Simulating vasogenic brain edema using chronic VEGF infusion

Abstract

OBJECTIVE-To study peritumoral brain edema (PTBE), it is necessary to create a model that accurately simulates vasogenic brain edema (VBE) without introducing a complicated tumor environment. PTBE associated with brain tumors is predominantly a result of vascular endothelial growth factor (VEGF) secreted by brain tumors, and VEGF infusion alone can lead to histological blood-brain barrier (BBB) breakdown in the absence of tumor. VBE is intimately linked to BBB breakdown. The authors sought to establish a model for VBE with chronic infusion of VEGF that can be validated by serial in-vivo MRI and histological findings. METHODS-MaleFischer rats (n = 182) underwent stereotactic striatal implantation of MRIsafe brain cannulas for chronic infusion of VEGF (2-20 μg/ml). Following a preinfusion phase (4-6 days), the rats were exposed to VEGF or control rat serum albumin (1.5 μl/hr) for as long as 144 hours. Serial MRI was performed during infusion on a high-field (9.4-T) machine at 12-24, 24-36, 48-72, and 120-144 hours. Rat brains were then collected and histological analysis was performed.RESULTS-Control animals and animals infused with 2 μg/ml of VEGF experienced no neurological deficits, seizure activity, or abnormal behavior. Animals treated with VEGF demonstrated a significantly larger volume (42.90 ± 3.842 mm 3 ) of T2 hyper-attenuation at 144 hours when compared with the volume (8.585 ± 1.664 mm 3 ) in control animals (mean difference 34.31 ± 4.187 mm 3 , p < 0.0001, 95% CI 25.74-42.89 mm 3 ). Postcontrast T1 enhancement in the juxtacanalicular region indicating BBB breakdown was observed in rats undergoing infusion with VEGF. At the later time periods (120-144 hrs) the volume of T1 enhancement (34.97 ± 8.99 mm 3 ) was significantly less compared with the region of edema (p < 0.0001). Histologically, no evidence Correspondence: Prashant Chittiboina, Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Diseases and Stroke, National Institutes of Health, 10 Center Dr., Rm. 3D20, Bethesda, MD 20892-1414. prashant.chittiboina@nih.gov. DisclosuresThe authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Regardless of histological type, brain tumors are frequently associated with neuronal dysfunction resulting in focal neurological deficits, or with more global impairments of neurological function such as seizure activity and changes in mental status. These tumor effects are often caused by tumor invasion into peritumoral brain, 23,24 but more often they result from peritumoral brain edema (PTBE). PTBE leads to an increase in brain volume and eventually affects intracranial pressure, which may eventually lead to brain herniation or even death. 6,30 Current treatment regimens targeting PTBE depend heavily on corticosteroid administration, but relief from edema may be short-lived and associated with significant systemic side effects. 10,12,30,43,45,57 Improved understanding of the cellular an...

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