Differential Pathophysiological Mechanisms of ...

Original Paper Cerebrovasc Dis 2010;29:328–335 DOI: 10.1159/000278928

Received: July 28, 2009 Accepted: November 4, 2009 Published online: January 30, 2010

Differential Pathophysiological Mechanisms of Stroke Evolution between New Lesions and Lesion Growth: Perfusion-Weighted Imaging Study Oh Young Bang a Gyeong Moon Kim a Chin Sang Chung a Suk Jae Kim a Keon Ha Kim b Pyoung Jeon b Jeffrey L. Saver c David S. Liebeskind c Kwang Ho Lee a Departments of a Neurology and b Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; c Department of Neurology, UCLA Medical Center, Los Angeles, Calif., USA

Key Words Ischemic stroke ⴢ Magnetic resonance imaging ⴢ Perfusion-weighted imaging ⴢ Stroke evolution

Abstract Background: Stroke evolution frequently occurs during the first week after stroke. However, the association between the type of stroke evolution and baseline perfusion severity has not been investigated. Methods: We analyzed clinical and serial MRI data on patients with acute middle cerebral artery infarcts. Multimodal MRIs were acquired before treatment and on day 7. Time to peak (Tmax) perfusion lesion maps were then generated, and changes in the day 7 diffusionweighted imaging (DWI) were classified; new lesions were defined as new DWI lesions not contiguous with initial abnormalities, and infarct growth as enlargement of DWI lesions. Results: Among 74 patients (mean age 64.2 years), 51 received recanalization therapy. The day 7 DWI revealed the presence of new lesions in 39 cases (52.7%) and infarct growth (mean 8 SD 20.0 8 4.3 ml) in 52. No correlation was observed between new lesion and infarct growth (r = 0.029, p = 0.805). Most new lesions were multiple and small, located in cortical/superficial areas and within the mild perfusion delay (2 ^ Tmax ! 4 s) regions, whereas infarct growth gener-

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ally occurred within the severer perfusion delay regions. Multiple regression analysis revealed that large mild perfusion delay was independently associated with new lesions, whereas large initial DWI lesions and a severer perfusion delay (4 ^ Tmax ! 8 s) were associated with infarct growth. In terms of treatment, endovascular therapy was associated with new lesions, whereas the degree of angiographic recanalization was inversely associated with infarct growth. Conclusions: The types of stroke evolution differed depending on the baseline hypoperfusion severity, and the mode and effect of recanalization therapy. A poor correlation was observed between new lesions and infarct growth. Copyright © 2010 S. Karger AG, Basel

Introduction

Stroke evolution frequently occurs during the first week following ischemic stroke. Changes in initial infarct lesions, either silent or symptomatic ischemic lesions, can easily be observed on serial diffusion-weighted imaging (DWI). Stroke evolution during the first week after the onset of stroke is a complex process and could be divided into at least two types, new lesions and enlargement of infarct size when compared to the initial lesions. Oh Young Bang, MD, PhD Department of Neurology, Stroke and Cerebrovascular Center Samsung Medical Center, Sungkyunkwan University School of Medicine 50 Irwon-dong, Gangnam-gu, Seoul 135-710 (South Korea) Tel. +82 2 3410 3599, Fax +82 2 3410 0052, E-Mail nmboy @ unitel.co.kr

