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Original Research |
1 All authors: Department of Radiology, Division of Neuroradiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, South Korea.
Received March 15, 2005;
accepted after revision October 21, 2005.
This work was partially supported by grants (03-PJ1-PG1-CH06-0001) from the
Korean Ministry of National Health and Welfare.
Abstract
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MATERIALS AND METHODS. Thirty-three acute ischemic stroke patients who were treated with intraarterial thrombolysis and underwent MRI within 6 hours of symptom onset were enrolled in this study. All study participants had either M1 or M2 occlusion on digital subtraction angiography before thrombolysis and underwent follow-up MRI 2-3 days after thrombolysis. Recanalization status was evaluated using the thrombolysis in myocardial infarction (TIMI) flow grade on digital subtraction angiography immediately after thrombolysis. The serial progression of the susceptibility sign on follow-up T2*-weighted imaging was compared with the MR angiographic findings. Baseline clinical parameters and clinical outcome were also reviewed.
RESULTS. A positive MCA susceptibility sign on the initial T2*-weighted imaging was detected in 16 (48%) of the 33 patients. The mean TIMI grade was higher in the patients with a positive sign on imaging than in those without the sign (2.3 vs 1.0, respectively; p < 0.005). In the risk factor analysis, a history of atrial fibrillation was significantly higher in the patients with the MCA susceptibility sign than in those with negative findings for the sign (13/16 [81%] vs 4/17 [24%], respectively). In 14 of the 16 patients with the positive sign, the sign disappeared on follow-up MRI, and that finding (i.e., disappearance of the sign) was well correlated with complete recanalization on follow-up MR angiography in 12 patients. Multivariate logistic regression analysis showed that this sign was not associated with a favorable functional outcome 30 days after thrombolytic treatment.
CONCLUSION. The MCA susceptibility sign can be indicative of acute thromboembolic occlusion and can be used to predict the immediate effectiveness of intraarterial thrombolysis. However, the appearance of this sign was not associated with a favorable clinical outcome after thrombolysis in our small series study.
Keywords: angiography • cerebral infarction • middle cerebral artery • MRI • susceptibility sign • thrombolysis
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Based on previous reports [1-4], we hypothesized that the MCA susceptibility sign on T2*-weighted gradient-echo images indicates acute occlusion of the MCA, with red thrombus containing erythrocytes and some fibrin, and that this sign is indicative of thrombi that will lyse. However, any paramagnetic substance that includes deoxyhemoglobin, intra- and extracellular methemoglobin, and hemosiderin can appear hypointense on T2*-weighted imaging. To exclude these potential pitfalls, we selected study patients using strict inclusion criteria based on clinical and imaging findings.
In most of the previous studies of the MCA susceptibility sign, researchers studied patients treated with IV thrombolysis and used MR angiography as the reference standard for vascular status. By contrast, we studied the MCA susceptibility sign in patients treated with IA thrombolysis, and we used digital subtraction angiography as the gold standard for vascular occlusion and recanalization.
We also expected that rapid recanalization associated with the MCA susceptibility sign results in a good clinical outcome; we evaluated the serial progression of this sign on follow-up T2*-weighted imaging and compared those findings with follow-up MR angiography findings.
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Stroke onset was defined as the last time a patient was known to be free of deficit. All patients were examined by an attending physician who specializes in treating stroke cases and underwent MRI. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score. The risk factors for stroke in each patient were assessed by retrospective review of computer-based clinical records.
Baseline clinical parameters were compared with the test for baseline differences between the patients with and those without the MCA susceptibility sign. For evaluation of clinical outcome after thrombolysis, the modified Rankin scale score (favorable, 0-2; poor, 3-5; death, 6) was determined 30 days after IA thrombolysis to assess functional disability, either at a follow-up examination or by telephone interview. The modified Rankin scale score was assigned without knowledge of recanalization status. The modified Rankin scale score 30 days after thrombolysis was also compared between the two groups. Our institutional review board approved this study, but patient informed consent was not required because this study was retrospective.
MRI Protocol
All patients were examined on a 1.5-T MRI unit (Signa, GE Healthcare) with
echo-planar capabilities. The acute stroke MR protocol, which was performed
during a single session within 20 minutes, consisted of
T2*-weighted gradient-echo imaging, diffusion-weighted imaging, 3D
time-of-flight (TOF) MR angiography, FLAIR imaging, perfusion-weighted
imaging, and 3D contrast-enhanced MR angiography. Patients with unstable vital
signs or with contraindications for MR study were excluded.
