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Highest Lesion Growth Rates in Patients With Hyperacute Stroke : When Time Is Brain Particularly Matters

Gabriel Broocks; Furqan Rajput; Uta Hanning; Tobias Djamsched Faizy; Hannes Leischner; Gerhard Schön; Susanne Gellißen; Peter Sporns; Milani Deb-Chatterji; Götz Thomalla; Andre Kemmling; Jens Fiehler; Fabian Flottmann

Background and Purpose—The early growth of ischemic lesions has been described as being nonlinear, with lesion growth rates at their highest during the earliest period after stroke onset. We hypothesized that the time gap from imaging to revascularization results in higher lesion growth in patients with hyperacute presentation.
Methods—Fifty-one patients with ischemic stroke with initial multimodal computed tomography (CT), follow-up CT after 24 hours, and successful endovascular recanalization were included and separated into 2 groups according to their median time from symptom onset to imaging (eg, hyperacute versus acute). The difference in Alberta Stroke Program Early CT Score (ASPECTS) between initial CT and follow-up CT was assessed, as well as volumetric lesion growth from early ischemic core in admission perfusion CT and total lesion volume in follow-up CT.
Results—The median time from onset to imaging was 1.85 hours. There was no significant difference in admission ASPECTS (mean, 8.5 versus 8.2) or time from imaging to recanalization in both groups (median, 2.7 versus 2.4 hours; P=0.4). The mean (SD) lesion growth assessed by ASPECTS difference was 2.7 (2.3) in the hyperacute group and 1.6 (1.3) in the acute group (P=0.03). The mean (SD) volumetric difference in the hyperacute group was 26.6 mL (43.2 mL) and 17.2 mL (26.3 mL; P=0.36) in the acute group, respectively. For every passing hour after onset, ASPECTS lesion growth was reduced by 0.4.
Conclusions—Patients in the hyperacute phase showed increased ASPECTS lesion growth from imaging to recanalization suggesting a particular benefit of faster recanalization times in this group of patients with stroke.

Randomized trials involving patients with acute stroke observed that endovascular thrombectomy was effectiveand safe when it was performed within 6 hours after the onset of stroke symptoms.1 In the more recent DEFUSE III (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) and DAWN (Diffusion Weighted Imaging [DWI] or Computerized Tomography Perfusion [CTP] Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention) trials, it was suggested that patients with a mismatch between clinical deficit and in- farct benefit from mechanical thrombectomy beyond 6 hours from symptom onset.2,3 However, it has also been described that lesion growth rates often follow a nonlinear, logarithmic growth curve and are the highest during the hyperacute phase (0–4 hours after onset).4 Regularly, there is a significant time gap be- tween imaging and revascularization, and during this time, thelesion is thought to expand into the area of the penumbra. Thus far, it has not been investigated whether different time windows from symptom onset to imaging, with the period between im- aging to recanalization remaining constant, result in different lesion growth volumes. These findings could encourage efforts to improve time frames, especially for patients presenting in the hyperacute time window. Based on the previously described non- linear lesion growth dynamics, we hypothesized that equal time intervals from imaging to recanalization would result in increased infarct growth in patients with hyperacute stroke.

Anonymized data from our stroke database were analyzed retrospec- tively in accordance with ethical review board approval, and no in- formed consent was necessary after review. The data that support thefindings of this study are available from the corresponding author on reasonable request. The data were compiled from 3 German stroke centers and included patients who were admitted between January 2014 and August 2016. The inclusion criteria can be found in the online-only Data Supplement.

Image Acquisitions
Please see the online-only Data Supplement for details.

Image Analysis
The rater was blinded for all other imaging data, and patient infor- mation was given in random order. Lesion growth between admis- sion and 24-hour postendovascular treatment follow-up imaging was assessed using 2 methods: (1) difference between the initial and fol- low-up Alberta Stroke Program Early CT Score (ASPECTS). The rating was performed by an experienced neuroradiologist (F.R.; >7 years of experience) and verified by a second attending neuroradiolo- gist; (2) volumetric difference between the total lesion volume in the follow-up CT and early core lesion volume, determined in the ad- mission computed tomography perfusion using volume of decreased cerebral blood volume, as described previously (Figure 1; Equations 1 and 2 in Methods in the online-only Data Supplement).5,6 The vis- ible cerebral blood volume lesion was segmented manually (Analyze 11.0, Biomedical Imaging Resource; Mayo Clinic, Rochester, MN).

