Associations of Ischemic Lesion Volume With Functional Outcome in Patients With Acute Ischemic Stroke
24-Hour Versus 1-Week Imaging
Background and Purpose—Ischemic lesion volume (ILV) on noncontrast computed tomography at 1 week can be used as a secondary outcome measure in patients with acute ischemic stroke. Twenty-four–hour ILV on noncontrast computed tomography has greater availability and potentially allows earlier estimation of functional outcome. We aimed to assess lesion growth 24 hours after stroke onset and compare the associations of 24-hour and 1-week ILV with functional outcome.
Methods—We included 228 patients from MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), who received noncontrast computed tomography at 24-hour and 1-week follow-up on which ILV was measured. Relative and absolute lesion growth was determined. Logistic regression models were constructed either including the 24-hour or including the 1-week ILV. Ordinal and dichotomous (0–2 and 3–6) modified Rankin scale scores were, respectively, used as primary and secondary outcome measures.
Results—Median ILV was 42 mL (interquartile range, 21–95 mL) and 64 mL (interquartile range: 30–120 mL) at 24 hours and 1 week, respectively. Relative lesion growth exceeding 30% occurred in 121 patients (53%) and absolute lesion growth exceeding 20 mL occurred in 83 patients (36%). Both the 24-hour and 1-week ILVs were similarly significantly associated with functional outcome (both P<0.001). In the logistic analyses, the areas under the curve of the receiver–operator characteristic curves were similar: 0.85 (95% confidence interval, 0.80–0.90) and 0.87 (95% confidence interval, 0.82–0.91) for including the 24-hour and 1-week ILV, respectively.
Conclusions—Growth of ILV is common 24-hour poststroke onset. Nevertheless, the 24-hour ILV proved to be a valuable secondary outcome measure as it is equally strongly associated with functional outcome as the 1-week ILV.
Improved functional outcome after additional intra-arterial treatment (IAT) versus standard care alone in the setting of acute ischemic stroke (AIS) has been proven by 5 randomized clinical trials.1–5 In patients treated for AIS, the final ischemic lesion volume (ILV) has been shown to be an objective prognostic measurement of clinical outcome.6–9 Consequently, it has been proposed that final ILV may serve as a surrogate imaging biomarker in early-phase clinical trials in place of 3-month modified Rankin Scale (mRS) score or the National Institutes of Health Stroke Scale (NIHSS) score.7 The predictive value of ILV assessed between 24 hours and 2 weeks after stroke on functional outcome has been proven for diffusion-weighted imaging, fluid-attenuated inversion recovery (FLAIR), and noncontrast computed tomography (NCCT) scans.6–8
Early assessment of patient outcome is beneficial in multiple ways. First, it is preferable to inform patient and relatives about future perspectives as soon as possible after a stroke event. Second, early outcome estimation enables the treating physician to adapt and personalize the treatment and rehabilitation plan. Third, early assessment of outcome by radiological imaging like final ILV is beneficial in clinical trials, as these scans are commonly more available than long-term follow-up imaging and thus may reduce loss to follow-up. Moreover, final ILV is valuable as a biomarker for treatment efficacy because it is objectively measurable and less influenced by non–stroke-related morbidity and mortality.
In recent studies, final ILV as a predictor for functional outcome was obtained as early as 24 hours with magnetic resonance imaging (MRI) and at 27 hours with NCCT imaging.6,8 The timing of final ILV assessment depends on the time course of infarct growth. Because infarcts may continue to grow because of ongoing ischemia, the term final may not be appropriate for these early lesion assessments. Indeed, Federau et al10 and Krongold et al11 showed infarct evolution 24 hours after stroke onset in patients treated with IAT, suggesting that final ILV assessment should take place beyond 24 hours because infarct volume may not have been stabilized. The problem is further compounded by cerebral edema that occurs later in the first week and that can artificially inflate lesion volume. Currently, it is unclear when infarct volumes are best measured on NCCT scans and when they are most suitable to be used as secondary outcome. To our knowledge, ILV (ie, infarcted tissue plus edema) growth after 24 hours of stroke onset measured on NCCT scans has not yet been investigated before. The recent MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), in which most patients received 24-hour and 1-week follow-up NCCT imaging, facilitated to identify and quantify the extent of lesion growth after 24 hours of stroke onset. Moreover, in the present study, we aimed to determine the association between 24-hour versus 1-week ILV and functional outcome.
