Vascular Targeting Enhancement of Radiosurgery for Cerebral Arteriovenous Malformations Rajesh Reddy M.B. B.S. F.R.A.C.S. Prince of Wales Medical Research Institute University of New South Wales Submitted as requirement for the degree of Master of Surgery University of New South Wales July 2010 2 Abstract Objective: Radiosurgical treatment of brain arteriovenous malformations (AVMs) has the significant shortcomings of being limited to lesions smaller than 3 cm diameter and of a latency to cure of up to 3 years. Stimulation of thrombosis using vascular targeting is attractive as a possible means of overcoming these limitations. This study examined the effect of the vascular targeting strategy lipopolysaccharide (LPS) and soluble tissue factor (sTF) in an animal model of AVM treated with radiosurgery. Methods: Stereotactic radiosurgery (SRS, 20 animals) or sham radiation (12 animals) was administered to an animal model of AVM in 32 male Sprague-Dawley rats. Twenty- four hours after intervention, animals received an intravenous injection of LPS/sTF conjugate or normal saline. Animals were sacrificed at 1, 7, 30, or 90 days after treatment. Angiography was performed immediately prior to sacrifice and model AVM tissue was harvested for histological analysis to assess vessel thrombosis rates. Results: There was no systemic toxicity or intravascular thrombosis remote from the target region in any of the animals. SRS combined with saline resulted in thrombosis of 12% of small AVM vessels (diameter < 200µm). Thrombosis occurred in 58% of small vessels in animals that received SRS and LPS/sTF. An intermediate thrombosis rate of 43% was observed in animals given the LPS/sTF agent but no radiation. Conclusion: This study demonstrated that vascular targeting can increase intravascular thrombosis after radiosurgery and that the vessel occlusion is selective and durable. i Declaration Originality Statement ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgment is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project’s design and conception or in style, presentation and linguistic expression is acknowledged.’ Rajesh Reddy July 2010 ii Acknowledgments It is hard to write an acknowledgement without sounding cliched or resorting to well worn aphorisms. Be that as it may, the graditude and thanks I express are sincere. The obstacles and trials I faced whilst undertaking this Masters project during my neurosurgical training were challenging. It would not have been possible without the guidance, tutelage, and support of my supervisor - Marcus Stoodley. His constant presence, accessibility, and friendship, helped me perserve through times and thoughts that I might not be able to accomplish what I sought to achieve. He is a source of respect and admiration for his ability to excel as an academic and a surgeon. I am also indebted to the key members of his lab. Jacob Fairhall, for his friendship, humour, and generally sharing the pain in the duality of research and surgical training. James Tu and Sarah Hemley, also for their friendship as well as always being around to answer my many questions about lab work. My partner, has also contributed to this work in many ways - the value of her relentless reminders as to complete the various stages of my project and thesis is unquestionable. More so she has been at my side to encourage me, accept my mistakes, and make me feel proud whenever I have tried my best. And lastly, my parents. They gave me my name, they gave me my education, and above all else they gave me my life. Words cannot describe my feelings to them and my appreciation of the efforts they have put into giving me the life I have now. iii This study was funded in part by grants from the Neurosurgical Society of Australasia and the Brain Foundation. Dr Reddy was supported by a grant from the Royal Australasian College of Surgeons iv Table of Contents Vascular Targeting Enhancement of Radiosurgery for Cerebral Arteriovenous Malformations Abstract ...................................................................................................................................... i Objective: ............................................................................................................................... i Methods:................................................................................................................................. i Results:................................................................................................................................... i Conclusion:............................................................................................................................. i Declaration ................................................................................................................................ ii Originality Statement ............................................................................................................ ii Acknowledgments.................................................................................................................... iii Figures..................................................................................................................................... vii Tables ....................................................................................................................................... ix Introduction ................................................................................................................................1 Clinical Overview ..................................................................................................................1 The History of AVMs ............................................................................................................2 The Pathology of AVMs ........................................................................................................3 AVM Classification..............................................................................................................10 AVM Treatment ...................................................................................................................11 Radiosurgery ........................................................................................................................12 History of Radiosurgery.......................................................................................................12 Physics of Radiosurgery.......................................................................................................13 Biology of Radiosurgery ......................................................................................................15 Radiosurgery Techniques and Current Devices...................................................................17 Role of Stereotaxy................................................................................................................21 The Effects of Radiosurgery on AVMs................................................................................23 Potential for Improvement of Radiosurgery.........................................................................24 Vascular Targeting ...............................................................................................................25 Potential for Vascular Targeting Strategies in AVMs .........................................................27 Hypotheses ...............................................................................................................................30 Aims .........................................................................................................................................31 Materials and Methods.............................................................................................................32 Overall experimental plan ....................................................................................................32 v Ethics and Animal care ........................................................................................................33 Morbidity and Mortality.......................................................................................................34 AVM Model Creation ..........................................................................................................34 Radiosurgery Dosimetry ......................................................................................................37 Radiosurgery Delivery Protocol...........................................................................................39 Administering TF and LPS ..................................................................................................40 Angiography.........................................................................................................................41 Perfusion Fixation ................................................................................................................43 Tissue Processing