Cerebral Collateral Research Articles

Demographic and Clinical Predictors of Leptomeningeal Collaterals in Stroke Patients

Leptomeningeal collaterals improve outcome after stroke, including reduction of hemorrhagic complications after thrombolytic or endovascular therapy, smaller infarct size, and reduction in symptoms at follow-up evaluation. The purpose of this study was to determine the demographic and clinical variables that are associated with a greater degree of cerebral collaterals. Clinical data of patients presenting with M1 occlusions of the middle cerebral artery (MCA) and associated computed tomography angiography studies after admission from 3 separate institutions were retrospectively compiled (n = 82). Occluded hemispheres were evaluated against the intact hemisphere for degree of collateralization in the MCA territory. Regression analysis of variance was conducted between clinical variables and collateral score to determine which variables associate with greater collateral development. Smaller infarct size corresponded to greater collateral scores, whereas older age and statin use corresponded to lower collateral scores (P < .001). Cerebral collateralization is influenced by age and statin use and influences infarct size.

Quantifying Cerebral Collaterals In Carotid Artery Dissection May Help Stratify Stroke Risk. (P3.110)

Quantifying Cerebral Collaterals In Carotid Artery Dissection May Help Stratify Stroke Risk. (P3.110)

Permissive Hypertension during Awake Eversion Carotid Endarterectomy: A Physiologic Approach for Cerebral Protection

Carotid endarterectomy (CEA) is often completed with general anesthesia and routine shunting; however, shunting is only required in a small group of at-risk patients to maintain adequate cerebral perfusion. Selective shunting during CEA is performed to normalize cerebral hemodynamics for patients determined to be at risk. Eversion CEA with selective shunting for neurologic dysfunction in patients that are awake/sedated is described, as well as routine use of permissive hypertension (PH), which uses standard cardiovascular medications to recruit the cerebral collateral network and reduce the need for shunting. A retrospective review of all CEA procedures performed from July 2006 to April 2013 was conducted. Procedures were divided into 3 groups: pre-PH phase (group A), PH-test phase (group B), and routine PH phase (group C). Operative reports and anesthesia documentation were reviewed for clamp time, need for shunting, and mean hemodynamics during each case. During the study period, 232 CEAs met inclusion criteria and were divided into 3 groups: group A (n = 75) was predominate reactionary shunting, group B (n = 41) was predominate reactionary blood pressure augmentation, and group C (n = 116) was pre-emptive PH. When combining groups A and B, the at-risk group consisted of 21 of 116 (18.1%) patients who had a neurologic compromise develop after clamping the internal carotid artery and required a shunt or altered blood pressure hemodynamics. In comparison with group C, routine use of PH pre-emptively before clamping as a standard intraoperative technique led to need for shunting in 1 of 116 (0.86%) (p ≤ 0.001) and significantly reduced operative time (p ≤ 0.0001). Routine use of PH during clamp time can recruit the cerebral collateral network and substantially reduce the at-risk group and need for shunting in awake/sedated patients.

Assessment of collateral flow in patients with cerebrovascular disorders

The ability to maintain cerebral parenchymal perfusion during states of acute or chronic ischemic insult depends largely on the capacity of the cerebral collateral circulation. Perfusion techniques, including perfusion-CT and arterial spin labeling, may not only describe the overall status of the collateral network, but can also quantify the pathophysiologic collateral reserve, which is occult to conventional imaging techniques. The following review details advanced imaging modalities capable of resolving pathophysiologic collateral circulation in a functional and dynamic manner, with regards to the evaluation of both acute ischemic penumbra and chronic cerebral vascular reserve. Specifically, the applications of perfusion-CT, arterial spin labeling MRI techniques, and transcranial Doppler are reviewed in the context of collateral circulation with emphasis on perfusion techniques and proposed clinical utility.

"Imaging Evaluation of Collaterals in the Brain: Physiology and Clinical Translation"

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 due to 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.

