Heinz Pannek

Focal cortical dysplasia of Taylor's balloon cell type: Mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis

Focal cortical dysplasia (FCD) is characterized by a localized malformation of the neocortex and underlying white matter. Balloon cells, similar to those observed in tuberous sclerosis, are present in many cases (FCDbc). In these patients, a hyperintense funnel‐shaped subcortical lesion tapering toward the lateral ventricle was the characteristic finding on fluid‐attenuated inversion recovery magnetic resonance imaging scans. Surgical lesionectomy results in complete seizure relief. Although the pathogenesis of FCDbc remains uncertain, histopathological similarities indicate that FCDbc may be related pathogenetically to tuberous sclerosis. Here, we studied alterations of the TSC1 and TSC2 genes in a cohort of patients with chronic, focal epilepsy and histologically documented FCDbc (n = 48). DNA was obtained after microdissection and laser‐assisted isolation of balloon cells, dysplastic neurons, and nonlesional cells from adjacent normal brain tissue. Sequence alterations resulting in amino acid exchange of the TSC1 gene product affecting exons 5 and 17 and silent base exchanges in exons 14 and 22 were increased in patients with FCDbc compared with 200 control individuals (exon 5, 2.3% FCDbc vs 0% C; exon 17, 35% FCDbc vs 1.0% C; exon 14, 37.8% FCDbc vs 15% C; exon 22, 45% FCDbc vs 23.8% C). Sequence alterations could be detected in FCDbc and in adjacent normal cells. In 24 patients, DNA was suitable to study loss of heterozygosity at the TSC1 gene locus in microdissected FCDbc samples compared with control tissue. Eleven FCDbc cases exhibited loss of heterozygosity. In the TSC2 gene, only silent polymorphisms were detected at similar frequencies as in controls. Our findings indicate that FCDbc constitutes a clinicopathological entity with distinct neuroradiological, neuropathological, and molecular genetic features. These data also suggest a role of the TSC1 gene in the development of FCDbc and point toward a pathogenic relationship between FCDbc and the tuberous sclerosis complex.

Comparison of Brain Extracellular Fluid, Brain Tissue, Cerebrospinal Fluid, and Serum Concentrations of Antiepileptic Drugs Measured Intraoperatively in Patients with Intractable Epilepsy

Summary:  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.

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.

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.

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.

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.

CD34-immunoreactive balloon cells in cortical malformations

Balloon cells are histopathological hallmarks of various cortical malformations, i.e., focal cortical dysplasia (Taylor’s type, FCD IIb), hemimegalencephaly (HME) or cortical tubers (tuberous sclerosis, TSC). Whether this intriguing cell type results from similar pathogenetic pathways remains to be shown. Here, we analyzed the immunohistochemical distribution pattern of the CD34 epitope in surgical specimens from 34 patients with FCD IIb, compared to that of 6 patients with TSC and 3 patients with HME. In normal brain, CD34 occurs only transiently during neurulation, but cannot be detected in mature neuroectodermal cell progenies. In contrast, 58% of our patients showed CD34 immunoreactivity within a subpopulation of balloon cells. Interestingly, CD34-positive balloon cells were confined to the white matter, but never observed in neocortical layers. Furthermore, balloon cells expressing neurofilament protein were also restricted to white matter, whereas GFAP-positive balloon cells were observed either in white or gray matter location. Clinical characteristics did not significantly differ between patients with CD34-positive versus CD34-negative lesions. No significant correlation was found between CD34 expression and genetic alterations of the TSC1 gene, which is affected in many FCD and TSC patients and which plays a role in the regulation of cell size. Further studies are warranted to clarify the restricted expression of CD34 in balloon cells of the white matter.

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.

Outcome of extratemporal epilepsy surgery experience of a single center.

OBJECTIVEOur aim was to determine the surgical outcome in adult patients with intractable extratemporal epilepsy and follow it over time. METHODSWe 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. RESULTSGroup 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). CONCLUSIONOur 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.

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.