Christian Rainer Wirtz

Intraoperative diagnostic and interventional magnetic resonance imaging in neurosurgery

OBJECTIVE The benefits of intraoperative magnetic resonance (MR) imaging for diagnostic and therapeutic measures are as follows: 1) intraoperative update of data sets for navigational systems, 2) intraoperative resection control of brain tumors, and 3) frameless and frame-based on-line MR-guided interventions. The concept of an intraoperative MR scanner in the sterile environment of operating theater is presented, and its advantages, disadvantages, and limitations are discussed. METHODS A 0.2-tesla magnet (Magnetom Open; Siemens AG, Erlangen, Germany) inside a radiofrequency cabin with a radiofrequency-shielded sliding door was installed adjacent to one of the operating theaters. A specially designed patient transport system carried the patient in a fixed position on an air cushion to the scanner and back to the surgeon. RESULTS In a series of 27 patients, intraoperative resection control was performed in 13 cases, with intraoperative reregistration in 4 cases. Biopsies, cyst aspirations, and catheter placements (mainly frameless) were performed under direct MR visualization with fast image sequences. The MR-compatible equipment and the patient transport system are safe and reliable. CONCLUSION Intraoperative MR imaging is a safe and successful tool for surgical resection control and is clearly superior to computed tomography. Intraoperative acquisition of data sets eliminates the problem of brain shift in conventional navigational systems. Finally, on-line MR-guided interventional procedures can be performed easily with this setting. As with all MR systems, individual testing with phantoms, application of correction programs, and determination of the optimal amount of contrast media are absolute prerequisites to guarantee patient safety and surgical success.

Clinical evaluation and follow-up results for intraoperative magnetic resonance imaging in neurosurgery.

OBJECTIVE The use of intraoperative magnetic resonance imaging (MRI) in neurosurgery has increased rapidly, and a variety of concepts have recently been presented. Although the feasibility of the procedure has been demonstrated repeatedly, no conclusive analysis of its effects on the surgical procedures, the extent of tumor removal, and outcomes, or its possible problems, has been performed. METHODS Of 242 operations performed with intraoperative MRI, 97 procedures for supratentorial glioma treatment were analyzed with respect to intraoperative imaging results and postoperative outcomes. Analysis of the images included assessment of imaging artifacts, image quality, and extent of tumor removal. Patients were monitored to determine radiological progression, survival times, postoperative complications, and morbidity rates. RESULTS No intraoperative complications related to the imaging procedure were observed. Image quality was good or fair in 85.5% of the cases. Different types of surgically induced imaging changes could be identified. In 56 cases, resection was continued using navigation with intraoperative MRI data sets (rereferencing accuracy, 0.9 mm). For high-grade gliomas, the percentage of cases in which residual tumor was identified by MRI could be significantly reduced from 62% intraoperatively to 33% postoperatively, which was paralleled by a significant increase in survival times for patients without residual tumor. Complication and morbidity rates were within the ranges reported for other studies. CONCLUSION Intraoperative MRI is safe and allows reliable updating of neuronavigational data, with compensation for brain shifting. Surgically induced imaging changes, which have been identified as a possible problem with intraoperative MRI in general, necessitated comparisons with preoperative scans and require future attention. The extent of tumor removal and survival times were increased significantly. Overall, patients seemed to benefit from the method.

A deformable digital brain atlas system according to Talairach and Tournoux

Brain atlases are valuable tools which assist neurosurgeons during the planning of an intervention. Since a printed atlas book has several disadvantages-among them the difficulty to map the information onto a patients individual anatomy-we have developed a digital version of the well-established stereotaxic brain atlas of Talairach and Tournoux. Our atlas system is mainly dedicated to assist neurosurgical planning, and its benefits are: (i) a three-dimensional (3D) representation of most brain structures contained in the Talairach atlas; (ii) a nonrigid matching capability which warps the standard atlas anatomy to an individual brain magnetic resonance imaging (MRI) dataset in a few minutes and which is able to take deformations due to tumors into account; (iii) the integration of several sources of neuroanatomical knowledge; (iv) an interface to a navigation system which allows utilization of atlas information intraoperatively. In this paper we outline the algorithm we have developed to achieve 3D surface models of the brain structures. Moreover, we describe the nonrigid matching method which consists of two tasks: firstly, point correspondences between the atlas and the patient are established in an automatic fashion, and secondly these displacement vectors are interpolated using a radial basis function approach to form a continuous transformation function. To generate appropriate target structures for the first of these tasks, we implemented a quick segmentation tool which is capable to segment the cortex and ventricles in less than 5 min. An evaluation shows that our nonrigid approach is more precise than the conventional piecewise linear matching, though it should be further improved for the region around the deep grey nuclei. Summarizing, we developed a Win32 program which permits the convenient and fast application of standardized anatomy to individual brains which potentially contain tumors.

