Imaging Evaluation of Collaterals in the Brain: Physiology and Clinical Translation
- 726 Downloads
The cerebral collateral circulation is a network of blood vessels designed to preserve cerebral blood flow when primary routes fail. Though recognized for hundreds of years, the beneficial influence of collateral flow has now gained significant attention because of widely available, rapid, and real-time non-invasive imaging techniques. Multimodal CT- and MRI-based techniques, with angiographic and perfusion assessments, are becoming mainstays in the care of patients with ischemic brain disease. These methods allow for precise delineation of the structural and functional aspects of cerebral blood flow and as such provide valuable information that can inform the diagnosis and treatment of cerebral ischemia in both the acute and chronic setting.
KeywordsStroke Angiography Perfusion Intracranial stenosis Thrombectomy Moyamoya
The cerebral collateral circulation is an evolutionarily conserved network of blood vessels designed to maintain consistent cerebral perfusion in the face of physiologic and pathophysiologic changes. Our recent ability to qualitatively and quantitatively define the structural and functional aspects of this system through non-invasive imaging techniques has revolutionized our approach to cerebral ischemia. From a diagnostic point of view, these methods identify brain territories at risk and inform the likely clinical course of the patient, in terms of progression of infarct in the case of acute ischemia, or recurrent stroke in the case of chronic disease. From a therapeutic point of view, these data are invaluable in determining which patients present a favorable vascular profile with tissue that could be saved with revascularization. Further, because reperfusion procedures in acute and chronic ischemic brain disease are imprecise and in many cases unproven [1••, 2, 3•, 4], demonstrating the degree of restoration of blood flow and correlating with clinical outcome is crucial in the development of these techniques. Ultimately, collateral imaging provides rich details on the flow of blood to different regions of the brain; it is the characteristics of this flow, and not those of the arterial lesion, that determine whether the underlying brain parenchyma lives or dies.
Collateral Circulation Anatomy
The cerebral collateral circulation is a system of redundancies within the neurovasculature designed to preserve cerebral blood flow when primary routes fail . It is the principle component of the brain’s homeostatic response to ischemic insults. As a result of this network of subsidiary vessels that includes components of both the arterial and venous circulation, the brain is able to survive occlusions of even large proximal arteries; almost 60 % of patients have been shown to tolerate complete occlusions of the internal carotid artery .
The anatomy of this circulation includes extracranial sources of blood flow that can be diverted to intracranial vessels as well as intracranial routes that can supplement other intracranial areas in need . Extracranial carotid branches that can shunt flow via anastomoses to the intracranial arteries include the facial, maxillary, middle meningeal, and occipital arteries. Common anastomotic routes include the ophthalmic artery, which may fill in a retrograde direction, as well as smaller and unnamed dural arteries.
Intracranial collateral routes can be further subdivided into primary and secondary routes. The primary pathways include the components of the circle of Willis, and the secondary pathways include less direct routes that develop over time. The anterior portion of the circle of Willis includes the anterior communicating artery, which allows for interhemispheric collateralization and blood flow from the contralateral carotid artery. This collateral route would result in blood flow reversal in the ipsilateral proximal anterior cerebral artery. The posterior portion contains the posterior communicating arteries, which allow for collateralization from the posterior circulation to the anterior circulation, or vice versa. Variability and asymmetry is the rule in population studies of circle of Willis anatomy, with an intact circle present in a minority of patients . Overall, the number and quality of collateralization is highest between anterior and middle cerebral arteries, with less robust connections between posterior cerebral and middle cerebral arteries . Dynamic changes in these Willisian routes may be chronicled with serial imaging of stroke patients, and ongoing studies may provide further dimension to the functional impact of specific configurations in this proximal network.
The robustness of the collateral network likely diminishes with age and other vascular comorbidities such as hypertension. The effect of aging was studied in middle cerebral artery occlusions in mice and was shown to lead to a proportional decrease in collateral vessels, with narrower diameter and increased tortuosity. Resistance of these vessels was increased, as was the ultimate infarct volume compared to younger animals . Hypertension has also been shown to lead to less robust collaterals in rodent models, with narrower resultant anastomoses and decreased blood flow . Ongoing studies are investigating such correlations with the human collateral circulation of the brain in a variety of stroke populations.
