Lima FO, Furie KL, Silva GS, Lev MH, Camargo ÉCS, Singhal AB, Harris GJ, Halpern EF, Koroshetz WJ, Smith WS, Nogueira RG. Prognosis of Untreated Strokes Due to Anterior Circulation Proximal Intracranial Arterial Occlusions Detected by Use of Computed Tomography Angiography. JAMA Neurol. 2014;71(2):151-157. doi:10.1001/jamaneurol.2013.5007
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Limited data exist regarding the natural history of proximal intracranial arterial occlusions.
To investigate the outcomes of patients who had an acute ischemic stroke attributed to an anterior circulation proximal intracranial arterial occlusion.
Design, Setting, and Participants
A prospective cohort study at 2 university-based hospitals from 2003 to 2005 in which nonenhanced computed tomography scans and computed tomography angiograms were obtained at admission of all adult patients suspected of having an ischemic stroke in the first 24 hours of symptom onset.
Anterior circulation proximal intracranial arterial occlusion.
Main Outcomes and Measures
Frequency of good outcome (defined as a modified Rankin Scale score of ≤2) and mortality at 6 months.
A total of 126 patients with a unilateral complete occlusion of the intracranial internal carotid artery (ICA; 26 patients: median National Institutes of Health Stroke Scale [NIHSS] score, 11 [interquartile range, 5-17]), of the M1 segment of the middle cerebral artery (MCA; 52 patients: median NIHSS score, 13 [interquartile range, 6-16]), or of the M2 segment of the MCA (48 patients: median NIHSS score, 7 [interquartile range, 4-15]) were included. Of these 3 groups of patients, 10 (38.5%), 20 (38.5%), and 26 (54.2%) with ICA, MCA-M1, and MCA-M2 occlusions, respectively, achieved a modified Rankin Scale score of 2 or less, and 6 (23.1%), 12 (23.1%), and 10 (20.8%) were dead at 6 months. Worse outcomes were seen in patients with a baseline NIHSS score of 10 or higher, with a modified Rankin Scale score of 2 or less achieved in only 7.1% (1 of 14), 23.5% (8 of 34), and 22.7% (5 of 22) of patients and mortality rates of 35.7% (5 of 14), 32.4% (11 of 34), and 40.9% (9 of 22) among patients with ICA, MCA-M1, and MCA-M2 occlusions, respectively. Age (odds ratio, 0.94 [95% CI, 0.91-0.98]), NIHSS score (odds ratio, 0.73 [95% CI, 0.64-0.83]), and strength of leptomeningeal collaterals (odds ratio, 2.37 [95% CI, 1.08-5.20]) were independently associated with outcome, whereas the level of proximal intracranial arterial occlusion (ICA vs MCA-M1 vs MCA-M2) was not.
Conclusions and Relevance
The natural history of proximal intracranial arterial occlusion is variable, with poor outcomes overall. Stroke severity and collateral flow appear to be more important than the level of proximal intracranial arterial occlusion in determining outcomes. Our results provide useful data for proper patient selection and sample size calculations in the design of new clinical trials aimed at recanalization therapies.
Quiz Ref IDA proximal intracranial arterial occlusion is an independent factor associated with poor functional outcomes and high mortality rates in patients with acute ischemic stroke.1- 3 Yet limited data exist about the natural history of proximal intracranial arterial occlusions. Most of the available information about the course of this disease comes from large intervention trials that might have limitations (such as limited generalizability) owing to their intrinsic design.1,2
Quiz Ref IDCurrently, the only approved pharmacological therapy for the treatment of acute ischemic stroke is intravenous (IV) tissue plasminogen activator (tPA) administered within 4.5 hours of symptom onset. Intra-arterial techniques, including mechanical thrombectomy, are rapidly evolving and may represent an option for those patients who have contraindications to IV tPA or for those patients for whom IV tPA is not effective. However, its efficacy remains to be proved in randomized trials. Further information on the natural history of proximal intracranial arterial occlusions is essential for the proper design of clinical trials to test the efficacy of endovascular approaches. In the present study, we sought to establish the rates and predictors of long-term outcomes of patients who had an acute ischemic stroke attributed to an anterior circulation proximal intracranial arterial occlusion and who did not undergo any reperfusion therapy.
