Download Characterization of Complicated Carotid Plaque With

Characterization of Complicated Carotid Plaque With
Magnetic Resonance Direct Thrombus Imaging in Patients
With Cerebral Ischemia
Alan R. Moody, FRCR; Rachael E. Murphy, MRCP; Paul S. Morgan, PhD; Anne L. Martel, PhD;
G.S. Delay, DCR; Steve Allder, MRCP; Shane T. MacSweeney, FRCS; William G. Tennant, FRCS;
John Gladman, FRCP; John Lowe, FRCPath; Beverley J. Hunt, FRCPath
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Background—Thromboembolic disease secondary to complicated carotid atherosclerotic plaque is a major cause of
cerebral ischemia. Clinical management relies on the detection of significant (⬎70%) carotid stenosis. A large
proportion of patients suffer irreversible cerebral ischemia as a result of lesser degrees of stenosis. Diagnostic techniques
that can identify nonstenotic high-risk plaque would therefore be beneficial. High-risk plaque is defined histologically
if it contains hemorrhage/thrombus. Magnetic resonance direct thrombus imaging (MRDTI) is capable of detecting
methemoglobin within intraplaque hemorrhage. We assessed this as a marker of complicated plaque and compared its
accuracy with histological examination of surgical endarterectomy specimens.
Methods and Results—Sixty-three patients underwent successful MRDTI and endarterectomy with histological examination. Of these, 44 were histologically defined as complicated (type VI plaque). MRDTI demonstrated 3 false-positive
and 7 false-negative results, giving a sensitivity and specificity of 84%, negative predictive value of 70%, and positive
predictive value of 93%. The interobserver (␬⫽0.75) and intraobserver (␬⫽0.9) agreement for reading MRDTI scans
was good.
Conclusions—MRDTI of the carotid vessels in patients with cerebral ischemia is an accurate means of identifying
histologically confirmed complicated plaque. The high contrast generated by short T1 species within the plaque allows
for ease of interpretation, making this technique highly applicable in the research and clinical setting for the
investigation of carotid atherosclerotic disease. (Circulation. 2003;107:3047-3052.)
Key Words: thrombus 䡲 plaque 䡲 carotid arteries 䡲 imaging 䡲 cerebral ischemia
A
therothrombotic carotid disease is a major cause of
cerebral ischemia. Embolization from the surface of an
atherosclerotic plaque to cerebral vessels can result in occlusion, which, if sufficiently prolonged, will result in cerebral
infarction. More transient vascular occlusion may result in
temporary ischemia, producing a neurological deficit that
recovers with little or no residual brain damage. Clinically,
transient ischemic attacks (TIAs) provide a warning of further
cerebral ischemic events; ⬇10% of patients who sustain a
TIA, left untreated, will suffer a definitive stroke in the
following year,1 followed by a rate of 5% per annum. A
warning TIA therefore offers the chance to intervene to
prevent future permanent cerebral damage. The North American2 and European3 endarterectomy trials have both shown
the positive benefit of surgery in patients with significant
stenosis. The trials also indicate that lesser degrees of carotid
disease are responsible for a significant number of strokes,
but the risks of surgery matched or outweighed the benefits.
Techniques have been sought to further define those among
the group with moderate stenosis who are at high risk.
In 1995, Stary et al,4 for the American Heart Association,
defined different atherosclerotic subtypes, the purpose being
to pathologically identify plaque more likely to cause symptoms. Complicated plaque was defined as that with surface
rupture or intraplaque or associated intraluminal hemorrhage
and was defined as type VI disease. The presence of these
features is associated with increased risk of thromboembolism and subsequent symptoms. In addition, it has been
shown that the stepwise progression of atheroma, either with
or without symptoms, in its latter accelerated phase is often
associated with intraplaque hemorrhage, thus providing further evidence of the importance of this form of complex
plaque in atherosclerotic disease.5 A means of identifying
type VI complicated plaque in vivo may therefore provide a
Received December 13, 2002; revision received March 31, 2003; accepted April 2, 2003.
From the Department of Academic Radiology, Medical School (A.R.M., R.E.M., P.S.M., A.L.M., G.S.D., S.A.), the Department of Vascular Surgery
(S.T.M., W.G.T.), the Ageing and Disability Research Unit (J.G.), and the Department of Neuropathology (J.L.), University Hospital, Nottingham, and
the Department of Haematology, Guy’s and St Thomas’s Trust, London (B.J.H.), UK.