For T2*-weighted imaging, the slice thickness was 5 mm and the intersection gap was 2 mm. For diffusion-weighted imaging using an echo-planar sequence, the slice thickness was 5 mm and the b values were 0 and 2,000 s/mm2. Additional parameters for the acute stroke MR protocol were as follows: for 3D TOF MR angiography, a TR/TE of 25/2 and flip angle of 20°; for FLAIR imaging, a TR/TE of 10,002/97; for perfusion-weighted imaging, a slice thickness of 5 mm, 10 axial slices, and an intersection gap of 2 mm; and for 3D contrast-enhanced MR angiography, a TR/TE of 6/1, flip angle of 20°, matrix number of 512 x 512, and field of view of 250 mm. Follow-up MRI including T2*-weighted imaging, and MR angiography was performed 2-3 days after IA thrombolysis in all patients.
Image Analysis
The imaging findings of all selected patients were retrospectively reviewed
by two neuroradiologists who had 5 and 11 years of experience, respectively,
in interpreting MR images of the brain. According to definitions reported
previously, the MCA susceptibility sign on the initial MR image was defined as
the presence of hypointensity within the MCA in which the diameter of the
hypointense signal within the vessel exceeded the diameter of the
contralateral vessel [2].
The two observers, who were blinded to the patients' clinical information, treatment assignment, and the findings obtained using the other MR sequences, independently evaluated for the presence or absence of the MCA susceptibility sign on the initial and follow-up T2*-weighted MR images independently. If the sign was present, the observers classified it according to its location (M1 or M2) but not according to its degree of signal intensity (e.g., mild, moderate, severe). Interobserver agreement was statistically assessed.
The immediate effectiveness of IA thrombolysis was evaluated by the dosage of thrombolytic drugs and the postthrombolytic recanalization status. Recanalization status after IA thrombolysis was determined using digital subtraction angiography immediately after IA thrombolysis. The degree of recanalization was classified according to the thrombolysis in myocardial infarction (TIMI) flow grade [5, 6] for perfusion and vessel status: 0 = no recanalization or reperfusion, 1 = minimal recanalization or reperfusion (< 20%), 2 = incomplete recanalization or reperfusion, and 3 = complete recanalization or reperfusion.
We also evaluated the serial progression of the MCA susceptibility sign on follow-up T2*-weighted images and correlated those changes with recanalization status on follow-up MR angiography. The presence of hemorrhagic transformation (HT) was also assessed on follow-up T2*-weighted gradient-echo MRI. In assigning the postthrombolytic TIMI grade and determining the presence or absence of HT, the two observers interpreted the images together and reached a final decision in consensus. The two groups were compared according to the TIMI score and the presence of HT after IA thrombolysis.
Thrombolytic Treatment
All selected patients were treated with IA thrombolysis within 6 hours of
the onset of symptoms. IA thrombolysis was administered with urokinase (up to
a maximum of 1,000,000 IU) infused at the site of the clot at the time of
angiography until recanalization was achieved or until the maximum dose was
reached.
Statistical Analysis
The SPSS statistics package (version 11.0 for Windows [Microsoft],
Statistical Package for the Social Sciences) was used for subsequent
statistical analysis. To assess the diagnostic reliability of the presence or
absence of the MCA susceptibility sign on initial and follow-up
T2*-weighted MR images, the interobserver agreement between the two
observers was assessed by calculating unweighted 
values. A
value of 0.20 or less indicated poor agreement; 0.21-0.40, moderate agreement;
0.61-0.80, good agreement; and 0.81-1.00, very good agreement.
The statistical significance of the differences in patient age, mean time to treatment, baseline score on the National Institutes of Health Stroke Scale (NIHSS), dosage of thrombolytic drugs, and TIMI flow grade after IA thrombolysis between patients with a positive MCA susceptibility sign and those with a negative MCA susceptibility sign were assessed using the Mann-Whitney U test. The statistical significance of the difference of sex between patients with a positive MCA susceptibility sign and those with a negative MCA susceptibility sign was assessed using the Fisher's exact test.
A p value of less than 0.05 was considered to indicate a significant difference. Multivariate logistic regression analysis was used to assess the association of the MCA susceptibility sign with the occurrence of HT on follow-up MR images and the favorable functional outcome 30 days after IA thrombolysis.
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= 1.000).
There were eight men (age range, 40-72 years; mean age, 60.7 years) and eight
women (age range, 52-79 years; mean age, 68.3 years) in the group with
positive findings for the MCA susceptibility sign and eight men (age range,
38-82 years; mean age, 62.5 years) and nine women (age range, 42-78 years;
mean age, 65.0 years) in the group with negative findings for the MCA
susceptibility sign. The differences between the two patient groups in terms
of patient age or sex was not statistically significant. The mean times from the stroke onset to thrombolytic treatment were 4.6 hours (range, 3.5-5.8 hours) and 4.8 hours (range, 3.3-5.5 hours) in patients with and without the MCA susceptibility sign, respectively (p > 0.05). The mean baseline NIHSS score at admission was 15.5 (range, 9-22) in all study patients, and this clinical parameter was not significantly different between the patients with a positive MCA susceptibility sign and those with a negative MCA susceptibility sign (16.7 vs 15.7, respectively; p > 0.05). Thirteen (81%) of the 16 patients with a positive MCA susceptibility sign and four (24%) of the 17 patients with a negative MCA susceptibility sign had a history of atrial fibrillation as a risk factor (p < 0.0005).
