Modeling cerebrovascular responses to assess the impact of the collateral circulation following middle cerebral artery occlusion.

OBJECTIVE: An improved understanding of the role of the leptomeningeal collateral circulation in blood flow compensation following middle cerebral artery (MCA) occlusion can contribute to more effective treatment development for ischemic stroke. The present study introduces a model of the cerebral circulation to predict cerebral blood flow and tissue oxygenation following MCA occlusion. METHODS: The model incorporates flow regulation mechanisms based on changes in pressure, shear stress, and metabolic demand. Oxygen saturation in cerebral vessels and tissue is calculated using a Krogh cylinder model. The model is used to assess the effects of changes in oxygen demand and arterial pressure on cerebral blood flow and oxygenation after MCA occlusion. RESULTS: An increase from five to 11 leptomeningeal collateral vessels was shown to increase the oxygen saturation in the region distal to the occlusion by nearly 100%. Post-occlusion, the model also predicted a loss of autoregulation and a decrease in flow to the ischemic territory as oxygen demand was increased; these results were consistent with data from experiments that induced cerebral ischemia. CONCLUSIONS: This study highlights the importance of leptomeningeal collaterals following MCA occlusion and reinforces the idea that lower oxygen demand and higher arterial pressure improve conditions of flow and oxygenation.

Comparison of methods between CT perfusion source images and CT angiography in collateral flow assessment.

BACKGROUND: The methods used for grading leptomeningeal collateral flow (LMF) on single-phase computed tomography angiography (CTA) are heterogeneous and limited by temporal resolution. PURPOSE: To compare the reliability of relative filling time delay (rFTD) on CT perfusion source images (CTP-SI) and the currently used single-phase CTA collateral assessment methods and evaluate their ability to predict clinical outcomes in acute ischemic stroke patients. MATERIAL AND METHODS: We analyzed consecutive middle cerebral artery or internal carotid artery occlusion patients who received multimodal CT before treatment and within 12 h of stroke symptom onset from October 2015 to December 2018. Patients were dichotomized using the 90-day mRS into good (0-1) versus adverse (2-6) outcomes. CTP-SI was used to identify the rFTD score. CTA images were reconstructed to assess collateral status using the collateral score (Cs) and region leptomeningeal collateral score (rLMCs). Two observers independently assessed images. RESULTS: The baseline characteristics (n = 54) were median age of 67 years and 68.5% of the participants were men. The baseline median NIHSS was 14. Good clinical outcomes were observed in 19 (35.2%) patients. The k value was higher for rFTDs (k = 0.779, P < 0.001) than Cs (k = 0.666, P < 0.001) and rLMCs (k = 0.763, P < 0.001). Higher rFTDs were correlated with lower rLMCs (Spearman's rho -0.68, P < 0.001) and Cs (rho -0.66, P < 0.001). In multivariate logistic regression, rFTD was associated with functional outcomes (P = 0.044). CONCLUSION: The rFTDs method is comparable to single-phase CTA-based assessments in assessing LMFs in acute ischemic stroke patients. Higher rFTDs is independently associated with adverse long-term functional outcomes.

Detection of impaired cerebrovascular reactivity in patients with chronic cerebral ischemia using whole-brain 7T MRA.

BACKGROUND: Cerebrovascular reactivity (CVR) to acetazolamide (ACZ) on single-photon emission computed tomography (SPECT) can be used to assess the severity of chronic cerebral ischemia; however, this is an invasive method. We examined whether whole-brain magnetic resonance angiography (MRA) at 7T could non-invasively detect impaired CVR in patients with chronic cerebral ischemia by demonstrating the leptomeningeal collaterals (LMCs). METHODS: Fifty-seven patients with symptomatic unilateral cervical stenosis underwent whole-brain time-of-flight MRA at 7T and cerebral perfusion SPECT before/after the ACZ challenge. MRA images were visually assessed based on 6-point grading systems to evaluate the development of LMCs toward the middle cerebral artery (MCA) and antegrade flow of MCA. CVR of the affected side was calculated from the SPECT data. Subsequently, we compared the LMC grades on MRA with CVR on SPECT. RESULTS: CVR was significantly lower in grades ≥ 2 of LMCs than in grades 0-1 (P < 0.05) when applying LMCs from the anterior cerebral artery (ACA) and/or posterior cerebral artery (PCA). These differences were more evident than those in the grading of the antegrade MCA flow. The LMC grades from ACA/PCA readily detected reduced CVR (< 18.4%) with a sensitivity/specificity of 0.79/0.82. CONCLUSION: The development of LMCs on whole-brain MRA at 7T can non-invasively detect reduced CVR with a high sensitivity/specificity in patients with unilateral cervical stenosis.

