ATPase N-ethylmaleimide-sensitive Fusion Protein: A Novel Key Player for Causing Spontaneous Network Excitation in Human Temporal Lobe Epilepsy.

The molecular basis for onset, maintenance and propagation of excitation along neuronal networks in epilepsy is still poorly understood. Besides different neurotransmitter receptors that control signal transfer at the synapse, one key regulator involved in all of these processes is the ATPase N-ethylmaleimide-sensitive fusion protein (NSF). Therefore, we analyzed receptor subunits and NSF levels in tissues from the medial temporal gyrus (MTG) of patients with pharmaco-resistant focal temporal lobe epilepsy resected during epilepsy surgery and autopsy controls. The resected tissues were further characterized by field potential recordings into tissues with and without spontaneous sharp wave activity. We detected increased levels of NSF, NMDA 1.1, 2A and GABAAγ2 receptor subunits associated with spontaneous sharp wave spiking activity. We further identified correlations between NSF, AMPA receptor subunit, metabotropic glutamate receptor and adenosine 1 receptor levels in the spontaneous sharp wave spiking tissues. Our findings suggest that NSF plays a key role in controlling spontaneous network excitation in epilepsy by two mechanisms of action: (1) directly via controlling transmitter release at the presynaptic side, and (2) indirectly via altering the function of possible receptor crosstalk and directing/integrating specific receptor compounds through/into the postsynaptic membrane.

Directional spread of activity in synaptic networks of the human lateral amygdala.

Spontaneous epileptiform activity has previously been observed in lateral amygdala (LA) slices derived from patients with intractable-temporal lobe epilepsy. The present study aimed to characterize intranuclear LA synaptic connectivity and to test the hypothesis that differences in the spread of flow of neuronal activity may relate to spontaneous epileptiform activity occurrence. Electrical activity was evoked through electrical microstimulation in acute human brain slices containing the LA, signals were recorded as local field potentials combined with fast optical imaging of voltage-sensitive dye fluorescence. Sites of stimulation and recording were systematically varied. Following recordings, slices were anatomically reconstructed using two-dimensional unitary slices as a reference for coronal and parasagittal planes. Local spatial patterns and spread of activity were assessed by incorporating the coordinates of electrical and optical recording sites into the respective unitary slice. A preferential directional spread of evoked electrical signals was observed from ventral to dorsal, rostral to caudal and medial to lateral regions in the LA. No differences in spread of evoked activity were observed between spontaneously and non-spontaneously active LA slices, i.e. basic properties of evoked synaptic responses were similar in the two functional types of LA slices, including input-output relationship, and paired-pulse depression. These results indicate a directed propagation of synaptic signals within the human LA in spontaneously active epileptic slices. We suggest that the lack of differences in local and in systemic information processing has to be found in confined epileptiform circuits within the amygdala likely involving well-known "epileptic neurons".

Hippocampal GABA transporter distribution in patients with temporal lobe epilepsy and hippocampal sclerosis.

PURPOSE: To determine hippocampal expression of neuronal GABA-transporter (GAT-1) and glial GABA-transporter (GAT-3) in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). METHODS: Hippocampal sections were immunohistochemically stained for GABA-transporter 1 and GABA-transporter-3, followed by quantification of the immunoreactivity in the hilus by optical density measurements. GABA-transporter 3 positive hilar cells were counted and GABA-transporter protein expression in sections that included all hippocampal subfields was quantified by Western blot. RESULTS: The hilar GABA-transporter 1 expression of patients with severe hippocampal sclerosis was about 7% lower compared to that in the mild hippocampal sclerosis/control group (p<0.001). The hilar GABA-transporter 3 expression was about 5% lower in the severe hippocampal sclerosis group than in the mild hippocampal sclerosis/control group (non-significant). Also, severe hippocampal sclerosis samples contained 34% less (non-significant) GABA-transporter 3 positive cells compared to that of controls. Protein expression as assessed by Western blot showed that GABA-transporter 1 was equally expressed in mild and severe hippocampal sclerosis samples, whereas GABA-transporter 3 was reduced by about 62% in severe hippocampal sclerosis samples (p<0.0001). CONCLUSION: These data confirm that GABA-transporter expression is spatially and isoform-specific reduced and GABA-transporter 3 positive cell numbers are unchanged in hippocampal sclerosis. Implications for the use of GABAergic antiepileptic therapies in hippocampal sclerosis vs non-hippocampal sclerosis patients remain to be studied.

