Elsevier

The Lancet Neurology

Volume 10, Issue 10, October 2011, Pages 909-921
The Lancet Neurology

Review
Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target

https://doi.org/10.1016/S1474-4422(11)70195-8Get rights and content

Summary

Ischaemic stroke results from acute arterial occlusion leading to focal hypoperfusion. Thrombolysis is the only proven treatment. Advanced neuroimaging techniques allow a detailed assessment of the cerebral circulation in patients with acute stroke, and provide information about the status of collateral vessels and collateral blood flow, which could attenuate the effects of arterial occlusion. Imaging of the brain and vessels has shown that collateral flow can sustain brain tissue for hours after the occlusion of major arteries to the brain, and the augmentation or maintenance of collateral flow is therefore a potential therapeutic target. Several interventions that might augment collateral blood flow are being investigated.

Introduction

Stroke continues to impose an overwhelming burden on global health, imparting devastating disability, but few therapeutic advances have been made despite decades of research. It is the second most common cause of death, with most of the 16 million cases occuring in developing countries.1, 2 Ischaemia, or restricted blood flow, is the main cause of stroke, typically due to occlusion of a cerebral artery as a result of progressive atherosclerosis or an embolus from the heart or neck vessels.1, 2, 3 In some patients, the blockage or occlusion can develop within small intracranial vessels, often because of uncontrolled hypertension or diabetes.4, 5 Irrespective of cause or mechanism of ischaemia, collateral flow—ie, perfusion via alternative, indirect pathways—might offset potential injury to the brain.6, 7, 8

Digital subtraction angiography has been used to identify collateral vessels in patients with acute stroke, but because of its invasive nature it has not gained widespread popularity. Newer imaging techniques, especially multimodal cranial CT scans, can assist with identification of pial collaterals. Evidence is emerging that this information could help to improve long-term prognosis. Additionally, patients with good collaterals might respond better to reperfusion therapy9 and have a lower risk of haemorrhagic complications from such treatments than do other patients.10

The pathophysiology of the evolving stroke has been well studied in animals and people.11, 12 Ischaemic thresholds have been established in in-vivo models; generally, these thresholds parallel cellular damage in other tissues of the body, but with a few important differences.13 Normal cerebral blood flow (CBF) is between 50 and 60 mL/100 g/min and is tightly controlled by cerebral autoregulation.13 The pace of cellular death in the brain after an arterial occlusion is closely linked to the severity of decrease in blood flow within the local environment. When blood flow is less than 10 mL/100 g/min, damage is rapid and most cells die within minutes of the insult.13, 14, 15 When CBF is between 10 and 20 mL/100g/min, neurons cease to function but remain structurally intact and are potentially revivable if normal blood flow is restored.15 Therefore, neuronal damage is not uniform when an intracranial artery is occluded, especially in the first few hours after the insult. Depending on the extent of collateral perfusion, infarction might not be complete for hours or even days.16

Modern neuroimaging techniques, particularly multimodal CT and MRI (including non-invasive angiography and perfusion imaging), allow identification of cerebral injury in the first few hours after arterial occlusion. Detailed imaging studies have shown that progression to complete infarction, especially after occlusion of the middle cerebral artery (MCA), is highly variable.9, 17 In some cases, infarction is complete in less than an hour, but other patients might show evidence of viable tissue for days, if not indefinitely.18 In patients whose tissue survives for a long period despite proximal arterial occlusion, retrograde filling of pial arteries (a surrogate indicator of leptomeningeal collateral vessels) is often evident in imaging studies and might have an important protective role.9

Enhancement of blood flow through collateral vessels might be therapeutically useful in the treatment of acute stroke. The notion of CBF augmentation by volume expansion and induced hypertension has been tested in several small trials dating from the 1970s.19, 20 Newer methods of CBF augmentation in acute ischaemic stroke have also been assessed.21

In this Review, we summarise the anatomy and physiology of the collateral circulation, and its potential as a therapeutic target in ischaemic stroke. We focus on the importance of emerging CT and MRI technologies that can be used to identify collateral blood vessels in the very early stages of ischaemic stroke. We present evidence that good collateral circulation can prevent or delay permanent neural damage, and assess how the presence of collateral blood vessels helps to improve patient outcomes with thrombolysis. Finally, we present information about therapies that have been used to enhance collateral blood flow in patients with acute ischaemic stroke.

Section snippets

Anatomy of the collateral circulation

Three principal anatomical features underlie collateral perfusion to the brain (figure 1). The first consists of large-artery communications between the extracranial and intracranial circulations. The external carotid artery gives rise to many branches in the neck that are a potential source of collateral flow, especially in the event of chronic stenosis or occlusion of the internal carotid artery. Important collateral circuits include flow through the ophthalmic (retrograde) and superficial

Physiology of collateral blood flow regulation

Normally, CBF is regulated by the metabolic demands of the brain itself, which vary regionally and with activity. Although the precise mechanisms underlying cerebral autoregulation are not fully understood, the process seems to be mediated at several levels, including neurons, neuropil, and cerebral blood vessels.35

Blood flow is also regulated by intrinsic and extrinsic innervations of the blood vessels.36, 37 The intrinsic nerves originate mainly in the brainstem and are distributed

Systemic changes during acute stroke that compromise collateral recruitment

Collateral flow could restrict the extent of infarction in ischaemic stroke. However, the effectiveness of collateral flow varies greatly between patients. Several systemic factors might adversely affect recruitment of collateral vessels, resulting in extensive infarction (panel 1).

In thrombotic and embolic stroke, intravascular pressure distal to the occlusion falls immediately. Concurrently, pressure within the pial vessels is relatively well preserved, resulting in a gradient that can

Augmentation of cerebral blood flow in acute stroke

Supportive medical care for patients with acute stroke, including adequate hydration and the avoidance of wide fluctuations in blood pressure, can help to maintain collateral flow capabilities. Optimisation of systemic factors (panel 1) could help to minimise the risk of collateral failure, particularly in patients with proximal arterial occlusions. Several interventions aimed at increasing CBF via collateral vessel recruitment or stabilisation might be therapeutically useful in acute ischaemic

Conclusions

In acute stroke, the severity of ischaemia determines how fast brain tissue might sustain irreversible damage. Pial collaterals, if well developed, might allow protracted tissue survival in the event of a proximal occlusion of a large intracranial blood vessel. Imaging of collateral blood flow is challenging, but multimodal CT and MRI techniques (perfusion combined with vessel imaging) seem to be the most promising methods for the routine assessment and quantification of this important

Search strategy and selection criteria

We searched Medline for all reports related to acute ischaemic stroke in which imaging techniques were used to measure collateral flow. We used “stroke”, “ischemia”, “collaterals”, “circle of Willis”, and “brain imaging” as search terms. We included reports from Jan 1, 1980, to July 31, 2011. Only papers published in English and German were considered. Additionally, we carefully examined the reference section of relevant reports to ensure that we had not missed any important previous references

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