The Erlangen Concept of Image-Guided Surgery is based on an installation of a Magnetom-Open (0.2 Tesla) MR-scanner in a "twin OR' combined with two neuronavigation systems. As a novel approach, direct neuronavigation within the magnetic field of the MR scanner is now possible with a newly developed navigation microscope (NC4, Zeiss). This concept offers the advantages of almost instantaneous MR resection control (similar to the GE 0.5 T Signa scanner) and full neuronavigation options, such as implementation of trajectories, tumor borders and functional data. The implementation of functional data of the human cortex into computer-assisted surgery offers the possibility of delineating the borders of tumors or other lesions and eloquent brain areas. Different techniques are available for functional brain imaging, however magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) are mainly used. PET, SPECT or MR-spectroscopy (MRS) are under investigation. Within the Erlangen Concept of Image-Guided Surgery we have performed 380 procedures since 1995. More than 200 patients were operated with intraoperative MR resection control. We have used functional neuro-navigation in more than 80 patients with lesions around the motor and visual cortex as well as in the vicinity of speech related areas. Although the evaluation of the long-term outcome renders only preliminary data about the benefit of this method compared to conventional microsurgery, the postoperative neurological results seem to be more favorable compared to conventional methods alone.

Currently adjuvant chemotherapy for glioblastoma patients can prolong survival time relative to patients who receive only surgery and radiotherapy. Despite these improvements and experimental and clinical efforts the prognosis for glioblastoma patients remains poor. At present, interest is focused on individual prognostic factors influencing patient responses to therapy. Photodynamic therapy may be a promising therapeutic option in the treatment of glioblastoma. In this investigation we examined whether uptake of hypericin (HY), a fluorescent photosensitization agent, by ex vivo glioblastoma cell lines correlates with prognosis of the individual from which the cell lines were derived. Twelve primary human glioma cell cultures were incubated with 20 μmol HY. Fluorescence intensity was measured using fluorescence microscopy. Three patients suffered from an anaplastic astrocytoma, WHO grade III, nine had a glioblastoma, WHO grade IV. In 6/12 patients complete tumour resection was possible. The mean survival time of the six patients in whom complete tumour resection was performed was 26 months, compared with 5 months for those who underwent incomplete resection. Eleven patients received radiation therapy. The five patients who received chemotherapy survived for a mean duration of 26 months, compared with the seven patients who survived for a mean duration of 5 months without chemotherapy. Statistical analysis using a parametric survival model based on the Weibull distribution showed that fluorescence intensity was the variable with the lowest p-value associated with survival (p=0.0225). An increase of 553 arbitrary units of fluorescence intensity is predicted to double survival time. Uptake of HY, a lipophilic molecule, is assumed to be related to low-density lipoprotein (LDL) uptake and metabolism. Cell proliferation is associated with a high turnover of cholesterol and membrane growth, which is related to cholesterol uptake by LDL. In summary, HY uptake by ex vivo glioblastoma cell cultures seems to be positively associated with survival of patients with malignant glioma.

Primary melanocytic tumours of the central nervous system (CNS) form a rare entity which is histologically and clinically distinct from metastatic cutaneous or retinal malignant melanoma. They can be classified into diffuse melanocytosis (diffuse melanosis), malignant melanoma and benign melanocytoma with a small number of intermediate variants. In this paper, 5 cases treated neurosurgically in our department for spinal or cerebral primary CNS malignant melanoma are reported. Primary tumors and further metastases were ruled out. Radiological, histological and clinical features are discussed. Compared to metastatic disease, primary CNS malignant melanoma shows a more benign clinical course with long-term tumour control and a good quality of life. A review of the literature which mainly consists of individual case reports, confirms this assessment. Although therapeutic experience for primary melanocytic lesions of the CNS is based on a small number of published cases, prognosis seems highly dependent on complete tumour resection. Adjuvant radiation seems to be of additional therapeutic benefit. Except for meningeosis melanomatosa chemotherapy must be regarded as experimental. Unfortunately, a standardised therapy concept is still lacking.

Retractors play an important role in surgery, especially using endoscopic techniques like microendoscopic discectomy. As a consequence of the minimally invasive approach the working space is frequently very restricted. All currently available systems still use tubular retractors with limitations regarding flexibility, stability and accessible working space. This paper discusses the technical aspects of a newly designed circular retractor system for endoscopic and microsurgical spinal interventions (SpineGate) and presents first clinical results in a series of 20 consecutive patients. The autoclavable system consists of a circular base plate and several valves varying in length. The variable fixation of the valves from different directions within the 360 degrees geometry of the base plate allows a continuously adjustable working space, depending on the individual anatomy. An additional fixation device is not necessary. The retractor is suitable for microendoscopic and microsurgical techniques. It is easy and safe to handle. The retractor system was successfully used in all cases without complications or instrumental malfunctions. All patients experienced good to excellent relief of their preoperative symptoms.

