Density and Shape as CT Predictors of Intracerebral
Hemorrhage Growth
Christen D. Barras, MBBS, BMedSc; Brian M. Tress, MD, FRACR, FRCR;
Soren Christensen, MMedSc; Lachlan MacGregor, MBBS, MMedSc, MBiostat;
Marnie Collins, BCom, BSc; Patricia M. Desmond, MD, FRACR; Brett E. Skolnick, PhD;
Stephan A. Mayer, MD; Joseph P. Broderick, MD; Michael N. Diringer, MD; Thorsten Steiner, MD;
Stephen M. Davis, MD, FRCP(Edin), FRACP;
for the Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators
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Background and Purpose—Intracerebral hemorrhage (ICH) growth predicts mortality and functional outcome. We
hypothesized that irregular hematoma shape and density heterogeneity, reflecting active, multifocal bleeding or a
variable bleeding time course, would predict ICH growth.
Methods—Three raters examined baseline sub-3-hour CT brain scans of 90 patients in the placebo arm of a Phase IIb trial
of recombinant activated Factor VII in ICH. Each rater, blinded to growth data, independently applied novel 5-point
categorical scales of density and shape to randomly presented baseline CT images of ICH. Density and shape were
defined as either homogeneous/regular (Category 1 to 2) or heterogeneous/irregular (Category 3 to 5). Within- and
between-rater reliability was determined for these scales. Growth was assessed as a continuous variable and using 3
binary definitions: (1) any ICH growth; (2) ⱖ33% or ⱖ12.5 mL ICH growth; and (3) radial growth ⬎1 mm between
baseline and 24-hour CT scan. Patients were divided into tertiles of baseline ICH volume: “small” (0 to 10 mL),
“medium” (10 to 25 mL), and “large” (25 to 106 mL).
Results—Inter- and intrarater agreements for the novel scales exceeded 85% (⫾1 category). Median growth was
significantly higher in the large-volume group compared with the small group (P⬍0.001) and in heterogeneous
compared with homogeneous ICH (P⫽0.008). Median growth trended higher in irregular ICHs compared with regular
ICHs (P⫽0.084). Small ICHs were more regularly shaped (43%) than medium (17%) and large (3%) ICHs (P⬍0.001).
Small ICHs were more homogeneous (73%) compared with medium (37%) and large (17%) ICHs (P⬍0.001). Adjusting
for baseline ICH volume and time to scan, density heterogeneity, but not shape irregularity, independently predicted ICH
growth (P⫽0.046) on a continuous growth scale.
Conclusions—Large ICHs were significantly more irregular in shape, heterogeneous in density, and had greater growth.
Density heterogeneity independently predicted ICH growth using some definitions. (Stroke. 2009;40:1325-1331.)
Key Words: density 䡲 growth 䡲 intracerebral hemorrhage 䡲 recombinant activated factor VII
䡲 predictors 䡲 shape
I
VII administered within 4 hours of symptom onset.6,7 In
contrast, the clinical outcomes in these trials were discordant
and the positive results were not replicated in the second,
larger trial.6,7 Attenuated hematoma growth has also been
suggested in an acute blood pressure reduction trial.8 Hence,
hematoma growth is a key therapeutic target in ICH therapy.
The identification of techniques to predict ICH expansion has
been expressed as a research priority by the National Institute
of Neurological Disorders and Stroke9 and the European
Stroke Workshop.10
ntracerebral hemorrhage (ICH) is the most sinister stroke
subtype with a high early mortality.1,2 Despite this, there is
convincing evidence that aggressive care can bring about
meaningful recovery, even in the worst initial prognostic
groups.3,4 CT scanning remains the standard diagnostic technique for ICH. Hematoma growth occurs in ⬎70% of patients
on CT performed within 3 hours of symptom onset and
independently predicts mortality and functional outcome.5
Hemostatic therapy has been demonstrated to attenuate ICH
growth in 2 pivotal studies of recombinant activated Factor
Received September 8, 2008; accepted October 22, 2008.