First, previous studies suggested that multiple ischemic lesions on DWI are common in acute stroke patients. Different prevalence and patterns of new lesions have been reported among different stroke subtypes and treatment modalities. For example, the stroke subtype of large-artery atherosclerosis and infarct pattern of initial multiple lesions on DWI are associated with lesion recurrence after the index stroke [1]. In addition, a higher prevalence of DWI lesions was reported after cerebrovascular procedures and devices, i.e. angioplasty and stenting [2, 3]. Second, enlargement of the infarct size by either ischemic neuronal deaths within the critically hypoperfused area [4] or delayed neuronal deaths [5] can be a mechanism of progressive stroke. Warach et al. [6] reported that lesion volumes increased by 180% among placebo-treated stroke patients from baseline to day 7. It was also reported that for patients who underwent intra-arterial thrombolysis, late secondary ischemic injury by day 7 occurred in 63% of patients with early DWI reversal, suggesting reperfusion injury [5]. The use of multiparametric MRI including DWI and perfusion-weighted imaging (PWI) in clinical practice is rapidly growing. The association between the type of stroke evolution (new lesions and infarct growth) and the pretreatment perfusion pattern has been investigated. However, most recent studies have only focused on either new lesions or infarct growth or they merged several types of stroke evolution together [7–12]. As a result, it is not clear if the perfusion status differs between these two types of stroke evolution. In addition, most studies evaluated the extent of hypoperfusion, but the severity of hypoperfusion was not considered. Our hypothesis was that patients with new lesions would show different clinical and MRI (including perfusion status) features compared to those with infarct growth on a follow-up image. In the present study, we analyzed the severity of perfusion delay using PWI to compare the baseline hemodynamic status of these two types of stroke evolution.

Methods and Patients Patient Selection We analyzed demographic, clinical, laboratory and radiographic data collected prospectively from consecutive patients admitted to Samsung Medical Center, Seoul, South Korea, for acute cerebral infarction from May 2005 to June 2008. The inclusion criteria for this study were as follows: (a) patients with acute ischemic lesions within the middle cerebral artery dis-

Impact of Baseline Perfusion Severity and Treatment Effects on Stroke Evolution

tribution on DWI, (b) who were eligible for recanalization therapy (NIH stroke scale, NIHSS, of 4 or more, onset to presentation less than 6 h, and not contraindicated to recanalization therapy) and (c) who underwent pretreatment DWI and PWI prior to recanalization therapy and DWI 7 days after the onset of symptoms. Patients with lacunar stroke were excluded. The local institutional review boards approved this study, and we obtained written informed consent from all patients and/or their first-degree relatives. MRI Methods and Image Analysis All patients underwent MRI using a 3.0-tesla unit (Achieva, Philips Medical Systems). The typical stroke MRI protocol consisted of DWI, gradient-recalled echo, fluid-attenuated inversion recovery, T2*-perfusion-weighted imaging and magnetic resonance angiography imaging of the cervical and intracranial vessels (3-dimensional time-of-flight and contrast-enhanced magnetic resonance angiography including extracranial internal carotid and vertebral arteries). DWI was obtained with two levels of diffusion sensitization (b-values of 0 and 1,000 s/mm2, 5–7 mm slice thickness and no gap). PWI was performed after a bolus of intravenous gadolinium using gradient-echo-echo-planar sequences (TR 2,000 ms; TE 60 ms; flip angle 90°; matrix 128 ! 128; FOV 24 cm; section thickness 5–7 mm; intersection gap 2 mm). We selected a definition based on the perfusion parameter Tmax, which is the time to peak of the residue function map generated by deconvolution of the tissue concentration over time curve using an arterial input function from the contralateral middle cerebral artery [13]. Data analysis was performed with software developed in-house using the Interactive Data Language produced by ITT Visual Systems (Boulder, Colo., USA). MRI volume measurements were performed by one of the authors, who had been blinded to the clinical information. For each patient, DWI and PWI lesion volumes were outlined automatically with subsequent manual corrections, and the volumes were calculated using a computer-assisted volumetric analysis program (Medical Image Processing, Analysis and Visualization, version 2.1, CIT, NIH). A 2-second (Tmax 62 s), 4-second (Tmax 64 s) and 8-second (Tmax 68 s) delay was used as the lower thresholds for the perfusion defect. Hypoperfusion regions were divided into severe (Tmax 68 s), moderate (4 ^ Tmax ! 8 s), mild (2 ^ Tmax ! 4 s) and no delay. Tmax 62 s was often used to define perfusion delay. Recently, a threshold of Tmax 64 s was reported to provide a more accurate estimation of penumbral tissue because Tmax 62 s may tend to overestimate true tissue at risk [14]. In a prior study using both voxel-by-voxel and volume analyses of serial MRI studies, it was found that PWI measures of ischemia intensity can differentiate irreversibly injured core from penumbral, salvageable tissue, with the best threshold for identifying core infarcted tissue adjusted to Tmax of 66 or 68 s [12]. Changes in the day 7 DWI were classified as follows: (a) new lesions, which were defined as new lesions not contiguous with initial abnormalities, and (b) infarct growth, which was defined as enlargement of DWI lesions contiguous with the initial abnormalities. Patients could have both new lesions and infarct growth. The degree of reperfusion was evaluated with the Thrombolysis in Cerebral Infarction (TICI) grading system [15], in selected patients, mostly who received endovascular therapy. This angiographic scale assigns patients to grade 0 (no perfusion), 1 (perfu-