From the MR CLEAN1 database of patients with AIS caused by anterior-circulation proximal artery occlusions, we selected all 282 patients who received a NCCT scan at ≈24-hour and 1-week follow-up (range, 3–9 days) to perform a post hoc analysis of the lesion volumes. A comprehensive description of patient inclusion and exclusion criteria of the MR CLEAN has been reported earlier.1 CT angiography at 24 hours was part of the MR CLEAN protocol. In practice, often NCCT imaging at 24 hours was also performed and added to the imaging database. Neuroimaging at 1 week was required to assess final ILV, being either NCCT or MRI. Because CT was the vast majority of follow-up imaging, this study only used NCCT. The 2 patients with follow-up MRI instead of CT were excluded to avoid comparison between the 2 modalities. Only thick sliced image data with slice width of ≈5 mm were included. The Figure I in the online-only Data Supplement shows a flowchart of all included and excluded patients in this study. After exclusion of 54 patients, 228 patients were included. In the Table I in the online-only Data Supplement, an overview of the baseline characteristics and outcome for our population, the full MR CLEAN population, and the excluded patients is given.
ILVs in 24-hour images were manually outlined using ITK-Snap12 by a trained observer (A.B.) with the supervision of 2 experienced interventional neuroradiologists (C.B.L.M.M. and J.C.J.B.). The observers were blinded to clinical information apart from the affected hemisphere side. A fixed and standardized window/level setting was used to prevent a variation of ILV assessment; window width 30 Hounsfield units (HU) and center level 35 HU. The ILV at 24 hours after stroke onset on NCCT was identified as intra-axial hypodense areas in the affected hemisphere side. Hyperdensities suspected for hemorrhage or contrast extravasation adjacent or in the hypodense areas were included in the ILV. Cerebral edema extending into the contralateral hemisphere or producing ventricular and sulcal effacement was included in the ILV. Other lesions in the contralateral hemisphere were not included. Lesions in the ipsilateral hemisphere with characteristics of old infarction were categorized as preexistent and were also not included in the ILV. Characteristics of old infarction included a more hypodense area than the appearance of acute infarction, well-defined borders, and no mass effect because of the absence of edema or as a result of atrophy.
The ischemic lesion on NCCT at 1-week follow-up was automatically segmented using previously developed and validated software.13 The software discriminates between normal brain tissue and infarction by calculating the difference in HU value of surrounding voxels. This software resulted in binary masks of the infarcted area. All segmentations were inspected and adjusted if necessary by 2 experienced observers blinded to outcome, as part of the MR CLEAN study. Final ILV was calculated by multiplying the number of voxels of the segmented ischemic lesions with its voxel size.
Both methods included the same definition of ILV. Note that in practice, the ILV including edema was outlined rather than only the ischemic tissue. See Figure 1 for an example of an ischemic lesion segmentation.
Ischemic Lesion Growth Assessment
Absolute and relative ischemic lesion growths between 24 hours and 1 week after stroke onset were determined. Absolute growth (in mL) was determined by subtracting the 24-hour ILV from the 1-week ILV. Absolute growth was dichotomized as present if the increase in final ILV equaled or exceeded 20 mL and absent if otherwise. Relative lesion growth (in percentage) was determined by dividing the absolute lesion growth by the 24-hour ILV. We dichotomized relative ischemic lesion growth by adapting the previously introduced definition of a relative growth of ≥30%.14
We hypothesize that patients with better reperfusion after IAT have a lower risk of ischemic lesion expansion. Therefore, we assessed the association of ischemic lesion growth with the degree of reperfusion in the subset of patients (n=89) who underwent IAT.
