The effects of chronic cerebral hypoperfusion associated with arteriovenous malformations

Abstract

Although recognised for over 300 years, the study of the effects of chronic cerebral hypoperfusion (both in association with cerebral arteriovenous malformations and in the field of cerebral ischaemia) has not been adequately explored using scientifically sound methods, with most information to date being of an anecdotal nature. The purpose of this thesis is to explore the effects of chronic cerebral hypoperfusion associated with arteriovenous malformations in a rat model. A chronic reduction in cerebral blood flow of 25-50% was maintained for 6 months after which in vitro neuronal structure and function and in vivo whole animal behaviour were studied and found to be compromised. Using light microscopy no evidence of cerebral infarction was found, however disorganization of cell body layers in the hippocampus as well as an increase in relative vascularity were noted. Electron microscopy of the CA1 pyramidal cell layer of the hippocampus revealed subtle neuronal and astrocytic changes along with an absence of an astrocytic foot process layer in a proportion of the capillaries. The results have obvious clinical relevance. The electrophysiological changes revolved around an impairment of the phenomenon of long-term potentiation in the hippocampus, which was examined in detail with possible mechanisms for the "perturbations explored. Finally, whole animal behavioural correlates showed perturbations in responses of animals as a result of the chronic cerebral hypoperfusion. Evidence is presented that may explain in part the oedema and haemorrhage that may follow the excision of a cerebral arteriovenous malformation when this is not the result of venous occlusion or technical problems. Overall, an overview of the effects of chronic cerebral hypoperfusion associated with arteriovenous malformations (of a known magnitude and maintained for a set duration) is obtained, an objective not previously satisfactorily addressed. New information is also presented on chronic cerebral ischaemia in general. Two major implications emerge from these experiments with respect to chronic cerebral ischaemia. Firstly, the thresholds of acute cerebral ischaemia deviate from normal in the presence of chronic cerebral ischaemia. Secondly, a new pathological category of cerebral ischaemia is defined between the two polarities of either neuronal normality or neuronal infarction found following acute ischaemia, whereby neuronal structure and function can be compromised in the absence of cerebral infarction following chronic hypoperfusion. Thus, through a broadly based examination of the effects of chronic cerebral hypoperfusion associated with arteriovenous malformations, this thesis provides a skeletal framework of the changes associated with this condition. This has clinical relevance and also supports a sound platform for further experimentation.