The impact of leptomeningeal collaterals in acute ischemic stroke

Objectives: Leptomeningeal collaterals provide an alternate pathway to maintain cerebral blood ow in stroke to prevent ischemia, but their role in predicting outcome is still unclear. So, our study aims at assessing the signicance of collateral blood ow (CBF) in acute stroke. Methods: Electronic databases were searched under different MeSH terms from Jan 2000 to Feb 2019. Studies were included if there was available data on good and poor CBF in acute ischemic stroke (AIS). The clinical outcomes included were modied rankin scale (mRS), recanalization, mortality, and symptomatic intracranial hemorrhage (sICH) at 90 days. Data was analyzed using random-effect model. Results: A total of 47 studies with 8,194 patients were included. Pooled meta-analysis revealed that there exist 2-fold higher likelihood of favorable clinical outcome (mRS ≤ 2) at 90 days with good CBF compared with poor CBF (RR: 2.27; 95%CI: 1.94-2.65; p<0.00001) irrespective of the thrombolytic therapy [RR with IVT: 2.90; 95%CI: 2.14-3.94; p<0.00001, and RR with IAT/EVT: 1.99; 95% CI: 1.55-2.55; p<0.00001]. Moreover, there exists 1-fold higher probability of successful recanalization with good CBF (RR: 1.31; 95% CI: 1.15-1.49; p<0.00001). However, there was 54% and 64% lower risk of sICH and mortality respectively in patients with good CBF in AIS (p<0.00001). Conclusions: The relative risk of favorable clinical outcome is more in patients with good pretreatment CBF. This could be explained due to better chances of recanalization, combined with lesser risk of intracerebral hemorrhage in good CBF status.


Introduction
Reversing the trend of morbidity caused by ischemic stroke in our modern era has still proven di cult and; thus, poses a signi cant global burden 1 . It is widely known that adequate blood ow to the brain by removing the clot forms the theoretical basis for management [2][3][4] . Therefore, thrombolytic therapies in the form of intravenous (IVT) or intra-arterial (IAT) aim for clot disruption, thus re-establishing the circulation 5 . The therapeutic implications of such interventions have been enhanced further by the presence of bypass vascular network channels, which provides an alternate pathway for cerebral blood ow to prevent permanent neurological damage [2][3][4] . Hence, these pial collaterals prolongs the time window for treatment after stroke and reduces the hemorrhagic transformation [2][3][4] . Thus, determination of collateral status before establishing any treatment is appealing because the coherence with adequate intervention can be improved. Consequently, there exists various ways to identify collateral circulation in the brain after acute ischemic stroke, although the effect of number of collaterals on clinical outcomes has not been assessed 6,7 .
To determine whether good or poor collateral blood ow (CBF) has any impact on clinical outcome in AIS, we reviewed randomized controlled trials, case-control, prospective cohort and retrospective studies in Statistical heterogeneity was further assessed using funnel plot, revealing asymmetrical distribution in the funnel plot. This could be due to publication bias, but we tried to minimize it by searching the unpublished literature as well. Though no study was included from the grey literature in our metaanalysis.

Discussion
Overall, there was a strong evidence of relationship between the collateral circulation and clinical outcomes in patients with AIS. This can be explained due to the fact that the expansion or reduction of penumbral tissue, immediately after the stroke, depends on collateral status 55 .
Clinical outcomes: In our meta-analysis, we demonstrated that the presence of good CBF was associated with increased likelihood of favorable clinical outcome, which validates the previous meta-analysis 24 (mRS at 3-6 months; p<0.0001). In addition, further analysis showed that there was higher probability of predicting better neurological outcome with either IVT or IAT/EVT. Our results, however, are contradictory to recent trial of DEFUSE 3 54 , which showed that good CBF does not predict the neurological status. Previous studies also revealed that IAT/EVT is e cient in clot-retrieval in stroke, combined with better neurological outcome [59][60][61] The degree of collateral circulation is essential to be determined prior to thrombolytic therapy. This status helps to determine the expansion of infarct, degree of reperfusion and e cacy of treatment. Although endovascular treatment is considered to be the treatment of choice for acute large-vessel occlusion, however, it was found that patients with poor collaterals had more odds of unfavorable clinical outcome (onset-to-puncture time: 300, 59% versus 300, 32%; OR, 0.24; P .011; puncture-to-reperfusion time: 60, 73% versus 60, 32%; OR, 0.21, P .011) as compared to those with good collaterals 63-64 . Therefore, collateral circulation helps in minimizing the neurological damage by limiting the extent of infarction as it maintains the viability of the penumbral tissue.

Recanalization:
Our study suggests that recanalization was better achieved in patients with good pretreatment collateral status (p<0.00001). This can be explained as collateral circulation sustain downstream perfusion and enhances ante grade perfusion to the distal arteries 57 . Besides, it increases the delivery of thrombolytic agents to the clot itself from different sides, thus increasing the e cacy of treatment 57 .
In previous literature, it was found that mechanical thrombectomy has higher rate of recanalization than IV treatment alone; like in a randomized trial EXTEND-IA, it was found that >90% recanalization was found in patients who received endovascular thrombectomy than those who received rt-PA 58 . MR CLEAN endovascular treatment.
Mortality and sICH: Our meta-analysis revealed the there was reduction in mortality with good CBF than poor CBF (p<0.00001). Though in previous study it was found that recanalization did not independently affect the mortality (p>.15) 59-60 , thus collateral status plays indispensable role in decreasing the mortality as evident in previous studies 62 .Our study identi ed signi cant reduction in sICH in good CBF compared to poor CBF, this could be explained as collaterals limits the growth of infarct core before revascularization 62 . This ultimately helps in reducing the risk of hemorrhagic transformation.
Our study has several limitations. Firstly, there is a possibility of selection and publication bias in our systematic review, since only two reviewers carried out this part of the process. They might therefore be more in uenced by the positive trial results than by the negative ones. However, we tried to limit such bias using the following steps: a gray literature review, in which we reviewed the abstracts from several meetings in order to capture any RCT that was presented as an abstract but not published because of a negative result. Second, in our meta-analysis there were different scales used to assess and de ne collateral circulation into good and poor CBF, therefore, resulting in a bias between two groups. Third, in our meta-analysis we didn't only restrict to anterior circulation stroke but also included posterior circulation stroke as well, this might have resulted in sampling bias. Fourth, there must be difference in ethnicity and co-morbidities, which might have led to sampling bias.

Conclusion
In conclusion, our meta-analysis points to a signal-of-e cacy of good CBF in the management of patients with acute ischemic stroke.However, further studies including randomized controlled trials are required to determine the effectiveness of thrombolytic therapy depending upon the collateral status.    Compared to poor collateral status, good pretreatment collaterals had 54% less relative risk of sICH at 90 days. The RR of sICH: 0.46; 95% CI: 0.35-0.60; p<0.00001