Search Results

You are looking at 1 - 10 of 15 items for

  • Author or Editor: Georg Widhalm x
Clear All Modify Search
Full access

Yasir A. Syed, Alexandra S. Baer, Gert Lubec, Harald Hoeger, Georg Widhalm and Mark R. Kotter

Object

Promoting repair of central nervous system (CNS) white matter represents an important approach to easing the course of a number of tragic neurological diseases. For this purpose, strategies are currently being evaluated for transplanting cells capable of generating new oligodendrocytes into areas of demyelination and/or enhancing the potential of endogenous stem/precursor cells to give rise to new oligodendrocytes. Emerging evidence, however, indicates that increasing the presence of cells capable of forming new myelin sheaths is not sufficient to promote repair because of unknown inhibitors that accumulate in lesions as a consequence of myelin degeneration and impair the generation of new oligodendrocytes. The aim of the present study was to characterize the nature of the inhibitory molecules present in myelin.

Methods

Differentiation of primary rat oligodendrocyte precursor cells (OPCs) in the presence of CNS and peripheral nervous system myelin was assessed by immunocytochemical methods. The authors further characterized the nature of the inhibitors by submitting myelin membrane preparations to biochemical precipitation and digestion. Finally, OPCs were grown on purified Nogo-A, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein, the most prominent inhibitors of axon regeneration.

Results

Myelin membrane preparations induced a differentiation block in OPCs that was associated with down-regulation of expression of the transcription factor Nkx2.2. The inhibitory activity in myelin was restricted to the CNS and was predominantly associated with white matter. Furthermore, the results demonstrate that myelin proteins that are distinct from the most prominent inhibitors of axon outgrowth are specific inhibitors of OPC differentiation.

Conclusions

The inhibitory effect of unknown myelin-associated proteins should be considered in future treatment strategies aimed at enhancing CNS repair.

Free access

Aygül Mert, Barbara Kiesel, Adelheid Wöhrer, Mauricio Martínez-Moreno, Georgi Minchev, Julia Furtner, Engelbert Knosp, Stefan Wolfsberger and Georg Widhalm

OBJECT

Surgery of suspected low-grade gliomas (LGGs) poses a special challenge for neurosurgeons due to their diffusely infiltrative growth and histopathological heterogeneity. Consequently, neuronavigation with multimodality imaging data, such as structural and metabolic data, fiber tracking, and 3D brain visualization, has been proposed to optimize surgery. However, currently no standardized protocol has been established for multimodality imaging data in modern glioma surgery. The aim of this study was therefore to define a specific protocol for multimodality imaging and navigation for suspected LGG.

METHODS

Fifty-one patients who underwent surgery for a diffusely infiltrating glioma with nonsignificant contrast enhancement on MRI and available multimodality imaging data were included. In the first 40 patients with glioma, the authors retrospectively reviewed the imaging data, including structural MRI (contrast-enhanced T1-weighted, T2-weighted, and FLAIR sequences), metabolic images derived from PET, or MR spectroscopy chemical shift imaging, fiber tracking, and 3D brain surface/vessel visualization, to define standardized image settings and specific indications for each imaging modality. The feasibility and surgical relevance of this new protocol was subsequently prospectively investigated during surgery with the assistance of an advanced electromagnetic navigation system in the remaining 11 patients. Furthermore, specific surgical outcome parameters, including the extent of resection, histological analysis of the metabolic hotspot, presence of a new postoperative neurological deficit, and intraoperative accuracy of 3D brain visualization models, were assessed in each of these patients.

RESULTS

After reviewing these first 40 cases of glioma, the authors defined a specific protocol with standardized image settings and specific indications that allows for optimal and simultaneous visualization of structural and metabolic data, fiber tracking, and 3D brain visualization. This new protocol was feasible and was estimated to be surgically relevant during navigation-guided surgery in all 11 patients. According to the authors' predefined surgical outcome parameters, they observed a complete resection in all resectable gliomas (n = 5) by using contour visualization with T2-weighted or FLAIR images. Additionally, tumor tissue derived from the metabolic hotspot showed the presence of malignant tissue in all WHO Grade III or IV gliomas (n = 5). Moreover, no permanent postoperative neurological deficits occurred in any of these patients, and fiber tracking and/or intraoperative monitoring were applied during surgery in the vast majority of cases (n = 10). Furthermore, the authors found a significant intraoperative topographical correlation of 3D brain surface and vessel models with gyral anatomy and superficial vessels. Finally, real-time navigation with multimodality imaging data using the advanced electromagnetic navigation system was found to be useful for precise guidance to surgical targets, such as the tumor margin or the metabolic hotspot.

