Early Collateral Recruitment After Stroke in Infants and Adults.

Stroke is a disorder affecting all age groups, particularly those at opposite ends of the age spectrum. At the perinatal period, arterial ischemic stroke (AIS) occurs in 1/2800 to 1/5000 live births. Groups at risk for perinatal AIS are newborns, especially full-term infants (between birth and 28 days of life), and children (>28 days to 20 years) with sickle cell anemia or congenital heart defects. In most cases, the onset date is unknown and the first obvious manifestation consists in seizures that may be observed early in the first 72 hours of life. Cerebral magnetic resonance imaging, which is performed systematically after any seizure, evidences the brain infarct that would go unnoticed otherwise. The current therapeutic strategy is mainly based on supportive care including the management of neonatal seizures such as hypothermia. The picture is different in adults. Stroke is currently the second leading cause of death in industrial countries with 6.24 million cases every year (WHO 2017), given the growing incidence of cardiovascular factors in nonindustrialized countries and insufficiently treated cardiovascular factors in industrialized countries. The only available treatment at the acute phase consists in pharmacological intravenous thrombolysis using recombinant tPA (tissue-type plasminogen activator), associated when possible with mechanical thrombectomy (MT). However, only about 7% of patients are treated with intravenous fibrinolytic molecule, and 4 to 13 patients are needed to treat to benefit from the pharmacological treatment. This percentage is even lower for MT with < 2% of eligible patients with 2.6 patients needed to treat to benefit from the therapy. The combination of both treatments reduces disability at 90 days and improves functional independence when performed within 6 hours poststroke, which widens the therapeutic window otherwise restricted to 4.5 hours with the intravenous fibrinolytic molecule only. In multimodal imaging-selected patients, the therapeutic window may be even extended up to 24 hours. Indeed, 49% of patients treated by thrombectomy between 6 and 24 hours after stroke onset had functional independence at 3 months. Although, the therapeutic window may be extended, the goal remains to restore the cerebral supply as soon as possible. In fact, for each 30-minute delay to obtain angiographic reperfusion, the likelihood of good clinical outcome will decrease by 10% to 20%. Still, time to recanalization is clearly not the only prognosis factor. Even when reperfusion therapies are performed within the first 4.5 hours for intravenous tPA or 6 hours for MT, > 50% of the patients will have a poor outcome. Spontaneous vascular adaptation may, however, take place after decreased cerebral blood flow (BF). Proximal cervical artery occlusion may induce rerouting of BF via the circle of Willis, while cerebral artery occlusion, downstream the Willis circle, may reroute BF via cortical collaterals recruitment. Indeed, progressive unilateral internal carotid artery (ICA) stenosis ultimately leading to occlusion may remain asymptomatic because of chronic contralateral carotid remodeling affecting internal diameter and wall thickness and allowing redistribution of BF through the Willis Circle (Figure 1). Conversely, sudden occlusion of a cerebral artery downstream the Willis circle (such as cardioembolic occlusion) resulting in an acute obstruction of a terminal vascular network can lead to a worse outcome, unless cortical collaterals are recruited from the adjacent vascular arteries. In line with these observations, poor superficial collaterals at the time of MT predict the absence of procedure success. Thus, location of the occlusion, progressive or sudden onset, and time mandatory for arterial remodeling or setting up of the cortical collateral supply may influence the extension of the brain damages. To promote early collaterals recruitment could be a therapeutic target per se. Clinical and preclinical tools, mainly applied in rodents, have been developed these past few years and have contributed to determine what factors initiate and enhance robust collaterals recruitment or inversely, which ones are responsible for dysfunctional collateral recruitment, both in quantitative and qualitative terms.