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Gradient Echo Magnetic Resonance Imaging in the Prediction of Hemorrhagic vs Ischemic Stroke
A Need for the Consideration of the Extent of Leukoariosis
Dong-Eog Kim, MD;
Hee-Joon Bae, MD;
Seung-Hoon Lee, MD;
Ho Kim, PhD;
Byung-Woo Yoon, MD, PhD;
Jae-Kyu Roh, MD, PhD
Arch Neurol. 2002;59:425-429.
ABSTRACT
| |
Background Multifocal signal loss lesion (MSLL) on gradient echo magnetic resonance
imaging (GE-MRI) may reflect bleeding-prone microangiopathy. However, MSLLs
are also known to be associated with leukoariosis; leukoariosis is commonly
associated with occlusive-type vascular lesions.
Objective To determine whether MSLL on GE-MRI is significantly associated with
the type of stroke—intracerebral hemorrhagic (ICH) stroke more often
than an ischemic stroke (infarction)—regardless of the extent of leukoariosis.
Patients and Methods We studied 91 patients who had an acute stroke and were admitted to
the Department of Neurology, Seoul National University Hospital, Seoul, South
Korea, from March 1, 1997, to July 31, 1998. These patients underwent both
conventional MRI and GE-MRI. The GE-MRI was used to count MSLLs. We also counted
lacunae and classified leukoariosis (none or mild and advanced). Multiple
logistic regression analysis was used to test for MSLL–leukoariosis
interaction association with the type of stroke (ICH over infarction) and
to evaluate the relative contribution of an MSLL—adjusted for age, sex,
and lacunae—in discriminating the type of stroke.
Results The association between MSLL and ICH statistically significantly differed
by leukoariosis (P = .003 for MSLL–leukoariosis
interaction term). The MSLL count on GE-MRI was significantly associated with
the type of stroke (ICH over infarction; odds ratio, 2.46; 95% confidence
interval, 1.38-4.39) when leukoariosis was classified as none or mild. When
leukoariosis was classified as advanced, there was a decrease in the odds
ratio of MSLL to 0.99 (95% confidence interval, 0.94-1.04).
Conclusions Our findings indicate that MSLL on GE-MRI is a predictor of ICH vs infarction
in patients with no or mild leukoariosis, but not in patients with advanced
leukoariosis. Therefore, in the evaluation of GE-MRI for a bleeding-prone
microangiopathy, the extent of leukoariosis should be considered.
INTRODUCTION
MULTIFOCAL SIGNAL loss lesions (MSLLs) on T2*-weighted gradient echo
magnetic resonance imaging (GE-MRI) represent previous microbleedings,1-5
which may be a direct marker of increased vascular fragility in patients with
various types of small vessel disease.1, 4
Many researchers speculate that GE-MRI might enable the recognition of bleeding-prone
microangiopathy and the prediction of a patient's hemorrhagic risk. Thus,
it is also believed to be helpful in the selection of patients for different
types of secondary prevention of stroke.4, 6
However, the same type of small vessel disease can cause ischemic lesions
or leukoariosis as well as intracerebral hemorrhages (ICH).5, 7-9
Since MSLL reflects microangiopathy,1 it may
be associated with leukoariosis6, 10-11;
the latter is commonly associated with occlusive-type vascular lesions. Therefore,
in advanced leukoariosis, there is a possibility that GE-MRI might not predict
a patient's risk of ICH over an ischemic stroke (Figure 1). To confirm this, we tried to determine whether an MSLL
on a GE-MRI is significantly associated with the type of stroke—ICH
more than an ischemic stroke (infarction)—regardless of the extent of
leukoariosis.
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Figure 1. A 69-year-old woman with hypertension
had advanced leukoariosis (A) and numerous multifocal signal loss lesions
(black arrow) (B); an acute ischemic lesion of internal capsule (C, white
arrow) developed, which is found to overlap with the nearby multifocal signal
loss lesions (black arrow, part B).
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PATIENTS AND METHODS
PATIENT POPULATION
The cohort consisted of 116 consecutive patients who had an acute stroke
and were admitted to the Department of Neurology, Seoul National University
Hospital, from March 1, 1997, to July 31, 1998, and underwent both conventional
MRI and GE-MRI. After exclusion of 25 subjects, 91 patients (58 men, 33 women;
mean [SD] age, 64.3 [9.7] years; age range, 37-89 years) were included. Exclusionary
criteria were (1) patients who did not have relevant imaging findings that
explained the neurologic symptoms, (2) transient ischemic attack without progression
to completed stroke, and (3) strokes due to miscellaneous causes such as an
aneurysm, vasculitis, moyamoya disease, hematologic disorders, hypercoagulable
states, arteriovenous malformation, and venous sinus thrombosis.