Determinants of leptomeningeal collateral flow in stroke patients with a middle cerebral artery occlusion.

INTRODUCTION: Poor leptomeningeal collateral flow is related to worse clinical outcome in acute ischemic stroke, but the factors that determine leptomeningeal collateral patency are largely unknown. We explored the determinants of leptomeningeal collateral flow and assessed their effect on the relation between leptomeningeal collateral flow and clinical outcome. METHODS: We included 484 patients from the Dutch acute stroke study (DUST) with a middle cerebral artery (MCA) occlusion. The determinants of poor leptomeningeal collateral flow (≤50 % collateral filling) were identified with logistic regression. We calculated the relative risk (RR) of poor leptomeningeal collateral flow in relation to poor clinical outcome (90-day modified Rankin Scale 3-6) using Poisson regression and assessed whether the determinants of leptomeningeal collateral flow affected this relation. RESULTS: Leptomeningeal collateral flow was poor in 142 patients (29 %). In multivariable analyses, higher admission glucose level (odds ratio (OR) 1.1 per mmol/L increase (95 % CI 1.0-1.2)), a proximal MCA occlusion (OR 1.9 (95 % CI 1.3-3.0)), and an incomplete posterior circle of Willis (OR 1.7 (95 % CI 1.1-2.6)) were independently related to poor leptomeningeal collateral flow. Poor leptomeningeal collateral flow was related to poor clinical outcome (unadjusted RR 1.7 (95 % CI 1.4-2.0)), and this relation was not affected by the determinants of leptomeningeal collateral flow. CONCLUSION: Our study shows that admission glucose level, a proximal MCA occlusion, and an incomplete ipsilateral posterior circle of Willis are determinants of leptomeningeal collateral flow that represent a combination of congenital, acquired, and acute factors. After adjustment for these determinants, leptomeningeal collateral flow remains related to clinical outcome.

A ruptured aneurysm arising at the leptomeningeal collateral circulation from the extracranial vertebral artery to the posterior inferior cerebellar artery associated with bilateral vertebral artery occlusion.

We report an extremely rare case of a small ruptured aneurysm of the leptomeningeal collateral circulation from the vertebral artery (VA) to the posterior inferior cerebellar artery (PICA); this aneurysm was associated with bilateral VA occlusion. A 72-year-old woman with sudden headache, nausea, and subarachnoid hemorrhage (SAH) was admitted to our hospital. On admission, no evidence of cerebral signs or cranial nerve palsy was found. Computed tomography imaging showed SAH predominantly in the posterior fossa, and digital subtraction angiography revealed bilateral VA occlusion and the left VA aneurysm located proximal to the VA union. In addition, a small aneurysm was observed at the leptomeningeal collateral circulation located between the extracranial left VA and the left PICA. The patient underwent radical surgery on the day of the onset of the symptoms associated with SAH. However, the VA aneurysm was unruptured and surgically trapped. The small aneurysm arising at the leptomeningeal collateral circulation was ruptured during the surgery and was electrocoagulated; the collateral circulation was preserved, and no neurologic deficits were observed. The postoperative course was uneventful. SAH with the occlusion of major vessels should be diagnosed with utmost caution to allow preoperative neurologic and radiological assessments.