ILV and Growth
The distributions of ILVs were tested for normality with the Kolmogorov–Smirnov test. Non-normal distributed variables are presented with the median value and interquartile range (IQR). Normally distributed variables are presented with their mean and SD. ILVs in patients allocated for IAT versus the control group were compared and tested for significant difference with the Mann–Whitney U test. The prevalence of ischemic lesion growth was presented as a proportion of population.
Association Between Ischemic Lesion Volume and Functional Outcome
To assess the associations between ILV and functional outcome defined as the 3-month mRS score, we used univariate and multivariable ordinal and binary logistic regression analyses to determine odds ratios (OR) and their confidence intervals (CI). Primary outcome measure was the ordinal mRS score on the entire scale. To enable easy comparison of the strength of associations, the dichotomous variable favorable outcome defined as a mRS score ≤2 was used as secondary outcome.
Variables that were associated with outcome in univariate analyses with a P<0.10 were included in the multivariable logistic models. All statistical models included either the 24-hour ILV (Model24h) or 1-week ILV (Model1w).
Because of the strong collinearity of NIHSS score at 24 hours (24hNIHSS), ILV, and mRS, the association of ILV with mRS may become unstable after adding 24hNIHSS to the statistical model.15 We, therefore, created variants of the statistical models without and with 24hNIHSS.
Association With Favorable Outcome: 24-Hour Versus 1-Week ILV
To compare the associations of the 24-hour and 1-week ILV with favorable outcome, receiver-operating characteristics curves and their corresponding area under the curve (AUC) were calculated.
To determine whether the association of 24-hour ILV with outcome strongly dependents on the course of the patient between 24 hours and 1 week, which may have prevented a 1-week follow-up scan (such as death and discharge), we performed a sensitivity analysis including all 24-hour ischemic lesions (thus including patients without 1-week follow-up imaging).
In patients who underwent IAT, we tested whether the degree of reperfusion, as defined with the modified Treatment in Cerebral Infarction (mTICI) score,16 differed significantly between patients who showed growth of ILV versus those who did not. Patients were divided into 2 groups (growth of ILV versus no growth), and mTICI scores were tested for difference with the Mann–Whitney U test.
Statistical analyses were performed using SPSS (IBM SPSS Statistics; version 23; 2015). A P value of <0.05 was considered statistically significant.
Mean age was 65 years (±13.6 years), and more than half of the population was men (58.3%). Nineteen patients (8.3%) were diagnosed with a previous ischemic stroke, and 112 patients (49.1%) experienced hypertension. Mean baseline NIHSS score was 17 (±5.6) and median Alberta Stroke Program Early CT Score (ASPECTS) was 9 (IQR, 8–10). Two hundred and two patients (88.6%) received intravenous thrombolysis and 107 patients (43.9%) were allocated for IAT (Table 1). The median 3-month mRS score was 4 (IQR, 2–4), and 69 patients had favorable outcome (30.3%).
Ischemic Lesion Volumes
The ILVs were not normally distributed (both P<0.001). The median ILV at 24 hours was 41.9 mL (IQR, 20.7–94.8 mL) and at 1 week was 63.8 mL (IQR, 30.1–120 mL), which was significantly different (P<0.001; Table II in the online-only Data Supplement). The distribution of 24-hour and 1-week ILVs for each mRS score is shown in Figure II in the online-only Data Supplement. Patients allocated to IAT had significantly smaller ILVs at both 24 hours and 1 week compared with the control group (Table II in the online-only Data Supplement). Median ILV at 24 hours was 32.9 mL (IQR, 15.2–92.2 mL) and 50.2 mL (IQR, 23.7–103 mL), in patients allocated to IAT and in the control groups, respectively (difference P=0.048). Median ILV at 1 week was 52.7 mL (IQR, 24.8–109 mL) and 79.4 mL (IQR, 34.1–127 mL) in patients allocated to IAT and the control groups, respectively (difference P=0.030).