Die Differenzialdiagnose intrakranieller, extraaxialer Tumoren ist für gewöhnlich limitiert. Liegen sie im Bereich des Kleinhirnbrückenwinkels, sind die Kriterien der verschiedenen Raumforderungen geläufig und stellen den Radiologen in der Regel nicht vor Probleme. Raumforderungen mit Bezug zum Meatus acusticus internus sind typischerweise Schwannome des Nervus vestibularis, die fälschlicherweise auch als Akustikusneurinome bezeichnet werden. Wesentlich seltener als der Nervus vestibulocochlearis ist der Nervus fazialis von Schwannomen betroffen. Aufgrund seines komplexen Verlaufs durch das Felsenbein sind die Wachstumsformen und Lokalisationen der Tumoren heterogen und ungewohnt. Unser Fallbeispiel zeigt einen großen Tumor, der zum weit überwiegenden Teil intrakraniell liegt, jedoch vom Fazialiskanal ausgeht. Diese für die Diagnose entscheidende Tatsache muss durch subtiles Akquirieren und Betrachten der Bilder herausgearbeitet werden. Nur die Kombination aus hochauflösender Felsenbein-Computertomographie (CT) und Magnetresonanztomographie (MRT) ermöglicht dabei eine Eingrenzung der Differenzialdiagnose. Im günstigen Fall kann präoperativ die Diagnose eines Fazialisschwannoms aufgrund seiner charakteristischen Bildgebung gestellt werden.

Background. Endoscopy has developed into an integral part of minimally invasive neurosurgery. For further technological innovations, detailed knowledge about the pathological anatomy is essential. The gross anatomy of the cerebral ventricular system has been meticulously investigated with ventriculography and casts. Extensive volumetric measurements based on neuroradiological images have been performed, but only little is known about the surgically relevant linear distances in patients with hydrocephalus.

BACKGROUND Epileptic foci are often located in the vicinity but not necessarily within the boundaries of intra-axial brain tumors. Resection of these tumors is based on two major goals: first, maximizing tumor removal without provoking new neurologic deficits, and second, minimizing epileptic seizure activity. Magnetic source imaging (MSI) depicts the generators of magnetic fields overlaid on individual magnetic resonance (MR) images. Established application areas are lesions located adjacent to or partly within the sensory and motor cortex, or in the depth of the brain, necessitating a surgical approach through functionally highly relevant cortical regions. Magnetoencephalography (MEG) is also applicable for epileptiform spike foci recording during interictal activity.CASE DESCRIPTION A patient with a recurrent glioma close to the Rolandic cortex scheduled for epilepsy and tumor surgery was investigated with MSI. The MSI data showed an epileptiform spike focus outside the tumor boundaries. The resulting MSI images were integrated into our neuronavigation system. This procedure allowed for the preoperative identification of the sensory and motor cortex, the precise localization of the epileptiform spike focus, and careful planning of the surgical procedure. In this case, we were able to safely resect the recurrent tumor and the epileptiform spike focus under general anesthesia using MSI-based neuronavigational guidance but no conventional intraoperative mapping techniques.CONCLUSION Magnetic source imaging can be a valuable, noninvasive method for planning and performing tumor resections in high-risk brain regions, especially if an epileptiform spike focus has to be localized and included into the resection strategy. (C) 2003 Elsevier Science Inc.

BACKGROUND:For the treatment of medically refractory movement disorders such as Parkinson's disease, essential tremor and primary dystonia, deep brain stimulation (DBS) has become one of the main treatment options. The targets for implantation of the stimulation electrodes are various nuclei within the basal ganglia or the thalamic and subthalamic area. Accurate target localisation is of major importance for outcome and patient safety. The goal of this study was to evaluate the role of image fusion in the determination of target co-ordinates.METHOD:We conducted a retrospective study on 10 patients in whom 17 DBS electrodes had been implanted. Coordinates of the anterior and posterior commissures and of the DBS targets were compared on pre- and postoperative computerised tomography (CT) and fused CT/magnetic resonance scans. The targets as defined on the images were further compared with the targets derived intra-operatively with microelectrode recordings (MER) and macrostimulation.FINDINGS:The achievable mean target accuracy was of the order of the diameter of the DBS electrode and of the accuracy of the image fusion algorithm, i.e. about 1 mm. However, the maximal differences were between 1.8 mm and 3.2 mm.INTERPRETATION:Image fusion is a helpful tool for accurate determination of target point co-ordinates in DBS. In combination with intraoperative, electrophysiological recordings and stimulation which are still considered to be the most reliable localisation methods, image fusion may help to discern the anatomical and functional three-dimensionality of the target nuclei. Image fusion may reduce the number of trajectories needed for intraoperative electrophysiological determination of the optimal electrode localisation and thus lower the risk of complications.