Correspondence to Dr Alan Moody, Department of Medical Imaging (Office AG57), Sunnybrook and Women’s College Health Sciences Centre, 2075
Bayview Ave, Toronto, Ontario, Canada, M4N 3 M5. E-mail [email protected]
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000074222.61572.44
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June 24, 2003
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surrogate marker of plaque activity and an improved method
of patient stratification and management.
MRI has the ability to discriminate between the different
stages of thrombus and hemorrhage formation. In the acute/
subacute phase, formation of methemoglobin results in shortening of T1, producing an increase in signal on a T1-weighted
sequence. We have used such a sequence to detect acute/subacute thrombus in a number of clinical settings, including
lower limb deep vein thrombosis6 and pulmonary embolus.7
In addition, we have also applied this technique in the setting
of acute cerebral infarction for the detection of intraplaque
hemorrhage.8 Imaging of the carotid bifurcations of patients
who had suffered an acute (⬍24 hours) stroke demonstrated
that 69% had high signal material within the carotid vessel
wall ipsilateral to the hemisphere of their cerebral infarct. Of
these, 45% had a stenosis ⬍50%. This therefore suggested an
association between the presence of high-signal material,
presumed to be methemoglobin from recent plaque hemorrhage (ie, complicated plaque), and cerebral infarction, even
in the absence of significant stenosis. To assess this further,
direct comparison between the imaging findings and the
pathophysiological process within the carotid vessel is
required.
A means of making this comparison is provided by the
histological examination of endarterectomy specimens after
in vivo magnetic resonance direct thrombus imaging
(MRDTI). The aim of this study, therefore, was to assess the
accuracy of MRDTI in identifying carotid complicated
plaque in vivo in patients suffering anterior cerebral circulation ischemia using histopathology as the “gold standard.” In
addition, the interobserver agreement for the detection of
carotid high signal using MRDTI was assessed.
Methods
Ethics committee approval and informed consent were obtained for
all patients entered into the trial. Between May 1998 and September
2001, 142 patients who were being assessed before carotid surgery
were considered for scanning. All were known to have significant
carotid stenosis (⬎70%) shown by ultrasound. Patients were recruited sequentially as dictated by availability of scanner time, which
was limited; patients were therefore not consecutive.
Imaging was performed on a 1.5-T scanner (Siemens) using a
receive-only quadrature neck array cervical spine coil. MRDTI used
a T1-weighted magnetization-prepared 3D gradient echo sequence
using a selective water excitation RF pulse (1:1 nonselective pulse),
acquired in the coronal plane (TR 10.3, TE 4.0, FA 15, TI 20, FOV
350⫻300 mm, matrix 256⫻140, 140 partitions, volume thickness
120 to 150 mm, 1 acquisition, bandwidth 195 Hz per pixel). The
number of partitions and TI were chosen such that the middle lines
of the k-space, ie, effective TI, occurred at a time to null blood. This
took into consideration the incomplete relaxation afforded by the
delay time of 1000 ms that was used. The resulting scan acquisition
was just over 5.5 minutes long. In the latter part of the study, no
delay time was used, reducing the scan time to 3.5 minutes with no
detrimental effects on image quality of the plaques.
The 3D MRI data set was viewed on the scanner workstation by
use of a multiplanar reconstruction package. A complicated plaque
was diagnosed if high-signal material was seen arising from the wall
of the carotid artery anywhere in the region of and 1 cm on either
side of the stenosis. High signal was defined as signal brighter than
that arising from the adjacent muscle.
After surgery, the carotid endarterectomy specimens were collected in 10% formal saline. After fixation, the specimens were
sectioned into blocks. The endarterectomy specimens were cut into
Figure 1. Recruitment of study population.
5-mm blocks, starting from the specimen base (the proximal or
common carotid end) and progressing distally toward the bifurcation
and beyond, until the whole length of the specimen had been cut.
Specimens were processed routinely for paraffin embedding. The
formalin-fixed, paraffin-embedded tissue blocks were serially sectioned at 4 ␮m onto slides and stored at room temperature until
viewed. The first section of each block was stained with Gill’s
hematoxylin and eosin 1%.