The mean dosage of urokinase was 280,000 IU in the patients with a positive MCA susceptibility sign and 340,000 IU in those with a negative MCA susceptibility sign (p > 0.05). The TIMI flow grade on digital subtraction angiography immediately after IA thrombolysis was significantly higher in patients with a positive MCA susceptibility sign than in those with a negative MCA susceptibility sign (2.3 vs 1.0, respectively; p < 0.005) (Table 1 and Figs. 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 2A, 2B, 2C, 2D, 2E, 2F, 2G, 3A, 3B, 3C, 3D, and 3E). In 14 of the 16 patients with a positive MCA susceptibility sign, this sign disappeared on follow-up T2*-weighted MRI after IA thrombolysis and was well correlated with complete recanalization on follow-up MR angiography in 12 patients (Figs. 2A, 2B, 2C, 2D, 2E, 2F, and 2G). HT was seen on follow-up T2*-weighted gradient-echo images in six (38%) of the 16 patients with a positive MCA susceptibility sign and in seven (41%) of the 17 patients with a negative MCA susceptibility sign (p > 0.05).
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Among the 16 patients with a positive MCA susceptibility sign, the functional clinical outcome 30 days after thrombolysis was favorable (modified Rankin scale, 0-2) in eight patients (50%) and was poor or indicated death (modified Rankin scale, 3-6) in eight (50%). Among the 17 patients without the MCA susceptibility sign, the functional outcome was favorable in eight (47%) and was poor or indicated death in nine (53%). Multivariate logistic regression analysis showed that this sign was not associated with a favorable outcome after thrombolysis and that the predictors of a favorable clinical outcome were a low baseline NIHSS score on admission and the site of the occlusion (M2 occlusion) (Table 2).
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The susceptibility-based sequence is the first sequence performed in our routine stroke MRI protocol and is used to rule out hyperacute parenchymal hemorrhage [9]. This technique is also sensitive to the susceptibility variation of paramagnetic deoxygenated hemoglobin, which is encountered in a high concentration in acute thromboembolism [10, 11]. Therefore, with standard T2*-weighted MRI, susceptibility changes associated with acute thromboembolism can be detected [1].
Flacke et al. [1] described the MCA magnetic susceptibility sign as a signal loss along the course of the artery on susceptibility-based perfusion-weighted MRI. The signal loss that helps to identify the susceptibility sign is explained by severe T2 shortening at an acute clot, which represents the magnetic susceptibility differences that arise from intracellular deoxyhemoglobin. This magnetic susceptibility effect produces a nonuniform magnetic field and a rapid dephasing of proton spins, which result in signal loss that is best seen on T2* susceptibility-weighted images [12, 13]. Other likely contributors to this signal loss are increased hematocrit levels and hemoglobin concentrations due to clot formation and retraction [14] and fibrin polymerization [15]. This sign was correlated with the hyperdense MCA susceptibility sign on conventional CT scans [1].
However, any paramagnetic substance— including intra- and extracellular methemoglobin and hemosiderin—can appear hypointense on T2*-weighted imaging. Therefore, blood clots of acute, subacute, and chronic stage can appear as signal loss on T2*-weighted images. In this study, to exclude these potential pitfalls, we selected patients using strict inclusion criteria such as clear symptom onset within 6 hours, no history of previous infarct, and ipsilateral hyperacute or acute infarct lesion on initial and follow-up diffusion-weighted MRI. Moreover, 13 (81%) of the 16 patients with a positive MCA susceptibility sign had a history of atrial fibrillation and no evidence of large-vessel atherosclerotic stenosis on digital subtraction angiography.
On the basis of both clinical and imaging findings, we hypothesized that the positive MCA susceptibility sign may be attributed mainly to acute red thrombi associated with cardioembolic origin. Nevertheless, the MCA susceptibility sign can be attributed to various factors as mentioned earlier, and this fact is a limitation of our study.