Augmenting Collateral Blood Flow during Ischemic Stroke via Transient Aortic Occlusion

Collateral circulation provides an alternative route for blood flow to reach ischemic tissue during a stroke. Blood flow through the cerebral collaterals is a critical predictor of clinical prognosis after stroke and response to recanalization, but data on collateral dynamics and collateral therapeutics are lacking. Here, we investigate the efficacy of a novel approach to collateral blood flow augmentation to increase collateral circulation by optically recording blood flow in leptomeningeal collaterals in a clinically relevant model of ischemic stroke. Using high-resolution laser speckle contrast imaging (LSCI) during thromboembolic middle cerebral artery occlusion (MCAo), we demonstrate that transiently diverting blood flow from peripheral circulation towards the brain via intra-aortic catheter and balloon induces persistent increases in blood flow through anastomoses between the anterior and middle cerebral arteries. Increased collateral flow restores blood flow in the distal middle cerebral artery segments to baseline levels during aortic occlusion and persists for over 1 hour after removal of the aortic balloon. Given the importance of collateral circulation in predicting stroke outcome and response to treatment, and the potential of collateral flow augmentation as an adjuvant or stand-alone therapy for acute ischemic stroke, this data provide support for further development and translation of collateral therapeutics including transient aortic occlusion.

Abstract 529: A Chloride Intracellular Channel-4 (Clic4) and VEGF-A Signaling Pathway Regulates Maturation of the Collateral Circulation

The density of native (pre-existing) cerebral collaterals in healthy tissues varies widely and is a major determinant of the wide variation in infarct volume in ischemic stroke. Collateral number in adults has been shown to be dependent on 3 processes: formation in the embryo, maturation in the perinate (i.e. slight pruning, increase in diameterand muralization) and maintenance thereafter. However, the mechanisms underlying these processes are not well understood. We previously found that collaterogenesis is led by a unique “arteriolar” angiogenic sprouting-like mechanism involving the VEGF-Notch signaling pathway. We also observed that mice lacking chloride intracellular protein 4 (Clic4), a protein which appears to reside upstream of VEGF-A in hypoxia-induced signaling, had fewer pial collaterals on postnatal day (P)1 that underwent greater pruning by P21, to yield lower collateral number and more severe stroke in adults. Therefore, herein we hypothesized that Clic4 is required for both formation and maturation of the collateral circulation. Wildtype and Clic4 -/- mice formed similar numbers of collaterals through embryonic day (E)18.5. Thus, collaterogenesis does not require Clic4. However, perinatal pruning was strongly augmented in Clic4 -/- mice, resulting in reduced collateral number and larger infarct volume in adults after MCA occlusion. Pial diameter was also reduced, consistent with our previous findings. Overexpression of VEGF-A in Clic4 -/- mice by crossing them to Vegf hi/+ mice did not affect collaterogenesis but inhibited the excessive perinatal pruning, resulting in adults with the abundant collaterals and small infarct volume seen in wildtype mice. We conclude that Clic4 is not required for embryonic collaterogenesis but is essential for perinatal stabilization of nascent collaterals through a mechanism involving VEGF signaling.

Abstract 390: Cardiovascular Risk Factors and Endothelial Dysfunction Cause Rarefaction of the Collateral Circulation and Impaired Recovery from Ischemia