We analyzed data from 741 consecutive patients enrolled in a prospective cohort study at 2 university-based hospitals from 2003 to 2005, the Screening Technology and Outcomes Project in Stroke (STOPStroke), in which nonenhanced computed tomography (CT) scans and CT angiograms (CTAs) were obtained at admission of all patients suspected of having an ischemic stroke in the first 24 hours of symptom onset. Patients were excluded if the administration of an iodinated contrast agent was contraindicated (ie, history of allergies to contrast agents, pregnancy, congestive heart failure, or renal insufficiency) or if there was evidence of intracranial hemorrhage on nonenhanced CT scans. The STOPStroke study received institutional review board approval at both participating institutions and was compliant with the Health Insurance Portability and Accountability Act. All participants or their proxies provided informed consent at enrollment.
Data on clinical history, laboratory results, demographics, and stroke risk factors of all patients were collected at baseline by direct interview or by review of the medical record by trained staff. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline as part of the 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 department. Time to CTA was calculated in a similar fashion. The STOPStroke study was designed to evaluate long-term outcome of ischemic stroke. Follow-up modified Rankin Scale (mRS) scores were obtained at 6 months in order to maximize stroke recovery while minimizing loss to follow-up and nonstroke-related events. For the present study, patients with an acute complete occlusion of the intracranial internal carotid artery (ICA) and/or of the M1 and/or M2 segments of the middle cerebral artery (MCA) were selected. Patients with bilateral and/or posterior circulation strokes, as well as those treated with IV tPA and/or endovascular therapy, were excluded from the analysis.
The detailed STOPStroke nonenhanced CT and CTA protocol is described elsewhere.4,5 All patients underwent nonenhanced CT, CTA, and postcontrast CT imaging. The CTA images were reconstructed as “thick maximum intensity projection” reconstructions. Image review was independently performed 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 with regard to the patients’ ages, 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 nonenhanced CT and CTA images. In all cases, the nonenhanced CT images obtained for acute stroke were reviewed first, followed by the CTA images. Reviewers rated the ischemic lesion on the nonenhanced CT scans according to the Alberta Stroke Program Early Computed Tomography Score (ASPECTS).6 Readers assessed the presence of complete occlusion of the intracranial ICA and MCA by thrombus after reviewing both the CTA source images and the thick maximum intensity projection reconstructions. The CTA source images were used to determine the presence of collateral vessels in the region of the leptomeningeal convexity. Contrast in leptomeningeal vessels distal to the occlusion was scored as 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 with extreme scores, the scale was collapsed into 3 ordinal groups: less than contralateral unaffected side (scores 1-2), equal to contralateral unaffected side (score 3), and greater than contralateral unaffected side (scores 4-5).
Continuous variables were reported as mean (standard deviation) or median (interquartile range [IQR]) values. Categorical variables were reported as proportions. A good clinical outcome was defined as having an mRS score of 2 or lower at 6 months of follow-up. Clinical and neuroimaging characteristics were compared according to the site of anterior circulation proximal intracranial arterial occlusion. Differences in continuous variables were assessed by 1-way analysis of variance and by use of the Kruskal-Wallis test in the case of nonnormally distributed data. Differences between proportions were assessed by use of the Fisher exact test or the χ2 test when appropriate.
We described rates of good clinical outcome and mortality according to the most proximal site of anterior circulation proximal intracranial arterial occlusion. The same analysis was performed for the selection of patients with baseline NIHSS scores of 10 or higher. Univariable analysis was used to test the association between different variables and the follow-up mRS scores. Differences in continuous variables were assessed by use of the independent samples t test or the Mann-Whitney U test in the case of nonnormally distributed data. Differences between proportions were assessed by use of the χ2 test. A logistic regression model was used to identify independent predictors of outcome. Given their known strong association with outcome, the variables of age, baseline NIHSS score, sex, ASPECTS, and site of intracranial occlusion were selected a priori and forced into the final model. Other variables were selected based on their association with the outcome in the univariable analysis. Those with P ≤ .10 in the univariate analysis were included in the multivariable model and were selected using a backward elimination process (P ≤ .10 for elimination). After the final model was obtained, the pattern of leptomeningeal collaterals was included to verify its effect on the model’s fit. The site of intracranial occlusion and the pattern of leptomeningeal collaterals were tested as ordinal variables in the regression analysis. The Hosmer-Lemeshow test was used to assess the goodness of fit of the models. To test whether the inclusion of the pattern of leptomeningeal collaterals improved the model, we used the log-likelihood ratio test. To test the possible effect of those patients lost to follow-up on the results, we performed a sensitivity analysis. The last known mRS score was carried forward and used as the final outcome score. The same analysis for the multivariable logistic regression modeling was performed. A 2-sided P < .05 was considered to be statistically significant. All statistical analyses were performed using SPSS software version 17.0 (SPSS Inc).
