The Pattern of Leptomeningeal Collaterals on CT Angiography Is a Strong Predictor of Long-Term Functional Outcome in Stroke Patients With Large Vessel Intracranial Occlusion
Background and Purpose—The role of noninvasive methods in the evaluation of collateral circulation has yet to be defined. We hypothesized that a favorable pattern of leptomeningeal collaterals, as identified by CT angiography, correlates with improved outcomes.
Methods—Data from a prospective cohort study at 2 university-based hospitals where CT angiography was systematically performed in the acute phase of ischemic stroke were analyzed. Patients with complete occlusion of the intracranial internal carotid artery and/or the middle cerebral artery (M1 or M2 segments) were selected. The leptomeningeal collateral pattern was graded as a 3-category ordinal variable (less, equal, or greater than the unaffected contralateral hemisphere). Univariate and multivariate analyses were performed to define the independent predictors of good outcome at 6 months (modified Rankin Scale score ≤2).
Results—One hundred ninety-six patients were selected. The mean age was 69±17 years and the median National Institute of Health Stroke Scale score was 13 (interquartile range, 6 to 17). In the univariate analysis, age, baseline National Institute of Health Stroke Scale score, prestroke modified Rankin Scale score, Alberta Stroke Programme Early CT score, admission blood glucose, history of hypertension, coronary artery disease, congestive heart failure, atrial fibrillation, site of occlusion, and collateral pattern were predictors of outcome. In the multivariate analysis, age (OR, 0.95; 95% CI, 0.93 to 0.98; P=0.001), baseline National Institute of Health Stroke Scale (OR, 0.75; 0.69 to 0.83; P<0.001), prestroke modified Rankin Scale score (OR, 0.41; 0.22 to 0.76; P=0.01), intravenous recombinant tissue plasminogen activator (OR, 4.92; 1.83 to 13.25; P=0.01), diabetes (OR, 0.31; 0.01 to 0.98; P=0.046), and leptomeningeal collaterals (OR, 1.93; 1.06 to 3.34; P=0.03) were identified as independent predictors of good outcome.
Conclusion—Consistent with angiographic studies, leptomeningeal collaterals on CT angiography are also a reliable marker of good outcome in ischemic stroke.
Proximal intracranial arterial occlusion (PIAO) is independently associated with poor functional outcomes and high mortality rates.1–3 Age, baseline National Institutes of Health Stroke Scale (NIHSS) score, and the initial volume of CT hypodensity have been identified as important prognostic variables in patients with this devastating disease.4 The presence of robust collateral flow on conventional angiography has been linked to improved clinical outcomes and reduced infarcts volumes.5–7 Although frequently evoked in clinical discussions, little is known about the pathophysiology of the cerebral collateral circulation and its relation with other important stroke predictors.
Conventional angiography provides the most complete and reliable information about the circle of Willis and leptomeningeal collaterals and is, therefore, considered the gold standard for collateral flow assessment. However, the applicability of catheter angiography is limited by its invasive nature and associated risks. Indirect assessment of collaterals can be accomplished by noninvasive methods, including transcranial Doppler, CT angiography (CTA), and MR angiography.8 Transcranial Doppler and MR angiography may provide important information about the status of the circle of Willis collaterals but do not possess enough spatial resolution to evaluate the more distal leptomeningeal vascular bed. CTA, alternatively, encompasses a higher degree of anatomic resolution and can, more accurately, depict the leptomeningeal collaterals (Figure). Few previous studies have used CTA to assess the degree of collateral circulation to the ischemic tissue.8–11
There are advantages of using CTA in the triage of patients with acute stroke.12 CTA is widely available, noninvasive, and provides a rapid assessment of the intra- and extracranial vasculature depicting with high accuracy vessel stenoses and occlusions. We hypothesized that a favorable pattern of leptomeningeal collaterals as visualized on CTA correlates with improved functional outcomes in patients with acute ischemic stroke.