Aging and cardiovascular risk factors (CVRF) such as diabetes, hypertension, dyslipidemia and metabolic syndrome have been associated with collateral insufficiency in animals and humans. Long-standing CVRF as well as collateral insufficiency associate with poorer outcomes following acute ischemic stroke or myocardial infarction. Evidence suggests that endothelial dysfunction (decreased eNOS activity and NO bioavailability) is caused by and contributes to CVRF, and promotes atherosclerosis and thrombosis in patients with CVRF. Aging and eNOS deficiency have been shown to cause rarefaction of native (pre-existing) cerebral and hindlimb collaterals in mice and to reduce collateral remodeling in response to arterial occlusion. To determine whether endothelial dysfunction and CVRF cause collateral rarefaction and/or impair remodeling, we examined recovery of perfusion following femoral artery ligation (FAL) and native cerebral pial collateral extent (density and diameter) in the following mouse models (all 7-8 mos-age): chronic L-NAME treatment (endothelial dysfunction), ob/ob (obesity), LDLR -/- on high-fat diet (hyperlipidemia), LDLR -/- ; ob/ob (metabolic syndrome), RenTgMK +/- (hypertension), and Akita (type-1 diabetes). Hindlimb perfusion immediately after FAL (dependent on native collateral extent) and recovery over 21 days (dependent on collateral remodeling) were impaired by chronic endothelial dysfunction, hypertension, metabolic syndrome, and diabetes (p&lt;0.05) but not by obesity and hyperlipidemia. Similarly, native pial collateral extent was significantly reduced in models of endothelial dysfunction, hypertension, metabolic syndrome and diabetes. The functional significance of CVRF-induced collateral rarefaction was evident as more severe ischemic injury and use impairment in hindlimb and larger infarction in brain after middle cerebral artery occlusion. Investigations into the mechanisms of CVRF-induced collateral rarefaction and treatments to prevent it are ongoing. These data show that CVRF not only impair collateral remodeling but also cause significant loss of native collaterals, resulting in worse ischemic tissue injury after acute obstruction and fewer collaterals available for remodeling.

The clinical relevance of fetal variant of the circle of Willis and its influence on the cerebral collateral circulation.

In a fetal variation of circle of Willis (CoW) there is an embryological defect of the primary collateral circulation. Besides the fact that collateral flow cannot develop between anterior and posterior circulation, the tentorium namely prevents cerebellar vessels from connecting to the supra-tentorium territory. Therefore patients with a fetal variation of circle of Willis could be more prone to develop vascular insufficiency. An association between the regional cerebral blood volume (rCBV) inter-hemispheric asymmetry and CoW collateralization was observed with a topographic significance of corona radiate rather than centrum semiovale. An overview of the literature is given. We propose a fetal variation of circle of Willis as a risk factor for stroke should be subject of further investigation.

Partial Aortic Occlusion and Cerebral Venous Steal

Acute ischemic stroke therapy emphasizes early arterial clot lysis or removal. Partial aortic occlusion has recently emerged as an alternative hemodynamic approach to augment cerebral perfusion in acute ischemic stroke. The exact mechanism of cerebral flow augmentation with partial aortic occlusion remains unclear and may involve more than simple diversion of arterial blood flow from the lower body to cerebral collateral circulation. The cerebral venous steal hypothesis suggests that even a small increase in tissue pressure in the ischemic area will divert blood flow to surrounding regions with lesser tissue pressures. This may cause no-reflow (absence of flow after restoration of arterial patency) in the ischemic core and "luxury perfusion" in the surrounding regions. Such maldistribution may be reversed with increased venous pressure titrated to avoid changes in intracranial pressure. We propose that partial aortic occlusion enhances perfusion in the brain by offsetting cerebral venous steal. Partial aortic occlusion redistributes blood volume into the upper part of the body, manifested by an increase in central venous pressure. Increased venous pressure recruits the collapsed vascular network and, by eliminating cerebral venous steal, corrects perifocal perfusion maldistribution analogous to positive end-expiratory pressure recruitment of collapsed airways to decrease ventilation/perfusion mismatch in the lungs.

Quantitative perfusion computed tomography measurements of cerebral hemodynamics: Correlation with digital subtraction angiography identified primary and secondary cerebral collaterals in internal carotid artery occlusive disease