Quiz Ref IDUnilateral anterior circulation proximal intracranial arterial occlusion was identified in 215 patients. Fifty-one patients (23.7%) were treated with IV tPA, 10 patients (4.6%) were treated with endovascular therapy, and 16 patients (7.4%) received both IV tPA and endovascular treatment. Treated patients and untreated patients were similar with regard to age (mean [SD] age, 68  years for treated patients vs 71  years for untreated patients; P = .19), sex (40% of treated male patients vs 47% of untreated male patients; P = .37), and ASPECTS (median [IQR] score, 8 [7-9] for treated patients vs 8 [5-10] for untreated patients; P = .93), but treated patients had higher NIHSS scores at baseline (median [IQR] score, 16 [12-19] vs 11 [5-16]; P < .001) and shorter times from stroke onset to hospital arrival (median [IQR] time, 1 hour [1-3 hours] vs 4 hour [2-12 hours]; P < .001) than did untreated patients. Of the 138 untreated patients, 12 (8.7%) were excluded owing to a lack of outcome data at 6 months. The remaining 126 patients met the inclusion criteria for the study.
Among these 126 patients, the mean (SD) age was 67.9 (16.5) years, the median (IQR) admission NIHSS score was 11 (5-16), 31 (24.6%) had minor strokes (NIHSS score of <5), 100 (79.4%) were white, and 51 (40.5%) were male patients. Twenty-six (20.6%), 52 (41.3%), and 48 (38.1%) patients had occlusion of the intracranial ICA, MCA-M1, and MCA-M2, respectively. Additional baseline clinical and imaging characteristics are shown in Table 1.
The 12 patients who were lost to follow-up had a higher mean (SD) age, 74 (13.1) years, a lower median admission NIHSS score, 7 (IQR, 1-12), and a higher median ASPECTS, 9.5 (IQR, 9-10). Comparable distributions of the sites of intracranial occlusions were observed with 3 (25.0%), 5 (41.7%), and 4 (33.3%) of the 12 patients lost to follow-up with occlusions of the intracranial ICA, MCA-M1, and MCA-M2, respectively.
As expected, the patients with a more proximal occlusion had lower ASPECTSs on nonenhanced CT scans at admission (with median scores of 7, 7, and 8, respectively; P = .01) despite similar presentation times. Fourteen of 26 patients with intracranial ICA (53.8%), 34 of 52 patients with MCA-M1 (65.4%), and 22 of 48 patients with MCA-M2 (45.8%) occlusions presented with baseline NIHSS scores of 10 or higher. Additional clinical and imaging characteristics according to the most proximal site of occlusion are shown in Table 2.
The median 6-month mRS score of the study cohort was 3 (IQR, 1-5). The rate of good outcome (6-month mRS score, 0-2) was 44.4% (56 of 126 patients) in the overall group and 38.5% (10 of 26), 38.5% (20 of 52), and 54.2% (26 of 48) in the group of patients with ICA, MCA-M1, and MCA-M2 occlusions, respectively. The good outcome rates were notably lower for patients with NIHSS scores of 10 or higher at admission (7.1% [1 of 14 patients], 23.5% [8 of 34 patients], and 22.7% [5 of 22 patients], respectively) than for patients with NIHSS scores of less than 10 (75.0% [9 of 12 patients], 66.7% [12 of 18 patients], and 80.8% [21 of 26 patients], respectively) (P < .01, determined by use of the χ2 test). Rates of good outcome according to the site of intracranial occlusion and other factors associated with outcome are shown in Table 3.
The 6-month mortality rate was 22.2% (28 of 126 patients) in the overall group and 23.1% (6 of 26 patients), 23.1% (12 of 52 patients), and 20.8% (10 of 48 patients) in the group of patients with ICA, MCA-M1, and MCA-M2 occlusions, respectively. Most of fatalities (19 of 28 [67.9%]) occurred during the hospitalization. The mortality rates were considerably higher for patients with NIHSS scores of 10 or higher at admission (35.7% [5 of 14 patients], 32.4% [11 of 34 patients], and 40.9% [9 of 22 patients], respectively) than for patients with NIHSS scores of less than 10 at admission (8.3% [1 of 12 patients], 5.6% [1 of 18 patients], and 3.8% [1 of 26 patients]) (P = .17, .04, and .003, respectively, determined by use of the Fisher exact test).