Structural Collateral Imaging Defines Vascular Lesions
The gold standard for the anatomic evaluation of the collateral circulation is digital subtraction angiography (DSA). This technique allows for dynamic visualizations of blood flow that cannot be attained through other traditional imaging modalities. It assesses all three major routes: extracranial to intracranial, through the circle of Willis, and through leptomeningeal vessels . The primary limitation of DSA is its invasive nature, as well as its reliance on iodinated contrast and ionizing radiation. In addition, there may be variability in the appearance of the cerebral vasculature, particularly smaller distal vessels, depending on the volume and pressure of the contrast injection 5].
Non-invasive techniques have now become standard in the initial assessment of primary and collateral cerebral circulations. CT angiography (CTA) is one of the most widely available and utilized diagnostic tools in assessing arterial occlusions in the setting of acute ischemic stroke and can be used to concurrently determine the presence or absence of structural collaterals. CTA data can be interpreted from the source images, or reformatted as maximal intensity projections (MIPs) or multiplanar reconstructions (MPRs). Dynamic CTA, also known as 4D CTA, is a more recently developed and promising new technique that allows for dynamic assessments of cerebral blood flow that results in data comparable to cerebral angiography. These data can been acquired through a 320-row CT scanner with dynamic acquisitions once per second or by reconstructions of data acquired utilizing CT perfusion acquisitions. This approach has demonstrated good correlation with cerebral angiography in detecting arteriovenous malformations . In acute ischemic stroke, the additional time-delayed images allow for enhanced delineation of the extent of arterial occlusions .
Functional Collateral Imaging Defines Territory at Risk
Beyond structural assessments of collateral circulation, advances in perfusion-based imaging have allowed for functional evaluations of the quality of collateral blood flow. These studies are of particular importance in both acute and chronic arterial occlusive disorders as they provide crucial information on the health of the underlying brain parenchyma. Regardless of the modality employed, a finding of hypoperfusion indicates a territory at risk, and hyperperfusion, in the setting of poor collaterals, may represent the potential risk of hemorrhagic transformation through increased permeability and blood-brain barrier disruption .
MR-based perfusion is also widely used in the assessment of ischemic brain disease. This study is most commonly performed using a bolus of contrast and assessing flow dynamics by monitoring the passage of the bolus through the vessels and parenchyma. A more recent technique known as arterial spin labeling (ASL) magnetically “labels” arterial blood water using radiofrequency pulses that then decay with T1 relaxation and allows for quantitative assessments of regional cerebral blood flow without the need for a tracer. This technique has been used in moyamoya disease , acute ischemic stroke , and chronic arterial stenoses . Compared to dynamic susceptibility contrast-enhanced perfusion MRI, ASL may demonstrate hyperperfusion more overtly .
Transcranial Doppler (TCD) can provide physiological information on the status of cerebral collaterals. Changes in flow directionality (i.e., in the ophthalmic artery or anterior communicating artery) can inform compensatory collateral changes. Similarly, flow diversion, defined as increased velocity in vessels ipsilateral to a stenosis or occlusion as compared to contralateral controls, has been shown to correlate with the presence of leptomeningeal collaterals .
Other methods of measuring cerebral perfusion include PET and nuclear medicine approaches such as SPECT. These techniques, in addition to the ones mentioned above, can be combined with a vasodilatory stimulus to determine the resilience of the cerebral circulation to ischemic insults, termed the cerebrovascular reserve (CVR). This measurement takes into account all the compensatory changes available to the brain to preserve cerebral blood flow in the setting of acute ischemia. Intravenous acetazolamide and inhaled CO2 are the most common vasodilatory stimuli, and an inability to recruit additional blood flow in response to their administration signifies impaired collateral flow and diminished CVR.
Collateral Grading Scales
A multitude of grading scales have been developed to describe the presence and quality of collaterals based on CT, MRI, TCD, and angiographic evaluations. These scales involve both structural and functional aspects of collateral flow. There is, however, significant inconsistency in how the grading and scaling is performed as well as the inter-rater reliability. For angiographic assessments, the ASITN/SIR scales  remain the most commonly used. This lack of consensus may contribute to an overall under appreciation of the fundamental role of collateral circulation in outcomes following acute ischemic stroke.