The aim of the present study was to assess hemodynamic variations in symptomatic unilateral internal carotid artery occlusion (ICAO) patients with primary collateral flow via circle of Willis or secondary collateral flow via ophthalmic artery and/or leptomeningeal collaterals. Thirty-eight patients with a symptomatic unilateral ICAO were enrolled in the study. Based on digital subtraction angiography (DSA) findings, patients were classified into 2 groups: primary collateral (n = 14) and secondary collateral (n = 24) groups. Collateral flow hemodynamics were investigated with perfusion computed tomography (PCT) by measuring the cerebral blood flow (CBF), cerebral blood volume (CBV) and time to peak (TTP) in the hemispheres ipsilateral and contralateral to ICAO. Based on the measurements, the ipsilateral to contralateral ratio for each parameter was calculated and compared. Irrespective of the collateral patterns, ipsilateral CBF was not significantly different from that of the contralateral hemisphere (P = 0.285); ipsilateral CBV and TTP was significantly increased compared with those of the contralateral hemisphere (P=0.000 and P = 0.000 for CBV and TTP, respectively). Furthermore, patients with secondary collaterals had significantly larger ipsilateral-to-contralateral ratios for both CBV (rCBV, P = 0.0197) and TTP (rTTP, P = 0.000) than those of patients with only primary collaterals. These two groups showed no difference in ipsilateral-to-contralateral ratio for CBF (rCBF, P = 0.312). Patients with symptomatic unilateral ICAO in our study were in an autoregulatory vasodilatation status. Moreover, secondary collaterals in ICAO patients were correlated with ipsilateral CBV and delayed TTP that suggested severe hemodynamic impairment, presumably increasing the risk of ischemic events.

Cerebral Arteriogenesis is Enhanced by Pharmacological as Well as Fluid-Shear-Stress Activation of the Trpv4 Calcium Channel

Objectives This study aimed to determine the importance of the shear-stress-sensitive calcium channels Trpc1, Trpm7, Trpp2, Trpv2 (transient receptor potential cation channel, subfamily V, member 2) and Trpv4 for cerebral arteriogenesis. The expression profiles were analysed, comparing the stimulation of collateral growth by target-specific drugs to that achieved by maximum increased fluid shear stress (FSS). Design A prospective, controlled study wherein rats were subjected to bilateral carotid artery ligature (BCL), or BCL + arteriovenous fistula, or BCL + drug application. Methods Messenger RNA (mRNA) abundance and protein expression were determined in FSS-stimulated cerebral collaterals by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. Drugs were applied via osmotic mini pumps and arteriogenesis was evaluated by post-mortem angiograms and Ki67 immunostaining. Results Trpv4 was the only mechanosensitive Trp channel showing significantly increased mRNA abundance and protein expression after FSS stimulation. Activation of Trpv4 by 4α-phorbol-12,13-didecanoate caused significantly enhanced collateral growth (length: 4.43 ± 0.20 mm and diameter: 282.6 ± 8.1 μm) compared with control (length: 3.80 ± 0.06 mm and diameter: 237.3 ± 5.3 μm). Drug application stimulated arteriogenesis to almost the same extent as did maximum FSS stimulation (length: 4.61 ± 0.07 mm and diameter: 327.4 ± 12.6 μm). Conclusions Trpv4 showed significantly increased expression in FSS-stimulated cerebral collaterals. Pharmacological Trpv4 activation enhanced cerebral arteriogenesis, pinpointing Trpv4 as a possible candidate for the development of new therapeutic concepts.

Nonenhanced ECG-gated time-resolved 4D Steady-state free precession (SSFP) MR angiography (MRA) for assessment of cerebral collateral flow: comparison with digital subtraction angiography (DSA)

To evaluate a nonenhanced time-resolved 4D SSFP MRA for dynamic visualization of intracranial collateral blood flow. 22 patients (59.0 ± 11.8 years) with steno-occlusive disease of brain-supplying arteries were included in this study. 4D SSFP MRA of the intracranial arteries was acquired with 15 temporal phases and a temporal resolution of 115 ms using 1.5 T MR. Cerebral DSA served as the reference standard and was available in all patients. Nonenhanced 4D SSFP MRA allowed for detailed dynamic visualization of blood flow in the circle of Willis and its branches in 21 of 22 (95.5%) patients. Collateral flow was excluded with both 4D SSFP MRA and DSA in 4 patients. In 17 patients, DSA detected anterior collateral flow (n = 8), posterior collateral flow via the right (n = 8) and left (n = 7) posterior communicating artery as well as patent EC-IC bypasses (n = 8). 29 of 31 collateral flow pathways were visualized by 4D SSFP MRA. As compared to DSA, 4D SSFP MRA showed a high sensitivity (92.3%), specificity (100%), positive predictive value (100%) and negative predictive value (95.2%) for visualization of intracranial collateral flow. 4D SSFP MRA is a promising non-invasive imaging technique for dynamic visualization of intracranial collateral flow.