Two adults presented with hydrocephalus due to idiopathic obstruction of the bilateral foramina of Monro, manifesting as clinical signs of chronically elevated intracranial pressure. No inflammation was present. The primary surgical treatment was neuroendoscopic reconstruction of the right foramen of Monro. A 37-year-old man had a spontaneous perforation of the septum pellucidum. The patient required a ventriculoperitoneal shunt, although postoperative ventriculography proved free passage of cerebrospinal fluid from the lateral ventricle into the third ventricle. A 62-year-old man underwent additional septostomy and third ventriculostomy, and the neuroendoscopic intervention relieved the presenting symptoms without additional treatment. The biopsy specimens showed no evidence of malignancy in either case. Neuroendoscopic intervention is an alternative treatment in the management of hydrocephalus due to idiopathic obstruction of the foramen of Monro. The procedure is less invasive than open microsurgical reconstruction and can even avoid ventriculoperitoneal or ventriculoatrial shunting.

Two cases of subdural hygroma occurred in a series of 77 neuroendoscopic procedures. An 8-year-old boy underwent neuroendoscopic cysto-cisternostomy of a left temporal arachnoid cyst. Routine postoperative magnetic resonance imaging 7 days later showed a large left-sided subdural hygroma without clinical symptoms. During the following 3 months, the subdural hygroma did not resolve spontaneously, so it was drained through a burr hole. A 3-month-old boy with aqueductal stenosis developed bilateral subdural hygromas after third ventriculostomy. Several punctures through the open anterior fontanelle relieved the hygromas but increasing head circumference required ventriculoperitoneal shunting 12 months later. Complications of neuroendoscopic procedures are increasingly reported, including various kinds of bleeding, infections, or damage of neuronal tissue. Only three previous cases of subdural hygroma or hematoma after neuroendoscopic interventions have been reported. The possible etiologies and clinical consequences of this rare complication have to be considered before selecting neuroendoscopy treatment.

Objective: Based on 2 casuistics, the intraoperative qualities of a new, non-adhesive liquid embolic agent (Onyx, Micro Therapeutics, Inc., Irvine, CA, USA) are to be compared to those of n-butyl 2-cyanoacrylate (NBCA) with regard to the histopathological results after preoperative embolization of a cerebral arteriovenous malformation (AVM). Patients and methods: In a case example, the intraoperative quality of the nidus after embolization of a parieto-occipital AVM with Onyx -a new, non-adhesive liquid embolic agent - consisting of ethylene-vinyl alcohol copolymer (EVOH), dimethyl sulfoxide (DMSO) and tantalum, is described. In the second patient, embolization of a frontal high-flow AVM was performed with NBCA. Both patients underwent surgery with complete resection of the AVM. Results: From a neurosurgical point of view, Onyx is suitable for preoperative embolization of AVMs, because the nidus intraoperatively remains elastic and formable and can be dissected from the surrounding brain tissue quite well by microsurgical technique. Inflammatory reactions can be found mainly in the lumina of the vessels. Conclusions: Onyx promises to be an embolic agent well suitable for subsequent neurosurgical resection. Further studies considering various intervals of time between embolization and resection as well as histopathological and electron microscopical examinations are necessary for evaluation of our first experience with this new embolization agent.

The primary sensory cortex has usually been regarded as a necessary step in the information processing stream leading to conscious awareness. Recently, it has been proposed that that higher order associative areas rather than the primary sensory areas are the neural basis of conscious perception. In two patients with tumors near the central region we recorded magnetic somatosensory evoked fields. Magnetic source imaging revealed early (40 ms) neural activation in primary somatosensory cortex and absence of later (>60 ms) neural activation in the primary and associative areas in these patients. None of the patients showed conscious awareness of somatosensory stimuli applied to the corresponding body site although the first component of the evoked field was within normal limits. The time course of the magnetic responses and additional evidence on intensity ratings of somatosensory stimuli suggest that early activity in the primary somatosensory cortex is not sufficient for conscious experience to emerge.

