Relationship between stroke etiology and collateral status in anterior circulation large vessel occlusion

Mechanical thrombectomy (MT) is the recommended treatment for acute ischemic stroke due to large vessel occlusion (LVO) of the anterior cerebral circulation [1]. With increasing experience and technical advances, successful recanalization can nowadays be achieved in up to 90% of all thrombectomy cases. However, successful recanalization does not always entail a favorable outcome after endovascular stroke treatment. In this context, the extent of leptomeningeal collateral perfusion has been identified as a major determinant of patients’ clinical prognosis [2]. Unfavorable collateral status on preinterventional angiography has been related to larger final infarct volumes and consequently a worse clinical outcome after MT [2, 3].

Previously, it has been assumed that chronically developing extracranial carotid artery stenosis (CAS) could enhance cerebral collateral flow, which might be related to a more favorable prognosis in acute stroke patients [4]. This raised the question, whether an underlying CAS would also lead to better leptomeningeal collaterals in patients with acute anterior circulation LVO stroke compared to those with more abrupt vessel occlusion due to proximal embolism (e.g. cardiogenic embolism from atrial fibrillation).

While small previous investigations showed inconsistent results on the predictive value of stroke etiology on collateral status in LVO patients, [5‐7] a very recent subanalysis of the MR-CLEAN Registry reported higher collateral recruitment in acute stroke patients with an underlying atherosclerotic carotid artery stenosis [8]. However, for yet unknown reasons, this might not translate into a higher chance for CAS patients to achieve functional independency after stroke [8].

We aimed at investigating preinterventional leptomeningeal collateral status in acute LVO patients according to the underlying putative stroke mechanism (atherosclerotic CAS ≥ 50% versus patients without significant ipsilateral CAS) and how this affects postinterventional adverse events and clinical outcome.

Over the study period, 346 patients had undergone MT for anterior circulation LVO. Of those, 65 patients were excluded due to missing CE angiography data or insufficient imaging quality (n = 44), ipsilateral carotid artery dissection (n = 9) or extracranial occlusion (n = 12) (Fig. 1). None of the studied patients had a significant intracranial artery stenosis.

Of the finally analyzed 281 patients (mean age 68.5 years, 48.8% female, Table 1), 46 patients had CAS-associated LVO stroke (16.4%).

The remaining 235 patients (83.6%) showed a non-CAS stroke that was mainly attributed to atrial fibrillation (58.8%). Of those, no patients with ulcerated high-risk non-stenosing carotid artery plaques were observed. Compared to a non-CAS etiology, CAS-related strokes were less prevalent in female patients (32.6% vs. 51.9%, p = 0.012), more often pretreated with antiplatelet agents (39.1% vs. 23.4%, p = 0.023) and had a higher rate of favorable collaterals on pretreatment angiography (76.1% vs. 46.0%, p < 0.001). Patients with underlying CAS more often had postinterventional adverse events (19.6% vs. 6.4%, p = 0.007), while functional outcome and mortality rates were similar in both groups (Table 1). Of note, no differences were observed between CAS patients of different degree of stenosis (50–70%, n = 18 versus ≥ 70%, n = 28) in terms of collateral status, adverse events and 90-day prognosis (p > 0.1).

Compared to patients with unfavorable collaterals (n = 138, 49.1%), patients with favorable collaterals (n = 143, 50.9%) had a lower prevalence of AF (45.1% vs. 56.1%, p = 0.063), better pre- and postinterventional ASPECT Scores (pre: median, 9.0 vs. 8.5, p = 0.035; post: median, 6.0 vs. 4.0, p < 0.001), were more often functionally independent (mRS 0–2: 59.4% vs. 35.5%, p < 0.001) and were less likely deceased at 90 days (mRS 6: 7.0% vs. 29.7%, p < 0.001) (Table 2).

Besides NIHSS at presentation (p < 0.001) and preinterventional ASPECTS (p = 0.033), favorable collateral status remained significantly associated with CAS-related stroke etiology in multivariable analysis (Odds ratio: 3.3, 95% confidence interval: 1.5–7.1, p = 0.002).

This study shows that the presence of preexisting ipsilateral CAS ≥ 50% is associated with more favorable collateral status in acute LVO stroke patients. However, this does not translate into a better functional outcome at 90 days, which might be attributed to a higher rate of adverse events after MT. Although occurring rarely, CAS patients with unfavorable collaterals on pretreatment angiography face a particularly high risk of poor outcome three months after the intervention (≈ 90%).