Ischemic Lesion Growth
The median absolute lesion growth was 12.0 mL (IQR, 0.8–27.9 mL) with a range of −140 to 250 mL. The median relative growth was 33.0% (IQR, 2.4%–83.0%) with a range of −100% to 1125%. Hundred and twenty-one patients (53%) were classified as having a relative ischemic lesion growth (Figure 2A) and 83 patients (36%) as having absolute growth (Figure 2B). From the patients with relative growth, 68 patients (56%) also showed absolute growth. From the 83 patients with absolute growth, 68 patients (82%) also showed relative growth.
The 24-hour and 1-week ILV were both similarly significantly associated with functional outcome; both OR 0.99 and 0.97 per mL ILV (P<0.001) for ordinal and dichotomized mRS scores, respectively. Only the CI differed slightly for the association with favorable outcome. All univariate associations of patient baseline characteristics with functional outcome are shown in Table III in the online-only Data Supplement.
After adjustment for confounders, both 24-hour and 1-week ILVs were significantly associated with functional outcome (both OR, 0.99; 95% CI, 098–0.99 per mL ILV; P<0.001; Table 2). In both models, the same parameters were independently associated with functional outcome: age, diabetes mellitus, sex, baseline systolic blood pressure, and treatment allocation.
After the addition of 24hNIHSS to the models, both the 24-hour and 1-week ILV remained significantly associated with functional outcome (OR, 0.99; 95% CI, 0.98–0.99 per mL ILV for both models; P=0.025 and P<0.001 for 24-hour and 1-week ILV, respectively). The 24-hour NIHSS score was also significantly associated with functional outcome in both models (OR, 0.82; 95% CI, 0.77–0.86 and OR, 0.82; 95% CI, 0.78–0.87 per point; both P<0.001, in Model24h and Model1w, respectively).
Also, in the multivariable models for dichotomized mRS scores, both 24-hour and 1-week ILVs were significant independently associated with favorable outcome (Table 3). Both models showed similar strength of association with favorable outcome: Model24h had an AUC value of 0.85 (95% CI, 0.80–0.90; Figure 3). The AUC of Model1w was slightly higher with a value of 0.87 (95% CI, 0.82–0.91). The sensitivity analysis including all patients with 24-hour NCCT imaging in MR CLEAN included 335 patients. For this larger group, the AUC was similar with a value of 0.86 (95% CI, 0.82–0.90).
Eighty-nine patients in our population underwent IAT and available digital subtraction angiography on which reperfusion status was scored using the mTICI score. In this subgroup, reperfusion status was not significantly different between patients with or without relative and absolute ischemic lesion growth (respectively P=0.87 and P=0.35).
This study showed that growth of ILV 24 hours after stroke onset as determined on NCCT imaging is common in patients with AIS caused by an occlusion in the anterior circulation. More than half of our study population showed relative growth and more than one third showed absolute growth. Despite that ILV at 24 hours cannot be considered final, the 24-hour ILV proved to be a valuable prognostic factor because it is associated with functional outcome as strong as the 1-week ILV.
The lesion growth as assessed on CT is in line with a previous MRI FLAIR-based study in which all patients showed infarct growth between 12-hour posttreatment and 5-day follow-up.10 The lower rate of infarct growth in our study could be because of several differences between the 2 studies. First, ILVs were measured in a different time window, namely, 12 hours versus 24 hours after stroke onset. Infarcts are more likely to grow after 12 hours than after 24 hours. Second, infarct volumes were measured using different techniques, FLAIR versus NCCT, which have different infarct conspicuity. Third, different definitions of growth are used. Federau et al10 classified growth as an absolute increase in volume versus our dichotomized definitions of growth by using 2 thresholds (≥30% and ≥20 mL). Fourth, only half of our population was randomized for IAT versus all patients receiving IAT in the previous study. Of note, the size of our study population was almost 7 times larger.
