✓Cerebral edema contributes strongly to symptoms associated with brain tumors. Although the introduction of corticosteroids has greatly simplified treatment of patients with newly diagnosed tumors, these drugs are associated with marked side effects during the long-term treatment that is often necessary in the recurrences. Therefore, a better understanding of mechanisms related to the evolution and clearance of tumor-related edema with the aid of modern imaging and molecular methodology is clearly necessary. Recently, researchers have focused on molecular mechanisms of edema development and have demonstrated alternative routes—such as the inhibition of vascular endothelial growth factor receptor inhibitors—to be explored for treating edema. In this review the author focuses on established and current concepts regarding the pathophysiology of cerebral edema and its treatment.
Berndt Wowra and Walter Stummer
Object. The authors assessed the efficacy of gamma knife radiosurgery (GKS) for nonfunctioning pituitary adenomas (NPAs) by sequential quantitative determinations of tumor volume and neurological and endocrinological follow-up examinations.
Methods. Through May of 2000, 45 patients with NPA were treated by GKS. Complete neurological and endocrinological follow-up information was obtained. In 30 patients (67%), follow-up examinations included stereotactic magnetic resonance imaging involving the GammaPlan software for sequential measurements of the NPA volume. These patients constitute the basis of this study. Sequential volume measurements after GKS were compared with initial tumor volumes at the date of GKS to quantify the therapeutic result. All data were stored prospectively in a computerized database. The median dose to the tumor margin was 16 Gy (range 11–20 Gy). The mean prescription isodose was 55% (range 45–75%). All except one patient (97%) underwent surgery for NPA before GKS. Fractionated radiotherapy was not administered. Median follow up after GKS was 55 months (range 28–86 months).
The actuarial long-term recurrence-free survival was 93% with respect to a single GKS and 100% if a repeated GKS was included. Neurological side effects were not detected. The actuarial risk of radiosurgery-induced pituitary damage was calculated to be 14% after 6 years. The volumetric analysis revealed a temporary swelling of the NPA in four patients, followed by shrinkage of the lesion. This is the first time this has been observed in pituitary adenomas.
Conclusions. Postoperative GKS for residual or recurrent small fragments of NPAs is effective and safe. With regard to the issues of radioprotection and therapeutic morbidity, it seems superior to fractionated radiotherapy. Quantification of tumor reduction is a valuable tool for documenting a therapeutic response and for identifying tumor recurrence. As part of a radiosurgical standard protocol, the follow-up examination for NPAs should include tumor volumetric analysis.
Paul Larson, Peter Nakaji, Walter Stummer, and John Pollina
Eric Suero Molina, Christian Ewelt, Nils Warneke, Michael Schwake, Michael Müther, Stephanie Schipmann, and Walter Stummer
Recent efforts to improve visualization of 5-aminolevulinic acid (5-ALA)–induced protoporphyrin IX (PPIX) fluorescence resulted in a dual-labeling technique, combining it with fluorescein sodium in a prototype setup. Fluorescein identifies regions with blood-brain barrier breakdown in gliomas. However, normally perfused and edematous brain fluoresces unselectively, with strong background enhancement. The aim of this study was to test the feasibility of a novel, integrated filter combination using porphyrins for selective tumor identification and fluorescein for background enhancement.
A microscope with a novel built-in filter system (YB 475) for visualizing both fluorescein and 5-ALA–induced porphyrins was used. Resection limits were identified with the conventional BLUE 400 filter system. Six patients harboring contrast ring-enhancing lesions were analyzed.
The complete surgical field could now be illuminated. Fluorescein was helpful for improving background visualization, and enhancing dura, edematous tissue, and cortex. Overlapping regions with both fluorophores harbored merged orange fluorescence. PPIX fluorescence was better visualized, even in areas beyond a normal working distance of approximately 25 cm, where the BLUE 400 filters recognized no or weak fluorescence.