In the logistic regression model, only younger age (odds ratio, 0.94 [95% CI, 0.91-0.98]) and lower baseline NIHSS score (odds ratio, 0.73 [95% CI, 0.64-0.83]) were independently associated with a good outcome (Table 4). There was a trend for lower glucose levels at admission to be associated with better outcomes (P = .08). The model provided an adequate fit for the data (P = .84, determined by use of the Hosmer-Lemeshow test). In the second model, besides age and baseline NIHSS, a favorable pattern of leptomeningeal collaterals was also independently associated with good outcome (odds ratio, 2.37 [95% CI, 1.08-5.20]) but did not change the effect of the other variables. The second model also provided an adequate fit for the data (P = .87, determined by use of the Hosmer-Lemeshow test). Notably, the level of proximal intracranial arterial occlusion (ICA vs MCA-M1 vs MCA-M2) was not independently associated with outcomes. Including the pattern of leptomeningeal collaterals improved the model fit (P = .01, determined by use of the log-likelihood ratio test) (Table 4). Carrying forward the last known mRS score for those patients who were lost to follow-up at 6 months, as a sensitivity analysis, essentially did not change the results from the previous analysis.
Quiz Ref IDIn the present study, using a large population of patients with anterior circulation proximal intracranial arterial occlusion determined by CTA, we found that more than a half of the patients (56%) did not achieve functional independence and that almost one-fourth (22%) of those patients were dead at 6 months, with most of the fatalities (67.9%) occurring during hospitalization. Patients with intracranial ICA and MCA-M1 occlusions had a lower frequency of functional independence than did patients with MCA-M2 occlusions (38% vs 54%). A particularly unfavorable behavior was observed in patients with an NIHSS score of 10 or higher at admission.
A previous analysis of the STOPStroke database, including both treated and untreated patients, showed that the presence of proximal intracranial arterial occlusion was associated with poor outcomes in acute ischemic stroke.3 Several factors might be implicated. These patients frequently have larger ischemic lesions at presentation, and their infarcts are more likely to grow over time compared with patients without proximal intracranial arterial occlusion. The low frequency of good outcomes found in our study is comparable to the control arm of previous trials. In the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial,2 only 38.6% of the patients in the control arm (with a median NIHSS score of 14) achieved good functional outcome. In the Prolyse in Acute Cerebral Thromboembolism II trial,1 only 25% of patients in the control arm (with a median NIHSS score of 17) achieved good functional outcome. In the placebo arm of the Echoplanar Imaging Thrombolytic Evaluation Trial (with a median NIHSS score of 10),7 only 40% achieved good functional outcome (with 23% and 47% of patients with good outcome with ICA and MCA occlusions, respectively). In the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy trial,8 only 26% and 10% of the patients in the penumbral (with a median NIHSS score of 16) and nonpenumbral (with a median NIHSS score of 20.5) control arms achieved good functional outcome, respectively.
Although patients with more distal occlusions presented with lower NIHSS scores, this was not statistically significant, probably because of the great overlap of values among the 3 groups. Also, patients with more distal occlusions had higher ASPECTSs. Interestingly, approximately half of the patients with a proximal intracranial arterial occlusion presented with ASPECTSs greater than 7 despite a relatively late time to CT imaging (median time, 6 hours [IQR, 3-16 hours]). Variations in the degree of collateral flow might explain, at least in part, the pleomorphic clinical presentation of strokes due to proximal intracranial arterial occlusions and why a significant proportion of those patients could be potential candidates for reperfusion trials.4
Previous multivariable models have consistently shown the importance of age and admission NIHSS score as independent variables in the prognosis of ischemic stroke.3,9 Consistent with these observations, in our final model, age and baseline NIHSS score were the only independent prognostic markers for patients who had an acute ischemic stroke attributable to a proximal intracranial arterial occlusion. Other studies3,4,10 have also shown the importance of neuroimaging markers as important prognostic factors in the acute phase of ischemic stroke. The degree of collateralization was associated with a favorable outcome that was independent of other important clinical and imaging variables, improving the model’s fit. However, including information about collaterals in the model did not influence the effect of other variables (no confounding effect), probably owing to the lack of association between the degree of collateralization and the other clinical variables. It is possible that the relatively small number of patients might have contributed to the lack of statistical significance of some imaging markers like the ASPECTS and the site of intracranial occlusion, which were previously shown to have prognostic value in acute ischemic stroke.
