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Despite the abundance of emerging multimodal imaging techniques in the field of stroke, there is a paucity of data demonstrating a strong correlation between imaging findings and clinical outcome. This study explored how proximal arterial occlusions alter flow in collateral vessels, and whether occlusion or extent of collaterals correlate with pre-hospital symptoms of fluctuation and worsening since onset, or predict in-hospital worsening.
Among 741 patients enrolled in a prospective cohort study involving CTA imaging in acute stroke, 134 cases with proximal MCA occlusion and 235 controls with no occlusions were identified. CTA was used to identify occlusions and grade the extent of collateral vessels in the sylvian fissure and leptomeningeal convexity. History of symptom fluctuation or progressive worsening was obtained on admission. Results: Pre-hospital symptoms were unrelated to occlusion or collateral status. In cases, 37.5% imaged within 1 hour were found to have diminished collaterals versus 12.1% imaged at 12–24 hours (p=0.047). No difference in worsening was seen between cases and controls with adequate collaterals, but cases with diminished sylvian and leptomeningeal collaterals experienced greater risk of worsening compared to controls, measured either by admission to discharge NIHSS increase ≥ 1 (55.6% versus 16.6%, p=0.001) or ≥ 4 (44.4% versus 6.4%, p<0.001).
Most patients with proximal MCA occlusion rapidly recruit sufficient collaterals and follow a clinical course similar to patients with no occlusions, but a subset with diminished collaterals is at high risk for worsening.
Collateral circulation is an important consideration in the acute management of ischemic stroke. In cases of proximal artery occlusion, collateral vessels may provide blood flow to preserve remaining viable tissue.1 Although CT angiography (CTA) source images and diffusion weighted MRI (DWI) are useful in delineating infarct volume,2–4 the ability to predict the stability of the infarct using clinical and imaging characteristics is limited. MR and CT perfusion parameters to predict the outcome of the ischemic penumbra have not been accurately established,5,6 although a small study of 29 patients has identified a relationship between perfusion images and clinical outcome in a pattern that suggests a protective effect of leptomeningeal collaterals.7
Certain attributes of collateral vessels remain hypothetical. A phenomenon of arterial collateral recruitment is frequently described,8 but with limited empirical evidence. Knowledge of whether collateral arterial channels are recruited or change in a time-dependent manner in the acute phase of ischemic stroke as a compensatory mechanism due to vessel occlusion would be useful in guiding treatments goals for volume expansion and blood pressure. Finally, it is unknown whether the absence of collateral vessels predicts evolution of symptoms. The purpose of this study is to explore whether (a) proximal arterial occlusions alter flow in collateral vessels, (b) a time-dependent collateral vessel recruitment phenomenon exists, (c) symptom fluctuation or worsening since initial onset correlate with the presence of a proximal arterial occlusion or the extent of active collaterals, and (d) whether extent of collaterals predicts further in-hospital worsening.
We analyzed data from 741 consecutive patients enrolled between March 2003 and January 2006 in a prospective cohort study at two university-based hospitals, part of the Screening Technology and Outcomes Project in Stroke (STOPStroke). All patients presenting with symptoms consistent with acute cerebral ischemia were considered eligible. Admission nonenhanced CT scans were obtained, followed by CT angiograms. Patients were excluded from enrollment for contraindication to iodinated contrast agent administration (history of contrast agent allergy, pregnancy, congestive heart failure, renal insufficiency) or if the nonenhanced CT scan showed evidence of intracranial hemorrhage. The study received institutional review board approval at both participating institutions and were Health Insurance Portability and Accountability Act compliant. At enrollment, all subjects gave informed consent for participation.