In previous stroke studies, ischemic lesion growth (commonly named infarct growth) between baseline (pretreatment) and follow-up has been measured more frequently than infarct growth posttreatment. When measured from baseline, relative growth occurs in 80% of patients within the first week.14 Similar to this, absolute growth is seen in 85% of patients within 5 days.15,17 We should note that infarct growth after pretreatment imaging is different than infarct growth 24 hours after stroke onset: It is generally accepted that most of the infarct growth occurs within the first hours after stroke onset and before (successful) treatment. This would explain the lower rate of lesion growth in our study. Moreover, inconsistent definitions of infarct growth in stroke have been used, which make it difficult to compare prevalence of growth. For example, infarct growth has been defined as visually evident recruitment,18 an increase of ≥30% of baseline ILV,14 whereas others categorize infarct growth into small, medium, and large growth with inconsistent cutoff values.
We confirmed the earlier established association between ILV and functional outcome.6–8 In line with our study, these studies defined favorable functional outcome as 3-month mRS score 0 to 2. The relationship between final ILV determined on NCCT, diffusion-weighted imaging, and FLAIR at a median time of 42 hours and favorable outcome in patients receiving IAT was confirmed before.7 Moreover, the ILV obtained at 27-hour FLAIR and NCCT imaging showed to be an independent predictor of 3-month functional outcome.6 In concordance with our results, both age and final ILV were independent predictors of outcome in previous studies.7,8 Furthermore, a predictive model similar to our associative model in which final ILV obtained with diffusion-weighted imaging at 24 to 48 hours after stroke onset predicts favorable outcome.8 This model was tested by constructing a receiver–operating characteristic curve with an AUC value of 0.75. Although our associative models show higher AUC values, the similar outcome supports our results.
In contrast to a previous study, sidedness was not associated with favorable outcome in our population.19 The side of infarction is expected to capture eloquence independent of ILV. However, this effect was not seen in our population.
In our population, the association between functional outcome and the 24-hour ILV was similar to the 1-week ILV. Apparently, growth, which is common as we have shown, does not strongly influence the association of 24-hour ILV. Moreover, the agreement of associative models with 24-hour and 1-week ILV may be explained by the strong correlation of these ILVs.
Notably, the univariable OR of treatment with IAT was similar to the ORs of treatment in the multivariable models containing the ILV. This finding suggests that there are other pathways between treatment and functional outcome than lowering the ILV. For example, the effect of IAT on outcome may be mediated through the negative effects of anesthesiology and procedure-related complications. Furthermore, infarct location, age, comorbidities, and more intensive care after IAT that can be offered in comprehensive stroke centers may also mediate the relation between ILV and functional outcome. The mediating effects of treatment allocation on the relation of ILV and functional outcome need additional investigation in further studies.
The results of our study have implications for the timing of ILV measurement in clinical trials in AIS because we showed that the 24-hour ILV could serve as a secondary outcome measure because it is as strongly associated with functional outcome as the 1-week poststroke lesion volume. Moreover, early estimation of prognosis poststroke is of great value to both patients and relatives as to clinicians in further decision making.
This study has some limitations. Our patient population was much smaller than the full population of the MR CLEAN population. This may have led to a difference in patient characteristics between this substudy and MR CLEAN trial. For example, patients who died before receiving 1-week follow-up imaging could not be included in our study. As a result, the number of death at 90 days in our population was 11.8% versus 29.8% in the excluded patient population. This bias may have increased the likelihood of favorable outcome and to an different association of ILV and outcome. However, the sensitivity analysis including all patients with 24-hour ILV showed similar results, suggesting that this bias is not strong.
Edema formation could have led to false comparison of lesion volumes because the 24-hour scan may contain less edema than the 1-week follow-up because of the influence of ionic and vasogenic edema, which are maximal at 3 to 5 days after an ischemic event. Moreover, edema formation is influenced by treatment such as osmotherapy and agents affecting the blood pressure,20,21 factors we did not take into consideration. To minimize false comparison between lesion volumes on 24-hour and 1-week follow-up scans because of the influence of edema, the ILV only included hypodense areas and adjacent or confluent hyperdensities. Nevertheless, this does not exclude all edema-related mass effect. Given the difficulty in distinguishing true infarct progression from edema formation, the extent to which each contributes to the observed lesion growth is unclear. The similar prognostication between 24-hour and 1-week ILVs and the nonassociated reperfusion status and lesion growth in patients treated with IAT suggest that much of this growth may be secondary to edema.