From the Departments of Neurology (C.B., S.D.), Radiology (C.B., B.T., S.C., P.D.), and Clinical Epidemiology (L.M.), Royal Melbourne Hospital,
The University of Melbourne, Melbourne, Australia; the Department of Mathematics and Statistics (M.C.), The University of Melbourne, Melbourne,
Australia; Novo Nordisk, Inc (B.S.), Princeton, NJ; Columbia University (S.A.M.), New York, NY; the University of Cincinnati (J.B.), Cincinnati, Ohio;
Washington University School of Medicine (M.D.), St Louis, Mo; and the University of Heidelberg (T.S.), Heidelberg, Germany.
Correspondence to Stephen M. Davis, MD, FRCP(Edin), FRACP, Department of Neurology, Royal Melbourne Hospital, Grattan Street, Parkville,
Victoria 3050 Australia. E-mail [email protected]
© 2009 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.108.536888
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Larger baseline ICH volume and earlier time to scan
predict subsequent ICH expansion.11,12 The recently reported
CT angiographic “spot sign”13–15 is an important predictor of
ICH growth and is being prospectively verified.16 Other
imaging predictors of poor outcome include early ICH
expansion,17 intraventricular extension,18,19 midline shift,20,21
and hydrocephalus.22 Rating systems have been used that
incorporate clinical and radiological features of ICH into a
variety of prognostic scores.23,24
In addition to volume and location, appearances of ICH on
CT vary widely. Two major imaging characteristics that have
received little attention are lesion shape (irregular versus
regular) and clot density variation (homogeneous versus
heterogeneous). Conceptually, a hematoma arising from a
solitary focus will tend to present a more regular expanding
lesion edge, growing from one epicenter, with more homogeneous density of blood. A hemorrhage arising from multiple foci is more likely to present an irregular lesion edge at its
expanding interface with the brain. A heterogeneous CT
density might reflect active hemorrhage, more variable hemorrhagic time course, and multifocality. Heterogeneous
bleeds are potentially fed by multiple bleeding vessels resulting in patches of hypoattenuating liquid blood from very
recent bleeding alongside hyperattenuating thrombus. We
therefore hypothesized that irregular shape and density heterogeneity on baseline CT ICH appearance would predict
ICH growth. To measure these characteristics, we created 2
novel categorical scales aimed at developing a simple
imaging-based prognostic instrument. We evaluated this hypothesis on the placebo data set from the proof-of-concept
trial of recombinant activated Factor VII.6
Methods
The data set comprised the baseline CT brain scans of the placebo
group of the randomized, double-blind, placebo-controlled Phase IIb
trial of recombinant activated Factor VII for ICH, reported previously, in which CT scans were obtained within 3 hours of ictus.6 Of
the 96 patients in this group, 90 baseline CT scans were transferred
for analysis from Bioimaging Technologies, Newtown, Pa. Six
patients’ scans could not be analyzed at our center because of file
compatibility reasons. Baseline volume, volume change at 24 hours,
and time-to-scan data did not vary significantly from the complete
data set. Baseline volume and volume change at 24 hours for each
included patient were derived from the previously published data set
using the planimetric ICH volume calculations of one neuroradiologist.25 Volume data were not recalculated for this study. Intraventricular blood, when present, was not included in the volume
calculations. The dependent variable, ICH growth between baseline
and 24-hour CT scan, was prespecified to be examined continuously
and using 3 binary growth definitions: (1) any ICH growth; (2)
ⱖ33% or ⱖ12.5 mL ICH growth; and (3) radial growth ⬎1 mm (the
median radial expansion for the data set).
Blinded to growth and clinical data, 2 novel 5-point categorical
scales were created, reflecting the spectrum of appearance of ICH
shape and Hounsfield unit density variation (Figure 1A), to provide
an agreed visual representation of the terms “regular/irregular” and
“homogeneous/heterogeneous.” The 2 scales ranged from Category
1 (most regular shape and most homogeneous density) to Category 5
(most irregular shape and most heterogeneous density). Each progressive category added an extra lesion edge irregularity on the shape
scale or degree of density variation on the density scale. In cases of
“satellite” bleed(s), progressive irregularity and heterogeneity features could be joined or separate from the principal hemorrhage. If a
hematoma had more numerous lesion edge irregularities or more
Figure 1. A, Shape (left) and density (right) categorical scales
and (B) examples of homogeneous, regular ICH (left) and heterogeneous, irregular ICH (right).
heterogeneous density than represented on the scale, they were
assigned a Category 5 (maximum) rating. Intraventricular blood,
when present, was not included in these ratings.