Cerebrovasc Dis 2010;29:328–335

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sion past the initial obstruction but limited distal branch filling with little or slow distal perfusion), 2A (perfusion of less than half of the vascular distribution of the occluded artery), 2B (perfusion of half or greater of the vascular distribution of the occluded artery) and 3 (full perfusion with filling of all distal branches). In this study, a score of 0–1 was designated as poor, 2–3 as good reperfusion.

Results

Of 140 patients who were admitted during the study period and eligible for recanalization therapy, a total of 74 patients were included in this study. The reasons for exclusion were: (a) pretreatment diffusion-perfusion MRI (n = 21) or day 7 DWI (n = 21) were not performed; (b) MRI was contraindicated (n = 9); (c) failure of postMRI processing, excessive patient motion or selection of the wrong arterial input function (n = 5), and (d) lacunar stroke (n = 10). Of the 74 patients, the mean age was 64.2 years (range 22–92), 47 were male, and the median pretreatment NIHSS was 10 (interquartile range, IQR, 7–14, full range 4–25). Fifty-one patients received recanalization therapy (intravenous lysis alone 14, endovascular therapy 11 and combined 26). MRI was performed before treatment, and the median time from the onset of symptoms to MRI was 2.9 h (IQR 2.0–3.8 h, full range 0.9–6.0 h). Pretreatment MRI revealed a DWI lesion volume of 20.1 8 44.9 ml (median 6.2 ml, IQR 1.6–13.6 ml, full range 0.1–314.7 ml). Day 7 DWI demonstrated new DWI lesions in 39 cases (52.7%), 330


12 DWI new lesions (n)

Statistical Analysis We analyzed the differences between groups using Pearson’s ␹2, a Student’s t test or one-way analysis of variance for the means of normally distributed variables or the Mann-Whitney U test or Kruskal-Wallis test for medians. The relationship between the number of new lesions and the size of infarct growth was evaluated using Spearman correlation coefficients. In addition, multiple linear regression models (stepwise method) were developed to predict the independent contribution of factors that influenced new lesions and lesion growth seen on day 7 DWI. Potential predictors considered for inclusion in these models were S-glucose levels [16], mode of recanalization therapy (none, intravenous tissue-type plasminogen activator, endovascular recanalization therapy with/without intravenous tissue-type plasminogen activator) [2, 3], the degree of reperfusion (TICI grading, range 0–3), the severity of stroke (NIHSS score on admission and baseline DWI lesion volumes), and the volume of DWI lesions and ischemic zone (mild, moderate and severe delay) on pretreatment MRI. All statistical analyses were performed using commercially available software (SPSS for Windows, version 13.0; SPSS Inc., Chicago, Ill., USA). p ! 0.05 was considered to indicate statistical significance.

14

10 8 6 4 2 0 –50

0

50

100

150

200

250

DWI infarct growth (ml)

Fig. 1. Relationship between DWI new lesions and DWI lesion

growth.