Preinterventional leptomeningeal collaterals have a significant impact on patients’ clinical prognosis after MT. In line with earlier investigations, this study also shows that favorable collateral status on pretreatment angiography was associated with smaller postinterventional infarct size and a better functional outcome at 90 days after the intervention [5‐7]. Conditions that could predict favorable leptomeningeal collaterals after acute cerebral artery occlusion are therefore of interest. In this context, chronic cerebral hypoperfusion was associated with improved cerebral collateral flow in experimental rat models and in patients with steno-occlusive disease of the carotid vasculature; and the effect increased with the degree of stenosis [4, 15, 16]. Moreover, repeated arterio-arterial (micro)embolism proceeding from aggressive carotid plaques could lead to recurrent and clinically silent cerebral ischemia, which might trigger better collaterals due to ischemic preconditioning [17].

Although recent studies only addressed primary collateral pathways in the circle of Willis, it seems plausible that CAS patients with acute intracranial LVO stroke would also be associated with favorable leptomeningeal collateral recruitment, which could further impact patients’ clinical prognosis.

While two small studies presented divergent results on that topic, [6, 7] a very recent MR-CLEAN Registry subanalysis showed that CAS-related LVO stroke patients had a better collateral status than those with cardioembolic stroke, [8] which is in line with our work. In contrast to our findings, the latter study showed slightly better median 90-days mRS scores in their CAS subgroup. This might be attributed to methodological differences between both studies: From a pathophysiological perspective, we decided to include all patients without an indication of symptomatic carotid stenosis ≥ 50% (according to the NASCET criteria) in our non-CAS group. As we did not observe patients with ulcerated carotid plaques, most non-CAS patients should have had a proximal (cardio)embolic stroke etiology, which is frequently missed on routine stroke work-up (e.g. in case of paroxysmal atrial fibrillation). However, such initially cryptogenic stroke patients are younger and have less comorbidities compared to the standard cardioembolic stroke patients [18]. The exclusion of such patients as it was done by the MR-CLEAN investigators might therefore explain the reported baseline imbalances in their subgroup analysis [8]. In contrast, our study provides comparable subgroups (CAS versus non-CAS) regarding age, medical history and prestroke mRS. Of note, the effect on outcome presented in the MR-CLEAN Registry subanalysis remained relatively low as there was no statistically significant benefit for CAS patients in terms of 90-day post-stroke dependency or mortality rates [8]. The authors concluded that larger thrombi and difficulties in gaining intracranial access due to proximal stenosis might have caused longer thrombectomy procedures compromising the positive impact of good collaterals on clinical prognosis. Our study also shows a trend towards longer interventions in CAS-related strokes, but additionally draws attention to postinterventional adverse events (predominantly vessel re-occlusions and symptomatic ICH) in CAS-related thrombectomy patients.

The high percentage of vessel re-occlusion (11%) we detected in our CAS subgroup might be also a result of more complex endovascular procedures (balloon dilatation: 43%, stenting of CAS: 24%) and residual stenosis leading to recurrent arterio-arterial embolism. Although data on vessel re-occlusion in the early phase after MT are scarce, this finding is in line with a small retrospective study, which has shown rather high rates of postinterventional re-stenosis/occlusion and a poor prognosis in LVO stroke patients with tandem pathologies [19].

Symptomatic intracerebral bleeding was the second most common adverse event in our study and might be partly attributed to extracranial artery stenting in the CAS subgroup, which required more intense antiplatelet therapy (i.e. dual antiplatelets) after the intervention. In addition, carotid artery stenting might enlarge reperfusion injury, which seems generally more pronounced in chronically ischemic tissues due to disturbances of cerebral autoregulation [9].

Of note, this is the first study that casts light on acute LVO patients with unfavorable collaterals despite underlying CAS, as they are at very high risk for postinterventional adverse events (37%) and functional dependency at 90 days (91%). Although the number of patients in this subgroup was rather small, this finding should be considered in the clinical management of such patients.

The major limitation of this study is the retrospective design and the fact that no blinding regarding stroke etiology and collateral status was possible. However, during rating, neuroradiologists were blinded to clinical information including adverse events and outcome. We decided to abstain from volumetry, but instead used pre- and postinterventional CT or MRI based ASPECT Scores to estimate the acute and final infarct, which is more feasible in daily clinical routine.

Moreover, we did not analyze the Circle of Willis for anatomical variants, which could have affected our results and should be addressed in future studies on cerebral collaterals.

Another restriction was, that not all patients underwent multi-phase CT/MR-angiography (≈ 34%). If collateral filling in the post venous phase occurs, collaterals could be underestimated when using the Tan Score in single-phase angiography. However, as this is not a frequent finding and collaterals were comparable to those of earlier investigations using multi-phase angiography, it should not have influenced our results to a major extent [20].

Finally, we cannot totally exclude that in few cases emboli broke off from the carotid stenosis leaving it less than 50%. However, patients with minor carotid artery stenosis < 50% did not meet the established ultrasound criteria for aggressive plaques (i.e. ulceration, intraplaque hemorrhage, etc.), which should exclude a major effect on the results of this investigation.