Three raters independently reviewed the scans: a neuroradiologist
(B.T.), a stroke imaging fellow (C.B.), and a brain imaging scientist
(S.C.). An initial training session was conducted to facilitate consensus application of the scales using images external to the trial
data set. Each observer, blinded to growth and clinical data, then
independently applied these 2 scales to randomly presented axial
CT scan slices allocating the most representative category. Each
rater received the same randomization generated using MATLAB
Version 7.4.0 (The MathWorks Inc). In addition, a randomly selected
set of 10% of images was represented to the raters to allow withinrater reliability studies. Shape and density scores were analyzed
using the largest ICH slice (usually the central axial slice in the
vertical dimension) as determined by an automated calculation of
slice-by-slice pixel count for each ICH. For this calculation, slice
dimensions were those derived from the regions of interest created
using Analyze (Mayo Clinic) imaging analysis software by the trial
neuroradiologist for planimetric volume calculation.
For descriptive purposes, baseline volumes were divided into tertiles
labeled “small” (0 to 10 mL), “medium” (10 to 25 mL), and “large” (25
to 106 mL). Shape Categories 1 and 2 were labeled “regular” and
Categories 3 to 5 “irregular.” Density Categories 1 and 2 were labeled
“homogeneous” and Categories 3 to 5 “heterogeneous” (Figure 1B).
To enable analysis of any interactions between shape, density, and
time and their effect on ICH growth, times to scan were dichotomized into 2 periods, ⱕ90 minutes and ⬎90 minutes.
Statistical Analysis
Standard tests for normality were applied. Given that many of the
outcomes were not consistent with a normal distribution, nonparametric methods were used for 2-group (Mann–Whitney U test) and
multiple-group (Kruskal-Wallis test) comparisons citing median
Barras et al
Density and Shape in Intracerebral Hemorrhage Growth
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Figure 2. A, Shape category and (B) density category histograms for the most experienced rater
(neuroradiologist), although other raters’ category
frequencies were almost identical.
values with interquartile ranges (IQRs). Crosstabulations were analyzed using Fisher exact test. Within- and between-rater reliability
tests were analyzed using measures of raw agreement as well as
kappa statistics. Growth was examined as a continuous variable in
an analysis of covariance using a general linear model, after
cube-root transformation of the dependent variable, to fulfill
normality assumptions applied to residuals. Binary logistic regression was used to model the relationships between the independent variables (shape category and density category) and 3
binary growth definitions adjusting for known growth predictors,
baseline ICH volume, and time to scan. Interactions between
shape, density, and time and their effect on growth as a continuous variable were also performed using the general linear model.
Analyses were performed using SPSS Version 15.0 software
(SPSS Inc, Chicago, Ill) A probability value ⬍0.05 was considered statistically significant.
Results
Between-observer raw agreement across over 750 CT images
(approximately 8 axial CT slices per patient) exceeded 85%
(⫾1 category) for both shape and density scales. Average raw
within-observer agreement (⫾1 category) exceeded 90% for
both scales. Shape and density category distributions show a
predominance of high shape (median score 5) and density
(median score 3) ratings (Figure 2A–B). Weighted kappa
values (0.61) express “moderate” to “substantial” agree-
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Figure 4. Proportions (%) of (A) regular/irregular and (B) homogeneous/heterogeneous hemorrhages for each tertile of baseline
volume. Between-group differences are statistically significant
(P⬍0.001).
Figure 3. Box plots of ICH growth between baseline and
24-hour CT scan depict greater growth in (A) large versus small
baseline volume bleeds (P⬍0.001); (B) heterogeneous versus
homogeneous density bleeds (P⫽0.008); and (C) irregular versus
regular shaped bleeds (P⫽0.084).
ment.26 Baseline median ICH volume was 14 mL (IQR, 28
mL). Median volume change was 2.5 mL (IQR, 11.5 mL).
Median time to baseline scan was 1.75 hours (IQR, 0.63
hours) from ictus.
