Figure. Representative intracranial plaque images acquired from patients with middle cerebral artery (MCA) stroke. A patient presented with a sudden onset of right-sided weakness, and brain magnetic resonance imaging (MRI) revealed an acute lacunar infarction involving the left corona radiata with normal plaque (A-D). Another patient presented with a sudden onset of right-sided weakness, and brain diffusion-weighted imaging revealed a left corona radiata infarction (in situ thrombosis). Although the time-of-flight magnetic resonance angiographic image disclosed subtle MCA stenosis, high-resolution MRI disclosed considerable plaque volume (E-H). Another patient presented with transient right-sided weakness and sensory aphasia. Brain MRI on hospital admission showed multiple scattered high signal intensities in the left MCA territory and stenosis in the proximal MCA. High-resolution MRI with gadolinium enhancement showed heterogeneous signal intensity, suggesting the presence of a vulnerable plaque (I-L).
Kim J, Jung K, Sohn C, Moon J, Han MH, Roh J. Middle Cerebral Artery Plaque and Prediction of the Infarction Pattern. Arch Neurol. 2012;69(11):1470-1475. doi:10.1001/archneurol.2012.1018
Author Affiliations: Departments of Neurology (Drs Kim, Jung, Moon, and Roh) and Radiology (Drs Sohn and Han), Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.
Background Intracranial atherosclerosis is associated with recurrent ischemic stroke. High-resolution magnetic resonance imaging can provide information about atheroma in vivo including plaque volume, composition, and activity.
Objective To evaluate atherosclerosis activity of the middle cerebral artery (MCA) by high-resolution magnetic resonance imaging and determine its relationship with infarction patterns.
Design Patients with MCA territory infarction or transient ischemic attack were enrolled and 3-T high-resolution magnetic resonance imaging was performed in the relevant MCA. We analyzed the status of the intracranial atheroma and infarction pattern in the corresponding vascular territory. Intracranial atheroma was defined as vulnerable symptomatic plaque when it was accompanied by intraplaque heterogeneous signal intensity and plaque enhancement, and as a stable symptomatic plaque otherwise. Cerebral infarction pattern was defined as artery-to-artery embolic infarction when multiple lesions were present within the MCA territory.
Setting A tertiary referral center.
Patients A total of 34 patients were enrolled in the study; 14 patients had stable symptomatic plaque, 12 had vulnerable symptomatic plaque, and 8 had no plaque (normal group).
Main Outcome Measures Intracranial atheroma stability and infarction pattern.
Results High-resolution magnetic resonance images were acquired from 34 patients, which revealed the presence of stable symptomatic plaque in 14 patients and vulnerable symptomatic plaque in 12 patients. The patients with vulnerable symptomatic plaque more commonly demonstrated an artery-to-artery embolic infarction pattern than the patients with stable symptomatic plaque (P = .02).
Conclusions Vulnerable symptomatic plaque as determined by a high-resolution magnetic resonance imaging technique is associated with artery-to-artery embolic infarction. This novel imaging technique can provide information about intracranial atherosclerosis in vivo, which can predict the infarction pattern.
Atherosclerotic disease of the intracranial vessels is commonly observed among Asian and African stroke patients, and several studies have demonstrated that its presence predicts the likelihood of frequent stroke recurrence in the future.1,2 The possible stroke mechanisms in middle cerebral artery (MCA) atherosclerosis are variable including thrombosis obstructing single or multiple perforating arteries, arterial emboli formation disseminating into the distal branches, and hemodynamic compromise in the watershed area.3- 5 Evaluation of intracranial atheromatous plaque is challenging because of limited imaging resolution and approach technique in conventional imaging modalities, although it may help to understand the pathology of intracranial atherosclerosis regarding plaque stability and mechanism of subsequent infarction.