Subjects and Methods
We analyzed data from 741 consecutive patients enrolled in a prospective cohort study at 2 university-based hospitals, the Screening Technology and Outcomes Project in Stroke (STOPStroke), in which admission nonenhanced CT scans (NCCT) and CTA were obtained in all patients suspected of having ischemic stroke (stroke, transient ischemic attack, or stroke mimics) in the first 24 hours of symptom onset. Patients were excluded if iodinated contrast agent administration was contraindicated (ie, history of contrast agent allergy, pregnancy, congestive heart failure, increased creatinine level) or if there was evidence of intracranial hemorrhage on NCCT. The STOPStroke study received Institutional Review Board approval at both participating institutions and was Health Insurance Portability and Accountability Act-compliant.
Data on clinical history, laboratory results, demographics, stroke risk factors, and prestroke modified Rankin Scale (mRS) score were collected on all patients at baseline by direct interview or by review of the medical chart by trained staff. NIHSS scores were obtained at baseline as part of patient admission workup. Time to hospital arrival was calculated as the amount of time elapsed between the onset of symptoms (last time seen normal for nonwitnessed symptom-onset patients) and the time of arrival to the emergency medicine department. Time to CTA was calculated in a similar fashion. Follow-up mRS was obtained at 6 months. For the present study, patients with acute complete occlusion of the intracranial internal carotid artery (intracranial ICA) and/or M1 and/or M2 segments of the middle cerebral artery (MCA) were selected. Patients with bilateral and/or posterior circulation strokes were excluded from the analysis.
Image Protocol and Review
The STOPStroke NCCT and CT angiographic protocol is described elsewhere.13 Image review was independently performed on a picture archiving and communication system workstation (Impax; AGFA Technical Imaging Systems, Richfield Park, NJ) by a board-certified neuroradiologist and a clinical neurologist experienced in stroke imaging interpretation. Disagreements in readings were resolved by consensus. Reviewers were blinded to follow-up clinical and imaging findings but had information in regard to the patients’ age, sex, and presenting clinical symptoms. Neither of the reviewers had participated in the selection of the patients. Variable window width and center-level settings were used for optimal ischemic hypoattenuation detection with NCCT and CTA images.14 In all cases, NCCT images obtained for acute stroke were reviewed first followed by CTA images. Reviewers rated the ischemic lesion on the NCCT scan images according to Alberta Stroke Programme Early CT Score (ASPECTS).15 For every image, each of 10 regions was reviewed for the presence or absence of ischemic lesions according to a 5-point level of certainty score (score 5, definitely present; score 4, probably present; score 3, equivocal; score 2, probably absent; and score 1, definitely absent). For the ASPECTS, just the regions assigned with scores 4 or 5 were used. After the CTA, readers assessed the presence of complete occlusion of the ICA and MCA by thrombus according to the same certainty scale. Just scores 4 or 5 were used as evidence of complete ICA or MCA occlusion as well. Leptomeningeal vascularity was graded in the following scores: 1, absent; 2, less than the contralateral unaffected side; 3, equal to the contralateral unaffected side; 4, more than the contralateral unaffected side; and 5, exuberant. Because of the very small number of patients in the extreme scores, the scale was collapsed into 3e ordinal groups: less than contralateral unaffected side (score 1 to 2), equal to contralateral unaffected side (score 3), and greater than contralateral unaffected side (scores 4 to 5).
All statistical analysis was performed using SPSS software (Version 17.0; SPSS Inc, Chicago, Ill). The following baseline clinical variables were included: age, sex, comorbidities (history of hypertension, congestive heart failure, coronary artery disease, diabetes, atrial fibrillation, and history of stroke or transient ischemic attack), smoking and alcohol consumption, baseline NIHSS score, prestroke mRS score (continuous and dichotomized: ≤2 versus >2), systolic blood pressure (continuous and dichotomized: <150 versus ≥150 mm Hg), glucose levels (continuous and dichotomized: <140 versus ≥140 mg/dL), ASPECTS (dichotomized: ≤7 and >7), intravenous thrombolytic use, intra-arterial therapy, time to hospital arrival, and time to CTA. Good clinical outcome was defined as an mRS ≤2 at 6 months follow-up.