Long non-coding RNA SNHG12 regulates leptomeningeal collateral remodeling via RGMa after ischemic stroke.

Leptomeningeal anastomoses or pial collateral arteries are crucial for restoring cerebral blood flow (CBF) after an ischemic stroke. Vascular smooth muscle cells (VSMCs) are hypothesized to regulate the extent of this adaptive response, while the specific molecular mechanisms underlying this process are still being investigated. SNHG12, a long non-coding RNA, has been shown to influence several diseases related angiogenesis, including osteosarcoma and gastric cancer. However, the role of SNHG12 in contractile VSMC dedifferentiation during collateral arteriogenesis-related strokes remains unclear. Here we demonstrated that SNHG12 is a positive regulator of MMP9 and VSMC dedifferentiation, which enhances pial collateral arteriogenesis following cerebrovascular occlusion. Pial collateral remodeling is limited by the crosstalk between SNHG12-MMP9 signaling in VSMCs, which is mediated through repulsive guidance molecule a (RGMa) regulation. Thus, targeting SNHG12 may represent a therapeutic strategy for improving collateral function, neural tissue health, and functional recovery following ischemic stroke.

Determining Clinically-Viable Biomarkers for Ischaemic Stroke Through a Mechanistic and Machine Learning Approach.

Assessment of distal cerebral perfusion after ischaemic stroke is currently only possible through expensive and time-consuming imaging procedures which require the injection of a contrast medium. Alternative approaches that could indicate earlier the impact of blood flow occlusion on distal cerebral perfusion are currently lacking. The aim of this study was to identify novel biomarkers suitable for clinical implementation using less invasive diagnostic techniques such as Transcranial Doppler (TCD). We used 1D modelling to simulate pre- and post-stroke velocity and flow wave propagation in a typical arterial network, and Sobol's sensitivity analysis, supported by the use of Gaussian process emulators, to identify biomarkers linked to cerebral perfusion. We showed that values of pulsatility index of the right anterior cerebral artery > 1.6 are associated with poor perfusion and may require immediate intervention. Three additional biomarkers with similar behaviour, all related to pulsatility indices, were identified. These results suggest that flow pulsatility measured at specific locations could be used to effectively estimate distal cerebral perfusion rates, and ultimately improve clinical diagnosis and management of ischaemic stroke.

Hemodynamics of Leptomeningeal Collaterals after Large Vessel Occlusion and Blood Pressure Management with Endovascular Treatment.

Endovascular therapy (EVT) is an effective treatment for ischemic stroke due to large vessel occlusion (LVO). Unlike intravenous thrombolysis, EVT enables visualization of the restoration of blood flow, also known as successful reperfusion in real time. However, until successful reperfusion is achieved, the survival of the ischemic brain is mainly dependent on blood flow from the leptomeningeal collaterals (LMC). It plays a critical role in maintaining tissue perfusion after LVO via pre-existing channels between the arborizing pial small arteries or arterioles overlying the cerebral hemispheres. In the ischemic territory where the physiologic cerebral autoregulation is impaired and the pial arteries are maximally dilated within their capacity, the direction and amount of LMC perfusion rely on the systemic perfusion, which can be estimated by measuring blood pressure (BP). After the EVT procedure, treatment focuses on mitigating the risk of hemorrhagic transformation, potentially via BP reduction. Thus, BP management may be a key component of acute care for patients with LVO stroke. However, the guidelines on BP management during and after EVT are limited, mostly due to the scarcity of high-level evidence on this issue. In this review, we aim to summarize the anatomical and physiological characteristics of LMC to maintain cerebral perfusion after acute LVO, along with a landscape summary of the literature on BP management in endovascular treatment. The objective of this review is to describe the mechanistic association between systemic BP and collateral perfusion after LVO and thus provide clinical and research perspectives on this topic.

Modelling the leptomeningeal collateral circulation during acute ischaemic stroke.