The participant centers of MR CLEAN were free to choose between follow-up MRI and CT imaging. In practice, the vast majority opted for CT because of its wider availability. Therefore, we have assessed ILVs on CT rather than the more commonly used MRI FLAIR in previous studies. It is expected that ILVs may appear different on CT compared with MRI. However, because of the lack of MRI in MR CLEAN, we could not address this difference.
The 1-week follow-up NCCT scan was performed in a variable time window ranging from 3 to 9 days. All infarcts in the contralateral hemisphere were not assessed, with the risk of loss of identification of infarcts in new territory.22 We choose this approach to ensure that we studied ischemic lesion growth rather than the occurrence of new infarcts. However, this may have altered the association between ILV and outcome. We did not take the location of ischemic lesion into account in the association with outcome, despite that infarction in, for example, the right parieto-occipital (M6) and left superior frontal (M4) regions is associated with unfavorable outcome.23 It has been shown that there is a strong agreement between automated and manually ILVs13; however, comparing human measurements with computer-assisted data may have led to a small bias. Furthermore, the definition of relative growth was adapted from a study based on diffusion-weighted imaging, whereas the validity of this threshold for NCCT has not yet been validated.
Because of the known strong association of 24hNIHSS with ILV and with mRS score, we investigated the effect of adding 24hNIHSS to our statistical models containing the ILVs. Because of the strong collinearity, the addition of 24hNIHSS may greatly influence the association of ILV and functional outcome. In some studies that generated predictive models and included both NIHSS score and ILV, NIHSS score was an independent predictor, and ILV was not. In other studies, ILV was independently predictive and NIHSS score was not. This illustrates the strong relation between 24-hour NIHSS score and ILV.7,15 In our study, both the ILV and the 24-hour NIHSS score showed to be independently associated with functional outcome after addition of the 24-hour NIHSS score in the statistical models.
CT-measured ischemic lesion growth 24 hours after stroke onset in patients with proximal artery occlusion in the anterior circulation because of AIS is common; in our population, more than half of patients (53%) showed relative growth defined as an increase of ≥30% and more than one third of patients (36%) showed absolute growth of ≥20 mL. Despite this growth after 24 hours, the 24-hour ILV is equally strongly associated with functional outcome at 3 months after stroke compared with the 1-week ILV, which suggests applicability of the 24-hour ILV as a secondary outcome measure in AIS trials.
Sources of Funding
The MR CLEAN trial was funded by the Dutch Heart Foundation and through unrestricted grants from AngioCare BV, Covidien/EV3, MEDAC Gmbh/LAMEPRO, and Penumbra Inc. A.M. Boers is supported by a personal grant from the Stichting Toegepast Wetenschappelijk Instituut voor Neuromodulatie (TWIN). W.H. van Zwam received speaker’s bureau fees to Maastricht University Medical Center (MUMC) from Codman.
A.M. Boers and H.A. Marquering are cofounders and shareholders of Nico-Lab. Dr Yoo received research grant (significant) from Penumbra, Inc, and research grant (modest) from Neuravi, Inc. Maastricht University MC, Erasmus MC University Medical Center, and Academic Medical Center Amsterdam received Speaker’s bureau fee from Stryker, Inc, for consultations by Dr Zwam, Dr Dippel, and Dr Majoie, respectively. Erasmus MC University Medical Center received funds from Bracco Imaging, Inc, for consultations by Dr Dippel. The other authors report no conflicts.
Guest Editor for this article was James C. Grotta, MD.
A related abstract of this work was presented at the 2nd European Stroke Organisation Conference in Barcelona, Spain, May 10–12, 2016.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.015156/-/DC1.
- Received August 31, 2016.
- Revision received January 26, 2017.
- Accepted February 7, 2017.
- © 2017 American Heart Association, Inc.
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