- Title
- A new understanding of factors regulating collateral blood flow during ischaemic stroke: elevated intracranial pressure is a potential cause of collateral failure in patients with stroke-in-progression
- Creator
- Beard, Daniel Joseph
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2015
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: Collateral vessels form an important network of anastomoses that link adjacent arterial territories. These anastomoses help redirect flow and keep the brain alive in the case of major arterial occlusion (ischaemic stroke). Important collateral vessels include the Circle of Willis, leptomeningeal collaterals and intraparenchymal collaterals (e.g. anterior choroidal artery (AChA)). Clinically, good flow through leptomeningeal collaterals (usually between the middle cerebral artery (MCA) and anterior cerebral artery (ACA)) is associated with larger baseline penumbra, less incorporation of the penumbra into the infarct core, greater rates of recanalisation with thrombolysis and better clinical outcomes following MCA occlusion (MCAo). Despite the importance of leptomeningeal collaterals, a reduction in flow through these vessels has been shown to occur in some patients. A reduction of flow through collaterals (collateral failure) is associated with infarct expansion and deterioration in patients with good collateral status on baseline advanced imaging, who do not achieve reperfusion (stroke-in-progression). The cause of collateral failure is unknown. Our laboratory team recently demonstrated that intracranial pressure (ICP) elevation occurs 24 hours after minor experimental stroke, corresponding to the timing of deterioration in patients with stroke-in-progression. We hypothesised that early ICP elevation following minor stroke is the cause of collateral failure and infarct expansion in stroke-in-progression. The aims of this PhD were to: 1) investigate the importance of an internal collateral vessel in experimental stroke outcome; 2) develop a method to quantify blood flow through individual leptomeningeal collateral vessels during MCAo- reperfusion; 3) determine changes in collateral and associated penetrating arteriole blood flow during MCAo-reperfusion; 4) investigate the effect of ICP elevation on collateral blood flow early after minor experimental stroke; 5) investigate the importance of cerebral oedema in ICP elevation at 24 hours after experimental stroke; 6) determine the effectiveness of mild hypothermia in preventing ICP elevation at 24 hours after experimental stroke; 7) determine the importance of the choroid plexus and the ischaemic penumbra in triggering ICP elevation 24 hours after minor experimental stroke. Publication I: Computed tomography perfusion imaging was used to identify the patency of an important internal collateral pathway between the AChA and MCA following intraluminal MCAo in rats. Inadvertent occlusion of the AChA during MCAo resulted in larger cortical and subcortical MCA territory strokes. Inadvertent occlusion of this collateral pathway with the intraluminal thread occlusion model explains much of the infarct variability in this model. Publication II: To determine the effect of ICP elevation on collateral flow I first developed a method to quantify single vessel leptomeningeal collateral flow. I showed that collateral vessels have bi-directional blood flow at baseline and varied blood flow profiles during reperfusion. Flow became unidirectional and significantly increased following MCAo, driven primarily by increases in blood flow velocity rather than changes in vessel diameter. ICP elevation caused a linear stepwise reduction in collateral blood flow (by reducing blood flow velocity). This suggests that collateral flow is primarily regulated by the pressure differential across the collateral vessel. ICP elevation may reduce collateral flow by reducing this pressure differential. Publication III: To determine the association between ICP elevation and oedema volume and the effectiveness of mild hypothermia to prevent ICP elevation, we performed a series of three experiments, using two different rat strains. ICP elevation at 24 hours was not associated with oedema volume. Mild short-duration hypothermia was highly effective in preventing ICP elevation. Publication IV: To determine the importance of choroid plexus ischaemia and the ischaemic penumbra in ICP elevation, we monitored ICP following submaximal and maximal cortical photothrombotic (PT) and permanent MCA strokes. ICP elevation occurred at 24 hours in animals with submaximal PT and MCA strokes and not in those animals with maximal strokes. There was no association between the degree of choroid plexus injury and ICP elevation in both models. This suggests that ICP elevation is not simply secondary to choroid plexus ischaemia but occurs in response to active cellular processes within the ischaemic penumbra. Conclusions: I have made a number of important findings that challenge the current thinking about the pathophysiology of stroke-in-progression. My findings confirm the importance of the collateral circulation, irrespective of location (i.e. leptomeningeal versus intraparenchymal) in influencing stroke outcome. I have shown that ICP elevation decreases collateral flow. Recent work illustrates that infarct expansion in stroke-in-progression occurs with the same timing as the ICP elevation we see in experimental stroke. Furthermore, I have demonstrated that ICP elevation occurs in an experimental model mimicking the circumstances of stroke-in-progression (permanent MCAo with good collaterals). Taken together these findings strongly suggest that ICP elevation is the likely cause of collateral failure and infarct expansion in patients with stroke-in-progression. ICP elevation occurs independent of oedema and good collaterals and a large penumbra may be required for this rise to occur. Short-duration mild hypothermia is an effective ICP elevation preventative that warrants future clinical investigation.
- Subject
- collaterals; intracranial pressure; experimental stroke; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1310082
- Identifier
- uon:21981
- Rights
- Copyright 2015 Daniel Joseph Beard
- Language
- eng
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