The Development of Cerebral Arteriovenous Malformations

Abstract

Cerebral arteriovenous malformations (cAVM) are a significant cause of morbidity and mortality, particularly in the young. They consist of a tangle of abnormal cerebral blood vessels with an artery feeding into a nidus, which drains into a vein, in the absence of capillaries. Angiogenesis refers to new vessel formation, which is detectable on an angiogram as a border of friable vessels immediately surrounding the nidus. The overall aim of this thesis is to understand the development of cAVMs by investigating angiogenesis through three projects. Catheter angiography is the gold standard investigation to study and assess cAVMs. We reviewed 100 cAVM patient angiograms and recorded their angioarchitectural features, including angiogenesis. We tested for any association between the latter and all other features. Inter-observer agreement and intra-observer agreement were assessed using 10 cases. We detected angiogenesis in 39 cAVMs. There were statistically significant associations between angiogenesis and artery: vein ratio and arterial ectasia. Mostly, strong intra-observer agreement and moderate inter-observer agreement was noted. Specifically, for angiogenesis, there was fair to substantial inter-observer agreement and substantial intra-observer agreement. We identified a lack of standardisation in cAVM reporting despite the publication of a consensus document in 2001. We predicted that few publications adhered to the recommendations. We conducted a systematic review to describe how cAVM angioarchitecture is reported in the literature, considering whether this consensus document was followed. Out of 4306 publications identified from the database search, 219 relevant articles were identified. Only 33 publications reported using the recommended terminology. Most authors only reported on size (78%), location (68%) and venous drainage (77%). The review confirmed our suspicions that few studies followed the guidelines. A reliable in vivo animal model for human cAVMs does not exist. There are problems with existing rodent models: the most important being that they produce a fistula with no nidus, not truly representing a cAVM. We combined a zebrafish genetic risk factor model (alk1 heterozygous mutant background, which causes vascular instability) with an environmental angiogenic stimulus (intracerebral haemorrhage) to produce an animal model to test for cAVM development in the future. We optimised an innovative protocol to visualise the neurovasculature in fixed and cleared whole adult alk1 zebrafish. We advanced our knowledge of cAVM development by reviewing angiograms, performing a systematic review on the reporting of cAVMs, and using the two-hit hypothesis to produce a zebrafish cAVM model as well as optimise a protocol for whole animal vascular imaging. Our studies have demonstrated that it is possible to reliably identify angiogenesis on cAVMs, there is a lack of uniformity when describing cAVMs, and that we have successfully developed a protocol to image the cerebral vasculature of an intact adult alk1 zebrafish.

Date of Award	9 Mar 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Hiren Patel (Main Supervisor), Paul Kasher (Co Supervisor) & Adrian Parry-Jones (Co Supervisor)