CLINICAL EVALUATION
All patients underwent systematic investigations, including complete
blood cell count, blood chemistry studies, lipid profiles, coagulation abnormalities,
urinalysis, chest x-ray film, electrocardiogram, computed tomographic scan
(CT), MRI, and MR angiography. In selected patients, transthoracic and transesophageal
echocardiography, including a microbubble contrast test, transcranial Doppler,
and catheter angiography, were also performed.
The following cerebrovascular risk factors were recorded for all patients:
hypertension, diabetes mellitus (history of diabetes mellitus with or without
current treatment or fasting blood glucose levels >140 mg/dL [>7.8 mmol/L]),
smoking (current or ex-smoker who had quit smoking <5 years before admission),
abnormal cholesterol levels (<160 or >239 mg/dL [<4.14 or >6.21 mmol/L]),
history of stroke, and previous medications (antiplatelet agents or anticoagulants)
received. Hypertension was considered to be present if a subject had 2 or
more of the following conditions: (1) repeated blood pressure readings above
160/95 mm Hg at intervals of 1 week, (2) a history of hypertension and/or
use of antihypertensives, (3) findings of target organ damage including hypertensive
retinopathy on optical fundus examination or left ventricular hypertrophy
on electrocardiography or echocardiography. The potential stroke mechanisms
were determined according to the criteria of the Trial of Org 10172 in Acute
Stroke Treatment (TOAST).12 Locations of ICH
were classified as deep (thalamus and basal ganglia), lobar, or infratentorial.
MRI EVALUATION
All MRI studies were performed on a 1.5-T superconducting magnet (Signa;
GE Medical Systems, Milwaukee, Wis). The standardized MRI protocol consisted
of axial T2-weighted spin-echo (repetition time, 2500-4500 milliseconds; echo
time, 80-112 milliseconds; flip angle, 20°; slice thickness, 5 mm; and
gap width, 2 mm), axial T2*-weighted GE sequences (repetition time, 200-500
milliseconds; echo time, 15 milliseconds; flip angle, 20°; field of view,
220x170 mm; acquisition matrix size, 256x192 pixels; number of
excitations, 2; slice thickness, 1.4 mm; and gap width, 0.7 mm). Brain CT
scan and T2-weighted MRI were used to identify leukoariosis, ICH, and infarction.
Leukoaraiosis was classified as absent, punctate, early confluent, or confluent
abnormalities according to Fazekas et al.13
Then, the former 2 were defined as no or mild leukoariosis and the latter
2 as advanced leukoariosis. This dichotomization was performed on the basis
of previous study findings that showed that punctate foci cannot be attributed
unequivocally to brain ischemia and more extensive abnormalities reflect a
true ischemic process.14-16
Areas of parenchymal ischemic destruction with a diameter of less than 10
mm were termed "lacunae" and counted. The GE-MRI was used to count focal areas
of homogeneous round signal loss with a diameter of up to 5 mm (MSLLs, Figure 1), unless CT scanning showed that
these areas were calcifications. Anatomical locations for MSLLs and ICH were
recorded. An MR angiography or catheter angiography were used to document
intracranial large artery diseases, which were defined as more than 50% luminal
narrowings in the internal carotid artery, anterior cerebral artery, middle
cerebral artery, posterior cerebral artery, basilar artery, or vertebral artery.
All radiographic scans were reviewed by 2 neurologists (H.-J.B. and S.-H.L.),
whose consensus determined the MRI findings. The reviewers were blinded to
clinical and demographic data.
