✓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.
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.
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.
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.
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.
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.
Eric Jose Suero Molina, Thomas Niederstadt, Vincent Ruland, Gian Kayser, Walter Stummer, Christian Ewelt and Jochen Rössler
Patients with Gorham-Stout disease (GSD), a rare disease of poorly understood etiopathophysiology, suffer from progressive osteolysis. Destruction of bone matrix is caused by lymphatic vessels, which can lead to CSF leakage if parts of bony structures adjacent to CSF spaces are involved. So far, fewer than 200 patients have been reported in the literature; only 4 of these patients presented with CSF leakage. The authors report the case of a 30-year-old man with GSD and CSF leakage due to dura mater involvement after progression of an osteolytic lesion in the thoracic spine. Neurosurgical intervention, including dura repair, was needed. Experimental medical therapy with rapamycin was started, leading to disease control for more than 12 months. Progression of GSD can lead to destruction of the meninges, causing CSF leakage. The authors review 4 other cases reported in the literature and discuss therapeutic options.
Report of 3 cases
Sevgi Sarikaya-Seiwert, Bernd Turowski, Daniel Hänggi, Giesela Janssen, Hans-Jakob Steiger and Walter Stummer
Pineal cysts are benign and often asymptomatic intracranial entities. Occasionally they can lead to neurological symptoms through growth or due to intracystic hemorrhage. The purpose of the current report is to describe their clinical characteristics and treatment options.
In the current study, the authors illustrate the course of disease in 3 patients who developed neurological symptoms due to hemorrhage into a pineal cyst. Two of their patients had additional cerebral disease, and regular MR imaging examinations were conducted. This circumstance allowed documentation of growth and intracystic hemorrhage. After the occurrence of new neurological symptoms with severe headache, MR images showed a fluid-fluid interface due to intracystic hemorrhage. The third patient presented with acute triventricular hydrocephalus and papilledema due to aqueductal stenosis caused by intracystic hemorrhage.
In all 3 cases, excision of the pineal cysts via an infratentorial/supracerebellar approach was performed. Histological examination revealed the characteristic structure of pineal cyst in all cases, with hemorrhagic residues in the form of hemosiderin deposits. All patients recovered fully after surgical removal of the cysts. Furthermore, resolution of occlusive hydrocephalus could be demonstrated in those cases with ventricular enlargement.
Pineal cysts without neurological symptoms are often discovered as incidental findings on cranial MR images. In contrast, neurological symptoms such as severe headache, diplopia, or Parinaud syndrome, may occur as a result of pineal apoplexy due to intracystic hemorrhage. The authors' cases confirm that MR imaging can identify intracystic hemorrhage by a characteristic fluid-fluid interface. Their experience suggests that microsurgical resection of cysts may be an effective and curative treatment option.
Bernhard Olzowy, Cornelia S. Hundt, Susanne Stocker, Karl Bise, Hans Jürgen Reulen and Walter Stummer
Object. Accumulation of protoporphyrin IX (PPIX) in malignant gliomas is induced by 5-aminolevulinic acid (5-ALA). Because PPIX is a potent photosensitizer, the authors sought to discover whether its accumulation might be exploited for use in photoirradiation therapy of experimental brain tumors, without injuring normal or edematous brain.
Methods. Thirty rats underwent craniotomy and were randomized to the following groups: 1) photoirradiation of cortex (200 J/cm2, 635-nm argon-dye laser); 2) photoirradiation of cortex (200 J/cm2) 6 hours after intravenous administration of 5-ALA (100 mg/kg body weight); 3) cortical cold injury for edema induction; 4) cortical cold injury with simultaneous administration of 5-ALA (100 mg/kg body weight) and photoirradiation of cortex (200 J/cm2) 6 hours later; or 5) irradiation of cortex (200 J/cm2) 6 hours after intravenous administration of Photofrin II (5 mg/kg body weight). Tumors were induced by cortical inoculation of C6 cells and 9 days later, magnetic resonance (MR) images were obtained. On Day 10, animals were given 5-ALA (100 mg/kg body weight) and their brains were irradiated (100 J/cm2) 3 or 6 hours later. Seventy-two hours after irradiation, the brains were removed for histological examination.
Irradiation of brains after administration of 5-ALA resulted in superficial cortical damage, the effects of which were not different from those of the irradiation alone. Induction of cold injury in combination with 5-ALA and irradiation slightly increased the depth of damage. In the group that received irradiation after intravenous administration of Photofrin II the depth of damage inflicted was significantly greater. The extent of damage in response to 5-ALA and irradiation in brains harboring C6 tumors corresponded to the extent of tumor determined from pretreatment MR images.
Conclusions. Photoirradiation therapy in combination with 5-ALA appears to damage experimental brain tumors selectively, with negligible damage to normal or perifocal edematous tissue.