Statistical Analysis
Kolmogorov-Smirnov tests were used to determine whether the data sets were normally distributed. Continuous variables are presented as means and SDs/95% CIs for normally distributed data or medi- ans/interquartile ranges for non-normally distributed data. For cate- gorical data, absolute and relative frequencies are given. The cohort was divided into 2 patient groups according to the median time from symptom onset to imaging (hyperacute versus acute). Baseline data of both resulting groups were compared by Student t test (normally distributed data) or Mann-Whitney U test (non-normally distributeddata) for metric outcome variables and by χ2 test for categorical out- come variables. To assess the equality of variances between lesion growth in the hyperacute versus acute group, Levene test was per- formed. ASPECTS differences between initial and follow-up im- aging were plotted against the time from symptom onset to imaging using linear regression (Figure I in the online-only Data Supplement). Finally, multivariate linear regression was used to model the asso- ciation between ASPECTS difference (admission to follow-up CT)and time from symptom onset to imaging, initial ASPECTS, initial ischemic core volume, and National Institutes of Health Stroke Scale (Figure II in the online-only Data Supplement). Backward selection was used to identify significant variables. A statistically significant difference was accepted at a P of <0.05. Analyses were performed using MedCalc (version; Mariakerke, Belgium) and R (R: A Language and Environment for Statistical Computing, 2017; R Foundation for Statistical Computing, Vienna, Austria). Visualization with the R package ggplot2 (Elegant Graphics for Data Analysis, 2009; Springer-Verlag, New York) Results Patients Fifty-one patients fulfilled all inclusion criteria (Table). The median time from symptom onset to imaging was 1.85 hours (interquartile range, 1.5 hours). Twenty-five patients were assembled in a hyperacute group (time from symptom onset to imaging, <1.85 hours), and the remaining 26 patients were assembled in an acute group (≥1.85 hours). The median time from imaging to recanalization was 2.5 hours (interquartile range, 1.2 hours) and did not differ significantly between the groups (P=0.40). The mean ASPECTS difference between admission and follow-up imaging was significantly higher in patients present- ing in the hyperacute time window (mean difference [SD], 2.7 [2.2] versus 1.6 [1.3]; P=0.04; Figure 2). The mean (SD) volu- metrically measured absolute lesion growth was 26.6 mL (42.2 mL) or 233% (450%) in the hyperacute group versus 17.3 mL (26.3 mL) or 108% (150%) in the acute group, although the dif- ference was not statistically significant (P=0.355 and P=0.188 for relative lesion growth). The variances for lesion growth vol- umes were higher for patients presenting in the hyperacute time window, both for absolute and relative lesion growth. Statistical significance of this observation was confirmed by Levene test (P=0.04 for absolute lesion growth and P=0.02 for relative lesion growth; Figure V in the online-only Data Supplement). In univariate linear regression for ASPECTS lesion growth and time as a constant variable plotting all patients,we identified a significant relationship between the param- eters. For each passing hour, ASPECTS lesion growth was reduced by an ASPECTS of 0.4 (95% CI, −0.57 to −0.07; P=0.02; Figure I in the online-only Data Supplement). Further multivariate analysis can be found in the online-only Data Supplement. Discussion The aim of this study was to investigate whether patients presenting in the hyperacute time window have comparably higher lesion growth volumes when the time from imaging to recanalization is kept relatively constant. To this end, we compared lesion growth using ASPECTS difference and vol- umetric measurements in patients who presented <1.85 hours after onset (hyperacute) with patients who presented 1.85 to 6 hours after onset (acute) with similar duration from imagingto recanalization. The main finding of our study is that a me- dian time from imaging to recanalization of 2.5 hours resulted in higher lesion growth in patients presenting in the hyper- acute time window when assessed according to differences in ASPECTS. Although volumetrically measured lesion growth from the initial core lesion to the 24-hour follow-up was not sta- tistically different between the groups (relative lesion growth, 233% versus 108%), it is remarkable that the variance of lesion growth was clearly higher in the hyperacute group (SD, 455% versus 146%), as confirmed statistically by Levene tests for both absolute and relative lesion growth. In the hyperacute time window, we observed partly reversible core lesions and simulta- neously patients with the highest lesion growth volumes (max- imum growth, 146 mL in hyperacute versus 76 mL in acute patients). This may be suggestive of a significantly increased lesion growth dynamic in the hyperacute time window. To our knowledge, this is