Thromboembolic stroke can be caused by WBC, mixed blood cell, and RBC clots. White thrombi consist of varying amounts of cellular debris, fibrin, and platelets but of only a few RBCs. Red thrombi contain erythrocytes and some fibrin [16, 17]. Cardiogenic emboli and venous thrombi are composed of red thrombi primarily, and arterial thrombi are composed of white thrombi [18]. White thrombi were found in the cerebral arteries in approximately one third of patients with an embolic occlusion in the distribution of the internal carotid artery. Researchers have reported that in patients with primary thrombosis of the internal carotid artery, the frequency of WBC clots in the cerebral arteries was even higher [16, 17]. The previous reports showed that the attenuation coefficient of whole blood measured with CT increased linearly with the concentration of hemoglobin and with the hematocrit level; therefore, it appeared feasible to classify in vitro thrombi as white, mixed, or red with the help of their CT attenuation values [2]. In our study, a history of atrial fibrillation was significantly higher in patients with a positive MCA susceptibility sign than in those without this sign.
Besides the nature of clots, several factors, including the transport pattern of thrombolytic drug by blood flow, can determine the rate and pattern of fibrinolysis [19, 20]. In a rabbit model of thromboembolic cerebral ischemia, IA thrombolysis with recombinant tissue plasminogen activator improved cerebral perfusion and reduced the infarct volume in red but not in white emboli [2]. It was postulated that the efficacy of thrombolysis increases with the proportion of erythrocytes within the thromboembolic material and decreases with its content of fibrin. These hypotheses are attributed to the following two facts: First, fibrin-rich white thrombi retract more than red thrombi, which results in reduced permeability to the bulk flow of thrombolytic agents, increased fibrin content per unit of clot volume, and decreased plasminogen content [18, 19]. Second, fibrin has large pores when formed in the presence of erythrocytes, and thrombolytic drug may possibly be transported into the thrombus by bulk flow [18].
Despite the immediate effectiveness of thrombolysis in patients with a positive MCA susceptibility sign, the occurrence of HT and favorable functional clinical outcome were not significantly different between the two groups. Previous studies have reported that the clinical value of thromboembolism as detected on early CT is controversial [21, 22]. As has been reported by various authors, the presence of the hyperdense MCA sign or the MCA susceptibility sign as a single prognostic factor is not associated with prognosis in spontaneous MCA stroke [23, 24]. In addition, the clinical outcome may be better predicted by considering additional clinical and imaging findings than by considering only MCA occlusion or signs of MCA occlusion [25, 26]. In our study, the low baseline NIHSS score and the distal MCA occlusion (M2 portion) were independent predictors for a favorable clinical outcome after thrombolytic treatment, and these results support those of previous reports.
Our study has some limitations. Although we selected study patients using strict inclusion criteria, the positive MCA susceptibility sign can be attributed to various factors and we observed the variable degree of the MCA susceptibility changes. However, we did not classify them into groups according to the signal intensity of the MCA susceptibility sign. Moreover, we did not consider thrombus burden. We believe that the reason not all of the T2*-positive cases resolved after thrombolysis can be attributed to the pitfalls mentioned earlier. Two of three patients with a positive MCA susceptibility sign and poor recanalization (TIMI grade 0 or 1) after thrombolysis showed a large burden of thrombus. No serial T2*-weighted images were obtained in the first days after symptom onset. Therefore, there are not enough data to establish the minimum time needed to study an acute thrombus on T2*-weighted images. For this reason, we cannot ensure that the high level of diagnostic accuracy obtained in this study will be reproduced in patients in whom the MR examination is performed within the first 3 hours of symptom onset.
One of three patients with the negative sign and good recanalization after thrombolysis was treated within 3 hours after symptom onset. The MCA susceptibility sign could have been underestimated on the basis of the slice thickness and intersection gap of the T2*-weighted images. However, because our T2*-weighted MR protocol had a 5-mm slice thickness and 2-mm intersection gap, this imaging protocol provided higher resolution than that of previous reports. The small sample size may have limited our ability to find a statistically significant relationship between the presence of the MCA susceptibility sign and quantification of the clinical outcome in patients with hyperacute ischemic stroke.
Unlike the previous reports regarding the MCA susceptibility sign, we studied patients treated with IA thrombolysis, we evaluated vascular occlusion and recanalization using digital subtraction angiography as the gold standard, and we assessed the MCA susceptibility sign using relatively high-spatial-resolution T2*-weighted imaging.
The results of our study suggest that the presence of the MCA susceptibility sign may indicate acute thromboembolic occlusion and may be used to predict the immediate effectiveness of IA thrombolysis in patients with hyperacute ischemic stroke. In our small series study, the presence of this sign was not independently associated with the functional clinical outcome and occurrence of HT after IA thrombolysis; however, a prospective study with a larger number of patients is required to more accurately determine the relationship between the presence of the MCA susceptibility sign and long-term clinical outcome including complications after thrombolytic therapy.
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