Continuous variables are reported as mean±SD or as median±interquartile range (IQR). Categorical variables were reported as proportions. Baseline characteristics were compared among the different leptomeningeal collateral patterns. Differences in continuous variables were assessed by 1-way analysis of variance or the Kruskal-Wallis test in case of nonnormally distributed data. Differences between proportions were assessed by the χ2 test. We also compared mortality, both in-hospital and at follow-up, according to the pattern of leptomeningeal collaterals.
Univariate analysis was used to test the association between different variables and the outcome (follow-up mRS). Multivariate logistic regression with backward elimination (probability value for elimination of 0.1) was used to identify independent predictors for good outcome (follow-up mRS ≤2). Variables significantly associated with a favorable outcome in the univariate analysis (P<0.1) were included in the multivariable model. Given their strong clinical association with clinical outcomes, we a priori planned to force the following variables into the model: age, baseline NIHSS, intravenous recombinant tissue plasminogen activator (rtPA), intra-arterial therapy, prestroke mRS, and the site of intracranial occlusion. The pattern of leptomeningeal collaterals was also forced into the model because it was the predictor of interest. The site of intracranial occlusion and the pattern of leptomeningeal collaterals were tested as ordinal variables in the regression analysis. To evaluate the importance of leptomeningeal collaterals in untreated patients, the same model was also used in a subset analysis including just cases with no intravenous rtPA and/or intra-arterial intervention. A 2-sided probability value <0.05 was considered significant.
Of the 741 patients include in the database, 196 subjects were identified as having isolated anterior circulation PIAO involving a single hemisphere and follow-up at 6 months available. The mean age was 69±16.7 years. Eighty-four (43%) were males. The majority of the study population was composed of whites (158 subjects [81%]). The median NIHSS at admission was 13 (IQR, 6 to 17). One hundred three patients (53%) had an ASPECTS >7 (Table 1).
Forty-eight (24%) subjects were treated with intravenous rtPA, 9 subjects (5%) received intra-arterial therapy, and 13 (7%) had combined intravenous and intra-arterial therapy. The median 6-month mRS of the study cohort was 3 (IQR, 1 to 6). At 6 months, 82 subjects (42%) had achieved a good outcome (mRS ≤2) and 49 subjects (28%) had died. Most of fatalities (67% [33 of 49]) occurred during hospitalization.
According to the pattern of leptomeningeal collaterals, 45 subjects (23%) were graded as less (score 1 to 2), 96 subjects (49%) were graded as equal (score 3), and 55 subjects (28%) were graded as greater (score 4 to 5) when compared with the contralateral unaffected hemisphere. There was no significant difference in the time from stroke onset to CT scan across the different patterns of leptomeningeal collaterals (P=0.6). Subjects with equal or greater CTA leptomeningeal collaterals had higher baseline ASPECTS as compared to subjects with less CTA leptomeningeal collaterals (P=0.02). Subjects with greater leptomeningeal collaterals had lower systolic blood pressure and lower prevalence of hypertension. In general, subjects with greater leptomeningeal collaterals had lower prevalence of other cardiovascular risk factors as well, but none of these reached statistical significance (Table 2).
There was a statistically significant difference in the rates of in-hospital mortality: 33% (14 subjects), 13% (12 subjects), and 13% (7 subjects) in patients graded as less, equal, and greater leptomeningeal collaterals, respectively (P=0.01). At 6 months, subjects with equal and greater leptomeningeal collaterals tended to have lower mortality (22% and 20%, respectively) when compared with subjects with less leptomeningeal collaterals (39%, P=0.06).
In the univariate analysis, younger age (P<0.001), lower prestroke mRS (P<0.001), lower baseline NIHSS (P<0.001), ASPECTS >7 on admission CT (P=0.02), lower admission glucose (P=0.04), equal or greater (as opposed to less) leptomeningeal collaterals (P=0.002) as well as the absence of history of hypertension (P=0.01), atrial fibrillation (P=0.001), congestive heart failure (P=0.01), and coronary artery disease (P=0.04) were significantly associated with good outcome at 6 months. Patients with occlusion of the M2 segment of the MCA had also significantly higher odds for a good outcome when compared with subjects with intracranial ICA occlusion (Table 3).