Long-term outcome and survival of surgically treated supratentorial low-grade glioma in adult patients

PurposeThe appropriate management of low-grade gliomas is still a matter of debate. So far, there are no randomized studies that analyze the impact of surgical resection on patient outcome. The value of the data obtained from the few retrospective reports available is often limited.Patients and methodsIn the present study, we performed an analysis on data of 130 adult low-grade glioma patients. Extent of the resection was evaluated in correlation to the overall survival (OS) and progression-free survival (PFS) using Cox regression multivariate analysis.ResultsExtended surgery was shown to prolong OS and PFS significantly. Re-surgery in the case of a tumor relapse has a significant impact on OS and PFS, too.ConclusionsIn summary, we could retrospectively evaluate a large case series of well-defined low-grade gliomas patients with a long follow-up period showing that extended surgery would be the most effective therapy for low-grade glioma patients even in recurrent diseases.PURPOSE The appropriate management of low-grade gliomas is still a matter of debate. So far, there are no randomized studies that analyze the impact of surgical resection on patient outcome. The value of the data obtained from the few retrospective reports available is often limited. PATIENTS AND METHODS In the present study, we performed an analysis on data of 130 adult low-grade glioma patients. Extent of the resection was evaluated in correlation to the overall survival (OS) and progression-free survival (PFS) using Cox regression multivariate analysis. RESULTS Extended surgery was shown to prolong OS and PFS significantly. Re-surgery in the case of a tumor relapse has a significant impact on OS and PFS, too. CONCLUSIONS In summary, we could retrospectively evaluate a large case series of well-defined low-grade gliomas patients with a long follow-up period showing that extended surgery would be the most effective therapy for low-grade glioma patients even in recurrent diseases.

Bortezomib primes glioblastoma including glioblastoma stem cells for TRAIL by increasing tBid stability and mitochondrial apoptosis

Purpose: Searching for novel approaches to sensitize glioblastoma for cell death, we investigated the proteasome inhibitor bortezomib. Experimental Design: The effect of bortezomib on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)–induced apoptosis signaling pathways was analyzed in glioblastoma cell lines, primary glioblastoma cultures, and in an in vivo model. Results: Bortezomib and TRAIL synergistically trigger cell death and reduce colony formation of glioblastoma cells (combination index < 0.1). Investigations into the underlying molecular mechanisms reveal that bortezomib and TRAIL act in concert to cause accumulation of tBid, the active cleavage product of Bid. Also, the stability of TRAIL-derived tBid markedly increases on proteasome inhibition. Notably, knockdown of Bid significantly decreases bortezomib- and TRAIL-mediated cell death. By comparison, silencing of Noxa, which is also upregulated by bortezomib, does not confer protection. Coinciding with tBid accumulation, the activation of Bax/Bak and loss of mitochondrial membrane potential are strongly increased in cotreated cells. Overexpression of Bcl-2 significantly reduces mitochondrial perturbations and cell death, underscoring the functional relevance of the mitochondrial pathway. In addition, bortezomib cooperates with TRAIL to reduce colony formation of glioblastoma cells, showing an effect on long-term survival. Of note, bortezomib profoundly enhances TRAIL-triggered cell death in primary cultured glioblastoma cells and in patient-derived glioblastoma stem cells, underlining the clinical relevance. Importantly, bortezomib cooperates with TRAIL to suppress tumor growth in an in vivo glioblastoma model. Conclusion: These findings provide compelling evidence that the combination of bortezomib and TRAIL presents a promising novel strategy to trigger cell death in glioblastoma, including glioblastoma stem cells, which warrants further investigation. Clin Cancer Res; 17(12); 4019–30. ©2011 AACR.

Initial experience with an ultrasound-integrated single-RACK neuronavigation system.

Summary A prototype ultrasound-integrated neuronavigation system was tested in 34 operations as regards image quality, stability, and handling during daily use in the operating theatre. The system consists of a high-end ultrasound scanner, a navigation computer, and an active optical positioning and digitiser system, all integrated in a single rack. An Ethernet interface between the two hardware devices enables digital data transfer between the ultrasound scanner and the navigation device without loss of image quality. The integration of an ultrasound scanner and a navigation device offers the opportunity of navigating directly to an intracranial or intraspinal lesion using intra-operative 3D ultrasound images. The brainshift problem is thus avoided. The ability to directly compare MR images and 3D ultrasound simplifies the interpretation of ultrasound images. The single-rack solution is an advantage in times of restricted space in the operating theatre caused by the increasing volume of technical equipment needed for a neurosurgical operation. In 30 cases the prototype system showed good reliability. In four cases the navigation system failed during the operation; however, the capacity of the ultrasound scanner was still available as a stand-alone function. With the single-rack concept, the flexibility of the system is high and the complete device can easily be moved from one operating theatre to another.