Human central nervous system tumors and glioma cell lines highly express the insulin-like growth factor-binding protein (IGFBP)-2. As IGFBP-2 can affect tumor growth, we studied the relationship between IGFBP-2 expression and the malignancy of brain tumors in vivo. To do so, we investigated by immunohistochemistry the accumulation of IGFBP-1, -2, and -3 in 50 human gliomas classified by the WHO Malignancy Scale. Double labeling using anti-CD68 (monocytes/macrophages), antiglial fibrillary acidic protein, and anti-CD3 (T cells) antibodies was performed to further characterize the IGFBP-1, -2, and -3(+) cells. The expression of IGFBP messenger RNAs (mRNAs) was tested by RT-PCR in tumor samples from nine gliomas of different grades and in eight cell lines representing the cellular composition of human glioma. As controls, the accumulation of IGFBP-2 was investigated in normal brain and in the rat C6 glioblastoma model. IGFBP-1 and -3 accumulated in endothelial and macrophage/microglial cells. IGFBP-2(+) macrophage/microglial and glioma cells clustered in the immediate vicinity of focal necrosis of the human gliomas as well as of the rat C6 glioblastoma. The labeling score of IGFBP-1 accumulation in endothelial cells correlated negatively (P: = 0.0229), and that of IGFBP-2 accumulation in glioma cells correlated positively (P: < 0.0006) with the tumor grade of the gliomas. In addition, RT-PCR analysis confirmed mRNA expression of IGFBP-1, -2, and -3 by the gliomas and glial cells. Small amounts of IGFBP-1 and -3 mRNA, but high amounts of IGFBP-2 mRNA, were detectable in macrophage-like and glioma cell lines. The results suggest cell type-specific accumulation of IGFBP-1, -2, and -3 in human glial tumors of the brain. The increase in IGFBP-2 expression with this malignancy suggests a role of IGFBP-2 in the biology of human gliomas.

Complete resection of a cerebral arteriovenous malformation (AVM) should eliminate the future risk of an associated intracranial bleeding. Because total removal of an AVM may be difficult to assess at the time of surgery, postoperative angiography has become the accepted standard for documenting that complete removal has been achieved. However, even angiographically confirmed excision of an AVM does not completely exclude the possibility of rebleeding. Regrowth of an AVM with subsequent haemorrhage has been documented in children and is attributed to forces acting on the immature vasculature. The authors report the case of a 21-year-old man whose AVM recurred 5 years after angiographically proven complete excision. According to the presented case, the authors emphasise that, even in adults, angiographic documentation of total removal does not always eliminate the risk of reformation of an AVM.

Proton magnetic resonance (MR) spectroscopy was evaluated for the differentiation of brain abscesses and cystic brain tumors. Proton MR spectroscopy was performed in vivo in two patients with brain abscess and eight patients with various cystic brain tumors (anaplastic astrocytoma, glioblastoma, and metastatic brain tumor). MR imaging with contrast medium demonstrated ring-like enhanced mass lesions in all patients. The various resonance peaks in proton MR spectra were assigned to metabolites according to chemical shifts. Treatment of the cystic brain lesions was based on the information from proton MR spectroscopy. Aspirated pus from one patient with brain abscess was examined using ex vivo proton MR spectroscopy. The in vivo spectra of brain abscess contained resonance peaks attributed to acetate, lactate, alanine, amino acids, and lipids in both cases, and an additional peak of succinate in one case. In vivo spectra of the neoplasms contained resonance peaks corresponding to lactate, lipids, choline, creatine, and N-acetyl aspartate. Proton MR spectroscopy is useful for discriminating brain abscess from cystic tumors with similar neuroimaging appearance, which is very important for determining the treatment strategy.

Parallel to the introduction of a minimally invasive method in a department, a documentation system should be introduced for quality management. The first step of quality management of an innovation is quality planning. During the course of patients being treated neuroendoscopically, the pre- and postoperative imaging, the intraoperative video recording, the patient-relevant files and the data of the planning have to be documented. These amounts of data require a multimedial documentation concept. We found the CD-ROM as an optimal documentation media because the discs are both cheap and easily accessible and once stored extremely robust against external influences. Therefore, every neuroendoscopically treated patient is documented with all relevant pictures, files and video sequences on a single CD-ROM.