Subjects with middle cerebral artery (MCA) M1 and/or M2 segment occlusion without evidence for occlusion in the contralateral MCA or internal carotid artery (ICA) were selected as study cases. Subjects with symptoms consistent with anterior circulation ischemia but no angiographic occlusions in the territory of either ICA or MCA were selected as controls. Time-to-imaging (TTI) was calculated as the amount of time elapsed between the onset of symptoms and the acquisition of the CT angiography segment of the neuroimaging protocol. Patients without time of onset data were excluded. Time of onset was defined as time of symptom onset for witnessed events, and time the subject was last known normal for unwitnessed events. For patients with unwitnessed events where the time last known normal could only be estimated as “AM” or “PM”, a conservative estimate of midnight for AM and noon for PM were used. Patients for whom TTI was greater than 24 hours were excluded.
Information was collected on the trajectory of subjects’ symptoms. At the time of initial evaluation, it was determined by interview of the patient and/or accompanying family or friends whether the subject’s neurological symptoms had definitely fluctuated, improved, worsened or remained unchanged since the time of initial onset. National Institutes of Health Stroke Scale (NIHSS) was measured at the time of initial presentation, at various time intervals during the course of hospitalization and at the time of discharge. Inhospital worsening is defined as a discharge NIHSS greater than admission NIHSS, and severe worsening as an increase ≥ 4 between admission and discharge, including death.
Nonenhanced CT and CT angiographic acquisitions were performed according to standard departmental protocols with 8- or 16-section multidetector CT scanners (LightSpeed; GE Healthcare, Milwaukee, Wis) (7,8). Nonenhanced CT was performed, with the patient in a head holder, in the transverse plane. Representative sample parameters, with minimal variations between scanners and sites shown as ranges, were as follows: 120–140 kVp, 170 mA, 2-second scan time, and 5-mm section thickness. Imaging with these parameters was immediately followed by biphasic helical scanning, performed at the same head tilt as was nonenhanced CT. CT angiography was performed after a 25-second delay (40 seconds for patients in atrial fibrillation) and administration of 100–140 mL of a nonionic contrast agent (Isovue; Bracco Diagnostics, Princeton, NJ) at an injection rate of 3 mL/sec by using a power injector (Medrad Power Injector; Medrad, Indianola, Pa) via an 18-gauge intravenous catheter. Parameters were 140 kVp, 220–250 mA, 0.8–1.0-second rotation time, 2.5-mm section thickness, 1.25-mm reconstruction interval, 3.75 mm per rotation table speed, and 0.75:1 pitch. Images were obtained from the C6 vertebral body level through the circle of Willis. Immediately afterward, a second set of images was obtained from the aortic arch to the skull base. Afterward, source images were reconstructed into standardized maximum intensity projection views of the intracranial and extracranial vasculature.
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 (M.H.L. and W.J.K., 15 and 25 years of neuroimaging review experience, respectively). 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.
For the primary analysis, patients who receive IV thrombolysis or intra-arterial therapy were excluded. Angiographic occlusions, with a 1 to 5 level of certainty rating, were recorded for 27 defined vessel segments. Lesions identified as subtotal or total occlusion of level 4 and 5 certainty (probably or definite) were defined as an occlusion. CTA-SI were used to assess for the presence of collateral vessels in the region of the sylvian fissure and the leptomeningeal convexity, and to assign separate grades for each. Collateral vessels were graded in a comparison manner for the symptomatic hemisphere against the contralateral hemisphere as follows: 1, absent; 2, less than the contralateral normal side; 3, equal to the contralateral normal side; 4, greater than the contralateral normal side; and 5, exuberant. Diminished is defined as grades 1–2, adequate as grades 3–5, and augmented as grades 4–5. The anterior communicating artery (ACom) and posterior communicating arteries (PCom) were graded as follows: 1, absent; 2, probably present; 3, hairline; 4, definitely present; 5, robust. Adequate ACom and PCom are defined as grades 4–5.