A novel model of the leptomeningeal collateral circulation is created by combining data from multiple sources with statistical scaling laws. The extent of the collateral circulation is varied by defining a collateral vessel probability. Blood flow and pressure are simulated using a one-dimensional steady state blood flow model. The leptomeningeal collateral vessels provide significant flow during a stroke. The pressure drop over an occlusion predicted by the model ranges between 60 and 85 mmHg depending on the extent of the collateral circulation. The linear transport of contrast material was simulated in the circulatory network. The time delay of peak contrast over an occlusion is 3.3 s in the model, and 2.1 s (IQR 0.8-4.0 s) when measured in dynamic CTA data of acute ischaemic stroke patients. Modelling the leptomeningeal collateral circulation could lead to better estimates of infarct volume and patient outcome.

Clinical characteristics and leptomeningeal collateral status in pediatric and adult patients with ischemic moyamoya disease.

AIM: Previous studies have found significant differences in clinical characteristics between pediatric and adult moyamoya disease (MMD) patients, but few studies have focused on the factors underlying these differences. We aimed to investigate the differences in leptomeningeal collateral (LMC) status between pediatric and adult MMD patients and to analyze the effects of LMCs on clinical characteristics and therapeutic prognosis. METHODS: We retrospectively analyzed 214 MMD patients from January 2014 to January 2016. Clinical characteristics and LMC status were compared between the pediatric and adult patients. LMC status was graded as good or poor depending on the retrograde flow from the posterior cerebral artery (PCA) on digital subtraction angiography (DSA). RESULTS: A total of 83 pediatric and 131 adult (1:1.6) MMD patients were analyzed. Pediatric patients were more likely to experience a transient ischemic attack (81%), whereas adult patients were more likely to experience infarction (51%). Regarding the different MMD stages (the early, medium, and advanced stages corresponded to Suzuki stages 1-2, 3-4, and 5-6, respectively), the prevalence of good LMC status was higher for pediatric patients than for adult patients in the early stage (P = 0.047) and the medium stage (P = 0.001), but there were no differences between these patient groups in the advanced stage (P = 0.547). Worse postoperative angiographic outcomes (P = 0.017) were found in adult patients than in pediatric patients in the medium stage. Poor LMC status had strong correlations with infarction (P < 0.001 and P = 0.017) and poor postoperative outcomes (P = 0.003 and P = 0.043) in both pediatric and adult patients. CONCLUSIONS: Pediatric MMD patients have greater patency and a greater ability to establish good LMC status than adult patients, and poor LMC status has a strong correlation with severe clinical symptoms and poor postoperative outcomes. LMC status may be an important factor in the differences in clinical characteristics and prognosis between pediatric and adult MMD patients.

Effect of direct angioplasty therapy on acute middle cerebral artery occlusion with good leptomeningeal collateral.

OBJECTIVE: The objective of this study was to investigate and discuss the effect of direct angioplasty therapy on acute middle cerebral artery occlusion (MCAO) patients with good leptomeningeal collateral circulation in 4.5 h. PATIENTS AND METHODS: We retrospectively reviewed our acute ischemic stroke database from January 2017 to January 2019, then selected consecutive patients with evidence of the proximal M1 segments of MCAO and good leptomeningeal collateral who have received angioplasty or mechanical thrombectomy (MT). The baseline characteristics and outcome of patients was statistical analysis, included age, gender and risk factors, baseline national institutes of health stroke scale (NIHSS) scores, preoperative alberta stroke programme early CT (ASPECT) score, time from door to needle, time of door to puncture, endovascular procedure time, 7d NIHSS score and the modified treatment in cerebral infarction (m-TICI) 2b or 3, symptomatic hemorrhage, average hospital stays, modified rankin scale (mRS) score 0-2 at 3-month and mortality. All the thrombi were analyzed by histopathology. All statistical analysis was done with t-test for continuous data and χ2 test for binary data. RESULTS: A total of 93 patients were included (direct angioplasty = 41 (44.1 %), MT = 52 (55.9 %)). There was no significant difference in baseline data between the two groups. The difference in the time of door to recanalization, the time of puncture to recanalization, symptomatic hemorrhage, and average hospital stays were significantly different between groups (P < 0.05). The other agents were not significantly different between groups (P > 0.05 each). Histopathological analysis showed all thrombi contained different amounts of platelets, fibrinogen, white blood cell, and red blood cell. CONCLUSION: Direct angioplasty therapy on acute MCAO with good leptomeningeal collateral may help to shorten the time of surgery, reduce symptomatic hemorrhage, and hospital stay.