STATISTICAL ANALYSIS
First, to determine the relationship with the extent of leukoariosis,
the number of MSLLs and lacunae of patients with advanced leukoariosis (early
confluent or confluent) were compared with those of patients with no or mild
leukoariosis (absent or punctate). Second, we divided the 91 patients into
2 groups, depending on whether they had an ICH or infarction. Various variables
(demographic, MRI, and risk factors) were compared between the ICH group and
the infarction group. The Mann-Whitney test was used for comparison of continuous
variables between the groups.  2 Analysis was used to compare
proportions between groups. Third, the ICH and infarction groups were further
subdivided into the no or mild group or the advanced leukoariosis group. The
MSLL counts were compared between the ICH and infarction groups in each of
the subdivided leukoariosis groups. We also tested for statistical significance
of the interaction between MSLLs and leukoariosis in predicting the type of
stroke (ICH over infarction) using a logistic model. Finally, in both leukoariosis
groups, multiple logistic regression analysis was used to evaluate the relative
contribution of MSLL—adjusted for age, sex, and lacunae—in discriminating
between an ICH and an infarction. Age, MSLL(s), and the numbers of lacunae
were used as continuous variables; sex was analyzed as a dummy variable.
Statistical significance was set at P<.05.
The Statistical Package of Social Sciences (Version 8.0; SPSS, Chicago, Ill)
was used for data analysis. All values are given as the mean (SD).
RESULTS
As shown in Figure 2A, the
number of MSLLs and lacunae were significantly higher (P = .00, Mann-Whitney test) in 30 patients with advanced leukoariosis
(5.0 [6.9] MSLLs and 18.5 [10.7] lacunae) than in 61 patients with no or mild
leukoariosis (2.1 [2.0] MSLLs and 9.7 [3.3] lacunae).
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Figure 2. Box plots showing the median (horizontal
line inside the box) interquartile range (box) of the number of lacunae and
multifocal signal loss lesions (MSLLs). Values defined as outliers (>1.5 box-lengths
from the upper or lower edge of the box) are indicated by circles; extreme
cases with values more than 3 box-lengths, by squares. The whiskers (vertical
lines extending up and down from each box) show the largest and smallest observed
values that are not outliers or extremes. A, The number of MSLLs and lacunae
are lower in patients who had no or mild leukoariosis than in those patients
who had advanced leukoariosis. B, With no or mild leukoariosis, a significantly
higher MSLL count is observed in the group with intracereberal hemorrhagic
(ICH) stroke than in the group with infarction. This is not the case when
leukoariosis is advanced. N indicates the number of patients.
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Table 1 data show that the
ICH group (n = 33) and the infarction group (n = 58) did not differ for age,
sex, and stroke risk factors including hypertension, diabetes mellitus, smoking,
abnormal cholesterol levels, history of stroke, and previous use of antiplatelet
agents or anticoagulants. In addition, no significant difference was found
for the number of lacunae or patients with advanced leukoariosis. However,
the ICH group had a significantly higher MSLL number (8.9 [13.4]) than the
infarction group (3.9 [13.5]). Results of the TOAST classification were as
follows: small artery infarction (n = 22 patients), large artery infarction
(n = 19 patients), cardioembolism (n = 6 patients), or undetermined (n = 11
patients). Locations of ICH were deep (n = 21 patients), lobar (n = 8 patients),
or infratentorial (n = 4 patients).
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Table 1. Demographic, Magnetic Resonance Imaging (MRI) and Angiography,
and the Risk Factor Variables of Patients With Ischemic Infarction and Intracerebral
Hemorrhagic (ICH) Strokes*
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After the subdivision of both groups, when leukoariosis was advanced,
the significance of the difference of MSLL number between the ICH (n = 13)
and infarction (n = 17) groups disappeared (P = .70).
However, the significance remained when the leukoariosis was classified as
none or mild (ICH group, n = 20; infarction group, n = 41; P = .00, Mann-Whitney test; Figure
2B). Logistic analysis showed that the association between MSLL
and ICH significantly differed by the extent of leukoariosis (P = .003 for MSLL–leukoariosis interaction term). The number
of MSLLs on GE-MRI was significantly associated with the type of stroke (ICH
over infarction; odds ratio [OR], 2.46; 95% confidence interval [CI], 1.38-4.39)
when leukoariosis was classified as none or mild (Table 2). When leukoariosis was advanced, MSLL on GE-MRI was not
a predictor of ICH or infarction (OR, 0.99; 95% CI, 0.94-1.04).
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Table 2. Logistic Regression Analysis of Stroke Type (Intracerebral
Hemorrhage vs Ischemic Infarction) When Leukoariosis Is Classified as None
or Mild*
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There was no significant difference in the previous medications between
groups that could predispose to bleeding. In the no or mild leukoariosis group,
3 of 7 patients who had used antiplatelet agents had ICH. All 3 patients with
ICH also had MSLLs, but the remaining 4 patients with an infarction did not.
