Angiographic, hemodynamic, and histological changes in an animal model of brain arteriovenous malformations treated with Gamma Knife radiosurgery

Abstract

B rain arteriovenous malformations (AVMs) are a major cause of stroke in children and young adults. Surgical excision of an AVM offers immediate protection from hemorrhage and is suitable for small and superficial lesions. Approximately 70% of small AVMs (< 3 cm in diameter) are completely obliterated by 2-3 years after Gamma Knife surgery (GKS).1,3,23 However, patients treated with GKS remain at risk for suffering hemorrhage during the latent period before AVM occlusion. 9,15 A large number of patients who have large and/or deeply located AVMs cannot be treated using current methods.9 An improved method of treating AVMs is required for these patients.One potential new treatment is to induce thrombosis in abbreviatioNs AVM = arteriovenous malformation; GKS = Gamma Knife surgery; LCCA = left common carotid artery; LEJV = left external jugular vein; LINAC = linear accelerator. obJect Brain arteriovenous malformations (AVMs) are a major cause of stroke. Many AVMs are effectively obliterated by stereotactic radiosurgery, but such treatment for lesions larger than 3 cm is not as effective. Understanding the responses to radiosurgery may lead to new biological enhancements to this treatment modality. The aim of the present study was to investigate the hemodynamic, morphological, and histological effects of Gamma Knife surgery (GKS) in an animal model of brain AVM. methods An arteriovenous fistula was created by anastomosing the left external jugular vein to the side of the common carotid artery in 64 male Sprague-Dawley rats (weight 345 ± 8.8 g). Six weeks after AVM creation, 32 rats were treated with a single dose of GKS (20 Gy); 32 animals received sham radiation. Eight irradiated and 8 control animals were studied at each specified time point (1, 3, 6, and 12 weeks) for hemodynamic, morphological, and histological characterization. results Two AVMs showed partial angiographic obliteration at 6 weeks. Angiography revealed complete obliteration in 3 irradiated rats at 12 weeks. Blood flow in the ipsilateral proximal carotid artery (p < 0.001) and arterialized jugular vein (p < 0.05) was significantly lower in the irradiated group than in the control group. The arterialized vein's external diameter was significantly smaller in GKS-treated animals at 6 (p < 0.05) and 12 (p < 0.001) weeks. Histological changes included subendothelial cellular proliferation and luminal narrowing in GKS-treated animals. Neither luminal obliteration nor thrombus formation was identified at any of the time points in either irradiated or nonirradiated animals. coNclusioNs GKS produced morphological, angiographic, and histological changes in the model of AVM as early as 6 weeks after treatment. These results support the use of this model for studying methods to enhance radiation response in AVMs.

Correlation of Appearance of MRI Perinidal T2 Hyperintensity Signal and Eventual Nidus Obliteration Following Photon Radiosurgery of Brain AVMs: Combined Results of LINAC and Gamma Knife Centers

“…13,31,33,34 The desired radiobiological effects of SRS of AVMs are morphologically, histologically, immunohistochemically and electron microscopically demonstrated by the hallmarks of both the small vessel wall changes and the proliferative and degenerative changes occurring in the connective tissue stroma of the AVM after stereotactic irradiation. 17,18,[35][36][37][38] Early post-SRS effects include swelling of endothelial cells, particularly in small blood vessels, as well as stromal granulation tissue formation and spindle cells (fibrocytes and fibroblasts) proliferation. 36,39,40 Months or years later, delayed radiation effects are seen as a proliferation of injured endothelium, intravascular thrombosis, stromal collagen accumulation, and hyaline degeneration.…”

“…17,18,[35][36][37][38] Early post-SRS effects include swelling of endothelial cells, particularly in small blood vessels, as well as stromal granulation tissue formation and spindle cells (fibrocytes and fibroblasts) proliferation. 36,39,40 Months or years later, delayed radiation effects are seen as a proliferation of injured endothelium, intravascular thrombosis, stromal collagen accumulation, and hyaline degeneration. 17,41 The thrombus formation is promoted by intimal injury, increased platelet aggregation, and turbulent blood flow that play an important role in the obliteration cascade of the small pathologic vessels of the AVM nidus.…”

In vivo imaging of endothelial cell adhesion molecule expression after radiosurgery in an animal model of arteriovenous malformation

“…An arteriovenous fistula (AVF) was created surgically in isoflurane-anesthetized 6-week old, male Sprague-Dawley rats (n = 48) by anastomosing the caudal end of the left external jugular vein to the left common carotid artery as described in detail previously [ 25 , 26 ]. The AVF was considered ready for Gamma Knife surgery (GKS) six weeks following creation.…”

“…Anesthetized rats (n = 24) were treated using a single-fraction stereotactic radiosurgical dose administered using a Leksell Gamma Knife Perfexion (Elekta Instruments, Stockholm, Sweden) at Macquarie University Hospital (Sydney, Australia). GKS planning by axial full-body CT scanning with 3D reconstruction and subsequent treatment was performed as described [ 25 ], with the exception that a single marginal 15 Gy dose of radiation was delivered.…”

Development of an angiogenesis animal model featuring brain arteriovenous malformation histological characteristics

“…In most of these models, vascular changes are seen that resemble in many cases those found in human bAVMs 6 9 10. Genetic mutations as observed in hereditary hemorrhagic telangiectasia have facilitated the development of AVM animal models and, especially mice models, that induce the bAVM phenotype through genetic transformations 7 11 12. These genetic mutations alter inflammatory factors, angiogenesis, vasculogenesis, and structural proteins 13.…”