Fazekas

Gudrun Roob, Anita Lechner, Reinhold Schmidt, Erich Flooh, Hans-Peter Hartung and Franz
Hemorrhage
Frequency and Location of Microbleeds in Patients With Primary Intracerebral
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Stroke
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2000;31:2665-2669 Stroke.
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Frequency and Location of Microbleeds in Patients With
Primary Intracerebral Hemorrhage
Gudrun Roob, MD; Anita Lechner, MD; Reinhold Schmidt, MD; Erich Flooh, MSc;
Hans-Peter Hartung, MD; Franz Fazekas, MD
Background and PurposeMRI is known to detect clinically silent microbleeds (MBs) in patients with primary
intracerebral hemorrhage (pICH), but the frequency and diagnostic and clinical significance of this finding are still
debated. Therefore, we investigated a consecutive series of pICH patients and analyzed the patterns of MB distribution
in the context of clinical variables and location of the symptomatic hematoma.
MethodsThe study population consisted of 109 patients with pICH. There were 59 women and 50 men aged 22 to 91
years (mean 64.6 years). MRI was obtained on a 1.5-T system with use of a gradient-echo T2*-weighted sequence. A
cohort of 280 community-dwelling asymptomatic elderly individuals who underwent the same imaging protocol served
for comparison.
ResultsMBs were seen in 59 (54%) patients and ranged in number from 1 to 90 lesions (mean 14, median 6). In the
majority of patients, MBs were located simultaneously in various parts of the brain, with a preference for
cortical-subcortical regions (39%) and the basal ganglia/thalami (38%). There was some tendency toward a regional
association between MB location and the site of the symptomatic hematoma, but we could not discern specific patterns
of MB distribution. Logistic regression analysis identified MBs, periventricular hyperintensity grades, and lacunes but
not risk factors as independent variables contributing to a correct classification of pICH and control individuals.
ConclusionsMBs can be detected in more than half of the patients with pICH and appear to be quite general markers
of various types of bleeding-prone microangiopathy. (Stroke. 2000;31:2665-2669.)
Key Words: etiology

hemosiderin

intracerebral hemorrhage

magnetic resonance imaging

microcirculation
M
agnetic resonance imaging (MRI) has the potential to
reveal residues of intracerebral bleeding throughout
life because of its high sensitivity for iron-containing com-
pounds. At the site of intracerebral hemorrhage (ICH),
hemosiderin remains stored in macrophages and leads to
focal dephasing of the MRI signal. This causes areas of past
bleeding to appear dark on T2-weighted images. Gradient-
echo techniques with high sensitivity for differences in
magnetic susceptibility enhance these effects of hemosider-
in.
1
Previous studies have called attention to the frequent
observation of small areas of signal loss in patients with
primary ICH (pICH), which were suggested to represent
residues of earlier clinically silent microbleeds (MBs).
2,3
Subsequently, this assumption was supported by correlative
histopathologic data, which confirmed perivascular hemosid-
erin deposition around angiopathic arterioles as the predom-
inant cause for such a finding.
4,5
The association with
small-vessel diseases explains that MBs were also reported in
patients with cerebral ischemic damage
5,6
and even in a small
proportion of asymptomatic elderly individuals.
7
However,
the clinical and diagnostic significance of this finding is not
yet fully understood.
In patients with pICH, the reported frequency of earlier
MBs ranges from 17% to 80%.
8
These large differences are
probably a consequence of small patient groups examined,
differences in patient selection, and the inconsistent use of
either conventional spin-echo or gradient-echo MR tech-
niques or both.
8
Although hypertensive microangiopathy
appears to be their prevailing cause, MBs have also been
strongly associated with the presence of cerebral amyloid
angiopathy.
9
In this context, a cortical-subcortical appearance
of MBs has been suggested to be an almost pathognomonic
finding.
