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
ReviewCollateral blood vessels in acute ischaemic stroke: a potential therapeutic target
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
References (94)
Collaterals in acute stroke: beyond the clot
Neuroimaging Clin N Am
(2005)- et al.
Modelling the circle of Willis to assess the effects of anatomical variations and occlusions on cerebral flows
J Biomech
(2007) - et al.
Widespread reductions in cerebral blood flow and metabolism elicited by electrical stimulation of the parabrachial nucleus in rat
Brain Res
(1985) - et al.
Neuronal messengers and peptide receptors in the human sphenopalatine and otic ganglia
Brain Res
(1999) - et al.
Stimulation of the intracranial trigeminally-innervated structure selectively increases cerebral blood flow
Brain Res
(1997) - et al.
Formation and maturation of the native collateral circulation
J Mol Cell Cardiol
(2010) - et al.
Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial
Lancet Neurol
(2008) - et al.
Neuroimaging, the ischaemic penumbra, and selection of patients for acute stroke therapy
Lancet Neurol
(2002) - et al.
Heart disease and stroke statistics—2010 update: a report from the American Heart Association
Circulation
(2010) - et al.
Stroke incidence and prevalence in Europe: a review of available data
Eur J Neurol
(2006)