The aim of the study was to characterize the interendothelial junctions in tumor microvessels of five cases of human glioblastoma multiforme. In addition to morphological analysis, tumors were screened for the expression of junctional proteins, such as occludin, claudin-1, ZO-1 and catenins. The expression of the tight junction protein claudin-1 was lost in the majority of tumor microvessels, whereas claudin-5 and occludin were significantly down-regulated only in hyperplastic vessels. As shown by freeze-fracture analysis, under the conditions of tumor growth tight junction particles of endothelial cells were almost exclusively associated with the exocytoplasmic fracture face, providing evidence for a switch of the particles from the protoplasmic to the external leaflet of the endothelial membrane. These results suggest a relationship between claudin-1 suppression and the alteration of tight junction morphology, which is likely to correlate with the increase of endothelial permeability. Underlining the undifferentiated state of tumor microvessels, plakoglobin, a crucial protein for mature endothelial junctions, was not detectable in most microvessels, whereas β-catenin was abundantly labeled. In this context, it is of particular interest that the majority of microvascular pericytes were negative for alpha-smooth muscle actin, which is a marker of differentiated pericytes, although pericytes were frequently found in electron micrographs. In conclusion, the data suggest that the increase in microvascular permeability in human gliomas, contributing to the clinically severe symptoms of brain edema, is a result of a dysregulation of junctional proteins.

Cyclooxygenases (COX, prostaglandin endoperoxide synthases, PGG/H synthases) are potent mediators of edema, impeding blood flow and immunomodulation in the pathologically altered brain. Two COX iso-enzymes have been associated with brain disease, the constitutively expressed COX-1 and the cytokine-inducible COX-2. We have used single and double labeling immunohistochemistry to analyse COX-1 and COX-2 expression in twenty-six primary WHO grade II oligodendrogliomas, sixteen primary WHO grade III anaplastic oligodendrogliomas, twenty-seven matched recurrences and ten neuropathologically unaltered brains. COX-1 immunoreactivity was predominantly observed in macrophages/microglial cells. The number of COX-1 expressing macrophages/microglial cells was significantly lower in primary oligodendrogliomas than in primary anaplastic oligodendrogliomas (P<0.0001) and in anaplastic oligodendroglioma relapses (P=0.011). Patients with low COX-1 labeling scores in the primary tumors had significantly longer time to progression and overall survival (P=0.0285) than those with high COX-1 labeling scores. COX-2 immunoreactivity was predominantly observed in disseminated neurons and astrocytes. In glioblastoma multiforme relapses, accumulation of COX-2 expressing astrocytes was observed surrounding areas of focal necrosis. The number of COX-2 expressing astrocytes was significantly (P=0.0471) lower in primary oligodendrogliomas than in high grade oligodendroglioma relapses. These data provide convincing evidence for the differential accumulation of cyclooxygenase isoforms during oligodendroglioma progression in vivo.

ABSTRACT The gene encoding a thermoactive pullulanase from the hyperthermophilic anaerobic archaeon Desulfurococcus mucosus ( apuA ) was cloned in Escherichia coli and sequenced. apuA from D. mucosus showed 45.4% pairwise amino acid identity with the pullulanase from Thermococcus aggregans and contained the four regions conserved among all amylolytic enzymes. apuA encodes a protein of 686 amino acids with a 28-residue signal peptide and has a predicted mass of 74 kDa after signal cleavage. The apuA gene was then expressed in Bacillus subtilis and secreted into the culture fluid. This is one of the first reports on the successful expression and purification of an archaeal amylopullulanase in a Bacillus strain. The purified recombinant enzyme (rapuDm) is composed of two subunits, each having an estimated molecular mass of 66 kDa. Optimal activity was measured at 85°C within a broad pH range from 3.5 to 8.5, with an optimum at pH 5.0. Divalent cations have no influence on the stability or activity of the enzyme. RapuDm was stable at 80°C for 4 h and exhibited a half-life of 50 min at 85°C. By high-pressure liquid chromatography analysis it was observed that rapuDm hydrolyzed α-1,6 glycosidic linkages of pullulan, producing maltotriose, and also α-1,4 glycosidic linkages in starch, amylose, amylopectin, and cyclodextrins, with maltotriose and maltose as the main products. Since the thermoactive pullulanases known so far from Archaea are not active on cyclodextrins and are in fact inhibited by these cyclic oligosaccharides, the enzyme from D. mucosus should be considered an archaeal pullulanase type II with a wider substrate specificity.