3
On the basis of this assumption, it could be
speculated that certain patterns in the distribution of MBs
may serve to indicate different types of microangiopathy. The
amount of predictive information contained in the detection
of MBs and possible concerns regarding the use of antico-
agulants in such patients have also been debated.
We attempted to provide further information on these
aspects by performing a detailed analysis of the frequency
and distribution patterns of MBs in the context of clinical
variables and hematoma location in a large consecutive series
of patients with pICH. We also performed a comparison with
Received June 9, 2000; final revision received July 3, 2000; accepted July 12, 2000.
From the Department of Neurology (G.R., A.L., R.S., E.F., H.-P.H., F.F.) and the MR Institute (A.L., R.S., F.F.), Karl-Franzens University, Graz,
Austria.
Correspondence to Franz Fazekas, MD, Department of Neurology, Karl-Franzens University, Auenbruggerplatz 22, A-8036 Graz, Austria. E-mail
franz.fazekas@kfunigraz.ac.at
2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
2665
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findings in a community-dwelling cohort of asymptomatic
elderly individuals, and a logistic regression analysis was
carried out to define the contribution of MBs to the correct
identification of pICH patients.
Subjects and Methods
The study population consisted of 109 patients with a final diagnosis
of pICH from consecutive referrals to MRI by the neurology
department of a university hospital. This included all patients
admitted with intracerebral bleeding who were able to undergo such
an examination. pICH was defined as spontaneous nontraumatic
intracerebral bleeding without evidence of any kind of vascular
malformation or a brain tumor as the source of the hematoma. The
patients ages ranged from 22 to 91 years (mean 64.9 years); there
were 59 women and 50 men. Other demographic and clinical
variables are shown in Table 1. Hypertension was diagnosed in the
case of a past history of increased blood pressure or if the blood
pressure recordings continued to repeatedly exceed 160/95 mm Hg
past the second week after the ICH. Diabetes mellitus was defined by
fasting blood sugar 140 mg% or previous treatment. Twenty-four
patients had suffered from a previous stroke, which was reportedly
hemorrhagic in 9 patients.
MRI was performed on a 1.5-T superconducting magnet. The
imaging protocol consisted of conventional spin-echo mixed inten-
sity and T2-weighted (repetition time [TR]/echo time [TE] 2300 to
2600/20 to 90 ms) or fast spin-echo T2-weighted (TR 29 900 ms, TE
120 ms) and cerebrospinal fluidsuppressed T2-weighted (fluid-
attenuated inversion recovery; TE 130 ms, TR 6000 ms, and
inversion time 1900 ms) scans, a T1-weighted (TR/TE 600/15 ms)
sequence, and a gradient-echo T2*-weighted (TR/TE 600 to 800/16
to 20 ms, flip angle 20 to 25) imaging series. Slice thickness was
uniformly 5 mm, and the interslice gap was 10%. All scans were
reviewed by an experienced investigator who recorded the size and
location of the clinically symptomatic hematoma and the presence of
additional parenchymal abnormalities unaware of the patients clin-
ical data. Symptomatic hematomas were grouped as (1) lobar,
involving the cortex and/or deep white matter regions, (2) basal
ganglionic/thalamic, or (3) infratentorial, involving the brain stem
and/or the cerebellum. In accordance with previous studies, MBs
were defined on gradient-echo T2*-weighted images as homoge-
neous rounded lesions with a diameter of 2 to 5 mm, and their
location and number in specific regions of the brain was recorded
(Figures 1 and 2).