Oscillatory dynamics track motor performance improvement in human cortex.

Improving performance in motor skill acquisition is proposed to be supported by tuning of neural networks. To address this issue we investigated changes of phase-amplitude cross-frequency coupling (paCFC) in neuronal networks during motor performance improvement. We recorded intracranially from subdural electrodes (electrocorticogram; ECoG) from 6 patients who learned 3 distinct motor tasks requiring coordination of finger movements with an external cue (serial response task, auditory motor coordination task, go/no-go). Performance improved in all subjects and all tasks during the first block and plateaued in subsequent blocks. Performance improvement was paralled by increasing neural changes in the trial-to-trial paCFC between theta ([Formula: see text]; 4-8 Hz) phase and high gamma (HG; 80-180 Hz) amplitude. Electrodes showing this covariation pattern (Pearson's r ranging up to .45) were located contralateral to the limb performing the task and were observed predominantly in motor brain regions. We observed stable paCFC when task performance asymptoted. Our results indicate that motor performance improvement is accompanied by adjustments in the dynamics and topology of neuronal network interactions in the [Formula: see text] and HG range. The location of the involved electrodes suggests that oscillatory dynamics in motor cortices support performance improvement with practice.

Multireceptor analysis in human neocortex reveals complex alterations of receptor ligand binding in focal epilepsies.

PURPOSE: A disturbed balance between excitatory and inhibitory neurotransmission underlies epileptic activity, although reports concerning neurotransmitter systems involved remain controversial. METHODS: We quantified densities of 15 receptors in neocortical biopsies from patients with pharmacoresistant focal temporal lobe epilepsy and autopsy controls, and searched for correlations between density alterations and clinical factors or the occurrence of spontaneous synaptic potentials in vitro. KEY FINDINGS: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, N-methyl-d-aspartate (NMDA), peripheral benzodiazepine, muscarinic (M)(1) , M(2) , nicotinic, α(1) , α(2h) , serotonin (5-HT)(1A) , and adenosine (A)(1) receptor densities were significantly altered in biopsies. The epileptic cohort was subdivided based on clinical (febrile seizures, hippocampal sclerosis, neocortical pathologies, surgery outcome) or electrophysiologic (spontaneous field potentials) criteria, resulting in different patterns of significantly altered receptor types when comparing a given epileptic group with controls. Only AMPA, kainate, M(2) , and 5-HT(1A) receptors were always significantly altered. γ-Aminobutyric acid (GABA)(A) , GABA(B) , and 5-HT(2) receptor alterations were never significant. Correlation patterns between receptor alterations and illness duration or seizure frequency varied depending on whether the epileptic cohort was considered as a whole or subdivided. SIGNIFICANCE: Neocortical temporal lobe epilepsy is associated with a generalized receptor imbalance resulting in a net potentiation of excitatory neurotransmission. Peripheral benzodiazepine receptor alterations highlight that astrocytes are also impaired by seizure activity.

Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex.

