Purpose: Recent analyses provided evidence that human adult cerebrospinal fluid (CSF) in addition to soluble proteins also contains membrane particles that moreover carry the somatic stem cell marker CD133. The significance of CD133 as a potential marker of cellular proliferation, including neurogenesis, remains unresolved. As adult neurogenesis has been implicated to be induced by epileptic seizures this study investigated whether patients with partial epilepsy show a varying amount of membrane-associated CD133 in CSF as compared to healthy adults.Methods: CSF samples of 34 partial epilepsy patients were analyzed and compared to 61 healthy controls. Following sequential centrifugation up to 200,000 g quantitative immunoblotting was performed using a mouse monoclonal antibody. Antigen-antibody complexes were detected using enhanced chemiluminescence, and visualized and quantified digitally.Results: The overall amount of membrane particle-associated CD133 was significantly increased in epilepsy patients compared to healthy controls (9.6 +/- 2.9 ng of bound CD133 antibody versus 7.4 +/- 3.8 ng; p < 0.01). There were no differences according to etiology of epilepsy (cryptogenic, neoplasia, dysplasia, ammon's horn sclerosis, and others). Dichotomization of the patients according to temporal versus extratemporal foci revealed a significant increase of membrane particle-associated CD133 in patients with temporal lobe epilepsy (10.88 +/- 1 3.3 ng of bound CD133 antibody versus 8.35 +/- 3.48 ng; p<0.05).Conclusion: The increased amount of membrane particle-associated CD133 in the CSF of patients with partial epilepsy contributes to the ongoing debate of the source of these particles potentially emerging from subventricular zone astrocytes serving as neural stem cells. As neurogenesis in adults is related to the hippocampus, the significance of the increase of membrane particle-associated CD133 especially in temporal lobe epilepsy needs further clinical correlation. (C) 2011 Elsevier B.V. All rights reserved.

Focal cortical dysplasias (FCD) which represent a composite group of cortical malformations are increasingly recognized as morphological substrate for severe therapy-refractory epilepsy in children and young adults. However, presurgical evaluation remains challenging as not all FCD variants can be reliably detected by high-resolution magnetic resonance imaging (MRI). Here, we studied a cohort of 52 epilepsy patients with neuropathological evidence for FCD using the 2011 classification of the International League against Epilepsy (ILAE) and systematically analysed those histopathologic features applicable also for MRI diagnostics. Histopathologic parameters included quantitative measurements of cellular profiles, cortical thickness, heterotopic neurons in white matter, and myelination that were compared between FCD subtypes and age-/localization-matched controls (n = 36) using multivariate analysis. Dysmorphic neurons in both FCD Type II variants showed significantly increased diameter of their cell bodies and nuclei. Cortical thickness was also increased with a distinct loss of myelin content specifying FCD Type IIb from IIa. The data further suggested that myelination deficits in FCD Type IIb result from compromised oligodendroglial lineage differentiation and we concluded that the "transmantle sign" is a unique finding in FCD Type IIb. In contrast, FCD Type Ia was characterized by a smaller cortical ribbon and higher neuronal densities, but these parameters failed to reach statistical significance (considering age- and location-dependent variability in controls). All FCD variants showed abnormal grey-white matter boundaries with increased numbers of heterotopic neurons. Similar results were obtained also at deep white matter location. Thus, many FCD variants may indeed escape visual MRI inspection, but suspicious areas with increased or decreased cortical thickness as well as grey-white matter blurring may be uncovered using post-processing protocols of neuroimaging data. The systematic analysis of well-specified histopathological features could be helpful to improve sensitivity and specificity in MRI detection during pre-surgical work-up of patients with drug-resistant focal epilepsies.

Department of Neurology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany Department of Neuroradiology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany Department of Neuropathology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany Department of Neurosurgery, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany Department of Epileptology, University of Bonn Medical Centre, Germany