Regional leptomeningeal collateral score by computed tomographic angiography correlates with 3-month clinical outcome in acute ischemic stroke.

PURPOSE: The aim of the study is to assess the correlation between regional leptomeningeal collateral (rLMC) Scores calculated on computed tomography (CT) angiography following acute anterior circulation ischemic stroke, with 3-month clinical outcome measured as modified Rankin Scale (mRS) and Barthel Index (BI). MATERIALS AND METHODS: A total of thirty patients were studied as per the exclusion and inclusion criteria and after informed consent. Multi-phase CT angiography was carried out within 24 h of stroke onset, and collateral scoring was done using rLMC score along with Alberta stroke programme early CT (ASPECT) scoring. At 3 months, patients were followed up to evaluate the clinical outcome using mRS and BI. Statistical analysis was performed to find out the correlation between rLMC score, ASPECT score, and clinical outcome and for association with demographic parameters and stroke risk factors. RESULTS: A strong correlation was noted between ASPECT and rLMC scores (P < 0.001) and between rLMC scores and clinical outcome at 3 months (mRS and BI). Correlation with mRS (P < 0.001) was nearly as strong as that of BI on follow-up (P < 0.001). The ASPECT score also was a predictor of clinical outcome and showed correlation with mRS (P < 0.001) and BI (P < 0.001). No significant association was found between various stroke risk factors and demographic parameters with rLMC scores. The rLMC scoring system showed substantial inter-rater reliability with Kappa = 0.7. CONCLUSIONS: rLMC score in CT angiography correlates with ASPECT Score and clinical outcome at 3 months. Hence, this scoring system can be used for collateral quantification as may be of use in predicting short-term clinical outcomes.

Elevated repulsive guidance molecule-a mRNA in peripheral blood mononuclear cells are associated with impaired leptomeningeal collaterals in patients with middle cerebral artery occlusions.

BACKGROUND: In the event of middle cerebral artery occlusion (MCAO), leptomeningeal collaterals (LMCs) play a crucial role in determining the survival of brain tissue distal to occlusion. Previous findings indicated that genes controlling arteriogenesis can impact the extent of LMCs. Therefore, probe for potential genetic parameters correlating of arteriogenesis may be clinically useful in predicting LMCs status in MCAO. During the screening process, we focused on repulsive guidance molecule a (RGMa), which has been reported to play a negative role in angiogenesis after stroke by decreasing the proliferation, migration, and tube formation of endothelial cells (ECs) in vivo and in vitro. Indeed, endothelial function plays a main role in arteriogenesis and is essential in determining the LMCs status. Therefore, in present study, we aimed to testify the hypothesis that RGMa might be associated with LMCs status in MCAO. METHODS: We prospectively enrolled patients with acute M1 MCA +/- intracranial internal carotid artery (ICA) occlusions (n=96) and healthy controls (n=33). Status of LMCs was evaluated according to computed tomographic angiography (CTA) on admission. Baseline RGMa mRNA expression was quantified by using quantitative real-time PCR. RESULTS: Patients with poor LMCs showed significantly higher RGMa mRNA levels than patients with good LMCs status (P=0.001) as well as healthy controls (P=0.002), respectively; whereas good LMCs group showed similar baseline RGMa levels than controls (P=1.000). RGMa mRNA level and baseline NIHSS score were independent predictors for impaired LMCs. CONCLUSIONS: In MCAO patients, elevated PBMCs RGMa mRNA levels were associated with impaired LMCs status, indicating that measurement of RGMa mRNA expression in the early phase of stroke, together with other clinical approaches, was logically expected to be useful for predicting LMCs status. Moreover, a role for RGMa in leptomeningeal arteriogenesis following ischemic stroke can be hypothesized.