26 of which involved patients who showed the lesion location within a mild perfusion delay region and 13 of which involved patients who showed at least 1 lesion outside the perfusion delay region. The number of new lesions on day 7 DWI varied from 1 to 13 (median 3, IQR 2–5), and 70.6% of new lesions were 10 mm or less in diameter. DWI infarct growth on day 7 was observed in 52 patients with a median volume of 10.1 ml (IQR 3.0–38.9 ml, full range 0.1–253.4 ml). Although both new lesions and infarct growth were frequently observed within perfusion delay regions, no correlation was observed between these two types of stroke evolution (r = 0.029, p = 0.805; fig. 1). It was rare to show both infarct growth 610 ml and 5 or more new lesions (n = 8, 10.8%). Most new lesions were multiple, small and located in cortical/superficial areas within mild perfusion delay regions, whereas infarct growth generally occurred within severe perfusion delay regions (fig. 2). Patients’ characteristics depending on the number of DWI new lesions and DWI lesion growth are shown in tables 1 and 2. The differential aspects of clinical and MRI features (including the severity of perfusion delay) influenced the DWI findings after 7 days of hospitalization. New lesions were more frequently observed in patients who showed a large mild (2 ^ Tmax ! 4 s) or moderate (4 ^ Tmax ! 8 s) perfusion delay on baseline MRI than in those with a small perfusion delay (p = 0.051 and 0.008, respectively). However, no association was obBang /Kim /Chung /Kim /Kim /Jeon / Saver /Liebeskind /Lee

Color version available online

a

b

Fig. 2. Serial diffusion-perfusion MRI findings of patients with DWI new lesions (a) and DWI lesion growth (b).

served between new lesions and a large DWI lesion or severe (Tmax 68 s) perfusion delay. Neither severity of stroke (NIHSS score on admission and baseline DWI lesion volumes) nor NIHSS score reduction on day 7 was different depending on the occurrence of new lesions on day 7 DWI. Patients who received endovascular recanalization therapy had a higher prevalence of new lesions than those who received conservative care or intravenous tissue-type plasminogen activator alone (p = 0.02; table 1). On the contrary, patients with severe stroke were more likely to have infarct expansion (table 2). A higher NIHSS score on admission and a larger infarct on initial DWI were associated with a greater degree of infarct growth (p = 0.005 and 0.012, respectively). Patients with a large moderate and severe perfusion delay were more likely to have infarct expansion (p = 0.015 and 0.008, respectively). The degree of infarct growth correlated with the NIHSS score reduction on day 7 (p = 0.018). Vascular reperfusion was assessed in 39 of 74 patients (37 who received endovascular therapy, 1 intravenous lysis and 1 no recanalization therapy). The presence and number of new lesions were not different depending on the degree of reperfusion (TICI 0–1 vs. TICI 2–3; table 1). On the contrary, there was a trend that the degree of infarct growth was different depending on the degree of angiographic reperfusion (p = 0.102). No or poor reperfusion (TICI 0–1) was observed in more than half of the patients with lesion growth 610 ml, whereas partial or complete reperfusion (TICI 2–3) was observed in

three quarters of patients with lesion growth !10 ml (table 2). Multiple regression analysis was performed to further evaluate the independent predictor for new lesions and lesion growth on day 7 DWI (table 3). Multiple regression analysis revealed that the volume of mild (2 ^ Tmax ! 4 s) perfusion delay and thrombolysis mode were independently associated with the number of new lesions (p = 0.001), whereas DWI lesion volume was independently associated with the degree of infarct growth, adjusting for other variables (p = 0.001). When the degree of angiographic reperfusion (TICI score) was entered into the same model (model 2), moderate (4 ^ Tmax ! 8 s) perfusion delay and the degree of angiographic reperfusion were associated with the degree of lesion growth on day 7 DWI (p = 0.005). Other factors did not significantly add value to the DWI changes on day 7. The degree of angiographic reperfusion was not associated with new lesions.



