Collateral Circulation in Ischemic Stroke: An Updated Review

Abstract

The collateral circulation plays a crucial role in maintaining perfusion to brain tissue in ischemic stroke, which prolongs the time window for effective therapies to be provided and ultimately avoids irreversible damage that may lead to worse clinical outcomes. The understanding of this complex vascular bypass system has advanced greatly in the past few years, yet effective treatments for its potentiation as a therapeutic target remain a challenge. The assessment of the collateral circulation is now part of the routine neuroimaging protocols for acute ischemic stroke, which provides a more complete pathophysiological picture in each patient that allows for a better selection for acute reperfusion therapies and a more accurate prognostication of outcomes, among other potential uses. In this review, we aim to provide a structured and updated approach to the collateral circulation while highlighting ongoing research areas with promising future clinical applications.

Keywords: Cerebrovascular circulation; Collateral circulation; Ischemic stroke; Thrombectomy; Thrombolytic therapy.

Figure 1.

Schematic representation of the collateral circulation of the brain. The anterior circulation is represented in dark red, the posterior circulation in light red, and the extracranial sources of blood flow in orange. (A) Antero-posterior and (B) lateral view of the main intracranial arteries. The persistent carotid-vertebrobasilar anastomoses are represented with a dashed dark red line. (C) Inferior view of the circle of Willis and a corresponding diagram showing each arterial component. (D) Lateral view of cranio-cervical arteries highlighting the main extra-intracranial anastomoses. Microvascular anastomoses between (1) the anterior cerebral artery (ACA) and the middle cerebral artery (MCA), (2) the ACA and the posterior cerebral artery (PCA), (3) the MCA and the PCA, and (4) the superior cerebellar artery and the posterior inferior cerebellar artery. (5) The postulated collateral pathways in the deep subcortical territory. Extra-intracranial anastomoses between (6) branches of the facial artery and the ophthalmic artery, (7) the supraorbital and supratrochlear arteries and branches of the ophthalmic artery, (8) branches of the occipital artery and the PCA, (9) the middle meningeal artery and the ACA, and (10) branches from ascending and deep cervical arteries and the vertebral artery. AcommA, anterior communicating artery; R A1, A1 segment of the right ACA; L A1, A1 segment of the left ACA; R ICA, right internal carotid artery; L ICA, left internal carotid artery; R PcommA, right posterior communicating artery; L PcommA, left posterior communicating artery; R P1, P1 segment of the right PCA; L P1, P1 segment of the left PCA; BA, basilar artery.

Figure 2.

Axial maximum intensity projection computed tomography angiography slices showing examples of circle of Willis (CoW) configurations. (A) A complete CoW. (B) A CoW with absence of the left posterior communicating artery (arrow).

Figure 3.

Sequential antero-posterior images in digital subtraction angiography after contrast injection in the right internal carotid artery in a patient with an occlusion of the M1 segment of the right middle cerebral artery (arrow). Notice the contrast filling of the left anterior circulation through the anterior communicating artery (dashed arrow) in the earliest image. The direction of the blood flow through the leptomeningeal collaterals from anterior cerebral artery to middle cerebral artery is shown with a curved arrow.

Figure 4.

Collaterogenesis occurs during the embryonic period. (A) The differentiation of endothelial cells into tip and stalk phenotypes is dependent on vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling. (1) Rabep2, whose genetic variations largely determine the differences on collateral extent in murine models, promotes the Rab4 recycling of VEGFR2 to the cell surface, increasing its availability. (2) VEGF binding to VEGFR2 induces endocytosis and signaling which (3) induces delta-like ligand 4 (Dll4). (4) Dll4 activates the transmembrane receptor Notch1, of which the Notch intracellular domain (NICD) is liberated and (5) induces several effects in the adjacent stalk cells, such as cell division. (B) Tip cells are guided by the VEGF gradient and direct the growing sprout while stalk cells follow behind and form the vascular lumen. This process leads to the fusion of two terminal arterioles, forming a new collateral. In the example, a new collateral is forming between terminal branches of the anterior cerebral artery (ACA) to middle cerebral artery (MCA). Rabep2, Rab GTPase-effector binding protein 2; Rab4, Rab GTPase 4.

Figure 5.

Examples of patients with acute large vessel occlusion (LVO) and their respective computed tomography agiography (CTA) and computed tomography perfusion studies. Each row sequentially shows axial maximum intensity projection images of the LVO and the three phases of CTA, followed by the ischemic core (defined as cerebral blood flow [CBF] <30% of contralateral side) and penumbra (defined as time-to-maximum [Tmax] >6 s) images with their respective automated volume calculation. (A) Left “T occlusion” (distal internal carotid artery, A1 and M1 segments, arrow) with good collaterals. Notice the filling of the left A2 segment from the contralateral side (dashed arrow). (B) Left M1 occlusion (arrow) with moderate collaterals. (C) Left “T occlusion” (arrow) with poor collaterals. Notice the retrograde filling of the left A1 segment and left posterior communicating artery (dashed arrows).

Figure 6.

The hypoperfusion index (HI=Tmax>10 s/Tmax>6 s) in fast versus slow progressors. (A) Fast progressor: patient with an acute left “L occlusion” (distal internal carotid artery extending into the middle cerebral artery [MCA], arrow) with imaging performed 90 minutes after onset of symptoms. HI=0.6. (B) Slow progressor: patient with an acute right MCA occlusion (arrow) with imaging performed 120 minutes after onset of symptoms. HI=0.2. CBF, cerebral blood flow.