Chronic Arterial Occlusive Disease
Assessments of both structural and functional aspects of collateral circulation are most commonly used in determinations of the risk of ischemia from arterial occlusive disorders. Carotid stenosis in particular is one of the most well-studied applications. An estimated 15–20 % of ischemic strokes have been attributed to ipsilateral carotid atherosclerotic disease , and while the degree of luminal narrowing is the measurement most commonly used to define hemodynamically significant stenosis, this measurement does not take into account the downstream hemodynamic changes. Such assessments may be particularly important in the case of asymptomatic carotid disease, in which case the utility of revascularization procedures is less clear, as the reduction in stroke risk may equal the surgical risk .
Several studies have evaluated the impairment in functional collateral flow in the setting of chronic stenosis or occlusion of the internal carotid or middle cerebral artery, and attempted to correlate those changes with risk of subsequent stroke or TIA [38, 39, 40, 41, 42, 43, 44]. A recent meta-analysis found a significant odds ratio of 4 between impairment in CVR and subsequent risk of ischemic disease in both symptomatic and asymptomatic carotid disease .
Similar approaches have been used to assess the risk of downstream ischemia in the setting of intracranial stenosis, one the most common causes of strokes worldwide . Treatment of symptomatic lesions with angioplasty and stenting has been shown to improve CVR [46, 47]. A recent trial of endovascular stenting for these patients, however, failed to demonstrate a reduction in the risk of stroke likely because of periprocedural complications . Even in the setting of demonstrable hypoperfusion using the techniques listed above, the optimal management strategy for this disorder remains unclear.
Moyamoya syndrome or disease is a scenario in which assessments of collateral flow play a pivotal role in clinical decision-making. This disorder is a potentially, progressive obliterative vasculopathy in which the normally large-caliber proximal vessels of the brain are obstructed and replaced by thin, ineffective perforating vascular channels . In a sense, moyamoya syndrome represents the most extreme example of collateral development and one of the greatest challenges to the secondary sources of blood supply to the brain. Patients with this disorder may come to medical attention as a result of symptoms associated with chronic cerebral hypoperfusion, such as headaches, ischemic TIA/stroke, or cognitive dysfunction. As in the case depicted in Fig. 1, perfusion studies are routinely used in patient selection for evaluation for revascularization and in follow-up assessments of efficacy [49, 50]. Functional collateral imaging has demonstrated a link between frontal lobe hypoperfusion and frontally mediated cognitive dysfunction, and, importantly, improvement in both parameters with revascularization [51, 52].
Acute Arterial Occlusive Disorders
Acute ischemic stroke is one of the most promising areas for real-time assessments of collateral flow and is also one of the areas with the greatest need for these techniques. Patient selection for acute revascularization procedures remains highly controversial, particularly in the case of endovascular thrombectomy [1••, 2]. The initial efforts in this field using intravenous thrombolysis did not include an evaluation of cerebral hemodynamics and instead used time from last known well as a proxy . As a result, the existing metrics to determine patient eligibility for intravenous thrombolysis, as well as endovascular reperfusion in many cases, are based on time alone . This approach, of course, does not take into consideration the significant variability in hemodynamic response due to collateral circulation anatomy. Without taking this factor into account, we may be under-treating patients with a robust collateral circulation who may be suitable for revascularization many hours after symptom onset and over-treating those with a meager response who may have already suffered infarction of the entire vascular territory well before the arbitrarily defined time point. More recent studies have begun to address this issue and found that patients with poor collaterals have been shown to present to the hospital earlier and have poorer outcomes from acute stroke. On the other hand, the ability to recruit collateral vessels has been shown to be time-dependent and correlate with stabilization of clinical symptoms . A recent assessment of intravenous thrombolysis moved to incorporate collateral assessments into the decision and found that in patients who are able to maintain perfusion to a suitable level in spite of an acute arterial occlusions, treatment at up to 6 h may be safe .
The presence of collaterals has been shown to have an impact on the ultimate injury associated with acute arterial occlusions. Regional assessments of collateral networks can predict the ultimate infarct area in the setting of comparable sites of occlusion . A favorable vascular profile consisting of an intact circle of Willis and MAP was shown to predict improved outcome after stroke . Diminished collateral scores based on CTA have been shown to correlate with larger territories of ischemia in the setting of occlusions of the internal carotid or middle cerebral artery [55, 59]. Conversely, the presence of CTA-defined leptomeningeal collaterals has also been shown to correlate with improved functional outcome in acute ischemic stroke [60, 61]. In addition, the finding of very low cerebral blood volume on perfusion imaging may predict hemorrhage after thrombolytic therapy even more than the volume of diffusion-weighted imaging positivity .