In the multivariate analysis, age (OR, 0.95; 0.93 to 0.98; P=0.001), baseline NIHSS score (OR, 0.75; 0.69 to 0.83; P<0.001), intravenous rtPA (OR, 4.92; 1.83 to 13.25; P=0.002), prestroke mRS (OR, 0.38; 0.22 to 0.76; P=0.01), history of diabetes (OR, 0.31; 0.01 to 0.98; P=0.046), and the pattern of leptomeningeal collaterals (OR, 1.93; 1.06 to 3.50; P=0.03) were significantly associated with good outcome at the 6-month follow-up (Table 4). When the multivariate analysis was applied to the untreated patients, only age (OR, 0.94; 0.91 to 0.98; P=0.01), admission NIHSS score (OR, 0.75; 0.67 to 0.84; P<0.001), and the pattern of leptomeningeal collaterals (OR, 2.89; 1.25 to 6.67; P=0.01) were significantly associated with a favorable outcome (Table 5).
In the present study, a favorable pattern of leptomeningeal collaterals, as measured by CTA, was associated with improved functional outcomes at 6 months in a cohort of patients with acute anterior circulation PIAO. In a multivariate model, robust leptomeningeal collaterals remained an independent predictor of good long-term outcomes along with younger age, lower prestroke mRS and baseline NIHSS scores, administration of intravenous rtPA, and absence of diabetes. More proximal intracranial occlusions showed a strong trend toward worst outcomes. When the analysis was restricted to patients not treated with intravenous rtPA and/or endovascular intervention, there was an even stronger association between the degree of leptomeningeal collaterals and good outcomes. Notably, the pattern of leptomeningeal collaterals on CTA was also associated with lower in-hospital mortality and a trend toward lower mortality at 6 months.
PIAO is associated with poor functional outcomes and high mortality rates.1,2 Indeed, a previous analysis of the STOPStroke database demonstrated that the presence of PIAO was one of the strongest predictors of nonfunctional outcomes (OR, 3.33; 0.24 to 0.45; P<0.001) and mortality (OR, 4.5; 2.7 to 7.3; P<0.001) at 6 months.3 Other studies have demonstrated that age and baseline NIHSS scores are among the most potent predictors of outcome in patients with PIAO.4,16,17 Although there is no dispute about the importance of collateral circulation in the setting of PIAO, its physiology and relationship with other clinical variables remains largely unknown.8 In our study, a history of hypertension was more frequently found among patients with fewer CTA leptomeningeal collaterals. We also found higher mean systolic blood pressure levels in patients with less or equal leptomeningeal collaterals. Liebeskind et al reported similar results showing that angiographic collateral flow was inversely associated with pretreatment systolic blood pressure and history of hypertension in stroke patients undergoing thrombectomy.18 Other factors such as statins have been also associated with increased collateralization in acute stroke but were not evaluated in the present study.19
Collateral circulation likely improves neurological outcome by limiting the extent of brain infarction. As demonstrated by the strong association between CTA collateral pattern and baseline ASPECTS, our results support the notion that adequate collateral perfusion is essential to the viability of the penumbral tissue. Good collateral circulation has been also linked to higher recanalization rates.20,21 Although we might simply argue in favor of sparing of the penumbral tissue, collateral flow may increase availability of the fibrinolytics to the clot and facilitate its dissolution or, as recently proposed, it may affect revascularization by altering the degree of thrombus impaction into the cerebrovasculature.16,22 Notably, we could not find a difference in time from stroke onset to CTA between patients with good and poor collaterals. This persistence of collateral flow might explain the findings of a recent MRI study, which demonstrated similar occurrence rates of diffusion–perfusion mismatch in patients with large vessel strokes who were imaged within <9 hours versus 9 to 24 hours from stroke onset.23 Despite its high spatial resolution, CTA provides very little information about flow itself. As a consequence, CTA may lead to an overestimation of the strength of the collateral circulation. Indeed, a much higher percentage of patients was classified as having good leptomeningeal collaterals in our CTA study as compared with previous angiographic studies.24