Low-field interventional MRI in neurosurgery: finding the right dose of contrast medium

Abstract MRI is increasingly being used as an interventional tool in neurosurgery. The field strength of “intraoperative” MR systems is usually lower than that of imagers commonly used for diagnostic purposes. However, lesion enhancement and apparent lesion extent depend on field strength. The aim of this study was to compare the contrast between intracranial, contrast-enhancing space-occupying lesions and the surrounding white matter obtained with low-field (0.2 T) and high-field (1.5 T) MR imaging and to find the contrast medium dosage for low-field MRI that produces the same lesion-to-white-matter contrast as the one obtained with high-field MRI after the administration of a standard dose of the contrast medium. A total of 38 patients with intracranial metastases or high-grade glioma were enrolled in this study. T1-weighted spin-echo sequences were acquired. High-field (1.5 T) studies were performed after the i. v. administration of 0.1 mmol gadolinium-DTPA /kg body weight. For low-field MRI (0.2 T) a dose escalation technique was used. T1-weighted sequences were repeated after each of three i. v. injections of 0.1 mmol gadolinium-DTPA/kg body weight. Thus, at the low-field examinations three T1-weighted sequences with a contrast medium dosage of 0.1, 0.2 and 0.3 mmol gadolinium-DTPA /kg body weight were obtained. Lesion-to-white-matter contrasts were calculated and compared. The average lesion-to-white-matter contrast obtained with high-field MR examinations was 1.63 (standard deviation 0.32). In the low-field MR examinations the average lesion-to-white-matter contrast was 1.34 (0.2) after a single dose, 1.57 (0.2) after a double dose, and 1.71 (.19) after a triple dose of contrast medium. The lesion-to-white-matter contrast of the high-field MR examination after a single dose of contrast medium was significantly higher than that of the low-field study after a single dose (P < 0.0001), but did not differ significantly from the low-field studies after a double (P = 0.28) or a triple dose (P = 0.17) of contrast medium. In a series of patients with contrast-enhancing space occupying brain lesions low-field MRI (0.2 T) after a double dose of contrast medium yielded the same lesion-to-white-matter contrasts as high-field MRI (1.5 T) after a standard dose. This is an important finding to avoid errors in intraoperative MRI due to the immanently lower degree of lesion enhancement in low-field MR imaging.

Surgery for Glioblastoma: Impact of the Combined Use of 5-Aminolevulinic Acid and Intraoperative MRI on Extent of Resection and Survival.

Background There is rising evidence that in glioblastoma(GBM) surgery an increase of extent of resection(EoR) leads to an increase of patient’s survival. Based on histopathological assessments tumor depiction of Gd-DTPA enhancement and 5-aminolevulinic-acid-fluorescence(5-ALA) might be synergistic for intraoperative resection control. Objective To assess impact of additional use of 5-ALA in intraoperative MRI(iMRI) assisted surgery of GBMs on extent of resection(EoR), progression free survival(PFS) and overall survival(OS). Methods We prospectively enrolled 33 patients with GBMs eligible for gross-total-resection(GTR) and performed a combined approach using 5-ALA and iMRI. As a control group, we performed a retrospective matched pair assessment, based on 144 patients with iMRI-assisted surgery. Matching criteria were, MGMT promotor methylation, recurrent surgery, eloquent location, tumor size and age. Only patients with an intended GTR and primary GBMs were included. We calculated Kaplan Mayer estimates to compare OS and PFS using the Log-Rank-Test. We used the T-test to compare volumetric results of EoR and the Chi-Square-Test to compare new permanent neurological deficits(nPND) and general complications between the two groups. Results Median follow up was 31 months. No significant differences between both groups were found concerning the matching criteria. GTR was achieved significantly more often (p <0.010) using 5-ALA&iMRI (100%) compared to iMRI alone(82%). Mean EoR was significantly(p<0.004) higher in 5-ALA&iMRI-group(99.7%) than in iMRI-alone-group(97.4%) Rate of complications did not differ significantly between groups(21% iMRI-group,27%5-ALA&iMRI-group,p<0.518). nPND were found in 6% in both groups. Median PFS (6mo resp.;p<0.309) and median OS(iMRI:17mo;5-ALA&iMRI-group:18mo;p<0.708)) were not significantly different between both groups. Conclusion We found a significant increase of EoR when combining 5-ALA&iMRI compared to use of iMRI alone. Maximizing EoR did not lead to an increase of complications or neurological deficits if used with neurophysiological monitoring in eloquent lesions. No final conclusion can be drawn whether a further increase of EoR benefits patient’s progression free survival and overall survival.