Patient selection for intra-arterial revascularization techniques also benefits from inclusion criteria that take into account cerebral perfusion . In patients undergoing endovascular revascularization therapy, higher collateral grades have been demonstrated to lead to improved recanalization rates; similarly, patients with poor collaterals were shown to not benefit even with successful recanalization of the occlusive lesion . Patients with poor collaterals tend to present with higher volumes of perfusion/diffusion mismatch versus areas of benign hypoperfusion compared to patients with robust collaterals, who had larger areas of benign hypoperfusion. Similarly, after recanalization therapy, patients with poor collaterals were more likely to suffer expansion of the infarction area in the region of impaired perfusion . After endovascular reperfusion, collateral status predicts hemorrhage rate as well .
The presence and quality of collateral circulation has become a fundamental feature in the evaluation and treatment of cerebral ischemia. Though recognized for hundreds of years, the beneficial influence of collateral flow has now gained significant attention due to widely available, rapid, and real-time non-invasive imaging techniques . Collateral imaging has become a cornerstone in the evaluation of patients with acute and chronic cerebral ischemia by informing the diagnosis, treatment, and follow-up for these patients. These modalities provide rich detail on the quality and quantity of cerebral blood flow, which in the end is the sole determinant of tissue viability.
Compliance with Ethics Guidelines
Conflict of Interest
Sunil A. Sheth declares no conflict of interest. David S. Liebeskind’s institution receives funding for his consultancy for Covidien and Stryker. His institution also receives funding through NIH/NINDS research grants.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.•• Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914–23. This pivotal study, known as MR RESCUE, was the first to use perfusion imaging in a large, randomized trial setting evaluating endovascular therapy for acute ischemic stroke. Though the study did not base treatment decisions on the findings of perfusion imaging, future trials will likely incorporate the imaging methodology established within this trial. Google Scholar
- 3.• Powers WJ, Clarke WR, Grubb RL, Videen TO, Adams HP, Derdeyn CP, et al. Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial. JAMA. 2011;306:1983–92. This trial, abbreviated COSS, evaluated patients with evidence of hemodynamic changes on PET imaging from carotid occlusions. Though the surgical intervention studied in the trial failed to show benefit, the approach of perfusion imaging to identify patients meriting additional treatment is likely to be continued. Google Scholar
- 13.Coyle P, Heistad DD. Development of collaterals in the cerebral circulation. J Vasc Res. 1991;28:183–9.Google Scholar
- 43.Ogasawara K, Ogawa A, Terasaki K, Shimizu H, Tominaga T, Yoshimoto T. Use of cerebrovascular reactivity in patients with symptomatic major cerebral artery occlusion to predict 5-year outcome: comparison of xenon-133 and iodine-123-IMP single-photon emission computed tomography. J Cereb Blood Flow Metab. 2002;22:1142–8.PubMedCrossRefGoogle Scholar
- 50.Schubert GA, Weinmann C, Seiz M, Gerigk L, Weiss C, Horn P, et al. Cerebrovascular insufficiency as the criterion for revascularization procedures in selected patients: a correlation study of xenon contrast-enhanced CT and PWI. Neurosurg Rev. 2009;32:29–35 discussion35–6.PubMedCrossRefGoogle Scholar
- 52.Song YS, Oh SW, Kim YK, Kim S-K, Wang K-C, Lee DS. Hemodynamic improvement of anterior cerebral artery territory perfusion induced by bifrontal encephalo(periosteal)synangiosis in pediatric patients with moyamoya disease: a study with brain perfusion SPECT. Ann Nucl Med. 2011;26:47–57.PubMedCrossRefGoogle Scholar
- 56.Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol. 2006;60:508–17.PubMedCrossRefGoogle Scholar
- 62.Campbell BCV, Christensen S, Butcher KS, Gordon I, Parsons MW, Desmond PM, et al. Regional very low cerebral blood volume predicts hemorrhagic transformation better than diffusion-weighted imaging volume and thresholded apparent diffusion coefficient in acute ischemic stroke. Stroke. 2009;41:82–8.PubMedCrossRefGoogle Scholar
- 67.http://clinicaltrials.gov/ct2/show/NCT00856661. Accessed 5 Nov 2013.