CONCLUSIONS

In this study, the authors defined a specific protocol for multimodality imaging data in suspected LGGs, and they propose the application of this new protocol for advanced navigation-guided procedures optimally in conjunction with continuous electromagnetic instrument tracking to optimize glioma surgery.

Full access

Matthias Millesi, Barbara Kiesel, Mario Mischkulnig, Mauricio Martínez-Moreno, Adelheid Wöhrer, Stefan Wolfsberger, Engelbert Knosp and Georg Widhalm

OBJECTIVE

One of the most important causes for recurrence of intracranial meningiomas is residual tumor tissue that remains despite assumed complete resection. Recently, intraoperative visualization of meningioma tissue by 5-aminolevulinic acid (5-ALA)–induced protoporphyrin IX (PpIX) fluorescence was reported. The aim of this study was to investigate the possible surgical benefits of PpIX fluorescence for detection of meningioma tissue.

METHODS

5-ALA was administered preoperatively to 190 patients undergoing resection of 204 intracranial meningiomas. The meningiomas' PpIX fluorescence status, fluorescence quality (strong or vague), and intratumoral fluorescence homogeneity were investigated during surgery. Additionally, specific sites, including the dural tail, tumor-infiltrated bone flap, adjacent cortex, and potential satellite lesions, were analyzed for PpIX fluorescence in selected cases.

RESULTS

PpIX fluorescence was observed in 185 (91%) of 204 meningiomas. In the subgroup of sphenoorbital meningiomas (12 of 204 cases), the dural part showed visible PpIX fluorescence in 9 cases (75%), whereas the bony part did not show any PpIX fluorescence in 10 cases (83%). Of all fluorescing meningiomas, 168 (91%) showed strong PpIX fluorescence. Typically, most meningiomas demonstrated homogeneous fluorescence (75% of cases). No PpIX fluorescence was observed in any of the investigated 89 dural tails. In contrast, satellite lesions could be identified through PpIX fluorescence in 7 cases. Furthermore, tumor-infiltrated bone flaps could be visualized by PpIX fluorescence in all 13 cases. Notably, PpIX fluorescence was also present in the adjacent cortex in 20 (25%) of 80 analyzed cases.

CONCLUSIONS

The authors' data from this largest patient cohort to date indicate that PpIX fluorescence enables intraoperatively visualization of most intracranial meningiomas and allows identification of residual tumor tissue at specific sites. Thus, intraoperative detection of residual meningioma tissue by PpIX fluorescence might in future reduce the risk of recurrence.

Restricted access

Klaus Novak, Georg Widhalm, Adauri Bueno de Camargo, Noel Perin, George Jallo, Engelbert Knosp and Vedran Deletis

Object

Thoracic idiopathic spinal cord herniation (TISCH) is a rare neurological disorder characterized by an incarceration of the spinal cord at the site of a ventral dural defect. The disorder is associated with clinical signs of progressive thoracic myelopathy. Surgery can withhold the natural clinical course, but surgical repair of the dural defect bears a significant risk of additional postoperative motor deficits, including permanent paraplegia. Intraoperative online information about the functional integrity of the spinal cord and warning signs about acute functional impairment of motor pathways could contribute to a lower risk of permanent postoperative motor deficit. Motor evoked potential (MEP) monitoring can instantly and reliably detect dysfunction of motor pathways in the spinal cord. The authors have applied MEPs during intraoperative neurophysiological monitoring (IOM) for surgical repair of TISCH and have correlated the results of IOM with its influence on the surgical procedure and with the functional postoperative outcome.

Methods

The authors retrospectively reviewed the intraoperative neurophysiological data and clinical records of 4 patients who underwent surgical treatment for TISCH in 3 institutions where IOM, including somatosensory evoked potentials and MEPs, is routinely used for spinal cord surgery. In all 4 patients the spinal cord was reduced from a posterior approach and the dural defect was repaired using a dural graft.