Recently, high-resolution magnetic resonance imaging (MRI) has emerged as a novel diagnostic technique that provides information about atheroma in vivo, such as plaque volume, its components, and surface morphology, thereby disclosing the pathomechanism of plaque rupture and subsequent thromboembolic event.6- 9 One study demonstrated the presence of MCA plaque with eccentric narrowing and enhancement in MCA stroke patients.10 Another study demonstrated that the patient groups with symptomatic and asymptomatic MCA stenosis had different vessel wall properties such as vessel wall area and remodeling ratio, although the degree of stenosis was similar in the groups.11 The next level of application of high-resolution plaque imaging would be its use in evaluating intracranial plaque stability and assisting in therapeutic strategy planning. In this study, we studied MCA stroke patients using a high-resolution MRI technique to evaluate the characteristics of intracranial atherosclerosis and determine the relationship between plaque stability and infarction pattern.
Between July 1, 2009, and August 31, 2011, the patients who were admitted with infarction involving the MCA territory or transient ischemic attack (TIA) due to MCA disease were enrolled in the study. Lacunar stroke patients were not excluded because the single-perforator vessel can be obliterated by large artery atherosclerosis, which was not disclosed by conventional imaging. All the patients had a focal neurologic deficit, and imaging studies were performed within 7 days after symptom onset. We performed conventional brain MRI with a 3-T unit (Signa, GE Medical Systems) and an 8-channel head coil including time-of-flight MR angiography (TOF-MRA). We excluded the patients (1) with potential cardioembolic source or symptomatic proximal artery disease; (2) who were diagnosed as having other vascular pathologies including dissection, inflammation, or Moyamoya disease; or (3) who were unable to undergo brain MRI studies owing to underlying medical conditions. The target MCA for high-resolution MRI evaluation was determined after TOF-MRA image review. The black blood technique with fat preregional saturation pulses of 80-mm thickness to saturate incoming arterial flow was used, and high-resolution MRI sequences using a 3-T unit (Verio; Siemens Healthcare) included T1-weighted images acquired with repetition time and echo time of 600 ms and 12 ms, respectively; T2-weighted images acquired with repetition time and echo time of 2910 ms and 70 ms, respectively; proton density images acquired with repetition time and echo time of 2500 ms and 30 ms, respectively; and T1-weighted images with gadolinium enhancement. All images were taken with a field of view of 120 × 120 mm, 2-mm slice thickness, matrix size of 384 × 269, and number of excitations = 4. We reviewed the vascular risk factors and laboratory data. Good outcome after stroke was defined as modified Rankin Scale score of 0 to 1 at hospital discharge. This study was reviewed and approved by the institutional review board of the Seoul National University Hospital (institutional review board no. H-1106-047-366).
Ischemic stroke pattern was categorized into 4 groups according to the diffusion-weighted images: (1) normal, suggesting TIA; (2) small-vessel occlusion caused by single-perforator occlusion; (3) in situ thrombosis when lesion diameter exceeded 20 mm on diffusion-weighted imaging, presumably due to multiple perforator occlusion; and (4) arterial embolization (AE) when 2 or more lesions were scattered within the subcortical and cortical areas supplied by the distal MCA. The degree of MCA stenosis was classified into 3 grades: (1) normal, (2) mild (signal reduction <50%), and (3) moderate to severe (signal reduction ≥50%). Intracranial atheromatous plaque was identified when there was an eccentric or focal signal intensity within the vessel lumen on high-resolution MRIs, and it was defined as vulnerable symptomatic (VS) plaque when it was accompanied by intraplaque heterogeneous signal intensity on T1 and T2 images and plaque enhancement on T1-enhanced images, and as stable symptomatic (SS) plaque in the absence of these findings. According to plaque stability, the patients were divided into 3 groups: (1) normal group when there was no discernible plaque, (2) SS plaque group, and (3) VS plaque group. The 2 investigators (J.M.K. and J.S.M.) who were blinded to the clinical information performed the imaging analysis, and discrepancies between the 2 readers were solved after visual consensus with the third reviewer (C.H.S.).