Median growth was significantly higher in the large baseline volume group (7.39 mL; IQR, 17.8) compared with the
small group (1.10 mL; IQR, 2.08; P⬍0.001; Figure 3A)
Median growth was higher in the heterogeneous than the
homogeneous group (5.07 mL; IQR, 18.01 versus 1.21 mL;
IQR 3.77; P⫽0.008; Figure 3B). There was a trend to higher
median growth in irregular ICHs (2.69 mL; IQR, 13.14)
compared with regular ICHs (1.32 mL; IQR, 4.51; P⫽0.084;
Figure 3C). Large ICHs were more irregularly shaped (97%)
than medium (83%) and small (57%) ICHs (P⬍0.001; Figure
4A). Similarly, large ICHs were more heterogeneous (83%)
compared with medium (63%) and small ICHs (17%;
P⬍0.001; Figure 4B).
In multivariate analysis, heterogeneous lesions underwent significantly greater mean growth, with growth
defined as a continuous variable, and after adjustment for
baseline ICH volume and time to scan (P⫽0.046). With a
binary radial growth definition, heterogeneous bleeds
showed a trend toward greater growth (P⫽0.07). Other
binary growth definitions showed no such association.
Irregular shape showed no significant independent relationship to growth (P⫽0.159, growth as a continuous
variable) regardless of growth model after adjustment for
baseline ICH volume and time to scan (Table).
There was a strong relationship between shape irregularity
and density heterogeneity. Irregularly shaped ICHs were more
likely to be rated as heterogeneous in density (P⬍0.001). After
dichotomizing times to scan into ⱕ90 minutes (n⫽28) and ⬎90
minutes (n⫽62) subgroups, there was no significant interaction
with either shape or density in their effect on volume change
using a continuous scale of growth. The association between
density heterogeneity and growth was consistent and significant at both time points. Although the effect of density
heterogeneity on growth appeared to diminish with time,
there was no significant difference in this effect between the
2 time categories.
Discussion
In this novel study, we have explored the prediction of acute
ICH growth by the assessment of hematoma shape and
Barras et al
Density and Shape in Intracerebral Hemorrhage Growth
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Table. Proportions of ICH Growth for Heterogeneous/Homogeneous Density Bleeds and Irregular/
Regular-Shaped Bleeds Using Various Growth Definitions (Percentages in Parentheses)*
Growth Definition
Binary Definitions
ICH Characteristic
Continuous Scale
Any Growth
ⱖ33% or ⱖ12.5 mL
⬎1-mm Radial Growth
Density
Heterogeneous
...
43/52 (82.7)
21/52 (40.4)
27/52 (51.9)
Homogeneous
...
30/38 (78.9)
11/38 (28.9)
11/38 (28.9)
0.046
0.614
0.273
0.07
P value
Shape
Irregular
...
60/71 (84.5)
25/71 (35.2)
30/71 (42.3)
Regular
...
13/19 (68.4)
7/19 (36.8)
8/19 (42.1)
P value
0.159
0.354
0.796
0.672
*P values are from multivariate analysis after adjustment for baseline ICH volume and time to scan.
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density using new, reliable measurement scales and statistical
adjustment for known growth predictors, baseline volume,
and time to scan. We have demonstrated that large hematomas are more irregular in shape, more heterogeneous in
density, and significantly more likely to expand when considered in isolation. These CT characteristics are consistent
features of larger hemorrhages and reflect the natural history
of the enlarging ICH. In a multivariate model, adjusting for
baseline volume and time to scan, we have shown that density
heterogeneity independently predicts ICH growth with
growth on a continuous scale.
Of the known ICH growth predictors, baseline volume is
easily calculated using the established ABC/2 technique27
with modification in the anticoagulated.28 However, precise
stroke onset time is frequently unknown, particularly in
wakeup strokes. This study suggests that without knowledge
of symptom onset time, ICH density heterogeneity, as measured by density Categories 3 to 5 on our novel visual scale,
may be the next best known growth predictor from baseline
noncontrast CT brain. Although our results indicate that
density heterogeneity on acute CT predicts ICH growth, this
association was not demonstrated across all growth definitions and requires further validation. Irregular shape was not
identified as an independent predictor of ICH growth regardless of the growth model used.
The identification of baseline CT predictors of ICH expansion
is an important goal with the potential to aid in selection of
patients for future hemostatic therapy, particularly when other
data may be limited or unavailable. In recent years, CT angiographic contrast enhancement and contrast extravasation, termed
the “spot sign,” have also been shown to predict ICH expansion.13–15,29 These studies were based on poor prognosis associated with contrast leakage on conventional angiography in ICH
identified over 30 years ago.30,31 Extravasation has also been
demonstrated on MRI with the use of gadolinium.32 In a study of
prognostic factors for growth using the full recombinant activated Factor VII trial data set, the only imaging factors identified
were the volume of baseline ICH and the time to scan.12
However, this analysis did not explore hematoma morphology.