the first computed tomogra- phy-based study that investigated the impact of the time gap from imaging to recanalization on ischemic lesion growth focusing on the hyperacute time window. Despite the cur- rent trend of extending the time window for stroke treat- ment, lesion growth rates were previously described as being the highest during the earliest period after stroke onset.2–4,7 Nevertheless, the extension of the time window for treatment might suggest having more time regarding initiation of treat- ment in the hyperacute setting than in patients who present later. However, a shorter time interval between stroke onset and imaging should by no means lead to less effort in pa- tient care, based on the reasoning that the patient is within the time window.8,9 Indeed, when considering the results of this study, the opposite may be true. The same initial ischemic core volume at admission in a hyperacute time window might indicate a more dynamic lesion expansion and would result in less time for effective treatment compared with patients presenting later.9 These findings should encourage efforts to reduce treatment delays, especially for patients presenting within the hyperacute timeframe. Limitations of our study include the relatively small number of patients because of the strict inclusion and ex- clusion criteria (eg, only analyzing patients with an M1 occlusion in the middle cerebral artery). The intention was to obtain a homogenous patient cohort. Definitions of early ischemic core using computed tomography perfusion are still a topic of current discussion and, therefore, potentially imprecise, especially in the setting of rapid and complete re- perfusion, as recently described.10 We decided to use cere- bral blood volume to define the early ischemic core volume as accurately as possible, particularly in light of the con- troversy of infarct core overestimation when using relative cerebral blood flow measurements.10,11 Differences in time from admission imaging to recanalization were not statisti- cally significant between groups but might explain a part of the observed infarct growth dynamics in the hyperacute time window. However, the time from symptom onset to admis- sion had a significant effect on ASPECTS lesion growth even after adjusting for the time from imaging to recanalization in multivariate analysis. Conclusions Lesion growth between imaging and recanalization was higher in patients presenting in a hyperacute time window (<1.85 hours from onset), which supports previously reported ele- vated lesion growth rates in the early time frame. The mark- edly increased variance of lesion growth volume, includingpartly reversible core lesions in the hyperacute group, could be a sign of a distinctive infarct dynamic in this time window. References 1. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al; HERMES Collaborators. Endovascular thrombec- tomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723–1731. doi: 10.1016/S0140-6736(16)00163-X 2. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al; DAWN Trial Investigators. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378:11–21. doi: 10.1056/NEJMoa1706442 3. Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega- Gutierrez S, et al; DEFUSE 3 Investigators. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378:708–718. doi: 10.1056/NEJMoa1713973 4. Gonzalez RG, Silva G, He J, Sadaghiani S, Wu O, Singhal AB. Abstract t p30: Logarithmic growth of ischemic lesions in major anterior circula- tion ischemic strokes. International Stroke Conference. 2015;46(suppl 1):ATP30. 5. Arenillas JF, Cortijo E, Garcia-Bermejo P, Levy EI, Jahan R, Goyal M, et al. Relative cerebral blood volume is associated with collateral status and infarct growth in stroke patients in swift prime. J Cereb Blood Flow Metab. 2018;38:1839–1847. doi: 10.1177/0271678X17740293 6. Ava L, Berkefeld J, Lauer A, Seiler A, Pfeilschifter W, Müller-Eschner M, et al. Predictive value of pooled cerebral blood volume map- ping for final infarct volume in patients with major artery occlusions. A retrospective analysis. Clin Neuroradiol. 2017;27:435–442. doi: 10.1007/s00062-017-0569-9 7. Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, et al; WAKE-UP Investigators. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379:611–622. doi: 10.1056/NEJMoa1804355 8. Fiehler J. The time-reset effect: thrombectomy trials challenge the existence of a time window. Clin Neuroradiol. 2017;27:3–5. doi: 10.1007/s00062-017-0561-4 9. Albers GW. Late window paradox. Stroke. 2018;49:768–771. doi: 10.1161/STROKEAHA.117.020200 10. Bivard A, Kleinig T, Miteff F, Butcher K, Lin L, Levi C, et al. Ischemic core thresholds change with time to AK 7 reperfusion: a case control study. Ann Neurol. 2017;82:995–1003. doi: 10.1002/ana.25109
11. Boned S, Padroni M, Rubiera M, Tomasello A, Coscojuela P, Romero N, et al. Admission CT perfusion may overestimate initial infarct core: the ghost infarct core concept. J Neurointerv Surg. 2017;9:66–69. doi: 10.1136/neurintsurg-2016-012494