Results

Motor evoked potential monitoring was feasible in all patients. Significant intraoperative changes of MEPs were observed in 2 patients. The changes were detected within seconds after manipulation of the spinal cord. Monitoring of MEPs led to immediate revision of the placement of the dural graft in one case and to temporary cessation of the release of the incarcerated spinal cord in the other. Changes occurred selectively in MEPs and were reversible. In both patients, transient changes in intraoperative MEPs correlated with a reversible postoperative motor deficit. Patients without significant changes in somatosensory evoked potentials and MEPs demonstrated no additional neurological deficit postoperatively and showed improvement of motor function during follow-up.

Conclusions

Surgical repair of the dural defect is effected by release and reduction of the spinal cord and insertion of dural substitute over the dural defect. Careful monitoring of the functional integrity of spinal cord long tracts during surgical manipulation of the cord can detect surgically induced impairment. The authors' documentation of acute loss of MEPs that correlated with reversible postoperative motor deficit substantiates the necessity of IOM including continuous monitoring of MEPs for the surgical treatment of TISCH.

Restricted access

Georgi Minchev, Gernot Kronreif, Mauricio Martínez-Moreno, Christian Dorfer, Alexander Micko, Aygül Mert, Barbara Kiesel, Georg Widhalm, Engelbert Knosp and Stefan Wolfsberger

OBJECTIVE

Robotic devices have recently been introduced in stereotactic neurosurgery in order to overcome the limitations of frame-based and frameless techniques in terms of accuracy and safety. The aim of this study is to evaluate the feasibility and accuracy of the novel, miniature, iSYS1 robotic guidance device in stereotactic neurosurgery.

METHODS

A preclinical phantom trial was conducted to compare the accuracy and duration of needle positioning between the robotic and manual technique in 162 cadaver biopsies. Second, 25 consecutive cases of tumor biopsies and intracranial catheter placements were performed with robotic guidance to evaluate the feasibility, accuracy, and duration of system setup and application in a clinical setting.

RESULTS

The preclinical phantom trial revealed a mean target error of 0.6 mm (range 0.1–0.9 mm) for robotic guidance versus 1.2 mm (range 0.1–2.6 mm) for manual positioning of the biopsy needle (p < 0.001). The mean duration was 2.6 minutes (range 1.3–5.5 minutes) with robotic guidance versus 3.7 minutes (range 2.0–10.5 minutes) with manual positioning (p < 0.001). Clinical application of the iSYS1 robotic guidance device was feasible in all but 1 case. The median real target error was 1.3 mm (range 0.2–2.6 mm) at entry and 0.9 mm (range 0.0–3.1 mm) at the target point. The median setup and instrument positioning times were 11.8 minutes (range 4.2–26.7 minutes) and 4.9 minutes (range 3.1–14.0 minutes), respectively.

CONCLUSIONS

According to the preclinical data, application of the iSYS1 robot can significantly improve accuracy and reduce instrument positioning time. During clinical application, the robot proved its high accuracy, short setup time, and short instrument positioning time, as well as demonstrating a short learning curve.

Free access

Barbara Kiesel, Matthias Millesi, Adelheid Woehrer, Julia Furtner, Anahita Bavand, Thomas Roetzer, Mario Mischkulnig, Stefan Wolfsberger, Matthias Preusser, Engelbert Knosp and Georg Widhalm

OBJECTIVE

Stereotactic needle biopsies are usually performed for histopathological confirmation of intracranial lymphomas to guide adequate treatment. During biopsy, intraoperative histopathology is an effective tool to avoid acquisition of nondiagnostic samples. In the last years, 5-aminolevulinic acid (5-ALA)–induced fluorescence has been increasingly used for visualization of diagnostic brain tumor tissue during stereotactic biopsies. Recently, visible fluorescence was reported in the first cases of intracranial lymphomas as well. The aim of this study is thus to investigate the technical and clinical utility of 5-ALA–induced fluorescence in a large series of stereotactic biopsies for intracranial lymphoma.

METHODS

This prospective study recruited adult patients who underwent frameless stereotactic needle biopsy for a radiologically suspected intracranial lymphoma after oral 5-ALA administration. During biopsy, samples from the tumor region were collected for histopathological analysis, and presence of fluorescence (strong, vague, or no fluorescence) was assessed with a modified neurosurgical microscope. In tumors with available biopsy samples from at least 2 different regions the intratumoral fluorescence homogeneity was additionally investigated. Furthermore, the influence of potential preoperative corticosteroid treatment or immunosuppression on fluorescence was analyzed. Histopathological tumor diagnosis was established and all collected biopsy samples were screened for diagnostic lymphoma tissue.