OBJECTIVE:The aim of this study was to investigate the correlation of ictal semiology with localization and/or lateralization by magnetoencephalography (MEG).METHODS:Seven patients from the Neurology Department of the University Hospital Erlangen who underwent resective surgery for frontal lobe epilepsy (FLE) with an Engel 1a outcome were investigated retrospectively. MEG localizations were classified according to five compartments (separate or combined) of the frontal lobe: frontal basal (FB), frontal lateral (FL), frontal polar (FP), frontal mesial (FM), and frontal precentral (FPr). On the basis of previous studies that investigated the value of ictal semiology in localization and lateralization, we compared the experiential localization and/or lateralization of the epileptogenic region deduced from ictal semiology, that is, both seizure history and ictal video/EEG monitoring, with MEG localization.RESULTS:It is easier to determine lateralization than localization from ictal semiology because of the variety of signs and fast propagation in FLE. All of the patients had specific MEG localizations according to favorable postoperative outcome. Three patients had MEG foci associated with ictal semiology; in another four, the MEG localization was adjacent to the estimated area suggested by ictal semiology. Head version signs could be observed in all compartments of the frontal lobe: clonic in FB and FP areas; postural in FPr, FL, and FM areas; hypermotor in FB, FP, FPr, and FM areas; sensation aura in FB, FL, and FM areas; and automatisms in FP, FPr, and FL areas. All patients had concordant lateralizing and limited valuable locating information from ictal semiology, but no complete correlation with MEG foci.CONCLUSION:Ictal semiology may indicate the involvement of a symptomatogenic brain region during a seizure, but extent of seizure onset in central motor or sensorimotor area is not reliable enough to indicate the seizure onset zone and favorable postoperative outcome in FLE. MEG provided specific localization of epileptic activity in a FLE compartment, and indicated the relationship between epileptogenic region and lesion. MEG can complement ictal semiology in establishing a noninvasive focal localization hypothesis.

PURPOSE:This study aimed to analyze magnetoencephalography (MEG) localizations of epileptic clusters in different cortical regions of the frontal lobe and relate these findings to postoperative outcomes associated with frontal lobe epilepsy (FLE). METHODS:Thirty-nine patients from the Epilepsy Center of Erlangen-Nuremberg University with or without lesions on their magnetic resonance imaging (MRI) scans underwent MEG measurements and operation and were then analyzed retrospectively. MEG data were obtained using systems with either 74 or 248 channels. Single dipole analysis assuming a spherical head model was performed for localization. KEY FINDINGS:Epileptic clusters were detected by MEG in 30 patients, corresponding to a sensitivity of 76.9%; there was a sensitivity of 66.7% (20 of 30) in patients with monofocal activity (70% had an Engel class 1 outcome) and 33.3% (10 of 30) in patients with multifocal activity (20% had an Engel class 1 outcome). Of the patients who had isolated clusters, the distance between the MEG localizations and the respective lesions was equal to or <3 cm in 90% (18 of 20) of patients (13 of them had an Engel class 1 outcome) and >3 cm in 10% (2 of 20) of patients (one of them had an Engel class 1 outcome). A statistical difference was found between the outcomes of patients with a single focus and with multiple foci (p < 0.05). SIGNIFICANCE:Patients with a single focus had better postoperative outcomes compared with patients with multiple foci. MEG localizations close to the lesion marked the lesion or its surrounding network as epileptogenic. Therefore, source localization can provide important information for the presurgical evaluation of patients with FLE.

In patients with pharmacoresistant focal epilepsy,we demonstrate that magnetoencephalography (MEG) detects spike-locked and spike-independent epileptic high gamma oscillations (HGOs) using combined MEG and invasive electroencephalography (iEEG) from subdural macroelectrodes. Six patients, who underwent presurgical workup for epilepsy surgery with preoperative simultaneous MEG and subdural iEEG recordings,were investigated. HGOs in iEEG were detected automatically and served as triggers for averaging and localization of simultaneous MEG data. iEEG-HGOs were detected in all patients and MEG-HGOs in five patients. HGOs were highly associated with epileptic networks and correctly identified seizure-onset zones in five (MEG) and six patients (iEEG). Minimum-norm source analysis of MEG data yielded concordant localizations. Noninvasive analysis of HGOs may allow investigation of epileptic networks independent of spikes and seizures. Determination of sensitivity and specificity, as well as development of MEG-HGO analysis without the need of iEEG should be addressed in a larger study.

Purpose:  Long‐term epilepsy associated tumors (LEATs) are a frequent cause of drug‐resistant partial epilepsy. A reliable tumor diagnosis has an important impact on therapeutic strategies and prognosis in patients with epilepsy, but often is difficult by magnetic resonance imaging (MRI) only. Herein we analyzed a large LEAT cohort investigated by 18fluoroethyl‐l‐tyrosine–positron emission tomography (FET‐PET).