Only a few studies have previously used CTA leptomeningeal vascular pattern as a surrogate for collateral flow and even fewer have linked CTA leptomeningeal vascular pattern to long-term outcomes.17 In a univariate analysis using a subset of patients with MCA occlusions, the STOPStroke investigators have previously demonstrated a relationship between poor CTA collaterals and in-hospital worsening.11 Rosenthal et al reported that CTA leptomeningeal collaterals had only a minimal positive impact in the outcomes of patients who did not achieve recanalization and no impact in the outcomes of patients who were completely recanalized.9 Tan et al reported that good CTA collaterals correlated with improved outcomes in uni- but not in multivariate analyses.10 In our study, the effect of the pattern of leptomeningeal collaterals on the outcome of untreated patients (presumably with a higher proportion of nonrecanalized patients) was higher as compared with the entire cohort. Our study is the largest one to evaluate the association of leptomeningeal collaterals as identified by CTA and long-term outcomes. Probably due to methodological differences (different level of occlusions, incorporation of complete occlusions only, higher number of patients, etc), our results differ from some of the previous studies.
Our study has some limitations. As a retrospective analysis, there is a potential for bias in the selection of the subjects. The use of a prospective collected cohort contributed to minimize this problem. The status of recanalization, an important predictor of outcome in ischemic stroke, was not assessed in our study. Finally, our patient cohort was composed primarily of a white population and this may limit the generalizability of our findings. Conversely, the exclusion of patients with partial occlusions or bilateral and/or posterior strokes contributed to the homogeneity of the cohort and made the comparisons between groups more powerful.
Because conventional angiography, an invasive approach, is impractical for most patients with ischemic stroke, the study of noninvasive methods such as CTA as a surrogate marker of collateral circulation may lead to a better understanding of its determinants and find potential treatments to enhance collateral flow to the ischemic tissue. Consistent with angiographic studies, leptomeningeal collaterals on CTA are also a reliable marker for good outcome in patients with acute ischemic stroke presenting with PIAO. The acquisition of this information, with no extra processing time, may greatly assist in the selection of patients who are potential candidates for reperfusion therapies.
Sources of Funding
This research was funded by a grant from the Department of Health and Human Services, Agency for Healthcare Research and Quality, grant number RO1- HS011392-01A1.
M.H.L. is a speaker for GE Healthcare, receives educational support from GE Healthcare, serves on a medical advisory board for CoAxia Inc, is a research consultant for Vernalis Ltd (modest), and is supported by National Institutes of Health (NIH) grant P50NS051343 (significant). A.B.S. is supported by NIH grants P50NS051343, R01NS051412, R01NS38477 (significant), and R01NS059775 (modest). W.S.S. has significant ownership interests and has served as a consultant to Concentric Medical Inc (significant). A.J.Y. is supported by a research grant from Penumbra Inc (significant). R.G.N. is a member of the Scientific Advisory Board for Concentric Medical Inc, ev3 Neurovascular Inc, and Coaxia Inc (modest).
Vladimir Hachinski, MD, DSc handled this paper.
- Received June 3, 2010.
- Accepted July 28, 2010.
Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. PROlyse in Acute Cerebral Thromboembolism. JAMA. 1999; 282: 2003–2011.
Ogawa A, Mori E, Minematsu K, Taki W, Takahashi A, Nemoto S, Miyamoto S, Sasaki M, Inoue T. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan. Stroke. 2007; 38: 2633–2639.
Smith WS, Lev MH, English JD, Camargo EC, Chou M, Johnston SC, Gonzalez G, Schaefer PW, Dillon WP, Koroshetz WJ, Furie KL. Significance of large vessel intracranial occlusion causing acute ischemic stroke and TIA. Stroke. 2009; 40: 3834–3840.