Spreading depolarization of cells in cerebral grey matter is characterized by massive ion translocation, neuronal swelling and large changes in direct current-coupled voltage recording. The near-complete sustained depolarization above the inactivation threshold for action potential generating channels initiates spreading depression of brain activity. In contrast, epileptic seizures show modest ion translocation and sustained depolarization below the inactivation threshold for action potential generating channels. Such modest sustained depolarization allows synchronous, highly frequent neuronal firing; ictal epileptic field potentials being its electrocorticographic and epileptic seizure its clinical correlate. Nevertheless, Leão in 1944 and Van Harreveld and Stamm in 1953 described in animals that silencing of brain activity induced by spreading depolarization changed during minimal electrical stimulations. Eventually, epileptic field potentials were recorded during the period that had originally seen spreading depression of activity. Such spreading convulsions are characterized by epileptic field potentials on the final shoulder of the large slow potential change of spreading depolarization. We here report on such spreading convulsions in monopolar subdural recordings in 2 of 25 consecutive aneurismal subarachnoid haemorrhage patients in vivo and neocortical slices from 12 patients with intractable temporal lobe epilepsy in vitro. The in vitro results suggest that γ-aminobutyric acid-mediated inhibition protects from spreading convulsions. Moreover, we describe arterial pulse artefacts mimicking epileptic field potentials in three patients with subarachnoid haemorrhage that ride on the slow potential peak. Twenty-one of the 25 subarachnoid haemorrhage patients (84%) had 656 spreading depolarizations in contrast to only three patients (12%) with 55 ictal epileptic events isolated from spreading depolarizations. Spreading depolarization frequency and depression periods per 24 h recording episodes showed an early and a delayed peak on Day 7. Patients surviving subarachnoid haemorrhage with poor outcome at 6 months showed significantly higher total and peak numbers of spreading depolarizations and significantly longer total and peak depression periods during the electrocorticographic monitoring than patients with good outcome. In a semi-structured telephone interview 3 years after the initial haemorrhage, 44% of the subarachnoid haemorrhage survivors had developed late post-haemorrhagic seizures requiring anti-convulsant medication. In those patients, peak spreading depolarization number had been significantly higher [15.1 (11.4-30.8) versus 7.0 (0.8-11.2) events per day, P = 0.045]. In summary, monopolar recordings here provided unequivocal evidence of spreading convulsions in patients. Hence, practically all major pathological cortical network events in animals have now been observed in people. Early spreading depolarizations may indicate a risk for late post-haemorrhagic seizures.

Radiofrequency lesioning for epileptogenic periventricular nodular heterotopia: a rational approach.

Periventricular nodular heterotopias (PNHs) are frequently associated with pharmacoresistant epilepsy. They are considered part of a dysfunctional network, connected to the overlying cortex. Therefore, removal of the PNHs and additional cortectomy or lobectomy seem to be essential for significant and long-lasting seizure reduction. These procedures, however, can have considerable limitations, especially in patients with functional eloquent cortex adjacent to the PNH. Alternatively, stereotactic neurosurgery can reduce the surgical trauma. Presented is a 56-year-old man who became seizure-free after stereotactically guided radiofrequency lesioning of a solitary PNH.

Long term outcome in patients not initially seizure free after resective epilepsy surgery.

PURPOSE: To assess the long-term seizure outcome and find predictors of outcome for patients who were not initially seizure free 6 months after epilepsy surgery. METHODS: We retrospectively reviewed all adult patients who underwent epilepsy surgery at the Epilepsy Center Bethel, between 1992 and 2003. There were 266 patients included in this analysis. RESULTS: Of the 266 patients who were included in this study, the probability of becoming seizure free was 12% (95%CI 8-16%) after 2 years, 19.5% (95%CI 15-24%) after 5 years and 34.7% (95%CI 28-41%) after 10 years. In patients who had auras only, the probability of being seizure free was 18.2% after 2 years, 25.5% after 5 years, and 39.1% after 10 years. In the multiregression analysis, the EEG carried out 2 years after surgery, a psychic aura, the frequency of postoperative focal seizures and hypermotor seizures predicted seizure remission in the long-term outcome. CONCLUSIONS: The frequency and type of postoperative seizures are critical determinants for long-term outcome. Seizure semiology may be the clue to a precise diagnosis and long-term prognosis of epilepsy.

Apical temporal lobe resection; "tailored" hippocampus-sparing resection based on presurgical evaluation data.