Formation and maturation of the native cerebral collateral circulation

The native (pre-existing) collateral circulation minimizes tissue injury if obstructive vascular disease develops. Evidence suggests that large differences in collateral extent exist among healthy individuals, presumably from as-yet unknown genetic and/or environmental factors. Little is known regarding when or how native collaterals form—information needed to identify these factors. We examined collateral development between the middle and anterior cerebral artery trees in BALB/c and C57BL/6 mouse embryos—strains with marked differences in adult collateral density and diameter (85% fewer, 50% smaller in BALB/c). The circulation was dilated, fixed and stained. By E15.5, a “primary collateral plexus” was beginning to form in both strains. By E18.5, plexus vessel number peaked but was 60% less and diameter smaller in BALB/c (P<0.001). Earlier time points were examined to determine if these differences correlated with differences in patterning of the general circulation. At ∼E9.0, the primary capillary plexus was similar between strains, but by E12.5 branching was less and diameter larger in BALB/c (P<0.05). Between E12.5-E18.5—during pial artery tree development—small differences in tree size, branch number and distance between branches did not correlate with the large difference in collaterogenesis. Pruning of nascent collaterals between P1-P21 was comparable in both strains, yielding the adult density, but diameter and tortuosity increased less in BALB/c. Pericyte recruitment to nascent collaterals was comparable, despite lower VEGF-A and PDGF-B expression in BALB/c mice. These findings demonstrate that collaterals form late during vascular development and undergo postnatal maturation and that differences in genetic background have dramatic effects on these processes.

Formation and maturation of the native cerebral collateral circulation

Formation and maturation of the native cerebral collateral circulation

Cerebral Collateral Circulation in Carotid Artery Disease

Carotid artery disease is common and increases the risk of stroke. However, there is wide variability on the severity of clinical manifestations of carotid disease, ranging from asymptomatic to fatal stroke. The collateral circulation has been recognized as an important aspect of cerebral circulation affecting the risk of stroke as well as other features of stroke presentation, such as stroke patterns in patients with carotid artery disease. The cerebral circulation attempts to maintain constant cerebral perfusion despite changes in systemic conditions, due to its ability to autoregulate blood flow. In case that one of the major cerebral arteries is compromised by occlusive disease, the cerebral collateral circulation plays an important role in preserving cerebral perfusion through enhanced recruitment of blood flow. With the advent of techniques that allow rapid evaluation of cerebral perfusion, the collateral circulation of the brain and its effectiveness may also be evaluated, allowing for prompt assessment of patients with acute stroke due to involvement of the carotid artery, and risk stratification of patients with carotid stenosis in chronic stages. Understanding the cerebral collateral circulation provides a basis for the future development of new diagnostic tools, risk stratification, predictive models and new therapeutic modalities. In the present review we discuss basic aspects of the cerebral collateral circulation, diagnostic methods to assess collateral circulation, and implications in occlusive carotid artery disease.

Diagnosis and therapy for an extracranial carotid aneurysm

Objective To describe the diagnostic means and therapy employed in three cases of extracranial carotid aneurysms. Methods Retrospective analysis of three cases. Results For the diagnosis we obtained real-time pictures of each aneurysm by color Doppler ultrasonography before the angiography. Based on the result of cerebral collateral flow evaluation, ligation of both ends of the aneurysm was performed in one case, embolization of the artery in another, and resection of the aneurysm in the other; vascular reconstruction was not necessary. Although a carotid artery balloon occlusion test must be done before the operation, color Doppler ultrasonography and/or a transcranial color Doppler-guided Matas’ test were performed instead, because these patients needed immediate management. Conclusion The diagnostic procedures were very useful to decide what action to take in such urgent cases.

