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.

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.

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.

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.

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 MRI detects abnormalities in relatives of patients with epilepsy and malformations of cortical development.

Malformations of cortical development (MCD) are a common etiology for epilepsy. Laminar heterotopia, bilateral subependymal heterotopia, and lissencephaly have a genetic basis. No gene mutations have yet been identified in patients with focal cortical dysplasias. The aim of this study was to use quantitative morphometric tools to determine if there were gray matter abnormalities in relatives of patients with MCD. We studied 19 relatives of 13 probands with MCD and 58 healthy controls with high-resolution MRI. The relatives and controls had no neocortical abnormalities on visual inspection. MRI data were analyzed with voxel-based morphometry and autoblock analysis. Voxel-based morphometry showed significant increases of gray matter in 9 of 10 probands, 5 of 19 relatives, and 5 of 58 controls. The autoblock analysis showed significant abnormalities in 7 of 8 probands, 8 of 19 relatives, and 2 of 57 controls. This finding suggests structural abnormality in the brains of a greater number of relatives of MCD patients than would be expected, and in the context, a reasonable inference is that this reflects subtle genetically determined cerebral abnormalities, although acquired pathologies are possible and are not excluded.

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.

Alterations of neuronal connectivity in area CA1 of hippocampal slices from temporal lobe epilepsy patients and from pilocarpine-treated epileptic rats.

PURPOSE: Neuronal network reorganization might be involved in epileptogenesis in human and rat limbic epilepsy. Apart from aberrant mossy fiber sprouting, a more widespread 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. METHODS: In slices from hippocampi of patients operated on for temporal lobe epilepsy (n = 134), from pilocarpine-treated rats (n = 74), and from control rats (n = 15), viable neurons were labeled with fluorescent dextran amines. RESULTS: In human hippocampi as well as in pilocarpine-treated rats, the degree of nerve cell loss varied. In 67 of 134 slices from human specimens with distinct Ammon's horn sclerosis and in 23 of 74 slices from pilocarpine-treated rats, a severe shrunken area CA1 presented with a similar picture: few damaged neurons were labeled, and aberrant fiber connections were not visible. This was in contrast to human resected hippocampi and hippocampi from pilocarpine-treated rats with no or moderate loss of neurons. In these cases, pyramidal cells remote from the injection site were labeled (human tissue, n = 59 of 134; pilocarpine-treated rats, n = 39 of 74). In human resected hippocampi without obvious pathology and in control animals, no pyramidal neurons were labeled apart from the injection site. CONCLUSIONS: Axon collaterals of CA1 pyramidal cells are increased in human temporal lobe epilepsy and in pilocarpine-treated rats. Adjacent CA1 pyramidal cells project via aberrant collaterals to the stratum pyramidale and the stratum radiatum of area CA1. This network reorganization can contribute to hyperexcitability via increased backward excitation.

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 Ammon's 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 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), N-methyl-D-aspartate (NMDA) and gamma-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.

A new epileptic seizure classification based exclusively on ictal semiology.

Historically, seizure semiology was the main feature in the differential diagnosis of epileptic syndromes. With the development of clinical EEG, the definition of electroclinical complexes became an essential tool to define epileptic syndromes, particularly focal epileptic syndromes. Modern advances in diagnostic technology, particularly in neuroimaging and molecular biology, now permit better definitions of epileptic syndromes. At the same time detailed studies showed that there does not necessarily exist a one-to-one relationship between epileptic seizures or electroclinical complexes and epileptic syndromes. These developments call for the reintroduction of an epileptic seizure classification based exclusively on clinical semiology, similar to the seizure classifications which were used by neurologists before the introduction of the modern diagnostic methods. This classification of epileptic seizures should always be complemented by an epileptic syndrome classification based on all the available clinical information (clinical history, neurological exam, ictal semiology, EEG, anatomical and functional neuroimaging, etc.). Such an approach is more consistent with mainstream clinical neurology and would avoid the current confusion between the classification of epileptic seizures (which in the International Seizure Classification is actually a classification of electroclinical complexes) and the classification of epileptic syndromes.

Psychosis after resection of ganglioglioma or DNET: evidence for an association.