BACKGROUND: It is the aim of epilepsy surgery in patients with lesional epilepsy for the surgeon to not only remove the lesion itself, but also the epileptogenic zone. Here, we report our experience with a modified temporal resection technique confined to the apical temporal lobe, i.e., sparing the hippocampal formation in patients with epileptogenic lesions in the anterior part of the temporal lobe. This apical temporal lobe resection (aTLR) includes tailored lesionectomy, amygdalectomy, and resection of the mesial structures only in the apex of the temporal lobe. This paper presents our surgical technical details and the outcome of aTLR. METHODS: Between 2001 and 2008, aTLR was performed in 61 patients. All patients underwent comprehensive presurgical evaluation including video-EEG monitoring, magnetic resonance imaging (MRI), and neuropsychological testing. All patients had a lesion in the apex of the temporal lobe and a normal hippocampus as seen in MRI, as well as intact memory functions in neuropsychological examination. There were 33 males (54.1%) and 28 females (45.9%). The mean age in years at epilepsy onset was 20.2 ± 13.4, the mean age at epilepsy surgery was 32.1 ± 11.9, the mean preoperative epilepsy duration was 11.8 ± 8.8 years and the mean duration of follow-up was 2.1 ± 1.3 years (range 0.5-6 years). RESULTS: Fifty-four (88.5%) of 61 patients were in Engel Class 1 at 6 months, 38 (80.9%) of 47 at 2 years and nine (81.8%) of 11 at the 5 year follow-up. Histopathological examination showed tumors in 31 patients, FCD in ten patients, amygdala sclerosis in seven patients, cavernomas in six patients, unspecific reactions in eight patients, and gliosis in one patient. Surgical complications occurred in four patients: one had a permanent and three had transient complications which could be successfully treated. Fifty (82%) resections were considered to be complete resections as evaluated by serial postoperative MRI, seven patients (11.5%) had incomplete resection of the preoperative MRI lesion and in four patients (6.6%) it remained unclear. Fifteen patients (29.4%) were withdrawn from antiepileptic drugs for more than 2 years without relapse. Postoperative neuropsychological examination revealed worsening of memory performance in two patients (3.2%) and improved or no changes in the rest of the patients. CONCLUSIONS: Apical temporal resection sparing the mesial temporal structures is an effective procedure with good long-term seizure outcome in patients with refractory epilepsy due to lesions confined to the apex of the temporal lobe.

Analysis of reoperation in mesial temporal lobe epilepsy with hippocampal sclerosis.

BACKGROUND: Most patients do well after epilepsy surgery for mesial temporal lobe sclerosis, and in only 8 to 12% of all operations, the outcome is classified as not improved. OBJECTIVE: To analyze the outcome of reoperation in cases of incomplete resection of mesial temporal lobe structures in patients with mesial temporal lobe sclerosis in temporal lobe epilepsy. METHODS: We analyzed 22 consecutive patients who underwent reoperation for mesial temporal lobe sclerosis (follow-up, 23-112 months; mean, 43.18 months) by evaluating noninvasive electroencephalographic/video monitoring before the first and second surgeries (semiology, interictal epileptiform discharges, ictal electroencephalography with special attention to the secondary contralateral evolution of the electroencephalographic seizure pattern after the initial regionalization), and magnetic resonance imaging (resection indices after the first and second surgeries on the amygdala, hippocampus, lateral temporal lobe). In 18 of 22 patients T2 relaxometry of the contralateral hippocampus was performed. RESULTS: Nine of 22 patients became seizure free; another 4 patients had a decrease in seizures and eventually became seizure free (range, 16-51 months; mean, 30.3). Recurrence of seizures is associated with (1) ictal electroencephalography with later evolution of an independent pattern over the contralateral temporal lobe (0 of 5 patients seizure free vs 5 of 7 patients non-seizure free; P = .046) and (2) a smaller amount of lateral temporal lobe resection in the second surgery (1.06 ± 0.59 cm vs 2.18 ± 1.37 cm; P = .019). No significant correlation with outcome was found for lateralization of interictal epileptiform discharges, change in semiology, other resection indices, T2 relaxometry, onset and duration of epilepsy, duration of follow-up, and side of surgery. CONCLUSION: Patients have a less favorable outcome with a reoperation if they show ictal scalp electroencephalography with secondary contralateral propagation and if only a small second resection of the lateral temporal lobe is performed.

Absolute spike frequency and etiology predict the surgical outcome in epilepsy due to amygdala lesions.

PURPOSE: To identify surgical prognostic factors for temporal lobe epilepsy (TLE) due to amygdala lesions. METHODS: We included 42 patients (mean age: 31.4 ± 11) who underwent presurgical evaluation including long-term video-EEG and in whom the high-resolution MRI showed amygdala lesions without hippocampal abnormalities. All patients had apical temporal lobe resection without hippocampectomy. We distinguished patients with frequent spikes (spike frequency ≥ 60/h) and with non-frequent spikes (< 60 spikes/h). RESULTS: At the 2-year postoperative evaluation, 30 patients (71%) were seizure-free. The presence of infrequent spikes (p = 0.013), tumor on the MRI (p = 0.027), and no epilepsy history in the family (p = 0.027) were independently associated with 2-year seizure-free outcome. Of 33 patients with infrequent spikes, 79% became seizure-free, while of 9 patients with frequent spikes only 4 had a favorable surgical outcome (44%). CONCLUSION: In TLE patients due to amygdala lesions, high spike frequency and family history of epilepsy predicted an unfavorable, while tumoral etiology a favorable outcome after apical temporal lobe resection without hippocampectomy. Seventy-one percent of patients with amygdalar epilepsy who underwent this novel type of epilepsy surgery became seizure-free. This is comparable with results of "classical" anterior temporal lobe resections where hippocampus is NOT spared. Moreover, the surgical outcome may be predictable.