The specimen was viewed at ⫻4 to ⫻20 magnification, and
complicated (type VI) plaque was diagnosed if any of the following
features were observed in any of the specimens: free red blood cells
within the intima or media not associated with the blood vessel
lumen; organized lamellar plaque or luminal adherent thrombosis
(lines of Zahn, platelets, fibrin, red blood cells, and white blood
cells); hemosiderin-containing macrophages; or surface defects or
rupture. Specimens were defined as either complicated (type VI) or
noncomplicated.
Images judged to be nondiagnostic because of patient motion or
insufficient removal of fat signal were not included. Histopathological specimens that were grossly fragmented were excluded. The
sensitivity, specificity, and positive and negative predictive values
were calculated from the results of one reader (A.R.M.) experienced
in interpreting the MRDTI scans. The histology was used as the gold
standard. A single (highest) rating was used for each technique, and
no attempt was made to match MRI and histology on a slice-by-slice
basis.
Intraobserver and interobserver variability were calculated for the
first 40 patients. Interobserver calculation compared the results with
those of a second reader (R.E.M.) trained specifically for this project.
Intraobserver and interobserver agreement was calculated by use of
␬ statistics. All interpretations of the histological or MRI data were
performed in a blinded manner. Calculations were performed by use
of the Statistical Package for Social Sciences software (SPSS).
Results
Sixty-three patients, each with interpretable MRDTI and
histological specimens for comparison, were recruited (Figure 1). Of these, 30 were women. The average age was 69
years (range, 47 to 86 years). Thirty-one (49%) had suffered
Moody et al
Characterization of Plaque With Direct Thrombus MRI
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Figure 2. Accuracy of MRDTI compared with histological
grading.
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TIA alone, 7 (11%) amaurosis fugax alone, 6 (10%) both TIA
and amaurosis fugax, 2 (3%) had had retinal artery occlusions, and 17 (27%) had recovered from anterior circulation
strokes. The median time from the onset of first symptom to
scanning was 12 weeks (interquartile range, 8 to 20 weeks).
Of the 63 specimens, 44 plaques were defined histologically as complicated (type VI) and 19 as noncomplicated
(Figure 2). MRDTI demonstrated 16 true-negative (noncomplicated) lesions (Figure 3) and 37 true-positive (complicated) lesions (Figures 4 and 5), with 3 false-positive and 7
false-negative results. Of the 7 false-negative results, 2 had
cap rupture/fissuring alone, 3 samples were slightly fragmented, and 2 had luminal thrombus alone. The sensitivity
and specificity for MRDTI detecting complicated plaque was
84%, with a positive predictive value of 93% and negative
predictive value of 70%. The ␬ statistics for interobserver and
intraobserver agreement for MRDTI were 0.75 and 0.9,
respectively (substantial agreement).
Discussion
Summary of Findings
The aim of this study was to assess the accuracy of MRDTI
in identifying carotid complicated plaque in vivo in patients
with anterior cerebral circulation ischemia using histopathology as the gold standard. We have shown that MRDTI has
relatively high sensitivity (84%) and specificity (84%) for
identifying complicated plaque; high signal on MRDTI had a
positive predictive value of 93% for complicated plaque. In
addition, the interobserver and intraobserver agreements for
MRDTI were 0.75 and 0.9, respectively (substantial
agreement).
Discussion of Findings
This is the first in vivo human study of carotid atheromatous
disease in a symptomatic population aimed specifically at
detecting complicated plaque by detecting intraplaque hemorrhage by MRI. On the basis of the hypothesis that complicated plaque is commonly associated with histological evidence of plaque hemorrhage or thrombosis, we used an MRI
technique that exploits the T1-shortening properties of recent
thrombus to identify carotid thrombus and thus complicated
plaque. Application of a similar technique elsewhere in the
Figure 3. A, MRDTI appearances of noncomplicated carotid
plaque within right internal carotid artery (arrow). MRDTI demonstrates no areas of high signal. B, Histological specimen demonstrates uniform fibrous plaque with no evidence of
hemorrhage.
vascular system has shown the rapid formation of the T1shortening species in thrombus (within 8 hours) and its
persistence for a number of weeks once formed.9 The high
prevalence (40/63, or 64%) of MRDTI-defined complicated
plaque in this selected symptomatic group supports the
correlation between its presence and symptoms. This rate of
detection is similar to that seen in our previous work, in
which 69% of acute stroke patients demonstrated ipsilateral
carotid high signal on MRI scanning. A larger study of
prevalence in symptomatic and asymptomatic arteries is
needed to investigate this further. The longevity of intraplaque signal is not known and also requires further study
before this technique can be used as a marker of recent plaque
disruption. However, if the MRI high signal can be shown to
be limited to a finite time span, its presence could be used to
accurately identify recent plaque thrombosis or hemorrhage.