Categorical variables were presented as absolute frequencies, and continuous variables were expressed as mean (standard deviation). We hypothesized that the VS plaque group would have a different clinical presentation than the SS plaque group, especially in terms of the degree of stenosis on TOF-MRA and infarction pattern on diffusion-weighted imaging. We compared the SS plaque group with the VS plaque group by using the Fisher exact test for categorical variables and by using the Mann-Whitney U test for continuous variables. To compare the mechanism of infarction between the 2 groups, we dichotomized the infarction pattern as AE and non-AE, which included normal (TIA), small-vessel occlusion, and in situ thrombosis. Significance was set at the 2-tailed P < .05 level, and all the statistical analyses were performed using SPSS version 18 (SPSS Inc).
There was a total of 39 patients with MCA infarction or TIA who had undergone high-resolution MRI. However, 5 patients with other vascular pathologies were excluded. Finally, 34 patients were enrolled for analysis, with 8 patients in the normal group, 14 patients in the SS plaque group, and 12 patients in the VS plaque group. The clinical and laboratory characteristics of the study population are illustrated in Table 1. There was no significant difference in the clinical and laboratory characteristics between the SS and VS plaque groups.
The degree of MCA stenosis is illustrated in Table 2. Conventional MRA revealed MCA stenosis in 16 patients, but atheromatous plaque was observed in 26 patients on high-resolution MRI, thereby detecting additional intravascular atheromatous plaque in 10 patients. Moderate to severe stenosis on TOF-MRA showed a tendency to be more frequently associated with the VS plaque from plaque imaging (P = .27; Fisher exact test). Some of the SS plaque was accompanied by either plaque enhancement or intraplaque heterogeneous signal intensity, separately.
The patients without plaque mostly had small-vessel occlusion, and the patients with SS plaque had heterogeneous infarction patterns (Table 3). However, the patients with VS plaque mostly showed the AE pattern: multiple lesions within the MCA territory. The infarction pattern was dichotomized as AE and non-AE and was compared between the 2 groups. The VS plaque group more frequently demonstrated the AE pattern than the SS plaque group (P = .02; Fisher exact test). The patients with SS plaque frequently presented as having small-vessel occlusion or in situ thrombosis. Representative cases are illustrated in the Figure. The proportion of good functional outcome was not different between the 2 groups. Two patients with a VS plaque were treated with intracranial balloon angioplasty.
In this study, high-resolution MRI could disclose intracranial atherosclerotic plaque burden and plaque stability, which may determine the infarction pattern. The vulnerable plaque was frequently associated with AE infarction, suggesting that several emboli arising from unstable or ruptured atheromatous lesions might have caused multiple ischemic lesions. The SS plaque might have encroached the orifices of single or multiple perforators arising from the MCA stem, and the patients presented with TIA, small-vessel occlusion, or in situ thrombosis. Patients without plaque mostly had small-vessel occlusion, which is already known to have the pathology of the perforating artery after sustained hypertension. More elaborate application of the high-resolution MRI technique may delineate stroke pathomechanism related to intracranial stenosis by providing information about the intracranial atheroma activity.
Recently, various imaging techniques have become available for evaluating the intracranial vascular status including conventional digital-subtraction angiography, computed tomographic or MR angiography, and transcranial Doppler imaging. However, until now, only high-resolution MRI can visualize the cross-section of plaque without an invasive procedure, and it can provide information about intraplaque composition and inflammation status. Its application has been widely studied among the patients with proximal carotid atherosclerotic disease, and a study revealed findings associated with risk for plaque rupture such as intraplaque hemorrhage, necrotic core, thinning of the fibrotic cap, and combined inflammation, which correlated with other pathology studies.7,12 Although the intracranial arterial plaque composition and biology may be similar to that of the proximal carotid plaque, it can be rarely studied in the pathologic specimen, and the caliber of the MCA is too small to apply the same measurement technique as that used in carotid artery studies. We chose the 2 parameters of plaque enhancement and intraplaque heterogeneous signal intensity, which may reflect active inflammation and heterogeneous composition such as lipid-rich necrotic core or hemorrhage within the plaque. Recently, one study demonstrated that intraplaque high signal intensity on T1-weighted imaging suggests a recent intraplaque hemorrhage, which was more common in symptomatic MCA stenosis.13 Other plaque imaging studies reported that symptomatic MCA stenosis was accompanied by plaque enhancement, which lasted for several months after symptom onset.10,14 To our knowledge, this is the first study to report the different infarction patterns in terms of plaque vulnerability.