In the advanced leukoariosis group, 2 patients had taken antiplatelet agents
and they presented with ICH. One of them had MSLLs; the other did not. Only
1 patient had used warfarin sodium therapy; the patient had no or mild leukoariosis
and presented with an infarction. As given in Table 3, locations for MSLLs and ICH did not differ significantly
between the 2 leukoariosis groups. Although there were more lobar ICHs in
the no or mild leukoariosis group (n = 6) than in the advanced leukoariosis
group (n = 2), the frequencies were similar (6 of 61 patients and 2 of 30
patients, respectively). In both groups, a few patients with lobar ICH had
more than 4 MSLLs with a lobar location only (n = 2 and n = 1, respectively).
In the advanced leukoariosis group, most of those with large or small artery
infarctions had MSLLs, which was contrary to the GE-MRI findings of absent
MSLLs in those who had infarction in the no or mild leukoariosis group. Together,
these indicate that when leukoariosis is advanced, MSLLs are associated with
ICH as well as infarctions.
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Table 3. Locations for Multifocal Signal Loss Lesions (MSLLs)*
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COMMENT
There is a growing consensus that GE-MRI may enable the recognition
of bleeding-prone microangiopathy, which has a clinical impact because a group
of individuals at high risk of ICH, both spontaneously and following anticoagulation
therapy, are expected to be identifiable.4, 6, 17
Our results showed that the ICH and the infarction groups differed for the
MSLL count only, providing evidence for the possible clinical usefulness of
GE-MRI.
However, it was recently indicated that MSLL did not discriminate between
major hemorrhagic or multiple lacunar stroke.17
Also, considering the close link between both ICH and ischemic injury with
leukoariosis,8-9,18-21
and the increasing MSLL numbers with advanced leukoraiosis6, 10-11
as shown by our results, there remains a case for determining whether GE-MRI
can be used for identifying patients at high risk of ICH in the presence of
advanced leukoariosis. Our study revealed that, when patients have no or mild
leukoariosis, 1 increment of the MSLL count approximately doubled the risk
of ICH over infarction (adjusted OR = 2.46). On the contrary, MSLLs on GE-MRI
was not a predictor of ICH vs infarction in patients with advanced leukoariosis.
These results were unchanged when we performed statistical analysis after
excluding patients with strokes of mechanisms other than small vessel disease
(data not shown). We believe that in the evaluation of GE-MRI for a bleeding-prone
microangiopathy, the extent of leukoariosis should always be considered.
Why did the GE-MRI lose discriminating power between ICH and infarction
in those patients with advanced leukoariosis? In the advanced leukoariosis
group most of those with large or small artery infarctions had MSLLs, which
formed a striking contrast to the GE-MRI findings of absent MSLLs in those
with infarction in the no or mild leukoariosis group. When one considers the
higher numbers of both lacunae and MSLLs in patients with advanced leukoariosis
than in those patients with no or mild leukoariosis, it is probably the case
that arteriosclerotic changes related to long-standing exposure to stroke
risk factors as the shared causative basis8
may have resulted in both occlusion and rupture.5, 22-23
For example, the cerebral complications of patients with hypertension may
vary; either rupture or occlusion of the diseased small artery may result
in parenchymal hemorrhage, lacunar infarction, or widespread leukoariosis
depending on the circumstances.3, 7-8,23
In support of these, pathologic changes in ICH such as lipohyalinosis,7 microaneurysms,15 and
fibrinoid degeneration24 have also been found
in subjects with chronic hypertension, lacunae, and leukoariosis.9 Clinically silent ischemic lesions as well as previous
hemorrhages are a common finding on the MRIs of patients with primary intracerebral
hematoma.1 Prior ischemic infarction was also
reported to be one of the risk factors for intracerebral hemorrhage.4, 8-9,25 Moreover,
some have argued26-27 and supported5 that ICH requires an underlying ischemic lesion to
set the chain of hemorrhagic events in motion.