Wechsler LR, Roberts R, Furlan AJ, Higashida RT, Dillon W, Roberts H, Rowley HA, Pettigrew LC, Callahan AS III, Bruno A, Fayad P, Smith WS, Firszt CM, Schulz GA. Factors influencing outcome and treatment effect in PROACT II. Stroke. 2003; 34: 1224–1229.
Bozzao L, Fantozzi LM, Bastianello S, Bozzao A, Fieschi C. Early collateral blood supply and late parenchymal brain damage in patients with middle cerebral artery occlusion. Stroke. 1989; 20: 735–740.
Liebeskind DS. Collateral circulation. Stroke. 2003; 34: 2279–2284.
Rosenthal ES, Schwamm LH, Roccatagliata L, Coutts SB, Demchuk AM, Schaefer PW, Gonzalez RG, Hill MD, Halpern EF, Lev MH. Role of recanalization in acute stroke outcome: rationale for a CT angiogram-based ‘Benefit of Recanalization’ model. AJNR Am J Neuroradiol. 2008; 29: 1471–1475.
Tan IY, Demchuk AM, Hopyan J, Zhang L, Gladstone D, Wong K, Martin M, Symons SP, Fox AJ, Aviv RI. CT angiography clot burden score and collateral score: correlation with clinical and radiologic outcomes in acute middle cerebral artery infarct. AJNR Am J Neuroradiol. 2009; 30: 525–531.
Maas MB, Lev MH, Ay H, Singhal AB, Greer DM, Smith WS, Harris GJ, Halpern E, Kemmling A, Koroshetz WJ, Furie KL. Collateral vessels on CT angiography predict outcome in acute ischemic stroke. Stroke. 2009; 40: 3001–3005.
Wintermark M, Meuli R, Browaeys P, Reichhart M, Bogousslavsky J, Schnyder P, Michel P. Comparison of CT perfusion and angiography and MRI in selecting stroke patients for acute treatment. Neurology. 2007; 68: 694–697.
Nogueira RG, Liebeskind DS, Sung G, Duckwiler G, Smith WS. Predictors of good clinical outcomes, mortality, and successful revascularization in patients with acute ischemic stroke undergoing thrombectomy: pooled analysis of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi MERCI trials. Stroke. 2009; 40: 3777–3783.
Liebeskind DS, Starkman S, Jo KJ, Ohanian AG, Sayre JW, Yun S, Kim D, Ali LK, Ovbiagele B, Towfighi A, Shah SH, Jahan R, Duckwiler GR, Vinuela F, Saver JL. Blood pressure in acute stroke is inversely related to the extent of collaterals. Stroke. 2008; 39: 538.
Ovbiagele B, Saver JL, Starkman S, Kim D, Ali LK, Jahan R, Duckwiler GR, Vinuela F, Pineda S, Liebeskind DS. Statin enhancement of collateralization in acute stroke. Neurology. 2007; 68: 2129–2131.
Jo KD, Saver JL, Starkman S, Kim D, Ali LK, Ovbiagele B, Bang OY, Yun S, Towfighi A, Shah SH, Vespa PM, Miller C, Tateshima S, Jahan R, Vinuela F, Duckwiler GR, Liebeskind DS. Predictors of recanalization with mechanical thrombectomy for acute ischemic stroke. Stroke. 2008; 39: 599.
Ringelstein EB, Biniek R, Weiller C, Ammeling B, Nolte PN, Thron A. Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization. Neurology. 1992; 42: 289–298.
Jovin TG, Gupta R, Horowitz MB, Grahovac SZ, Jungreis CA, Wechsler L, Gebel JM, Yonas H. Pretreatment ipsilateral regional cortical blood flow influences vessel recanalization in intra-arterial thrombolysis for MCA occlusion. AJNR Am J Neuroradiol. 2007; 28: 164–167.
Arnold M, Nedeltchev K, Mattle HP, Loher TJ, Stepper F, Schroth G, Brekenfeld C, Sturzenegger M, Remonda L. Intra-arterial thrombolysis in 24 consecutive patients with internal carotid artery occlusions. J Neurol Neurosurg Psychiatry. 2003; 74: 739–742.