RESULTS

The final study cohort included 41 patients with intracranial lymphoma. Stereotactic biopsies with assistance of 5-ALA were technically feasible in all cases. Strong fluorescence was found as maximum level in 30 patients (75%), vague fluorescence in 2 patients (4%), and no visible fluorescence in 9 patients (21%). In 28 cases, samples were obtained from at least 2 different tumor regions; homogenous intratumoral fluorescence was found in 16 of those cases (57%) and inhomogeneous intratumoral fluorescence in 12 (43%). According to histopathological analysis, all samples with strong or vague fluorescence contained diagnostic lymphoma tissue, resulting in a positive predictive value of 100%. Analysis showed no influence of preoperative corticosteroids or immunosuppression on fluorescence.

CONCLUSIONS

The data obtained in this study demonstrate the technical and clinical utility of 5-ALA–induced fluorescence in stereotactic biopsies of intracranial lymphomas. Thus, 5-ALA can serve as a useful tool to select patients not requiring intraoperative histopathology, and its application should markedly reduce operation time and related costs in the future.

Free access

Matthias Millesi, Barbara Kiesel, Adelheid Woehrer, Johannes A. Hainfellner, Klaus Novak, Mauricio Martínez-Moreno, Stefan Wolfsberger, Engelbert Knosp and Georg Widhalm

Object

Subtotal resection (STR) of spinal tumors can result in tumor recurrence. Currently, no clinically reliable marker is available for intraoperative visualization of spinal tumor tissue. Protoporphyrin IX (PpIX) fluorescence induced by 5-aminolevulinic acid (5-ALA) is capable of visualizing malignant gliomas. Fluorescence-guided resections of malignant cerebral gliomas using 5-ALA have resulted in an increased rate of complete tumor removal. Recently, the application of 5-ALA has also been described in the first cases of spinal tumors. Therefore, the aim of this observational study was to systematically investigate 5-ALA–induced fluorescence characteristics in different spinal tumor entities.

Methods

Three hours before the induction of anesthesia, 5-ALA was administered to patients with different intra- and extradural spinal tumors. In all patients a neurosurgical resection or biopsy of the spinal tumor was performed under conventional white-light microscopy. During each surgery, the presence of PpIX fluorescence was additionally assessed using a modified neurosurgical microscope. At the end of an assumed gross-total resection (GTR) under white-light microscopy, a final inspection of the surgical cavity of fluorescing intramedullary tumors was performed to look for any remaining fluorescing foci. Histopathological tumor diagnosis was established according to the current WHO classification.

Results

Fifty-two patients with 55 spinal tumors were included in this study. Resection was performed in 50 of 55 cases, whereas 5 of 55 cases underwent biopsy. Gross-total resection was achieved in 37 cases, STR in 5, and partial resection in 8 cases. Protoporphyrin IX fluorescence was visible in 30 (55%) of 55 cases, but not in 25 (45%) of 55 cases. Positive PpIX fluorescence was mainly detected in ependymomas (12 of 12), meningiomas (12 of 12), hemangiopericytomas (3 of 3), and in drop metastases of primary CNS tumors (2 of 2). In contrast, none of the neurinomas (8 of 8), carcinoma metastases (5 of 5), and primary spinal gliomas (3 of 3; 1 pilocytic astrocytoma, 1 WHO Grade II astrocytoma, 1 WHO Grade III anaplastic oligoastrocytoma) revealed PpIX fluorescence. It is notable that residual fluorescing tumor foci were detected and subsequently resected in 4 of 8 intramedullary ependymomas despite assumed GTR under white-light microscopy.

Conclusions

In this study, 5-ALA–PpIX fluorescence was observed in spinal tumors, especially ependymomas, meningiomas, hemangiopericytomas, and drop metastases of primary CNS tumors. In cases of intramedullary tumors, 5-ALA–induced PpIX fluorescence is a useful tool for the detection of potential residual tumor foci.

