✓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.
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.
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.
Ralph J. Medele, Walter Stummer, Arthur J. Mueller, Hans-Jakob Steiger and Hans-Jürgen Reulen
Object. The syndrome of retinal or vitreous hemorrhage in association with subarachnoid hemorrhage (SAH) is known as Terson's syndrome. The authors' purpose was to determine whether intraocular hemorrhage occurs with similar incidence when caused by severe brain injury accompanied by acutely raised intracranial pressure (ICP).
Methods. Prospective ophthalmological examination was performed in 22 consecutive patients with SAH or severe brain injury and elevated ICP. Thirteen patients were admitted for SAH (World Federation of Neurological Surgeons Grades II–IV) and nine for severe brain injury (Glasgow Coma Scale scores 3–10). Monitoring of ICP was performed at the time of admission via a ventricular catheter. Initial ICP exceeded 20 mm Hg in all patients. Indirect ophthalmoscopy without induced mydriasis was performed within the 1st week after the acute event. Retinal or vitreous hemorrhage was seen in six (46%) of 13 patients with SAH and in four (44%) of nine patients with severe brain injury. Ocular bleeding was found bilaterally in three patients with SAH and in one patient with severe brain injury (18%). Six of the 10 patients with Terson's syndrome died as a result of their acute event.
Conclusions. The present results indicate that Terson's syndrome may be related to acute elevation of ICP, independent of its causes, and may occur with similar incidence in patients with severe brain injury and those with SAH. Because recognition and treatment of Terson's syndrome may prevent visual impairment and associated secondary damage to the eye, increased awareness of this entity in all patients with acute raised intracranial hypertension is recommended.
Heading : Manas Panigrahi
Peter A. Winkler, Walter Stummer, Rainer Linke, Kartik G. Krishnan and Klaus Tatsch
The indications for cranioplasty after decompressive craniectomy are cosmetic repair and, mainly, restoration of cerebral protection. Although neurological improvement after cranioplasty is repeatedly noted, the reasons for this still remain unclear. Few observations concerning the impact of CSF hydrodynamic and/or atmospheric pressure were published during the last decades. Relevant data concerning the cerebrovascular reserve capacity and cerebral glucose metabolism before and after cranioplasty have been lacking until now. To gain further insight, the present study was undertaken to investigate the impact of cranioplasty on indices of cerebral blood flow regulation and metabolism.
Thirteen patients in whom extensive craniectomies had been performed underwent a meticulous study of blood flow velocities in the middle cerebral artery (MCA) and extracranial internal carotid artery (ICA), as assessed by transcranial Doppler (TCD) ultrasonography during postural maneuvers (supine and sitting positions) and during stimulation with 1 g of acetazolamide for the interpretation of cerebrovascular reserve (CVR) capacity. Twelve patients underwent 18-fluorodesoxyglucose positron emission tomography. These measurements were made before and 7 days after cranioplasty.
Cranioplasty improved preoperative differences in MCA blood flow velocities when comparing the injured with the noninjured hemisphere. Similarly, cranioplasty resolved decreases in extracranial ICA blood flow in the injured hemisphere that were induced by postural changes, which was a constant finding prior to this procedure. More strikingly, however, the CVR capacity, which was severely impaired in both hemispheres, significantly increased after the procedure. Metabolic deficits, which were observed in the injured as compared with the noninjured hemisphere, were found to improve after reimplantation of the skull bone flap.
Cranioplasty appears to affect postural blood flow regulation, CVR capacity, and cerebral glucose metabolism markedly. Thus, early cranioplasty is warranted to facilitate rehabilitation in patients after decompressive craniectomy.
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.
Kerim Beseoglu, Sabrina Lodes, Walter Stummer, Hans-Jakob Steiger and Daniel Hänggi
In 2003 the authors introduced a minimally invasive transorbital keyhole approach. Because this approach requires removal of the orbital rim and orbital roof, there have been concerns regarding perioperative morbidity, long-term morbidity, and cosmetic results. The authors evaluated approach-related morbidity and cosmetic results in their patients to determine the rate of complications and compared this to published reports of similar approaches.
Seventy-one patients (41 female, 30 male) underwent operations using this approach between 2004 and 2008. Immediate approach-related morbidity was recorded after the operation. Late morbidity was determined after 7 months by an independent examiner while cosmetic results were self-rated by the patient using a questionnaire.
Fifty-one (72%) of 71 patients had no postoperative complications and 12 (16.9%) had minor complications, the most common of which was subgaleal CSF collection (7.0%). Other minor complications included facial nerve palsy (2.8%), hyposphagma (2.8%), periorbital swelling due to periorbital hematoma (2.8%), and subdural hematoma (1.4%). Major complications requiring surgical revision occurred in 4 patients (5.6%); these were CSF fistulas in 2 patients, pneumocephalus in 1 patient, and a hematoma in 1 patient. Forty-nine (90.7%) of all 54 examined patients rated the cosmetic results as very good or good. Major long-term morbidity was hyposmia or anosmia (14 patients) followed by hypoesthesia around the scar (9 patients).
The transorbital keyhole approach is a feasible approach with a low-risk profile for postoperative or long-term morbidity and excellent cosmetic outcome.