Inhibition of NF-κB Signaling Ablates the Invasive Phenotype of Glioblastoma

Glioblastoma multiforme, the most common primary brain tumor, is highly refractory to therapy, mainly due to its ability to form micrometastases, which are small clusters or individual cells that rapidly transverse the brain and make full surgical resection impossible. Here, it is demonstrated that the invasive phenotype of glioblastoma multiforme is orchestrated by the transcription factor NF-κB which, via metalloproteinases (MMP), regulates fibronectin processing. Both, cell lines and tumor stem cells from primary glioblastoma multiforme, secrete high levels of fibronectin which when cleaved by MMPs forms an extracellular substrate. Subsequently, forming and interacting with their own microenvironment, glioblastoma multiforme cells are licensed to invade their surroundings. Mechanistic study revealed that NF-κB inhibition, either genetically or pharmacologically, by treatment with Disulfiram, significantly abolished the invasive phenotype in the chick chorioallantoic membrane assay. Furthermore, having delineated the underlying molecular mechanism of glioblastoma multiforme invasion, the potential of a disulfiram-based therapy was revealed in a highly invasive orthotrophic glioblastoma multiforme mouse model. Implications: This study defines a novel therapeutic approach that inhibits micrometastases invasion and reverts lethal glioblastoma into a less aggressive disease. Mol Cancer Res; 11(12); 1611–23. ©2013 AACR.

Intraoperative MRI to control the extent of brain tumor surgery

Purpose: The main aim of our study was to find out whether the combined use of neuronavigation and intraoperative MRI can increase the rate of “complete tumor removal”. The second aim was to characterize the different forms of surgically induced enhancement in order to differentiate them from residual tumor. Materials and methods: Surgery was performed in 18 patients with high-grade glioma. Using a neuronavigation device, the surgeons operated up to the point where they would otherwise have terminated surgery. Intraoperative MRI was then performed to determine whether residual enhancing had been left behind and to update the neuronavigation device. If necessary, feasible surgery was continued. On days 1–3 after surgery early postoperative MRI (1.5 T) was performed. The proportion of patients in whom the enhancing tumor was completely removed was compared with a series of 60 patients with glioblastoma multiforme, who had been operated on using neither neuronavigation nor intraoperative MRI . We also looked for and characterized different types of surgically induced enhancement. Results: Intraoperative MRI definitely showed residual tumor in 6 of the 18 patients and resulted in ambiguous findings in 3 patients. In 7 patients surgery was continued. Early postoperative MRI showed residual tumor in 3 patients and resulted in uncertain findings in 2 patients. The rate of patients in whom complete removal of enhancing tumor could be achieved was 50 % at the time of the intraoperative MR examination and 72 % at the time of the early postoperative MR control. The difference in proportion of patients with “complete tumor removal” between the groups who had been operated on using neuronavigation (NN) and intraoperative MRI (ioMRI) and those who had been operated on using only modern neurosurgical techniques except NN and ioMRI was statistically highly significant (Fisher exact test; P = 0.008). Four different types of surgically induced contrast enhancement were observed. These phenomena carry different confounding potentials with residual tumor. Conclusion: Our preliminary experience with intraoperative MRI in patients with enhancing intraaxial tumors is encouraging. Combined use of neuronavigation and intraoperative MRI was able to increase the proportion of patients in whom complete removal of the enhancing parts of the tumor was achieved. Surgically induced enhancement requires careful analysis of the intraoperative MRI in order not to confuse it with residual tumor.ZusammenfassungAuch für erfahrene Neurochirurgen ist es außerordentlich schwierig bis unmöglich, intraoperativ die Grenze eines hirneigenen Tumors zu erkennen und entsprechend dieser Grenze eine „Totalentfernung“ des Tumors durchzuführen. Verschiedene Studien zeigten die Unzuverlässigkeit der intraoperativen Einschätzung der Operationsradikalität. Während intraoperative CT-Kontrollen und intraoperative Ultraschallkontrollen bereits seit längerem eingesetzt werden, wurde der Magnetresonanztomographie – der bildgebenden Methode mit der höchsten Weichteilauflösung – dieser Anwendungsbereich erst kürzlich durch die Entwicklung „offener“ MR-Systeme erschlossen. Im Operationstrakt der neurochirurgischen Klinik der Universität Heidelberg wurde ein offener MR-Tomograph installiert, an dem neben Biopsieentnahmen und neurochirurgischen Interventionen auch intraoperative MR-Kontrollen der Operationsradikalität durchgeführt werden. Unsere ersten Erfahrungen deuten darauf hin, daß durch den Einsatz intraoperativer MRT die Operationsradikalität neurochirurgischer Eingriffe gesteigert werden kann. Allerdings war bei allen Patienten durch die chirurgische Manipulation selbst verursachtes Kontrastmittelenhancement nachweisbar, das z. T. Verwechslungspotential mit Resttumor besaß.