The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we assessed the neurogenic potential in the human hippocampal dentate gyrus by isolating adult human neural stem cells from 23 surgical en bloc hippocampus resections. After proliferation of the progenitor cell pool in vitro we identified two distinct patterns. Adult human neural stem cells with a high proliferation capacity were obtained in 11 patients. Most of the cells in the high proliferation capacity cultures were capable of neuronal differentiation (53 ± 13% of in vitro cell population). A low proliferation capacity was observed in 12 specimens, and only few cells differentiated into neurons (4 ± 2%). This was reflected by reduced numbers of proliferating cells in vivo as well as granule cells immunoreactive for doublecortin, brain-derived neurotrophic factor and cyclin-dependent kinase 5 in the low proliferation capacity group. High and low proliferation capacity groups differed dramatically in declarative memory tasks. Patients with high proliferation capacity stem cells had a normal memory performance prior to epilepsy surgery, while patients with low proliferation capacity stem cells showed severe learning and memory impairment. Histopathological examination revealed a highly significant correlation between granule cell loss in the dentate gyrus and the same patient's regenerative capacity in vitro (r = 0.813; P < 0.001; linear regression: R²(adjusted) = 0.635), as well as the same patient's ability to store and recall new memories (r = 0.966; P = 0.001; linear regression: R²(adjusted) = 0.9). Our results suggest that encoding new memories is related to the regenerative capacity of the hippocampus in the human brain.

Visual field deficits due to optic radiation injury are a common complication of temporal lobectomy in epilepsy surgery. In this prospective study, diffusion tensor imaging (DTI) based fiber tracking was performed on 48 patients who had temporal lobectomy for pharmaco-resistant epilepsy. Pre- and intra-operative DTI based fiber tracking was used to visualize the optic radiation and to predict the post-operative visual field defects. The course of the optic radiation could be successfully reconstructed by DTI based fiber tracking. There was a significant correlation between the fiber tracking estimation and the outcome of visual field deficits after surgery. The Receiver Operating Characteristic (ROC) curve analysis confirmed the accuracy and validity of prediction of the post-operative visual field deficits comparing pre- and intra-operative fiber tracking results. Intra-operative visualization of the optic radiation may help in avoiding post-operative visual field deficits.

The dentate gyrus (DG) plays a pivotal role in the functional and anatomical organization of the hippocampus and is involved in learning and memory formation. However, the impact of structural DG abnormalities, i.e., granule cell dispersion (GCD), for hippocampal seizure susceptibility and its association with distinct lesion patterns in epileptic disorders, such as mesial temporal sclerosis (MTS) remains enigmatic and a large spectrum of pathological changes has been recognized. Here, we propose a clinico-pathological classification of DG pathology based on the examination of 96 surgically resected hippocampal specimens obtained from patients with chronic temporal lobe epilepsy (TLE). We observed three different histological patterns. (1) A normal granule cell layer was identified in 11 patients (no-GCP; 18.7%). (2) Substantial granule cell loss was evident in 36 patients (referred to as granule cell pathology (GCP) Type 1; 37.5%). (3) Architectural abnormalities were observed in 49 specimens, including one or more of the following features: granule cell dispersion, ectopic neurons or clusters of neurons in the molecular layer, or bi-lamination (GCP Type 2; 51%). Cell loss was always encountered in this latter cohort. Seventy-eight patients of our present series suffered from MTS (81.3%). Intriguingly, all MTS patients displayed a compromised DG, 31 (40%) with significant cell loss (Type 1) and 47 (60%) with GCD (Type 2). In 18 patients without MTS (18.7%), seven displayed focally restricted DG abnormalities, either cell loss (n = 5) or GCD (n = 2). Clinical histories revealed a significant association between DG pathology patterns and higher age at epilepsy surgery (p = 0.008), longer epilepsy duration (p = 0.004), but also with learning dysfunction (p < 0.05). There was no correlation with the extent of pyramidal cell loss in adjacent hippocampal segments nor with postsurgical seizure relief. The association with long-term seizure histories and cognitive dysfunction is remarkable and may point to a compromised regenerative capacity of the DG in this cohort of TLE patients.

Objectives: To localize overlooked tumor remnants by updating navigation with intraoperative magnetic resonance imaging compensating for the effects of brain shift. Methods: In 112 patients among 805 patients that were investigated by combined use of intraoperative high-field (1.5 T) magnetic resonance imaging and navigation, mostly glioma cases (n = 85), an update of the navigation was performed. Intraoperative image data were rigidly registered with the preoperative image data, the tumor remnant was segmented, and then the initial patient registration was restored so that the registration coordinate system of the preoperative image data was applied on the intraoperative images, allowing navigation updating without intraoperative patient re-registration. Results: Navigation could be updated reliably in all cases. Potential positional shifting impairing the initial update strategy was observed only in 2 cases so that a patient re-registration was necessary. The target registration error of the initial patient registration was 1.33 ± 0.63 mm, and registration of preoperative and intraoperative images could be performed with high accuracy, as proven by landmark checks. Updating of navigation resulted in increased resections or correction of a catheter position or biopsy sampling site in 94%. In the remaining 7 patients, the intraoperative images were used for correlation with the surgical site but without changing the surgical strategy. Conclusions: Navigation can be reliably updated with intraoperative image data without repeated patient registration, facilitating the update procedure. Updated navigation allows achieving enlarged resections and compensates for the effects of brain shift.