2,4
Larger areas of signal loss were considered to
represent old hematomas. Hyperintensities of the deep and subcor-
tical white matter were specified and graded into absent, punctate,
early confluent, and confluent. Periventricular hyperintensities were
described as caps or lining, bands, or irregular extending into the
TABLE 1. Demographic, Clinical, and Morphological Variables
for Patients With pICH and Control Subjects
Variable pICH (N109) Controls (N280) P
Age, y (meanSD) 64.912.3 59.96.1 0.001*
Males, n (%) 50 (45.8) 149 (53.2) 0.19
Hypertension, n (%) 67 (61.5) 89 (31.8) 0.001
Diabetes, n (%) 15 (13.8) 13 (4.6) 0.002
White matter hyperintensity,
n (%)
Punctate 33 (30.3) 149 (53.2) 0.001
Early confluent 27 (24.8) 28 (10)
Confluent 31 (28.4) 11 (3.9)
Periventricular
hyperintensity, n (%)
Caps/lining 54 (49.5) 109 (38.9) 0.001
Bands 15 (13.8) 11 (3.9)
Irregular 27 (24.8) 0
Lacunae, n (%) 57 (52.3) 23 (8.2) 0.001
Infarcts, n (%) 11 (10.1) 6 (2.1) 0.002
MBs, n (%) 59 (54.1) 18 (6.4) 0.001
Pearson
2
test was used for frequency comparisons.
*Student t test.
Figure 1. Patient (aged 78 years) with pICH in left thalamus
extending into basal ganglia. a and b, Fluid-attenuated inversion
recovery (TE 130 ms, TR 6000 ms, and inversion time 1900 ms)
images show site of bleeding, irregular periventricular hyperin-
tensity, and cribriform state of basal ganglia. c and d, Gradient-
echo T2*-weighted images (TR/TE 600/16 ms, ip angle 20)
reveal multiple foci of signal loss suggestive of old MBs within
the basal ganglia and less numerous foci in cortical-subcortical
regions (arrows).
Figure 2. Patient (aged 63 years) with subacute bleeding in
right parietal lobe. a, T1-weighted (TR/TE 600/15 ms) scan is
shown. b and c, Gradient-echo T2*-weighted images (TR/TE
600/16 ms, ip angle 20) show multiple cortical-subcortical foci
of signal loss around the hematoma (arrows). d, Two MBs are
also seen in basal ganglia (arrows).
2666 Stroke November 2000
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deep white matter.
10
Areas of ischemic parenchymal destruction, ie,
lesions exhibiting signal isointensity with cerebrospinal fluid in their
centers, were diagnosed as lacunes (10 mm in diameter) or infarcts.
A cohort of 280 asymptomatic elderly participants of the Austrian
Stroke Prevention Study (ASPS) who underwent the same imaging
protocol while our study group of pICH patients was being selected
served as a comparison. The rationale and design of the ASPS and
the MRI findings of this cohort have been published previously.
7,11
In short, MRI examinations with a gradient-echo T2*-weighted
sequence revealed that MBs may be found even in neurologically
normal elderly individuals. The clinical and imaging data of the
ASPS cohort that are relevant to the present study are summarized in
Table 1.
Statistical analysis was performed with the Statistical Package of
Social Sciences (SPSS, Inc). We used the Pearson
2
test to compare
the frequency distribution of categorical variables between groups.
Continuous variables were compared with the Student t test. A
logistic regression analysis was used to define those demographic,
clinical, and morphological variables that independently contributed
to a correct classification of individuals as pICH patients or controls.
Results
The clinically symptomatic hematoma was lobar in 43 (39%)
patients, it was located in the basal ganglia/thalami in 50
(46%) patients, and it involved the brain stem/cerebellum in
14 (13%) patients. Two patients had 1 acute bleeding at
different sites. MBs were seen in 59 (54%) of pICH patients,
and their number ranged from 1 to 90 lesions (mean 14,
median 6). Patients with MBs were significantly more often
hypertensive and more frequently had a previous stroke
history (Table 2). Patients with MBs had significantly higher
grades of deep white matter and periventricular hyperinten-
sities, and they more commonly showed lacunes and larger
areas of hemosiderin deposition from old hematomas (Table 3).