Vagus nerve stimulation: outcome and predictors of seizure freedom in long-term follow-up.

OBJECTIVES: To present long-term outcome and to identify predictors of seizure freedom after vagus nerve stimulation (VNS). METHODS: All patients who had undergone VNS implantation in the Epilepsy Centre Bethel were retrospectively reviewed. There were 144 patients who had undergone complete presurgical evaluation, including detailed clinical history, magnetic resonance imaging, and long-term video-EEG with ictal and interictal recordings. After implantation, all patients were examined at regular intervals of 4 weeks for 6-9 months. During this period the antiepileptic medication remained constant. All patients included in this study were followed up for a minimum of 2 years. RESULT: Ten patients remained seizure-free for more than 1 year after VNS implantation (6.9%). Seizures improved in 89 patients (61.8%) but no changes were observed in 45 patients (31.3%). The following factors were significant in the univariate analysis: age at implantation, multifocal interictal epileptiform discharges, unilateral interictal epileptiform discharge, cortical dysgenesis, and psychomotor seizure. Stepwise multivariate analysis showed that unilateral interictal epileptiform discharges (IEDs), P=0.014, HR=0.112 (95% CIs, 0.019-0.642), cortical dysgenesis P=0.007, HR=0.065 (95% CIs, 0.009-0.481) and younger age at implantation P=0.026, HR=7.533 (95% CIs 1.28-44.50) were independent predictors of seizure freedom in the long-term follow-up. CONCLUSION: VNS implantation may render patients with some forms of cortical dysgenesis (parietooccipital polymicrogyria, macrogyria) seizure-free. Patients with unilateral IEDs and earlier implantation achieved the most benefit from VNS.

Sublobar dysplasia--A clinicopathologic report after successful epilepsy surgery.

We report the clinical presentation, neuroradiologic characteristics, and detailed histopathologic findings in a unique case of drug-resistant focal epilepsy due to sublobar dysplasia (SLD), treated successfully by resection of the malformed cortex. Histopathology with leptomeningeal and subcortical heterotopia, disturbance of cortical lamination and marked cortical and subcortical astrocytosis, but absence of balloon cells, points to a disorder of neuronal migration and organization rather than proliferation in SLD. The additional presence of a lateral proboscis and meningocele in our case as well as further associated callosal and cerebellar anomalies may suggest an etiologic unknown damage of pathways controlling the embryogenesis of craniofacial field processes.

Long-term outcome and determinants of quality of life after temporal lobe epilepsy surgery in adults.

AIM OF THE STUDY: To find determinants of quality of life (QOL) in long-term follow-up after temporal lobe epilepsy (TLE) surgery in adults. METHODS: The QOLIE-31 questionnaire was sent to 400 of 524 patients who were operated on for refractory TLE between 1991 and 2003 in the Bethel Epilepsy Centre fulfilling the inclusion criteria of this study. Mainly patients with severe cognitive deficits and patients with progressive brain disorders were excluded. There were 222/400 patients who replied to the QOLIE-31 questionnaire and 147/222 of these patients replied to an additional questionnaire. RESULTS: Univariate analyses showed that seizure freedom, presence of auras, intake of antiepileptic drugs (AEDs), severity of AED side effects, and driving a car were significantly correlated with all subscales of QOLIE-31. Furthermore, employment status, psychiatric problems, tumors and hippocampus sclerosis pathology, the presence of a partner, age at reply, age at surgery and medical co-morbidities were significantly correlated with some subscales of the QOLIE-31. Multivariate analyses (stepwise regression analyses) revealed that especially the time since the last seizure and the severity of AED side effects had a strong impact on QOL. However, aura at last follow-up, psychiatric treatment and employment were seen in the multivariate analyses as significant predictors of some QOL subscales as well. Most subscales of QOL showed a steep, non-linear increase within the first years of seizure freedom and remained relatively stable except for cognitive function which showed continuous improvement parallel to seizure freedom. For patients who were seizure free since surgery, side effects of AED and/or psychiatric treatment were the strongest determinants of QOL. CONCLUSION: Duration of seizure freedom and AED side effects have the strongest impact on QOL in the long-term follow-up. Therefore it is important not only to register intake of AEDs but also to assess side effects of AEDs. Persistence of auras also had an impact on different facets of QOL, but was significantly correlated with intake of AEDs. Apart from factors directly related to epilepsy QOL was dependent of psychosocial factors as employment status, psychiatric complications, and driving a car underlining the necessity of postoperative rehabilitation in this group.