To explore the question of a time-dependent collateral vessel recruitment phenomenon, case subjects were divided into the following TTI groups: 0–1 hour, 1–2 hours, 2–3 hours, 3–6 hours, 6–9 hours, 9–12 hours and 12–24 hours and the Mantel-Haenszel trend test was used to evaluate for a time-variant relationship between extent of collaterals and time of imaging. The relationship between collaterals and and clinical outcomes (pre-hospital symptom fluctuation and worsening, and in-hospital worsening and severe worsening) was performed by evaluating outcome of subjects dichotomized into groups with diminished or adequate collaterals using Fisher’s exact test. The relationship between anterior and ipsilateral posterior communicating artery and in-hospital worsening and severe worsening was assessed by Fisher’s exact test. Student’s t test was used for continuous data.
In a secondary analysis, patients who received IV thrombolysis and/or intra-arterial therapy were included and all analyses repeated,
Of the 741 subjects enrolled in the study, 134 met criteria as cases and 235 as controls. An additional 59 cases and 27 controls who received thrombolytic therapy were included for secondary analysis. The characteristics of the subjects included in the primary analyses are summarized in Table 1. There were no significant differences in age or sex between groups. Case subjects had significantly higher initial and discharge NIHSS scores (9.8 versus 4.2 and 9.9 versus 3.3, both p<0.0001). There was no difference in time-to-imaging between groups (8.1 versus 8.2 hours, p=0.87). Nearly 1 in 6 case and control subjects had a reported history of fluctuation of symptoms, or had evolved worsening of symptoms since the time of initial symptom onset, and there was no difference between the groups. With respect to in-hospital worsening, there was no significant difference in the rate of all in-hospital worsening, although cases experienced a significantly greater rate of severe worsening compared with controls (13.4% versus 6.4%, p=0.035).
Based on the 1 to 5 rating scale, no difference in the average extent of visualized collaterals was found between the case and control groups in the region of the sylvian fissure (2.93 versus 2.93, p=1.0) or leptomeningeal convexity (3.04 versus 2.95, p=0.09). Nearly all control subjects were found to have equal (grade 3) extent of arterial tree filling, whereas half of case subjects showed either augmented or diminished flow in the symptomatic hemisphere.
In the TTI analysis, 50% of case subjects imaged within 1 hour had diminished collaterals compared with 14.5% imaged between 12 and 24 hours (p=0.12 for trend). The same apparent trend was present for both the sylvian (50% to 19.4%, p=0.21) and leptomeningeal collaterals (50% to 9.7%, p=0.31). Inclusion of subjects who had received thrombolysis showed the same trend, which achieved significance with the increased number of subjects (37.5% to 12.1%, p=0.047). No time-dependent changes were seen in the extent of collaterals of control patients.
The key results of the clinical outcomes analysis is summarized in Table 2. No relationship could be demonstrated between reports of pre-hospital symptom fluctuation or worsening since onset and the extent of collaterals in the sylvian fissure or leptomeningeal convexity (symptoms present in 16.1% with adequate versus 27.8% with diminished collaterals, p=0.31). The relationship between reduced collaterals and in-hospital worsening was marked. There was no difference in the rate of worsening or severe worsening between cases with adequate sylvian and leptomeningeal collaterals and controls. Diminished sylvian and leptomeningeal collaterals nearly quadrupled the rate of worsening when studied separately (34.1% and 45.8% versus 16.6% in controls, p=0.019 and p=0.002 respectively) or in patients where both sylvian and leptomeningeal collaterals were diminished compared with controls (55.6% versus 16.6%, p=0.001). The effect was nearly identical for severe worsening (diminished sylvian 24.4%, diminished leptomeningeal 33.3% and both diminished 44.4% versus 6.4% for controls, p=0.002, 0.001 and <0.001 respectively). Likewise, the protective effect of collaterals was magnified in subjects with absent (grade 1) collaterals. When compared with controls, 66.7% of subjects with either absent sylvian and leptomeningeal collaterals experienced severe worsening (versus 6.4% controls, p=0.017 for both). The rates of in-hospital worsening and severe worsening for cases in which both the ACom and PCom were adequate versus cases in which neither were adequate were not significantly different (worsening 23.3% versus 23.0%, p=1.0 and severe worsening 10.0% versus 16.2%, p=0.32).