Discussion

The results of this study demonstrate that patients with acute ischemic stroke had a high frequency of new lesions and infarct lesion growth. Indeed, approximately 50% of these patients had new lesions, while about two thirds of these patients had varying degrees of infarct growth on day 7 DWI. Furthermore, it is interesting that 331

Table 1. DWI new lesions on the day 7 MRI

DWI new lesions none Patients Age, years Male sex NIHSS score on admission NIHSS score reduction on day 7 S-glucose levels on admission, mg/dl Pretreatment MRI volume, ml DWI lesions Tmax >8 s 4 < Tmax ≤ 8 s 2 < Tmax ≤ 4 s Time from symptom onset to MRI scanning, min Recanalization therapy None Intravenous thrombolysis Endovascular treatment1 Recanalization rate TICI 0–1 TICI 2–3

p value 1–4

≥5

35 (47.3) 65.1814.3 22 (62.9) 11.987.3 5.884.9 140.9851.1

23 (31.1) 64.4812.9 16 (69.6) 10.285.1 5.183.5 147.9861.3

16 (21.6) 62.1813.2 9 (56.3) 10.484.0 5.886.4 123.6831.7

28.8859.6 63.9893.5 32.5835.4 26.9830.3 181.5877.9

15.9829.7 38.3848.3 40.2829.2 35.3829.4 175.4881.9

7.589.8 51.0848.9 67.7846.8 50.4836.1 172.9849.2

15 (42.9) 8 (22.9) 12 (34.3) n = 13 6 (46.2) 7 (53.8)

6 (26.1) 4 (17.4) 13 (56.5) n = 13 4 (30.8) 9 (69.2)

2 (12.5) 2 (12.5) 12 (75.0) n = 13 5 (38.5) 8 (61.5)

0.759 0.693 0.512 0.860 0.345 0.252 0.443 0.008 0.051 0.912 0.020

0.723

Figures in parentheses are percentages. 1 With/without intravenous thrombolysis.

Table 2. DWI lesion growth on the day 7 MRI

DWI lesion growth none Patients Age, years Male sex NIHSS score on admission NIHSS score reduction on day 7 S-glucose levels on admission, mg/dl Pretreatment MRI volume, ml DWI lesions Tmax >8 s 4 < Tmax ≤ 8 s 2 < Tmax ≤ 4 s Time from symptom onset to MRI scanning, min Recanalization therapy None Intravenous thrombolysis Endovascular treatment1 Recanalization rate TICI 0–1 TICI 2–3

p value 8 s 4 < Tmax ≤ 8 s 2 < Tmax ≤ 4 s Treatment modea NIHSS scoreb S-glucose levelsb TICI score R2, % a

New lesions

Lesion growth model 1 (preangiographic state)

model 2 (postangiographic state)

␤-coefficient

p

␤-coefficient

p

␤-coefficient

p

1.327 0.012 0.123 0.181 0.032 1.151 –0.114 –0.083

0.149 0.478 0.388 0.586 0.008 0.010 0.080 0.969

2,200.3 385.17 0.158 244.10 0.049 –0.053 0.163 0.103

0.769 0.001 0.405 0.053 0.652 0.877 0.534 0.990

26,541.5 0.067 0.105 376.96 –0.177 0.202 0.040 0.036 –14,143.8 26

0.039 0.993 0.983 0.019 0.662 0.865 0.997 0.977 0.006

20

19

None versus intravenous tissue-type plasminogen activator versus endovascular treatment. b On admission.

there was no correlation between new lesions and infarct growth. The results of our study indicate that the type of stroke evolution differed depending on the baseline perfusion status. Specifically, new lesions occurred in patients with a large area of mild perfusion delay, whereas infarct growth occurred in patients with a large area of severer perfusion delay. We recently reported that the severity of hypoperfusion within an oligemic field is largely independent of the size of the oligemic region [17, 18]. Thus, both aspects of hypoperfusion seem to be differently involved in the pathophysiology of stroke evolution. New DWI lesions within the mild hypoperfusion may be related to the thromboembolic mechanism, whereas infarct growth may represent infarction expansion within the severely hypoperfused area. First, in the present study, most new lesions were small infarcts, usually multiple, and located in the cortex or superficial area and associated with large mild hypoperfusion regions. Although hypoperfusion and embolism are traditionally considered separate causes of stroke, Caplan and Hennerici [19] have posted that impaired washout is an important mechanism of brain infarction in patients with cerebral hypoperfusion. They suggested that hypoperfusion enhances thrombus formation, promoting embolization of fresh thrombi and limiting the ability of the bloodstream to clear or wash out emboli [19, 20]. The results of the present study indicated that even mildly hypoperfused defects are not benign. Regions having these subtle hypoperfusion may show multiple small diffusion lesions