It is recognized that these events may occur in the absence of
stenosis, but no information regarding the relationship between stenosis and MRI high signal was obtained from this
study, because all recruited patients had, by trial entry
criteria, ⬎70% stenosis. By detecting complicated plaque
noninvasively, MRDTI offers the attractive potential of
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June 24, 2003
Figure 4. A and B, Focal area of highsignal material is seen on MRDTI
sequence within right carotid artery
(coronal [arrow]; axial [arrowheads]). C,
Correlation with endarterectomy specimen from same location identifies presence of intraplaque hemorrhage (arrow).
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studying both the natural history of plaque and its response to
interventions as well as identifying asymptomatic disease and
symptomatic disease in nonstenotic vessels.
The ease of scan interpretation is reflected in the high
interobserver agreement. Detection of complicated plaque is
therefore relatively straightforward, allowing application in
the research and clinical setting. Alternative imaging strategies require the measurement of stenosis or differentiation of
plaque contents to characterize carotid disease, all of which
are operator dependent; studies of interobserver variability
using these criteria have shown significant variation.10,11 We
have not attempted to assess the extent of intraplaque high
signal and its relationship to other plaque constituents such as
cholesterol pool, cap thickness, or neovessels, although the
interplay between each of these may have a significant role in
symptom development and plaque progression.
Strengths of the Present Study
This technique is easy to apply on most commercially
available scanners, requiring no additional hardware or software. Image acquisition is not operator dependent except for
the routine scan setup. Like other MRI techniques, it is
noninvasive, requires no ionizing radiation, and is quick to
perform (3.5 minutes). All these attributes led to improved
Figure 5. A and B, More extensive area
of intraplaque hemorrhage is demonstrated on coronal (arrow) and axial
(arrowheads) views. C, Intraplaque hemorrhage is seen on histological specimen
(arrow).
Moody et al
Characterization of Plaque With Direct Thrombus MRI
patient acceptability and ease of performing follow-up studies. Being a 3D acquisition, reconstruction allows multiplanar
visualization of vessel-wall disease and the potential for
segmentation of hemorrhage volume. As with other blackblood techniques,12 removal of high blood signal diminishes
flow artifacts that may cause image degradation. Because
disease detection does not depend on stenosis, disease overestimation by artifactual signal loss seen with magnetic
resonance angiography of flowing blood is not an issue. The
use of a water excitation pulse to remove fat signal has
recently been shown to be faster and to produce improved
image quality in comparison with other fat-removing
techniques13
Limitations of the Present Study
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This technique is reliant on the removal of high fat signal
normally seen on T1-weighted images. Failure of the water
excitation RF pulse to achieve this results in the high-signal
complex plaque being undetectable. We found that manual
shimming of the magnet at the beginning of the imaging
procedure resulted in the most consistent diagnostic images.
Although the overall scan acquisition time was short, movement, especially swallowing, could lead to nondiagnostic
scans because of motion artifacts, and this accounted for most
of the cases of uninterpretable MRI scans. Some of the
differences between MRI and pathology resulted from using
the broader histologically defined complicated (type VI)
plaque as the gold standard. A number of different features
that are invisible to the MRI technique described here were
used to define complicated plaque histologically. These
included the presence of hemosiderin-laden macrophages and
the presence of fibrous cap fissuring alone. In addition, the
makeup of intraluminal thrombus, with fewer trapped red
blood cells, may have different signal characteristics compared with a hemoglobin-rich intraplaque hemorrhage.14 Despite these differences, we wished to test the usefulness of
this technique in a clinical setting, which required all types of
complicated plaque to be included. As a result, 2 falsenegative studies were caused by plaque erosion/rupture alone;
2 were caused by intraluminal thrombus alone; and 3 were in
slightly fragmented specimens, which could have resulted in
perioperative hemorrhage. Furthermore, the time delay between the patients’ first symptoms and scanning may also
have led to some loss of high signal on MRI. Despite
strenuous attempts to avoid perioperative and postoperative
alteration in the surgical specimens, loss of superficial plaque
thrombus could have occurred during postoperative handling,
producing the 3 false-positive results seen in the study.