Intracranial vessel stenosis is associated with a high rate of stroke recurrence and poor functional outcome.15,16 In previous studies, the degree of MCA stenosis had been shown to determine the infarction pattern.4,17,18 Several studies have demonstrated that patients with MCA stroke with severe stenosis more frequently presented with multiple cortical infarctions than the patients in the mild to moderate stenosis group by TOF-MRA data analysis, suggesting that risk for an arterial embolic event increases as the atheroma increases in size.4,17 The vulnerability of atheroma is known to correlate with plaque burden, although other factors such as necrotic core size and fibrous cap thinning influence its rupture risk.19 Our results showed that most patients with moderate to severe stenosis had VS plaque, but the relationship between the degree of stenosis and plaque instability was not evident. Application of high-resolution MRI would strengthen our understanding of intracranial artery stenosis and the mechanism of subsequent infarction. It is an accurate diagnostic modality for studying the intracranial vessels because some of our patients did not have a noticeable stenosis on TOF-MRA but still had considerable plaque volume as was demonstrated with the use of this novel imaging technique. It can provide clear distinction between branch atheromatous disease and lacunar stroke. Moreover, it can reveal the intracranial plaque composition, which will help us understand the stroke mechanism and determine the therapeutic plan. Intensive lipid-lowering treatment promoted atheroma regression measured by intravascular ultrasound in more than 60% of patients with coronary artery disease.20 Intracranial artery angioplasty has shown beneficial effects among selected groups of patients, although large-scale clinical trials have failed to prove its efficacy.21 Information obtained from plaque imaging may help to determine the therapeutic option, predict stroke occurrence, and evaluate treatment efficacy in patients with intracranial stenosis. Follow-up imaging studies would provide information about the temporal course of intracranial atherosclerosis and the treatment effect, which could enhance the clinical significance of this novel imaging and improve stroke treatment schemes.
Several limitations exist in this study. There was a lack of correlation between the MRI findings and the pathologic specimen. Because the VS plaque was defined based on the imaging findings, its definition should be confirmed in studies including pathologic data or involving larger population samples. In this study, the SS plaque did not indicate a more clinically stable plaque than the VS plaque because all the patients with SS plaque also had accompanying infarction or TIA, and 3 of them demonstrated an AE pattern. Biological factors associated with plaque vulnerability should be validated to strengthen the clinical significance of plaque imaging findings. We compared several blood markers that may be associated with plaque characteristics including total cholesterol, low-density lipoprotein, high-density lipoprotein, C-reactive protein, and fibrinogen, as well as vascular risk factors between the VS plaque group and the SS plaque group, but there was no significant difference probably owing to the small number of enrolled patients. Lastly, selection bias may exist because patients were not consecutively included in the study.
In summary, infarction associated with MCA atherosclerosis may have different patterns according to plaque stability on high-resolution MRI. Plaque imaging can suggest the possible stroke mechanism because it can detect intracranial atheroma more accurately than conventional TOF-MRA and can provide information about plaque vulnerability.
Correspondence: Jae-Kyu Roh, MD, PhD, Department of Neurology, Seoul National University Hospital, 28, Yongon-dong, Chongro-gu, Seoul, 110-744, South Korea (email@example.com).
Accepted for Publication: March 26, 2012.
Published Online: August 20, 2012. doi:10.1001/archneurol.2012.1018
Author Contributions:Study concept and design: Sohn and Roh. Acquisition of data: Kim, Jung, Sohn, Moon, and Han. Analysis and interpretation of data: Kim and Moon. Drafting of the manuscript: Kim. Critical revision of the manuscript for important intellectual content: Jung, Sohn, Moon, Han, and Roh. Statistical analysis: Kim and Moon. Administrative, technical, and material support: Sohn. Study supervision: Jung, Han, and Roh.
Conflict of Interest Disclosures: Dr Roh has received research funding from the Ministry of Science and Technology, Republic of Korea.
Funding/Support: This research was supported by the Brain Research Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science, and Technology (2012-0005825).