The novel filter system improved general tissue brightness and background visualization, enhancing fluorescence-guided tumor resection. Furthermore, it appears promising from a scientific perspective, enabling the simultaneous and direct observation of areas with blood-brain barrier breakdown and PPIX fluorescence.
Eric Suero Molina, Johannes Wölfer, Christian Ewelt, André Ehrhardt, Benjamin Brokinkel, and Walter Stummer
Fluorescence guidance with 5–aminolevulinic acid (5-ALA) helps improve resections of malignant gliomas. However, one limitation is the low intensity of blue light for background illumination. Fluorescein has recently been reintroduced into neurosurgery, and novel microscope systems are available for visualizing this fluorochrome, which highlights all perfused tissues but has limited selectivity for tumor detection. Here, the authors investigate a combination of both fluorochromes: 5-ALA for distinguishing tumor and fluorescein for providing tissue fluorescence of adjacent brain tissue.
The authors evaluated 6 patients who harbored cerebral lesions suggestive of high-grade glioma. Patients received 5-ALA (20 mg/kg) orally 4 hours before induction of anesthesia. Low-dose fluorescein (3 mg/kg intravenous) was injected immediately after anesthesia induction. Pentero microscopes (equipped either with Yellow 560 or Blue 400 filters) were used to visualize fluorescence. To simultaneously visualize both fluorochromes, the Yellow 560 module was combined with external blue light illumination (D-light C System).
Fluorescein-induced fluorescence created a useful background for protoporphyrin IX (PPIX) fluorescence, which appeared orange to red, surrounded by greenly fluorescent normal brain and edematous tissue. Green brain-tissue fluorescence was helpful in augmenting background. Levels of blue illumination that were too strong obscured PPIX fluorescence. Unspecific extravasation of fluorescein was noted at resection margins, which did not interfere with PPIX fluorescence detection.
Dual labeling with both PPIX and fluorescein fluorescence is feasible and gives superior background information during fluorescence-guided resections. The authors believe that this technique carries potential as a next step in fluorescence-guided resections if it is completely integrated into the surgical microscope.
Walter Stummer, Alexander Novotny, Herbert Stepp, Claudia Goetz, Karl Bise, and Hans Jürgen Reulen
Object. It has been established that 5-aminolevulinic acid (5-ALA) induces the accumulation of fluorescent porphyrins in glioblastoma multiforme (GBM), a phenomenon potentially exploitable to guide tumor resection. In this study the authors analyze the influence of fluorescence-guided resection on postoperative magnetic resonance (MR) imaging and survival in a series of patients who underwent surgery in the authors' department.
Methods. Fifty-two consecutive patients with GBM received oral doses of 5-ALA (20 mg/kg body weight) 3 hours before induction of anesthesia. Intraoperatively, tumor fluorescence was visualized using a modified operating microscope. Fluorescing tissue was removed whenever it was considered safely possible. Residual enhancement on early postoperative MR imaging was quantified and related to each patient's characteristics to determine which factors influenced resection. Survival was analyzed using the Kaplan—Meier method and multivariate analysis was performed in which the Karnofsky Performance Scale (KPS) score, residual fluorescence, patient age, and residual enhancement on MR images were considered.
Intraoperatively, two fluorescence qualities were perceived: solid fluorescence generally reflected coalescent tumor, whereas vague fluorescence mostly corresponded to infiltrative tumor. Complete resection of contrast-enhancing tumor was accomplished in 33 patients (63%). Residual intraoperative tissue fluorescence left unresected for safety reasons predicted residual enhancement on MR images in 18 of the 19 remaining patients. Age, residual solid fluorescence, and absence of contrast enhancement in MR imaging were independent explanatory factors for survival, whereas the KPS score was significant only in univariate analysis. No perioperative deaths and one case of permanent morbidity were encountered.
Conclusions. The observations in this study indicate the usefulness of 5-ALA—induced tumor fluorescence for guiding tumor resection. The completeness of resection, as determined intraoperatively from residual tissue fluorescence, was related to postoperative MR imaging findings and to survival in patients suffering from GBM.