The majority of patients with MBs exhibited multiple
lesions, which were noted simultaneously in various parts of
the brain (Figures 1 and 2). MBs were observed in cortical-
subcortical regions in 43 patients, in the basal ganglia and
thalami in 41 patients, in the brain stem in 24 patients, in the
cerebellum in 23 patients, and in the deep white matter in 12
patients. Figure 3 shows the regional distribution of MBs
according to the site of the acute hematoma. As can be seen,
there was some tendency toward a higher frequency of MBs
in the basal ganglia and infratentorial region in patients with
basal ganglionic/thalamic bleeds compared with those pa-
tients with a lobar hematoma. However, these differences in
the distribution of MBs reached statistical significance only
for cerebellar MBs, which were seen in 1 of 43 patients with
a lobar bleed and in 17 of 33 patients with a symptomatic
hematoma in the basal ganglia or thalami (P0.001). In
parallel, patients with basal ganglionic/thalamic bleeds
showed a significantly greater mean number of MBs in the
basal ganglia (3.15.9 versus 0.951.9, P0.02) and in the
cerebellum (1.02.1 versus 0.020.15, P0.02) than did
individuals with a lobar pICH (Figures 1 and 2). No signifi-
cant differences between pICH subgroups were noted in
regard to the presence and number of MBs in cortical-
subcortical regions. We also did not find significant differ-
ences in the distribution of MBs related to the presence or
absence of hypertension. Among the 15 patients with MBs
and normal blood pressure, 12 (80%) showed MBs in
cortical-subcortical regions, and 8 (53%) had MBs in the
basal ganglia/thalami. MBs were seen in a cortical-
subcortical location in 31 (70%) of 44 patients with hyper-
tension and in the basal ganglia/thalami in 33 (75%) hyper-
tensive patients with MBs.
Comparison of the pICH study group with the cohort of
neurologically asymptomatic elderly individuals showed
highly significant differences in regard to almost all clinical
and morphological variables assessed (Table 1). Therefore,
we used logistic regression analysis to define those variables
that would best allow us to correctly separate pICH patients
and control subjects. Three variables emerged that indepen-
dently contributed to such classification. These variables
were the presence of MBs, the grade of periventricular
hyperintensity, and the number of lacunes (Table 4). No
clinical or demographic variable entered this model.
Discussion
We found evidence of old MBs in 54% of patients with pICH
by using gradient-echo T2*-weighted MRI. This frequency
corresponds closely to that of 57% recently reported by
Tanaka et al
5
in a smaller series of 30 patients. Earlier
investigations that have reported a smaller rate of MBs in
association with ICH have used conventional MRI sequences
in all or most of their patients.
2,12
Therefore, these lower
numbers most likely resulted from the inferior sensitivity of
conventional T2-weighted scans in the detection of small
hemosiderin deposits. A much higher detection rate of MBs
has recently been documented with the use of a gradient-echo
technique compared with conventional T2 sequences in a
direct comparison.
5
Greenberg et al
3
observed MBs in 80% of
TABLE 2. Demographic and Clinical Variables for pICH
Patients With and Without MBs
Variable
With MBs
(N59)
Without MBs
(N50) P
Age, y (meanSD) 6612 6313 0.13
Males, n (%) 32 (54.2) 27 (54) 0.6
Hypertension, n (%) 44 (74.6) 23 (46) 0.003
Diabetes, n (%) 8 (13.6) 7 (14) 0.6
Previous stroke, n (%) 18 (30.5) 8 (16) 0.04
TABLE 3. Concomitant Morphological Findings for pICH
Patients in Relation to Presence of MBs
Variable
With MBs
(N59)
Without MBs
(N50) P
White matter hyperintensity, n (%)
Punctate 14 (23.7) 19 (38) 0.001
Early confluent 14 (23.7) 13 (26)
Confluent 28 (47.5) 3 (6)
Periventricular hyperintensity, n (%)
Caps/lining 26 (44.1) 28 (56) 0.001
Bands 6 (10.2) 9 (18)
Irregular 25 (42.4) 2 (4)
Lacunae, n (%) 39 (66.1) 18 (36) 0.008
Infarcts, n (%) 9 (15.3) 2 (4) 0.2
Old hematoma, n (%) 24 (40.7) 5 (10) 0.001
Roob et al MRI Evidence of Microbleeds and ICH 2667
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their patients, but this sample was small and was composed
only of patients with lobar hemorrhage.