Restricted access

Georg Widhalm, Wolfgang Dietrich, Leonhard Müllauer, Berthold Streubel, Werner Rabitsch, Mark R. Kotter, Engelbert Knosp and Karl Roessler

✓ The authors report the unusual case of a 35-year-old woman suffering from left leg numbness and radiculopathy due to multiple lesions in the central nervous system: one right parietal extracranial–intracranial lesion with invasion of the sensory cortex, and two intraspinal, intradural lesions compressing the spinal cord at T3–5 and S1–4. Biopsy sampling of the extracranial part of the parietal lesion led to a diagnosis of myeloid sarcoma. Further examination revealed no evidence of leukemic disease or myeloproliferative disorder. An aggressive multimodal approach to treatment in this patient with a combination of chemotherapy, whole-body radiotherapy, and allogeneic bone marrow transplantation was started immediately. The patient experienced full neurological recovery and complete disappearance of all lesions. At the 7-year follow-up examination, there was no evidence of disease. To the authors’ knowledge, this is the first report of a myeloid sarcoma with both intracranial and intraspinal manifestations in a patient without leukemia.

Full access

Barbara Kiesel, Mario Mischkulnig, Adelheid Woehrer, Mauricio Martinez-Moreno, Matthias Millesi, Ammar Mallouhi, Thomas Czech, Matthias Preusser, Johannes A. Hainfellner, Stefan Wolfsberger, Engelbert Knosp and Georg Widhalm

OBJECTIVE

Glioblastoma (GBM) is characterized by distinct intratumoral histopathological heterogeneity with regard to variable tumor morphology, cell proliferation, and microvascularity. Maximum resection of a GBM results in an improved prognosis and thus represents the aim of surgery in the majority of cases. Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is currently widely applied for improved intraoperative tumor visualization in patients with a GBM. Three intratumoral fluorescence levels (i.e., strong, vague, or no fluorescence) can usually be distinguished during surgery. So far, however, their exact histopathological correlates and their surgical relevance have not been clarified sufficiently. Thus, the aim of this study was to systematically analyze tissue samples from newly diagnosed GBMs with different fluorescence levels according to relevant histopathological parameters.

METHODS

This prospective study recruited patients who underwent 5-ALA fluorescence-guided resection of a newly diagnosed radiologically suspected GBM. Each patient received 5-ALA approximately 3 hours before surgery, and a modified neurosurgical microscope was applied for intraoperative visualization of 5-ALA–induced fluorescence. During surgery, tissue samples with strong, vague, or no fluorescence were collected. For each sample, the presence of tumor tissue, quality of tissue (compact, infiltrative, or no tumor), histopathological criteria of malignancy (cell density, nuclear pleomorphism, mitotic activity, and presence of microvascular proliferation/necrosis), proliferation rate (MIB-1 labeling index [LI]), and microvessel density (using CD34 staining) were investigated.

RESULTS

Altogether, 77 patients with a newly diagnosed, histopathologically confirmed GBM were included, and 131 samples with strong fluorescence, 69 samples with vague fluorescence, and 67 samples with no fluorescence were collected. Tumor tissue was detected in all 131 (100%) of the samples with strong fluorescence and in 65 (94%) of the 69 samples with vague fluorescence. However, mostly infiltrative tumor tissue was still found in 33 (49%) of 67 samples despite their lack of fluorescence. Strong fluorescence corresponded to compact tumors in 109 (83%) of 131 samples, whereas vague fluorescence was consistent with infiltrative tumors in 44 (64%) of 69 samples. In terms of the histopathological criteria of malignancy, a significant positive correlation of all analyzed parameters comprising cell density, nuclear pleomorphism, mitotic activity, microvascular proliferation, and necrosis with the 3 fluorescence levels was observed (p < 0.001). Furthermore, the proliferation rate significantly and positively correlated with strong (MIB-1 LI 28.3%), vague (MIB-1 LI 16.7%), and no (MIB-1 LI 8.8%) fluorescence (p < 0.001). Last, a significantly higher microvessel density was detected in samples with strong fluorescence (CD34 125.5 vessels/0.25 mm2) than in those with vague (CD34 82.8 vessels/0.25 mm2) or no (CD34 68.6 vessels/0.25 mm2) fluorescence (p < 0.001).

CONCLUSIONS

Strong and vague 5-ALA–induced fluorescence enables visualization of intratumoral areas with specific histopathological features and thus supports neurosurgeons in improving the extent of resection in patients with a newly diagnosed GBM. Despite the lack of fluorescence, tumor tissue was still observed in approximately half of the cases. To overcome this current limitation, the promising approach of complementary spectroscopic measurement of fluorescence should be investigated further.