Relationship to Other Work
Lusby et al15 elegantly showed the high incidence of intraplaque hemorrhage in patients presenting with cerebral
ischemia. The same authors also demonstrated the role of
acute hemorrhage in rapid stenotic progression, even to
occlusion, which was potentially reversible. Histological
examination of these specimens did not necessarily show
endothelial disruption, even in association with surface intraluminal thrombus. This observation has led some to
hypothesize that intimal neovessels play a significant role in
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the triggering of acute atherosclerotic events16 by the production of intraplaque hemorrhage.
The majority of previous work using MRI for the investigation of vessel-wall disease has concentrated on T2-weighted
sequences. When T1-weighted sequences were used, it was
with the aim of visualizing plaque lipid. These were initially
studies of specimens in in vitro17 or in vivo18 animal experiments at low and high field strengths.19 –21 In 1996, Toussaint
et al22 applied similar techniques using standard clinical
scanner technology to visualize plaque morphology in vivo.
This again relied on T2 contrast generation and was able to
discriminate between the lipid core, fibrous cap, calcification,
normal media, and adventitia; intraplaque hemorrhage and
thrombus were also identified. Recent studies have used
multicontrast MRI to identify fibrous cap rupture, which is
also capable of stratifying plaque into complicated and
noncomplicated subtypes.23,24 Recent animal experiments
have also shown the ability of MRI to accurately identify and
age intraluminal14 thrombus and that arising from induced
plaque rupture.25
Implications and Future
In the future, dedicated surface coils for the imaging of the
carotid bifurcation will provide improved spatial resolution,26
allowing accurate correlation between the site of high signal
within the MR image and the histological specimen. An
alternative approach would be to re-image the endarterectomy specimens in vitro at higher field strength and for
prolonged imaging times to produce high-resolution images.
These images can then be “fitted” to the histological studies
by computer manipulation to allow more accurate identification of the short-T1 species within the specimen. Combination
with immunostaining for other constituents within the plaque,
such as matrix metalloproteins, tissue factor, fibrin, macrophages, and circulating markers of atheromatous plaque
activity,27 may also shed light on the pathophysiological
process within the plaque. Accepting that this technique does
identify complicated plaque, further study of these appearances and how they relate to the natural history of vessel wall
disease is needed. Importantly, this will determine the lifespan of the high signal and its relationship to plaque progression and symptoms. The results of this study should define
the clinical applications of this technique, its role as a marker
of vulnerable plaque, and its use as a surrogate marker of
disease progression or regression in clinical or therapeutic
trials.
Conclusions
In conclusion, 3D T1-weighted imaging of the carotid vessels
in patients with cerebral ischemia is an accurate means of
identifying histologically confirmed complicated plaque. The
high contrast generated by short-T1 species within the plaque
allows for ease of interpretation, making this technique highly
applicable in the research and clinical setting for the investigation of carotid atherosclerotic disease.
Acknowledgments
This work was supported by the Stroke Association of the United
Kingdom, grant No. TSA12/99. The authors thank the MRI radiog-
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June 24, 2003
raphers at Queen’s Medical Center; Avril Fearon, secretary to Alan
Moody; and the “one-stop” vascular clinic staff and secretaries.
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Characterization of Complicated Carotid Plaque With Magnetic Resonance Direct
Thrombus Imaging in Patients With Cerebral Ischemia
Alan R. Moody, Rachael E. Murphy, Paul S. Morgan, Anne L. Martel, G.S. Delay, Steve Allder,
Shane T. MacSweeney, William G. Tennant, John Gladman, John Lowe and Beverley J. Hunt
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Circulation. 2003;107:3047-3052; originally published online June 9, 2003;
doi: 10.1161/01.CIR.0000074222.61572.44
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2003 American Heart Association, Inc. All rights reserved.
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