Long-term outcome after temporal lobe epilepsy surgery in 434 consecutive adult patients.

OBJECT: The aim of this study was to evaluate the long-term efficacy of temporal lobe epilepsy (TLE) surgery and potential risk factors for seizure recurrence after surgery. METHODS: This retrospective study included 434 consecutive adult patients who underwent TLE surgery at Bethel Epilepsy Centre between 1991 and 2002. RESULTS: Hippocampal sclerosis was found in 62% of patients, gliosis in 17.3%, tumors in 20%, and focal cortical dysplasia (FCD) in 6.9%. Based on a Kaplan-Meier analysis, the probability of Engel Class I outcome for the patients overall was 76.2% (95% CI 71-81%) at 6 months, 72.3% (95% CI 68-76%) at 2 years, 71.1% (95% CI 67-75%) at 5 years, 70.8% (95% CI 65-75%) at 10 years, and 69.4% (95% CI 64-74%) at 16 years postoperatively. The likelihood of remaining seizure free after 2 years of freedom from seizures was 90% (95% CI 82-98%) for 16 years. Seizure relapse occurred in all subgroups. Patients with FCD had the highest risk of recurrence (hazard ratio 2.15, 95% CI 0.849-5.545). Predictors of remission were the presence of hippocampal atrophy on preoperative MR imaging and a family history of epilepsy. Predictors of relapse were the presence of bilateral interictal sharp waves and versive seizures. Six-month follow-up electroencephalography predicted relapse in patients with FCD. Short epilepsy duration was predictive of seizure remission in patients with tumors and gliosis; 28.1% of patients were able to discontinue antiepileptic medications without an increased risk of seizure recurrence (hazard ratio 1.05, 95% CI 0.933-1.20). CONCLUSIONS: These findings highlight the role of etiology in prediction of long-term outcome after TLE surgery.

Outcome of extratemporal epilepsy surgery experience of a single center.

OBJECTIVE: Our aim was to determine the surgical outcome in adult patients with intractable extratemporal epilepsy and follow it over time. METHODS: We retrospectively studied the operative outcome in 218 consecutive adult patients with extratemporal lesions who underwent resective surgical treatment for intractable partial epilepsy in the Bethel Epilepsy Center, Bielefeld, Germany, between 1991 and 2005. Patients were divided into three groups according to the 5-year period in which the surgical procedure took place. RESULTS: Group I (1991-1995) consisted of 64 patients. The postoperative Engel Class I outcome was 50% at 6 months, 44.4% at 2 years, and 45.2% at 5 years. Group II (1996-2000) included 91 patients. Engel Class I outcome was 57.1% at 6 months, 53.8% at 2 years, and 53.5% at 5 years. In Group III (2001-2005), there were 63 patients. Engel Class I outcome was 65.1% at 6 months, 61.3% at 2 years, and 60.6% at 5 years. Short duration of epilepsy, surgery before 30 years of age, pathological findings of neoplasm, and well-circumscribed lesions on the preoperative magnetic resonance imaging scan were good prognostic factors. Poor prognostic factors were one or more of the following: psychic aura, generalized tonic-clonic seizure, versive seizure, history of previous surgery, and focal cortical dysplasia. On multivariate analysis, only the presence of well-circumscribed lesions on preoperative magnetic resonance imaging predicted a positive outcome (P = 0.001). CONCLUSION: Our results indicate that extratemporal epilepsy surgery at the Bethel Epilepsy Center has become more effective in the treatment of extratemporal epilepsy patients over the years, ensuring continuous improvement in outcome. This improvement can be attributed mainly to more restrictive patient selection.