Several considerations must be given to our study. First, although consecutively
collected, the hospital-based stroke cases of relatively small sample size
in this study may not be representative of the total patient population. Although
the distribution pattern of ICH and infarction subtypes in this study were
similar to those of previous reports,28-30
the relatively small number of patients with ICH in the advanced leukoariosis
group still remains as a weak point. Second, we did not exclude patients with
territorial infarctions or lobar hemorrhages, and this nonhomogeneity of subjects
may have altered our results in some way. However, we believe that the study
group is closer to and more representative of the actual clinical situation,
in which patients with small artery disease are not free from ICH or infarction
due to large artery disease4, 30
or cerebral amyloid angiopathy.4, 8, 31
Except for 4 cases, large artery disease was preponderantly observed in the
infarction group, which is consistent with the findings of previous reports.30 The MSLL can represent underlying amyloid angiopathy
in cases of lobar ICH,2 but the frequencies
of lobar ICH in the no or mild leukoariosis group were similar to those seen
in the advanced leukoariosis group. In addition, there were only a few patients
with lobar ICH who had MSLLs with a lobar location only. Therefore, exclusion
of these patients would not have affected our study results. Third, in the
no or mild leukoariosis group, 3 of 7 patients who had used antiplatelet agents
had ICH. All 3 with ICH had MSLLs, but the remaining 4 patients with infarctions
did not. This suggests that "in a properly selected group" there exist potential
clinical roles for GE-MRI in the prediction of hemorrhagic complications of
a therapy.
CONCLUSIONS
The number of MSLLs on GE-MRI is a predictor of ICH vs infarction in
patients with no or mild leukoariosis, but not in those with advanced leukoariosis.
A GE-MRI, if used alone to decide on different types of secondary prevention
for stroke, without consideration of the extent of leukoariosis, may act as
a "double-edged sword" affording a prediction of hemorrhagic complications
at the no or mild leukoariosis classification and raising the possibility
of relapsing ischemic stroke in the case of advanced leukoariosis.
AUTHOR INFORMATION
Accepted for publication November 6, 2001.
Author contributions: Study
concept and design (Drs D.-E. Kim, Bae, Lee, H. Kim, and Roh); acquisition of data (Drs Bae, Lee, and Yoon); analysis and interpretation of data (Drs D.-E. Kim and H. Kim); drafting of the manuscript (Drs Bae, Lee, and Yoo); critical revision of the manuscript for important intellectual
content (Drs D.-E. Kim, H. Kim, and Roh); statistical
expertise (Dr H. Kim); administrative, technical,
and material support (Dr D.-E. Kim); study supervision (Drs Yoon and Roh).
This study was presented as a poster at the 26th International Stroke
Conference, Fort Lauderdale, Fla, February 14, 2001.
We thank Dr Yun-Young Lee, MD, and John Roberts, PhD, for their helpful
suggestions.
Corresponding author and reprints: Jae-Kyu Roh, MD, PhD, Department
of Neurology, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu,
Seoul 110-744, South Korea (e-mail: rohjk{at}snu.ac.kr).
From the Department of Neurology, Seoul National University College
of Medicine (Drs D.-E. Kim, Lee, Yoon, and Roh), Department of Neurology,
Eulji General Hospital, Eulji University School of Medicine (Dr Bae), and
the Department of Epidemiology and Biostatistics, School of Public Health,
Seoul National University (Dr H. Kim), Seoul, South Korea.
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Clinical and Radiologic Differences Between Primary Intracerebral Hemorrhage With and Without Microbleeds on Gradient-Echo Magnetic Resonance Images
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Arch Neurol 2004;61:905-909.
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Frequency of Asymptomatic Microbleeds on T2*-Weighted MR Images of Patients with Recurrent Stroke: Association with Combination of Stroke Subtypes and Leukoaraiosis
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Am. J. Neuroradiol. 2004;25:714-719.
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Comparative analysis of the spatial distribution and severity of cerebral microbleeds and old lacunes
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J. Neurol. Neurosurg. Psychiatry 2004;75:423-427.
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Thalamic Lesions in Vascular Dementia: Low Sensitivity of Fluid-Attenuated Inversion Recovery (FLAIR) Imaging
Bastos Leite et al.
Stroke 2004;35:415-419.
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Cerebral microbleeds are regionally associated with intracerebral hemorrhage
Lee et al.
Neurology 2004;62:72-76.
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Cerebral Cavernous Malformations With Dynamic and Progressive Course: Correlation Study With Vascular Endothelial Growth Factor
Jung et al.
Arch Neurol 2003;60:1613-1618.
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Low Concentration of Serum Total Cholesterol Is Associated With Multifocal Signal Loss Lesions on Gradient-Echo Magnetic Resonance Imaging: Analysis of Risk Factors for Multifocal Signal Loss Lesions
Lee et al.
Stroke 2002;33:2845-2849.
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