Topographic correlation of infarct area on CT perfusion with functional outcome in acute ischemic stroke.

OBJECTIVE: The role of CT perfusion (CTP) in the management of patients with acute ischemic stroke (AIS) remains a matter of debate. The primary aim of this study was to evaluate the correlation between the areas of infarction and penumbra on CTP scans and functional outcome in patients with AIS. METHODS: This was a retrospective review of 100 consecutively treated patients with acute anterior circulation ischemic stroke who underwent CT angiography (CTA) and CTP at admission between February 2011 and October 2014. On CTP, the volume of ischemic core and penumbra was measured using the Alberta Stroke Program Early CT Score (ASPECTS). CTA findings were also noted, including the site of occlusion and regional leptomeningeal collateral (rLMC) score. Functional outcome was defined by modified Rankin Scale (mRS) score obtained at discharge. Associations of CTP and CTA parameters with mRS scores at discharge were assessed using multivariable proportional odds logistic regression models. RESULTS: The median age was 67 years (range 19-95 years), and the median NIH Stroke Scale score was 16 (range 2-35). In a multivariable analysis adjusting for potential confounding variables, having an infarct on CTP scans in the following regions was associated with a worse mRS score at discharge: insula ribbon (p = 0.043), perisylvian fissure (p < 0.001), motor strip (p = 0.007), M2 (p < 0.001), and M5 (p = 0.023). A worse mRS score at discharge was more common in patients with a greater volume of infarct core (p = 0.024) and less common in patients with a greater rLMC score (p = 0.004). CONCLUSIONS: The results of this study provide evidence that several CTP parameters are independent predictors of functional outcome in patients with AIS and have potential to identify those patients most likely to benefit from reperfusion therapy in the treatment of AIS.

Endovascular treatment of a ruptured flow aneurysm of the heubner artery as part of a moyamoya collateral network in a young patient with an occluded middle cerebral artery.

A young woman with an occluded middle cerebral artery presented with a ruptured flow aneurysm distal on a Heubner artery as part of a moyamoya collateral network. Leptomeningeal collateral supply was tested by occlusion of the A1 origin of the Heubner artery. This test occlusion demonstrated ample collateral leptomeningeal supply over the hemispheres to the M2. Subsequently, the Heubner artery harbouring the aneurysm could be safely proximally occluded with coils.

Computer modeling of anterior circulation stroke: proof of concept in cerebrovascular occlusion.

BACKGROUND: Current literature emphasizes the role of the Circle of Willis (CoW) in salvaging ischemic brain tissue but not that of leptomeningeal anastomoses (LA). We developed a computational model of the cerebral circulation to (1) evaluate the roles of the CoW and LA in restoring flow to the superficial compartment of the middle cerebral artery (MCA) territory and (2) estimate the size of the LA required to maintain flow above the critical ischemic threshold (>30% of baseline) under simulated occlusion. METHODS: Cerebral vasculature was modeled as a network of junctions connected by cylindrical pipes. The experiments included occlusion of successive distal branches of the intracranial arteries while the diameters of LA were varied. RESULTS: The model showed that the region of reduced flow became progressively smaller as the site of occlusion was moved from the large proximal to the smaller distal arteries. There was no improvement in flow in the MCA territory when the diameters of the inter-territorial LA were varied from 0.0625 to 0.5 mm while keeping the intra-territorial LA constant. By contrast, the diameter of the inter-territorial LA needed to be >1.0 mm in order to provide adequate (>30%) flow to selected arteries in the occluded MCA territory. CONCLUSION: The CoW and inter-territorial LA together play important supportive roles in intracranial artery occlusion. Computational modeling provides the ability to experimentally investigate the effect of arterial occlusion on CoW and LA function.