Simulating vasogenic brain edema using chronic VEGF infusion

OBJECTIVETo 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.METHODSMale Fischer rats (n = 182) underwent stereotactic striatal implantation of MRI-safe 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.RESULTSControl 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 mm3) of T2 hyper-attenuation at 144 hours when compared with the volume (8.585 ± 1.664 mm3) in control animals (mean difference 34.31 ± 4.187 mm3, p < 0.0001, 95% CI 25.74–42.89 mm3). 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 mm3) was significantly less compared with the region of edema (p < 0.0001). Histologically, no evidence of necrosis or inflammation was observed with VEGF or control infusion. Immunohistochemical analysis demonstrated astrocyte activation, vascular remodeling, and increased claudin-5 expression in juxtacanalicular regions. Aquaporin-4 expression was increased in both control and VEGF animals in the juxtacanalicular regions.CONCLUSIONSThe results of this study show that chronic brain infusion of VEGF creates a reliable model of VBE. This model lacks necrosis and inflammation that are characteristic of previous models of VBE. The model allows for a precise investigation into the mechanism of VBE formation. The authors also anticipate that this model will allow for investigation into the mechanism of glucocorticoid action in abrogating VBE, and to test novel therapeutic strategies targeting PTBE.

Progressive perianeurysmal edema induced after endovascular coil embolization

✓The authors report three cases of progressive vasogenic brain edema surrounding a cerebral aneurysm after endovascular coil embolization. In all three cases embolization was incomplete due to the aneurysms' large sizes and wide necks. Follow-up magnetic resonance imaging revealed de novo vasogenic brain edema surrounding the aneurysms 3 to 6 months after the initial treatment. The edema progressed in parallel with regrowth of the aneurysms. All three aneurysms were deep in the brain parenchyma and showed intramural enhancement, suggesting hemorrhage or inflammation. Each patient underwent a second embolization for the aneurysm regrowth, which resulted in improvement of the edema. Based on the findings in these cases and review of the literature, it is suggested that incomplete occlusion of larger aneurysms that are deep within the brain may lead to a disorganized intraluminal thrombosis, aneurysm pulsing, and intramural hemorrhage or inflammation, all of which are associated with brain edema following aneurysm recanalization and regrowth. It should be kept in mind that incomplete embolization of larger aneurysms may cause such malignant change and that this complication may occur after endovascular treatment.