infantile spasms (West-Syndrome), gives a view of the aetiology and course of the West-Syndrome. According to the time of occurrence of the lesions three groups could be established: one group of six cases with only embryofetal lesions, one group of ten cases with combined embryofetal and peri/postnatal lesions and one group of eight cases with only peri/postnatal lesions. It is significant, that the time of onset of infantile spasms depends on time of manifestation of lesions. In the groups with combined embryofetal and peri/postnatal lesions the seizures were manifested at the same time as in the cases with isolated embryofetal lesions. Even in the group with combined lesions, microdysgenesis was interpreted as being embryofetal. These embryofetal lesions, as opposed to the peri/postnatal lesions thus appear to dominate and thereby to be pathoplastic. From this correlation two thirds of the cases of infantile spasms can be regarded as fetal epilepsies. The question is open if the infantile spasms which are manifested later on and develop mostly a Lennox-Syndrome indeed should be classified as a separate group together with the isolated peri/postnatal lesions.

Temporal-lobe epilepsy: comparison of CT and MR imaging.

In 50 patients with temporal-lobe epilepsy, CT and MR findings were compared. Axial CT scans were obtained before and after administration of contrast material. Coronal MR imaging was carried out with two spin-echo (SE) sequences with a repetition time of 1600 msec and echo times of 35 or 70 msec (SE 1600/35, SE 1600/70). A focal lesion was detected by CT in 12 cases and by MR in 16 cases. If discrete attenuation or signal abnormalities are also taken into account, CT provided a positive finding in 13 cases and MR imaging in 20 cases. With the exception of a small calcification, all the lesions revealed on the CT scans were also detected on the MR images. Among the examinations assessable for temporal-lobe asymmetry, signs of a unilateral reduction in temporal-lobe size were seen on two of 35 CT scans and on 15 of 38 MR images. In three patients who had temporal-lobe resection, a subsequent comparison was made between CT, MR imaging, and pathology. Histologically proven glial reactions that could not be detected on CT were demonstrated as high-signal-intensity lesions on the SE 1600/70 image. We conclude that MR scanning, with its higher sensitivity, superior image quality, and ability of multiplanar imaging, should be the imaging technique of choice in the diagnosis of temporal-lobe epilepsy.

[A stereological study of the angioarchitecture of the cerebral cortex in rabbits]. / Stereologische Untersuchung der Gefässarchitektur der Grosshirnrinde des Kaninchens.

An attempt is made to describe the vascular architecture of the cortex employing a stereological method. Brains perfused with india ink were sectioned in frontal, sagittal and tangential levels. The course of the vessels was described as a spatial vector from the center to the penetration point of the globe or radius 1. In order to present a two-dimensional image, we projected the penetration point together with the longitudinal and horizontal meridians of the globe in an orthograde fashion into the level of the image. The frontal and sagittal sections were projected in an equatorial image, the tangential level was projected to an axis. Direct observations and stereological imaging demonstrated that, in lamina 4, there is a relatively constant hexagonal vascular net with branching angles of 60 degrees at an edge length of 50--60 microns.

Memory assessment during the intracarotid amobarbital procedure: influence of injection order.

OBJECTIVE: To analyze, in patients with unilateral regional epilepsy, the influence of intracarotid amobarbital injection order on the level of recognition memory, with both injections performed within approximately half an hour, when the order was varied by a first injection into either the epileptogenic or the nonepileptogenic hemisphere. METHODS: Of a series of 74 consecutive intracarotid amobarbital procedures (IAP), 61 valid bilateral tests were extracted for analysis. The protocol was changed from a congruent sequence (epileptogenic hemisphere injected first; n = 32) to an incongruent sequence (nonepileptogenic hemisphere injected first; n = 29). Memory was quantified by the percentage of presented items recognized before the recovery of full motor power (corrected for guessing). RESULTS: The congruent group showed a poorer recognition percentage after injection into the nonepileptogenic hemisphere than after injection into the epileptogenic hemisphere. The incongruent group had a similar recognition percentage after both injections. This was especially apparent in patients with a right epileptogenic hemisphere. CONCLUSIONS: The commonly used congruent injection order leads to a poorer recognition by the epileptogenic hemisphere than the nonepileptogenic hemisphere. This relation cannot be found with an incongruent sequence. The results raise doubts about the internal validity of the IAP in describing isolated hemispheric memory functions.