The importance of this study is the objective demonstration of time-dependent collateral recruitment and the correlation of collateral status with clinical outcome measures. A history of symptom fluctuation or progressive worsening since initial onset of stroke has traditionally been viewed as indicating that an at-risk area of brain is receiving diminished perfusion near the threshold for normal function.9 Despite conventional wisdom, no correlation could be demonstrated between a history of pre-hospital fluctuation or worsening and either the finding of diminished collaterals or as a predictor of greater risk for in-hospital worsening. Although the clinical history of pre-hospital symptom change was not predictive of clinical status, the extent of collaterals was. Despite the presence of a proximal MCA occlusion, the risk for in-hospital worsening for patients with adequate collaterals was not significantly greater compared with subjects who had no occlusions, regardless of whether an inclusive or strict definition was used for worsening. In contrast, the rate of worsening was nearly 4 times greater in subjects with proximal MCA occlusion but diminished collaterals.
Major clinical trials have used either change in NIHSS ≥ 1 or ≥ 4 to define worsening. In this study, the impact of collaterals was significant whether a broad definition of NIHSS ≥ 1 was used, or NIHSS ≥ 4 to target severe worsening. Whereas the occlusion patients with normal or increased collateral flow fared no worse than stroke patients with no visible occlusions, the fraction with diminished flow experienced a significantly greater risk of in-hospital progression of stroke deficits, to the point that patients with absent collaterals had a ten-fold increased risk of severe worsening or death. Diminished or absent collaterals, while only affecting only one-quarter of subjects with proximal MCA occlusion, was a clear harbinger of further worsening of stroke severity. Thus, the disparity in outcomes between case subjects and controls reported in Table 1 is accounted for by the minority of cases with diminished collaterals.
Patients presenting with proximal MCA occlusions showed a time-dependent recruitment of flow to the symptomatic hemisphere through collateral vessels. Overall, half of such patients showed a symmetric extent of collaterals between hemispheres, and the remaining half was evenly divided between one subset that experienced augmented flow through collateral vessels (26%), and another with diminished flow in the same regions (26%). The fraction of patients with augmented flow remained constant. Although most patients appear to eventually achieve adequate collateral flow, the ability to generate augmented flow to the affected hemisphere appears to be established within the first hour. These findings suggest a possible intrinsic capacity for collateral flow that is important for clinical outcome.
This study contributes important advances in the current understanding of how collateral vessels influence outcome in acute stroke. First, data is presented to demonstrate an alteration in the extent of collaterals in the context of proximal arterial occlusion. Second, a time-dependent trend is identified implying a successful early (<1 hour) recruitment of collaterals in approximately three-fourths of stroke patients with proximal arterial occlusion, as well as a slow secondary recruitment phenomenon. Finally, CTA imaging can identify a unique subset of patients with diminished or absent collateral vessels in the symptomatic hemisphere. This group of patients experiences markedly higher risk for further worsening. Despite the abundance of emerging multimodal imaging techniques in the field of stroke, there is a paucity of data demonstrating a strong correlation between an imaging finding and clinical outcome.
There are inherent limitations involved with evaluating the role of collateral vessels. Ascertaining a history of fluctuation or progression relies on patient and family being capable of observing and correctly interpreting signs attributable to multiple domains of neurological function, which is fraught with limitations. Use of the NIHSS by properly trained staff is a more objective measure than report of pre-hospital symptoms. Use of CTA reveals the extent of patent arterial collaterals by observing contrast filling of vessel lumens, but cannot account for any difference in volume of flow within collateral vessels that may be induced by occlusion. Furthermore, the technique of identifying collaterals depends on an approximation based on vessels visualized in the sylvian fissure and leptomeningeal convexity region.