Mesial temporal sclerosis (MTS) is the most common lesion in chronic, intractable temporal lobe epilepsies (TLE) and characterized by segmental neuronal cell loss in major hippocampal segments. Another histopathological hallmark includes granule cell dispersion (GCD), an architectural disturbance of the dentate gyrus encountered in approximately 50% of patients with mesial temporal sclerosis. Reelin, which plays a key role during hippocampal development and maintenance of laminar organization, is synthesized and released by Cajal-Retzius cells of the dentate molecular layer, and previous studies have shown that Reelin transcript levels are downregulated in human temporal lobe epilepsies specimens. To investigate whether epigenetic silencing by Reelin promoter methylation may be an underlying pathogenetic mechanism of GCD, DNA was harvested from 3 microdissected hippocampal subregions (i.e. molecular and granule cell layers of the dentate gyrus and presubiculum) from 8 MTS specimens with GCD, 5 TLE samples without GCD, and 3 autopsy controls. Promoter methylation was analyzed after bisulfite treatment, cloning, and direct sequencing; immunohistochemistry was performed to identify Cajal-Retzius cells. Reelin promoter methylation was found to be greater in TLE specimens than in controls; promoter methylation correlated with GCD among TLE specimens (p < 0.0002). No other clinical or histopathological parameter (i.e. sex, age, seizure duration, medication or extent, of MTS) correlated with promoter methylation. These data support a compromised Reelin-signaling pathway and identify promoter methylation as an epigenetic mechanism in the pathogenesis of TLE.

Background: Surgical treatment of brainstem cavernous angioma involving eloquent fiber tracts is one of the most challenging areas of contemporary neurosurgery. Diffusion tensor imaging-based fiber tracking adds essential information for preoperative planning in neurosurgical practice. Integration of the tractography into neuronavigation system makes it possible for the intraciperative visualization of the major fiber tracts. It may help increase the likelihood of the total resection of tumors adjacent to the eloquent fiber tracts and avoid new neurologic deficits after surgery.Case Description: We report our valuable experience of such integration for the resection of a deeply located brainstern cavernous angioma.Conclusion: Inclusion of tractography in standard imaging protocols for neuronavigation systems can provide important information regarding neural tracts for the planning of brainstern surgery. It can also increase the safety of neurosurgical intervention near white matter tracts in the brainstem. (c) 2007 Elsevier Inc. All rights reserved.

Small nonfunctioning pituitary (micro)adenomas are encountered frequently as incidental findings. Large (macro)adenomas present with visual compromise, hypopituitarism or headache. Indications for surgery include loss of vision, diplopia, other symptoms of a space occupying intracranial lesion and documented tumor progression during serial imaging. Their primary treatment is surgical resection. To exclude medical treatment options, a preoperative endocrinological investigation is mandatory. To date, more than 90% of operations in patients with nonfunctioning pituitary adenomas are performed via the transsphenoidal route. There are several variations of transnasal surgery available, with and without dissection of the nasal septum. Only tumors where the predominant mass lesion is essentially located outside the sella require transcranial operations. These are usually performed via a frontotemporal or frontolateral craniotomy. Surgical decompression of visual pathways is usually followed by a rapid improvement of vision. Whether or not the tumor mass can be completely resected depends on the size and localization of the adenoma and the surgical expertise. Several patients experience an improvement of pituitary function. Potential complications of surgery include loss of vision, vascular injury, cerebrospinal fluid fistula, meningitis and hypopituitarism. Modern technical developments, such as the use of the endoscope, intraoperative magnetic resonance imaging and neuronavigation, are being increasingly appreciated by neurosurgeons throughout the world.

To visualize the course of the pyramidal tract in the surgical field during glioma resection by implementation of fiber tract navigation supported by intraoperative imaging. In 57 patients with glioma (25 female; 32 male; World Health Organization Grade I, three patients; Grade II, 11 patients; Grade III, 22 patients; Grade IV, 21 patients), a three-dimensional (3-D) object representing the pyramidal tract was visualized in the surgical field. The fiber tract seeding was based on a multiple volume of interest approach, and functional magnetic resonance imaging data identified the motor gyrus as a major start region. A tensor deflection algorithm was used for tracking. The minimum distance between pyramidal tract and glioma was measured in 3-D. Hulls wrapping the fiber tract bundle visualized safety margins. Intraoperative high-field magnetic resonance imaging scans were used to update the fiber tract data, compensating for the effects of brain shift. In all patients, the pyramidal...