Increased Intravascular Flow Rate Triggers Cerebral Arteriogenesis

Peripheral arteriogenesis is distinctly enhanced by increased fluid shear stress. Thus, the aim of this study was to investigate in the rat brain whether increased fluid shear stress can also stimulate cerebral arteriogenesis. To increase fluid shear stress in the cerebral circulation, we developed different shear stress models as the ligature of both common carotid arteries (Double-Ligature model), bilateral carotid ligature followed by creation of a unilateral arterio-venous fistula (two-stage protocol, Ligature-Shunt model), and unilateral arterio-venous fistula-creation alone (Solo-Shunt model). Blood flow changes were monitored in vivo by quantitative magnetic resonance imaging-analysis. Cerebral arteriogenesis was analyzed by magnetic resonance imaging and contrast agent-angiography. For proliferation and accumulation of mononuclear cells, immunohistochemistry was performed. During the 14 days-observation period, blood flow increased maximal by 5.5-fold in the A. basilaris and 10.3-fold in the fistula-sided A. cerebri posterior of the Ligature-Shunt model. Considerable vessel growth was found in all shear stress-stimulated arteries. Comparative analysis of vessel length and diameter versus blood flow indicated a correlation between the growth of cerebral collaterals and rising intravascular flow rates (R2=0.90/0.96). Immunohistochemistry showed the typical phases of arteriogenesis and accumulation of mononuclear cells. In conclusion, we provide evidence that fluid shear stress is not only the pivotal trigger of peripheral but also of cerebral arteriogenesis.

Of Mice and Men: Essential Considerations in the Translation of Collateral Therapeutics

To the Editor: Shin and colleagues detail an elegant study of collateral perfusion in the ischemic penumbra of mice treated with induced hypertension after distal middle cerebral artery occlusion (MCAO).1 Using optical imaging techniques, they demonstrate that early augmentation of systemic blood pressure with phenylephrine after MCAO improves collateral flow from ipsilateral leptomeningeal branches of the anterior and posterior cerebral arteries. Such collateral perfusion is noted to markedly improve cerebral blood flow (CBF) in penumbra and core, with associated enhancement of oxygenation and cerebral metabolic rate of oxygen in these ischemic regions. After prompt reversal of distal MCAO, infarct size is reduced by induced hypertension in concentric fashion around a focus emanating from the site of distal MCAO. There are subtle yet critical details embedded in this sophisticated cerebrovascular pathophysiology experiment that must be considered regarding the potential of induced hypertension and other therapeutic approaches using collateral perfusion in acute ischemic stroke patients.2 Changes …

Blood blister–like aneurysms of the internal carotid artery trunk causing subarachnoid hemorrhage: treatment and outcome

The object of this study was to evaluate cases of subarachnoid hemorrhage (SAH) from ruptured blood blister-like aneurysms (BBAs) of the internal carotid artery (ICA) trunk. The authors performed a single-center, retrospective study. Data analyzed were patient age, sex, Hunt and Hess grade, Fisher grade, time from SAH to hospitalization, aneurysm size and location, collateral capacity of the circle of Willis, time from hospitalization to aneurysm repair, type of aneurysm repair, complications, and Glasgow Outcome Scale (GOS) score at follow-up. A total of 211 patients suffered SAH from ICA aneurysms. Of these, 14 patients (6.6%) had ICA trunk BBAs; 6 men and 8 women. The median age was 47.8 years (range 29.9-67.7 years). The Hunt and Hess grade was IV or V in 7 cases, and SAH was Fisher Grade 3 + 4 in 6. All aneurysms were small (< 1 cm), without relation to vessel bifurcations, and usually located anteromedially on the ICA trunk. Three patients were treated with coil placement and 11 with clip placement. Of the 7 patients in whom the ICA was preserved, only 1 had poor outcome (GOS Score 2). In contrast, cerebral infarcts developed in all patients treated with ICA sacrifice, directly postoperatively in 2 and after delay in 5. Six patients died, 1 survived in poor condition (GOS Score 3; p < 0.001). Internal carotid BBAs are rare, small, and difficult to treat endovascularly, with only 2 of 14 patients successfully treated with coil placement. The BBAs rupture easily during surgery (ruptured in 6 of 11 surgical cases). Intraoperative aneurysm rupture invariably led to ICA trap ligation. Sacrifice of the ICA within 48 hours of an SAH led to very poor outcome, even in patients with adequate collateral capacity on preoperative angiograms, probably because of vasospasm-induced compromise of the cerebral collaterals.