Outcome of frontal lobe epilepsy surgery in adults.

Our aim is to investigate seizure outcome and prognostic factors after pure frontal lobe epilepsy (FLE) surgery. We retrospectively studied the operative outcome in 97 consecutive adult patients who underwent resective surgery for intractable partial epilepsy between 1991 and 2005. Based on Kaplan-Meier, the probability of an Engel Class I outcome was found to be 54.6% (95% CI 44-64) at 6 months, 49.5% (95% CI 39.3-59.6) at 2 years, 47% (CI 34-59) at 5 years and 41.9% (CI 23.5-60.3) at 10 years. If the patient was seizure free at 2-year follow-up, the probability of remaining seizure free up to 10 years was 86% (95% CI 76-98). For 13.6% of the patients a running down of seizures could be shown. Factors predictive of poor long-term outcome were incomplete resection, using of subdural grids, IED in follow-up EEG, tonic seizures and an unspecific aura or a postoperative aura. Factors predictive of good long-term outcome were the presence of a well-circumscribed lesion in preoperative MRI, ipsilateral IED in preoperative EEG, surgery before age of 30 and short epilepsy duration prior to surgery. In the multivariate analysis, preoperative well-circumscribed lesion in MRI predicts seizure remission whereas persistent postoperative auras predict seizure relapse. FLE surgery should depend on restrictive patient selection to assure favorable outcome.

Long-term outcome of extratemporal epilepsy surgery among 154 adult patients.

OBJECT: The goal of this study was to evaluate the long-term outcome of patients who underwent extratemporal epilepsy surgery and to assess preoperative prognostic factors associated with seizure outcome. METHODS: This retrospective study included 154 consecutive adult patients who underwent epilepsy surgery at Bethel Epilepsy Centre, Bielefeld, Germany between 1991 and 2001. Seizure outcome was categorized based on the modified Engel classification. Survival statistics were calculated using Kaplan-Meier curves, life tables, and Cox regression models to evaluate the risk factors associated with outcomes. RESULTS: Sixty-one patients (39.6%) underwent frontal resections, 68 (44.1%) had posterior cortex resections, 15 (9.7%) multilobar resections, 6 (3.9%) parietal resections, and 4 (2.6%) occipital resections. The probability of an Engel Class I outcome for the overall patient group was 55.8% (95% confidence interval [CI] 52-58% at 0.5 years), 54.5% (95% CI 50-58%) at 1 year, and 51.1% (95% CI 48-54%) at 14 years. If a patient was in Class I at 2 years postoperatively, the probability of remaining in Class I for 14 years postoperatively was 88% (95% CI 78-98%). Factors predictive of poor long-term outcome after surgery were previous surgery (p = 0.04), tonic-clonic seizures (p = 0.02), and the presence of an auditory aura (p = 0.03). Factors predictive of good long-term outcome were surgery within 5 years after onset (p = 0.015) and preoperative invasive monitoring (p = 0.002). CONCLUSIONS: Extratemporal epilepsy surgery is effective according to findings on long-term follow-up. The outcome at the first 2-year follow-up visit is a reliable predictor of long-term Engel Class I postoperative outcome.

Angiocentric glioma: report of clinico-pathologic and genetic findings in 8 cases.