Prior studies have employed angiographic techniques to assess cerebral arterial collaterals in the context of acute to subacute ischemic stroke (see Table 3). Tan et al10 compared the techniques used to visualize collateral vessels employed in earlier studies by Schramm3 and Kim11 and found that the less subjective ordinal scale used by Kim et al had higher interobserver agreement (κ = 0.669) and correlated significantly with infarct volume both in patients with persistent arterial occlusion and those who showed recanalization. Rosenthal et al12 employed a multivariable analysis model to study clinical and radiologic predictors of patient outcomes. More recently, arterial spin labeled MRA has been shown to accurately image collateral flow.13 Although other imaging techniques have successfully visualized leptomeningeal vessels in acute stroke, no correlation was found between abnormal visualization of leptomeningeal vessels and clinical status.14 This may have been due to small numbers of patients studied.
Given the predictive clinical implications of diminished or absent collateral vessels, CTA based assessment of collaterals may provide a clinically useful method of selecting patients likely to benefit from intra-arterial therapies. Further research correlating extent of collateral vessels, extent of perfusion defect-infarct core mismatch and clinical outcome may lead to advances in patient care. Other studies have found a relationship between perfusion parameters such as regional cerebral blood volume and cerebral blood flow and delayed contrast arrival on perfusion source images that suggests the role of collateral vessels.7 Future research to explore those relationships would be useful. Likewise, future research into treatments directed at improving cerebral blood flow, such as induced hypertension, may employ collateral vessel grading in their selection of patients. Some patients with diminished collateral vessels may not respond to such treatments despite being identified as a good candidate by perfusion mismatch, or they may prove to be the ideal candidates for such treatment due to their propensity for progression of deficits.
In patients presenting with acute cerebral ischemia and proximal MCA occlusion, initial recruitment of collaterals occurs rapidly. A secondary, gradual recruitment effect occurs over at least 24 hours, and pathological diminution of flow diminishes over time. Although most individuals demonstrate collateral circulation sufficient to show adequate filling of the distal arterial tree following acute proximal MCA occlusion, approximately one-fourth are unable to generate substantial collateral flow measured by sylvian fissure and leptomeningeal convexity vessels on CTA. While nearly all patients with MCA occlusions and adequate collaterals experience stable deficits with in-hospital improvement similar to patients with no angiographic occlusions, the subset with diminished collaterals is at very high risk for worsening. This group may be an ideal population for blood flow enhancing treatments such as intra-arterial therapies.
Sources of Funding: Supported by National Institutes of Health grant AHRQ R01 HS11392. Matthew B. Maas supported by National Institutes of Health grant P50NS051343. We gratefully acknowledge the support of the Deane Institute for Integrative research in Stroke and Atrial Fibrillation and the Lakeside Foundation.
Conflicts of Interest: Matthew B. Maas, MD- none.
Michael H. Lev, MD- is a speaker for GE Healthcare, Waukesha, WI, receives educational support from GE Healthcare, serves on a medical advisory board for CoAxia, Maple Grove, MN, and is a research consultant for Vernalis, Winnersh, England.
Hakan Ay, MD- none.
Aneesh B. Singhal, MD- none.
David M. Greer, MD, MA- has served on the speaker’s bureau for Boehringer-Ingelheim Pharmaceuticals, Ridgefield, CT.
Wade S. Smith, MD, PhD- owns stock and has stock options in Concentric Medical, Inc., Mountain View, CA, is a paid consultant for Concentric Medical, Inc., and has a research grant from Boerhinger-Ingelheim Pharmaceuticals, Ridgefield, CT.
Gordon J. Harris, PhD- none.
Elkan Halpern, PhD- none.
André Kemmling, MD- none.
Walter J. Koroshetz, MD- none.
Karen L. Furie, MD, MPH- served on Advisory Committee for GE Healthcare.