on day 7, although these new lesions were not associated with clinical deterioration. Second, our data suggest that infarct growth is the major pathophysiological mechanism of stroke evolution in patients with severe neurological deficits and severe perfusion delay. Infarct growth was not related to the extent of mild hypoperfusion but was associated with a severer hypoperfusion. These findings are in good agreement with those of a previous study. Thijs et al. [21] reported that the degree of expansion of the initial DWI lesion was correlated with the severity of the initial perfusion defect. In the present study, the degree of reperfusion as well as pretreatment severity of hypoperfusion was associated with infarct growth, suggesting a benefit from reperfusion in preventing infarct growth, even in patients with large areas of severely hypoperfused regions. A large area of DWI lesions and severe hypoperfusion regions on pretreatment MRI were associated with infarct growth. However, if the angiographic state was considered, the degrees of reperfusion (TICI grade) but not DWI lesion volumes were independently associated with infarct growth. These findings suggest the importance of reperfusion over the baseline DWI-PWI status. Immediate posttreatment reperfusion may be the determinant of threatened tissue outcome, even 3 h after symptom onset [22]. Previous studies have focused on the association of multiple small superficial lesions on the baseline DWI [23] or recurrent lesions on the follow-up DWI within 1 week [1, 24] with delayed recurrent stroke. The results



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of the present study suggested that pretreatment PWI may provide information on the type of stroke evolution: new lesions and infarct growth. Both new DWI lesions and infarct growth could be associated with early worsening following ischemic stroke. Thus, targeted intervention for the prevention of each type of stroke evolution after acute ischemic stroke could be guided by analysis of the pretreatment perfusion status, such as preventing thromboembolisms in patients with a large mild hypoperfusion region and embolic sources, and enhancing cerebral perfusion to prevent infarct growth in patients with severe neurological deficits or severe perfusion delay. In addition, our results suggest that vascular reperfusion and treatment mode as well as baseline perfusion severity may affect the type of stroke evolution. Although vascular reperfusion with aggressive therapy may reduce the size of infarct growth, new lesions may accompany it. However, further studies are needed, because vascular reperfusion was assessed only in selected patients. Strengths of our study included the consecutive prospective recruitment of a relatively large number of patients who underwent serial MRI. However, the results of this study should be interpreted with caution for the following reasons. First, patients were heterogeneous with respect to recanalization therapy; patients were treated with a variety of recanalization therapies, and some patients were treated conservatively. Further studies with cohorts of more homogeneous patients and control of the treatment mode are needed to evaluate the effects of therapeutic mode or recanalization on stroke evolution. Second, collateral grade was not considered in the present study. We have recently reported that pretreatment col-

lateral grade, which may be related to baseline severity of perfusion defects, was independently associated with infarct growth, but that recanalization degree was not [17, 25]. Third, this was a single-center trial with a modest sample size of selected patients. We have recently reported that perfusion status in acute stroke patients differs depending on the patients’ characteristics (including race and ethnicity) [26]. Thus, the results of this study cannot be generalized to whole stroke patients. Multicenter trials with larger cohorts and different study populations are warranted. Lastly, several medical conditions may be associated with stroke evolution, including febrile illness and variation in blood pressure, which were not considered in the present study. In addition, edema formation, proximal reocclusion and distal occlusion by migration of thrombi may also be associated with infarct growth or new lesions. Overall, the results of our study indicate that the type of stroke evolution differs depending on the baseline perfusion status, and mode and result of recanalization therapy. Although reperfusion following treatment is important in lesion reduction, our results emphasize the impact of pretreatment hypoperfusion severity on the type of stroke evolution observed on 7 day MRI.

Acknowledgements This study was supported by a grant from the Korean Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A080044), and the Samsung Medical Center Clinical Research Development Program grant (No. SBRI C-A9216-1).

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