Angiocentric glioma has recently been described as a novel epilepsy associated tumor with distinct clinico-pathologic features. We report the clinical and pathologic findings in 8 additional cases of this rare tumor type and extend its characterization by genomic profiling. Almost all patients had a history of long-standing drug-resistant epilepsy. Cortico-subcortical tumors were located in the temporal and parietal lobes. Seizures began at 3 to 14 years of age and surgery was performed at 6 to 70 years. Histologically, the tumors were characterized by diffuse growth and prominent perivascular tumor cell arrangements with features of astrocytic/ependymal differentiation, but lacking neoplastic neuronal features. Necrosis and vascular proliferation were not observed and mitoses were sparse or absent. MIB-1 proliferation indices ranged from <1% to 5%. Immunohistochemically, all cases stained positively for glial fibrillary acidic protein, vimentin, protein S100B, variably for podoplanin, and showed epithelial membrane antigen-positive cytoplasmic dots. Electron microscopy showed ependymal characteristics in 2 of 3 cases investigated. An analysis of genomic imbalances by chromosomal comparative genomic hybridization revealed loss of chromosomal bands 6q24 to q25 as the only alteration in 1 of 8 cases. In 1 of 3 cases, a high-resolution screen by array-comparative genomic hybridization identified a copy number gain of 2 adjacent clones from chromosomal band 11p11.2 containing the protein-tyrosine phosphatase receptor type J (PTPRJ) gene. All patients are seizure free and without evidence of tumor recurrence at follow-up times ranging from 1/2 to 6.9 years. Our findings support 2 previous reports proposing that angiocentric glioma is a novel glial tumor entity of low-grade malignancy.

Comparison of brain extracellular fluid, brain tissue, cerebrospinal fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy.

PURPOSE: The mechanisms of drug resistance in epilepsy are only incompletely understood. According to a current concept, overexpression of drug efflux transporters at the blood-brain barrier may reduce levels of antiepileptic drugs (AEDs) in epileptogenic brain tissue. Increased expression of drug efflux transporters such as P-glycoprotein has been found in brain tissue surgically resected from patients with medically intractable epilepsy, but it is not known whether this leads to decreased extracellular (interstitial) AED concentrations in affected brain regions. This prompted us to measure concentrations of AEDs in the extracellular space of human neocortical tissue by using intraoperative microdialysis (IOMD) in those parts of the brain that had to be removed for therapeutic reasons. For comparison, AED levels were determined in brain tissue, subarachnoid CSF, and serum. METHODS: Concentrations of carbamazepine (CBZ), 10-hydroxy-carbazepine (10-OH-CZ, metabolite of oxcarbazepine), lamotrigine (LTG), levetiracetam (LEV), topiramate, or phenytoin were determined by using one to four catheters during IOMD in the medial temporal gyrus. Furthermore, to calculate the individual recovery of every catheter, an in vitro microdialysis was performed with ultrafiltrate of serum concurrently obtained from the respective patient. In addition, AED levels were determined in the resected brain tissue, CSF, and serum of the same patients. Altogether 22 pharmacoresistant epilepsy patients (nine male, 13 female patients; age 15-54 years) with complex partial seizures or secondarily generalized seizures were involved. In a first series, IOMD samples 40 min after beginning of the microdialysis (flow rate, 1 microl/min), and in a second series, continuous measurements 25, 30, 35, and 40 min from the beginning were evaluated (flow rate, 2 microl/min). With in vitro recovery data of the individual catheters, the concentration in the extracellular space (ECS) was estimated. RESULTS: AED concentrations in the ECS of the cortex measured by catheters located at a distance of 0.6 cm differed markedly in some patients, whereas concentrations in the ultrafiltrate of the serum of the respective patients measured with the same catheters varied only slightly. Furthermore, ECS concentrations related to the ultrafiltrate of serum showed considerable interindividual variations. The high intra- and interindividual variation of ECS concentrations is demonstrated by the low correlation between concentrations in ECS and the ultrafiltrate of serum (CBZ, r= 0.41; 10-OH-CZ, r= 0.42; LTG, r= 0.27) in contrast to the high correlation between brain tissue concentration and the ultrafiltrate of serum (CBZ, r= 0.97; 10-OH-CZ, r= 0.88; LTG, r= 0.98) in the same group of patients. When comparing AED concentrations in the ECS with those in the CSF, ECS concentrations were significantly lower for CBZ, 10-OH-CZ, LTG, and LEV. CONCLUSIONS: The data demonstrate that AED concentrations show a considerable intraindividual and interindividual variation in the ECS of cortical regions. Furthermore, the ECS concentration of several AEDs is significantly lower than their CSF concentration in patients with intractable epilepsy. However, in the absence of data from nonepileptic tissues, it is not possible to judge whether the present findings relate to overexpression of multidrug transporters in the brain. Instead, the present study illustrates the methodologic difficulties involved in performing IOMD studies in patients and may thus be helpful for future approaches aimed at elucidating the role of multidrug transporters in epilepsy.