Although there is incontestable evidence about the benefit of IV tPA for acute stroke, the low frequency of recanalization in patients who present with ICA or MCA-M1 occlusions is also known.11 Previous studies12,13 have demonstrated a strong association between recanalization and outcome in acute ischemic stroke. When we consider the increasing use of endovascular therapies for acute ischemic stroke that specifically target those lesions, the appropriate knowledge of their natural history is of paramount importance in the treatment decisions and in the design of new clinical trials.
To date, only 1 randomized controlled trial1 showed the superiority of endovascular treatment over medical treatment. Recently published trials on endovascular treatment failed to show the superiority of the endovascular approach over IV tPA.14 The reasons that might explain those failures are the selection of patients “too good to be treated” and the relatively low rates of recanalization achieved with old mechanical devices and techniques compared with the new ones. Higher rates of recanalization and improved functional outcomes with the new stent retrievers were demonstrated in 2 recently published randomized trials.15,16 Recanalization status was not assessed in the present study. Also, delayed time to treatment might have also played an important role because collateral failure tends to develop over time. Because CTA provides only a static picture of the cerebral vasculature (without providing any information about flow), the inclusion of perfusion imaging in the analysis might have added valuable additional information.
Our study has some limitations. Because the data were collected from 2 tertiary care centers, it might not necessarily reflect the natural history of the greater patient population who present to smaller centers. Also, patients who received IV tPA and endovascular treatment were excluded from this analysis, which might bias our results toward worse outcomes. However, for the duration of our study, endovascular stroke therapy was not commonly offered in 1 of the 2 institutions and was only typically used in the early time window (ie, the first 6-8 hours) in the other one as reflected by the overall low number of treated patients (12% of patients with proximal intracranial arterial occlusions). In addition, our results are comparable to the control arm of previous trials; no significant differences in important clinical variables such as age, sex, and ASPECTS were observed, and, on the contrary, treated patients presented with higher NIHSS scores.
On the other hand, the prospective nature of our study contributed to increasing the quality of the data collection while limiting the potential for misclassification. The use of CTA, which provides a rapid assessment of the intracranial and extracranial vasculature with high accuracy and is widely available, makes our results more robust and generalizable to smaller centers with limited access to other methods such as magnetic resonance imaging.
Quiz Ref IDOur results provide useful information on the natural history of anterior circulation proximal intracranial arterial occlusions, highlighting their variable behavior (depending on the patient’s initial NIHSS score and age and on the imaging features) and their overall poor prognosis. This type of data is essential for proper selection of patients and for the calculation of sample sizes in the design of new clinical trials focused on recanalization therapies.
Accepted for Publication: August 29, 2013.
Corresponding Author: Raul G. Nogueira, MD, Neuroendovascular and Neurocritical Care Services, Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine, 80 Jesse Hill Dr, SE, Room 398, Atlanta, GA 30303 (firstname.lastname@example.org).
Published Online: December 9, 2013. doi:10.1001/jamaneurol.2013.5007.
Author Contributions: Drs Lima and Nogueira had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lev, Koroshetz, Nogueira.
Acquisition of data: Lima, Furie, Silva, Lev, Camargo, Singhal, Harris, Koroshetz, Smith.
Analysis and interpretation of data: Lima, Furie, Lev, Halpern, Nogueira.
Drafting of the manuscript: Lima, Nogueira.
Critical revision of the manuscript for important intellectual content: Furie, Silva, Lev, Camargo, Singhal, Harris, Halpern, Koroshetz, Smith.
Statistical analysis: Lima, Halpern, Nogueira.
Obtained funding: Lev.
Administrative, technical, or material support: Furie, Lev.
Study supervision: Lev, Koroshetz.
Conflict of Interest Disclosures: Dr Lev is a speaker for and receives educational support from GE Healthcare. Dr Singhal receives research support from the NIH/National Institute of Neurological Disorders and Stroke, Pfizer, and PhotoThera; serves on event adjudication committees for the Thrombolysis in Myocardial Infarction Study Group; and has served as a medical expert witness in individual cases concerning stroke in young adults. Dr Smith has served on scientific advisory boards for Stryker/Concentric Medical. Dr Nogueira has served on scientific advisory boards for Stryker/Concentric Medical, Covidien/ev3 Neurovascular, CoAxia, Penumbra, Rapid Medical, Reverse Medical, and Neurointervention. No other disclosures were reported.
Funding/Support: This research was funded by grant RO1-HS011392-01A1 from the US Department of Health and Human Services/Agency for Healthcare Research and Quality.
Role of the Sponsor: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.