PURPOSE: David Taylor and Murray Falconer suggested that some patients may develop a psychotic illness after resection of a ganglioglioma that led to intractable seizures. They implied that the mechanism of this association remained unclear. This concept is currently not universally accepted (M. Trimble, personal communication). METHODS: We studied six children or young adults from four centers who developed psychosis after resection of a ganglioglioma or dysembryoplastic neuroepithelioma (DNET). RESULTS: All patients were operated on because of intractable epilepsy. The lesions involved mainly the temporal lobe. Patients had good outcomes for seizure control. In none of the six was potentially psychogenic medication used nor were the psychotic symptoms postictal in nature. The psychosis was schizophreniform with paranoid features and prominent depressive symptoms. Although some behavioral abnormalities were described preoperatively, none had been psychotic before operation. This type of psychotic reaction was not encountered in the four centers in a comparable period after resection of other types of lesions. This complication is rare; it occurred in only one of 39 patients who had such a lesion resected. CONCLUSIONS: Psychotic illness may rarely occur after resection of a ganglioglioma or DNET for treatment of intractable epilepsy. This does not seem to occur after removal of other types of lesions. Because the patients had good outcomes for seizures, the mechanism may be related to "forced normalization." The original observations of Taylor and Falconer are confirmed by this study; the reasons for the selective occurrence, however, remain speculative.

Regional changes in hippocampal T2 relaxation and volume: a quantitative magnetic resonance imaging study of hippocampal sclerosis.

OBJECTIVE: The principal MRI features of hippocampal sclerosis are volume loss and increased T2 weighted signal intensity. Minor and localised abnormalities may be overlooked without careful quantitation. Hippocampal T2 relaxation time (HT2) can be quantified, but previously has only been measured on a few thick coronal slices with interslice gaps. In this study HT2 was measured along the entire length of the hippocampus on contiguous slices and used, with quantitative measures of hippocampal volume (HV) and distribution of atrophy, to better define the range of hippocampal sclerosis. METHODS: Thirty patients with temporal lobe epilepsy, 10 patients with extratemporal localisation related epilepsy and extratemporal lesions, and 20 control subjects were studied using MRI T2 relaxometry and volumetry. RESULTS: In controls and patients, HT2 was higher in the anterior than the posterior hippocampus. Using HV, morphometric, and HT2 data, patients with temporal lobe epilepsy were classified as unilateral diffuse hippocampal sclerosis (n=16), unilateral focal (n=6), bilaterally affected (n=6), and normal (n=2). In patients with unilateral hippocampal sclerosis, the anterior hippocampus was always affected. In three patients with normal HV, HT2 measurements disclosed unilateral focal abnormalities that corresponded to the EEG lateralisation of epileptic activity. Patients with bilateral hippocampal involvement had an earlier onset of epilepsy than patients with unilateral hippocampal sclerosis. CONCLUSIONS: Measurement of regional abnormalities of HT2 along the length of the hippocampus provides further refinement to the MRI assessment of the hippocampi in patients with temporal lobe epilepsy and is complementary to volumetric and morphological data.

Semiological seizure classification.

We propose an epileptic seizure classification based exclusively on ictal semiology. In this semiological seizure classification (SSC), seizures are classified as follows: a. Auras are ictal manifestations having sensory, psychosensory, and experiential symptoms. b. Autonomic seizures are seizures in which the main ictal manifestations are objectively documented autonomic alterations. c. "Dialeptic" seizures have as their main ictal manifestations an alteration of consciousness that is independent of ictal EEG manifestations. The new term "dialeptic" seizure has been coined to differentiate this concept from absence seizures (dialeptic seizures with a generalized ictal EEG) and complex partial seizures (dialeptic seizures with a focal ictal EEG). d. Motor seizures are characterized mainly by motor symptoms and are subclassified as simple or complex. Simple motor seizures are characterized by simple, unnatural movements that can be elicited by electrical stimulation of the primary and supplementary motor area (myoclonic, tonic, clonic and tonic-clonic, versive). Complex motor seizures are characterized by complex motor movements that resemble natural movements but that occur in an inappropriate setting ("automatisms"). e. Special seizures include seizures characterized by "negative" features (atonic, astatic, hypomotor, akinetic, and aphasic seizures). The SSC identifies in detail the somatotopic distribution of the ictal semiology as well as the seizure evolution. The advantages of a pure SSC, as opposed to the current classification of the International League Against Epilepsy (ILAE), which is actually a classification of electroclinical syndromes, are discussed.

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.

[Semiologic classification of epileptic seizures]. / Die semiologische Klassifikation epileptischer Anfälle.

Recent advances in epileptology and epilepsy surgery require revision of the currently used International Classification of Epileptic Seizures, which was published 1981. We present a classification of epileptic seizures which is based purely on the clinical seizure semiology. The advantages of a semiological seizure classification are stressed.

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.