The overall number of MBs in individual patients in our
series was quite variable and ranged from 1 to 90 lesions.
Most frequently, MBs were seen in cortical-subcortical re-
gions or in the basal ganglia including the thalami. MBs in the
brain stem and cerebellum were less frequent, and the white
matter was relatively spared. Typically multiple MBs were
found scattered throughout the brain. Therefore, a separation
of patient subgroups based on a specific location of MBs was
impossible, and a grading of regional preferences from the
absolute number of MBs appeared problematic because of
differences in the size of the regions to compare (eg,
cortical-subcortical versus brain stem). Therefore, we decided
to compare the distribution of MBs between patients on the
basis of the site of the symptomatic hematoma. This analysis
revealed some correspondence between pICH location and
MB topography, as illustrated in Figure 3; ie, frequency and
number of MBs in the basal ganglia/thalami and the infrat-
entorial region were greater in patients with a pICH at these
sites than in patients with a lobar hematoma. However,
concerning cortical-subcortical MBs, no clear differences
emerged between pICH subgroups. Thus, we were unable to
confirm a specific pattern of MBs strongly suggestive of
cerebral amyloid angiopathy in this unselected series.
3
In this
context, the probably rather small number of patients with
cerebral amyloid angiopathy in our sample has to be consid-
ered. Moreover, histopathologic findings suggest a combina-
tion of cerebral amyloid angiopathy with hypertensive mi-
croangiopathy as the cause of a more widespread distribution
of MBs in some patients.
4
Interestingly, however, a prefer-
ential cortical-subcortical location of MBs was not even
found in the normotensive pICH patients of our study
population.
In line with previous studies,
2,5
we found highly significant
associations between the presence of MBs and other morpho-
logical signs of cerebral microangiopathy, such as lacunes
and extensive periventricular and deep white matter dam-
age,
13
and we confirmed hypertension as the single most
important clinical risk factor for the occurrence of MBs. A
significantly higher frequency of a preceding stroke in pa-
tients with MBs can be viewed as further clinical evidence of
a globally more pronounced vasculopathy of these patients.
Comparison with a cohort of normal elderly control subjects
showed the expected differences regarding a significantly
higher rate of hypertension and also of diabetes mellitus in
pICH patients. However, only MRI findings emerged as
independent discriminating variables in a logistic regression
model. These morphological variables were the presence of
MBs and the grade of periventricular hyperintensity and the
number of lacunes. CT studies have already associated
lacunes and leukoaraiosis with a higher risk of intracerebral
bleeding either spontaneously
14
or after anticoagulant thera-
py.
15
This analysis supports MBs as a further important
marker of bleeding-prone small-vessel diseases. In this con-
text, Greenberg et al
16
have recently shown the accumulation
of MBs over time on repeated MRI examination of a small
group of patients with intracerebral bleeding. Large-scale
prospective studies using gradient-echo T2*-weighted MRI
in elderly individuals are now needed to substantiate these
assumptions.
Figure 3. Frequency of MBs in different regions
of the brain in relation to site of symptomatic
hematoma (2 patients with 1 acute bleeding not
included).
TABLE 4. Logistic Regression Analysis: Significant and Independent
Discriminators Between pICH Patients and Control Subjects
Variable Regression Coefficient B Standard Error Wald P Exp (B)
MBs 1.634 0.371 19.384 0.000 5.124
PVH grade 1.275 0.231 30.389 0.000 3.580
No. of lacunes 0.958 0.314 9.322 0.002 2.608
PVH indicates periventricular hyperintensity grade.
2668 Stroke November 2000
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