Hans-Jakob Steiger, Daniel Hänggi, Walter Stummer, and Peter A. Winkler
The extradural anterior petrosectomy approach to the pons and midbasilar artery (mid-BA) has the main disadvantage that the extent of resection of the petrous apex cannot be as minimal as desired given that the surgical target field is not visible during bone removal. Unnecessary or excessive drilling poses the risk of injury to the internal carotid artery, vestibulocochlear organ, and seventh and eighth cranial nerves. The use of a custom-tailored transdural anterior transpetrosal approach can potentially avoid these pitfalls.
A technique for a transdural anterior petrosectomy was developed in the operating theater and anatomy laboratory. Following a subtemporal craniotomy and basal opening of the dura mater, the vein of Labbé is first identified and protected. Cerebrospinal fluid ([CSF] 50–100 ml) is drained via a spinal catheter. The tent is incised behind the entrance of the trochlear nerve toward the superior petrosal sinus (SPS), which is coagulated and divided. The dura is stripped from the petrous pyramid. Drilling starts at the petrous ridge and proceeds laterally and ventrally. The trigeminal nerve is unroofed. The internal acoustic meatus is identified and drilling is continued laterally as needed. The bone of the Kawase triangle toward the clivus can be removed down to the inferior petrosal sinus if necessary. Anterior exposure can be extended to the carotid artery if required. It is only exceptionally necessary to follow the greater superior petrosal nerve toward the geniculate ganglion and to expose the length of the internal acoustic canal.
The modified transdural anterior petrosectomy exposure has been used in nine patients—two with a mid-BA aneurysm, two with a dural arteriovenous fistula, one with a pontine glioma, three with a pontine cavernoma, and one with a pontine abscess. In one patient with a mid-BA aneurysm, subcutaneous CSF collection occurred during the postoperative period. No CSF fistula or approach-related cranial nerve deficit developed in any of these patients. There was no retraction injury or venous congestion of the temporal lobe nor any venous congestion due to the obliteration of the SPS or the petrosal vein.
The custom-made transdural anterior petrosectomy appears to be a feasible alternative to the formal extradural approach.
Benjamin Brokinkel, Johanna Sicking, Dorothee Cäcilia Spille, Katharina Hess, Werner Paulus, and Walter Stummer
Darius C. Widenka, Ralph J. Medele, Walter Stummer, Karl Bise, and Hans J. Steiger
Object. The role of nitric oxide (NO) in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH) is not well understood. Nitric oxide is a well-established vasodilatory substance; however, in SAH, NO may become a major source for the production of injurious free-radical species, leading to chronic cerebral vasospasm. Reactive overproduction of NO to counteract vascular narrowing might potentiate the detrimental effects of NO. The focus of the present study is to determine the extent of reactive induction of inducible nitric oxide synthase (iNOS) after experimental SAH.
Methods. Chronic vasospasm was induced in male Wistar rats by an injection of autologous blood (100 µl) into the cisterna magna followed by a second injection 24 hours later. A control group of 10 animals was treated with injections of 0.9% sodium chloride solution. Vasospasm was verified by pressure-controlled angiography after retrograde cannulation of the external carotid artery 7 days later. In 11 of 15 animals radiographic evidence of cerebral vasospasm was seen. The animals were perfusion fixed and their brains were removed for immunohistochemical assessment. With the aid of a microscope, staining for iNOS was quantified in 40-µm floating coronal sections.
Immunohistochemical staining for iNOS was markedly more intense in animals with significant angiographic evidence of vasospasm. Virtually no staining was observed in control animals. Seven days after the second experimental SAH, labeling of iNOS was found in endothelial cells, in vascular smooth-muscle cells, and, above all, in adventitial cells. Some immunohistochemical staining of iNOS was observed in rod cells (activated microglia), in glial networks, and in neurons.
Conclusions. The present study demonstrates induction of iNOS after experimental SAH.