Shape, strictly speaking, is a characteristic of form that
remains independent of object size (scale) and position
(orientation).33 To date, the examination of shape characteristics as a predictor of hemorrhage growth has been limited.
These have been qualitative and nonvalidated descriptors at
different times after ICH onset and using varying definitions
of ICH growth. The first attempted shape classification of
ICH, by Fujii et al, used 3 categories: “round, with round and
smooth margins”; “irregular, with irregular, multinodular
margins”; and “separated, with a fluid level in the cavity.”34
The authors then dichotomized shape into 2 categories and
reported irregular shape as being an independent predictor of
ICH growth in a multivariate analysis of 627 patients.35 Other
investigators have applied various shape definitions in studies
of amyloid and hypertensive bleeds (round, lobular, or
irregular),36 warfarin-related hemorrhages (round to ellipsoid
with smooth margins, irregular with frayed margins, multinodular to separated),28 and in an analysis of ICH growth
predictors in a small study of patients undergoing hemodialysis (round and irregular groups).37
In contrast, we used a scale that was validated by testing
within- and between-observer agreement, studied patients at
relatively homogeneous times after onset of symptoms, and
used standardized growth definitions. These scales are the
first attempt to visually categorize the spectrum of shape and
density variation in ICH morphology. Raw agreement values
in excess of 85% (⫾1 category) for within- and between-rater
reliability demonstrated the applicability of the scales.
Strengths of our study included the validation of these simple
visually based shape and density categorical scales. Moreover, multiple growth definitions have been used exploring
growth as a continuous variable and then as a range of binary
variables.12 We added radial growth, which can be conceptualized as the growth of a sphere of equivalent volume to the
ICH in question. This measure overcomes some of the
descriptive limitations of percentage and absolute growth. For
a given radial growth, a small baseline volume ICH will have
undergone large percentage but small absolute growth. In
contrast, a large baseline volume hematoma undergoing the
same extent of radial expansion would have small percentage
but large absolute growth. Although shape is independent of
size, in this study, limited to the axial plane, no attempt was
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made to standardize shape sizes so as not to separate the
methodology from routine clinical application.
Density of blood on CT in ICH is related to the age of the
blood, the time course and number of foci of the hemorrhage
as well as to hematocrit.38 – 41 One early CT study used basic
qualitative density assessments of hematomas in various body
regions, including some intracranial hemorrhages, to assess
the influence of density variation on bleeding evolution.42
The authors concluded that density reflected the time course
of bleeding. Liquid blood from active hemorrhage hypoattenuates on CT scans relative to surrounding brain or associated organized hyperattenuating thrombus.38 As clots retract, hypoattenuating serum is released.43 Later, as thrombi
progressively liquefy into breakdown products, sites of hemorrhage are less dense on CT. To a varying extent, hypoattenuating edematous changes in the perihematoma region
evolve due at least in part to red blood cell hemolysate
products such as thrombin and iron with associated blood–
brain barrier disruption.44
The heterogeneous hematoma appearances of some actively bleeding extradural hematomas, first described in the
1960s,45 correspond with operative findings46 and have been
termed the “swirl sign.”43,47 In these hyperacute hemorrhages,
a “swirl” of hypoattenuating liquid blood could sometimes be
seen to emanate from a bleeding dural vessel. Presumably
inspired by this extra-axial finding, this sign was retrospectively examined in ICH as one of many characteristics of an
ICH data set with a late median time to scan of 13 hours.15
This “swirl sign” was not found to be independently predictive of hematoma growth or mortality.15 In our 90 patient
sub-3-hour data set, we found that density heterogeneity
independently predicted ICH growth on a continuous scale.
Heterogeneous ICHs are also significantly more likely to be
large and irregularly shaped (P⬍0.001). Large and irregularly
shaped hemorrhages probably reflect multifocal bleeding in
many cases. Large hemorrhages are also more likely to
exhibit the contrast enhancement and extravasation phenomena shown by other investigators.13,14
Our finding that median growth was significantly greater in
lesions of heterogeneous density supports current hypotheses
regarding the pathophysiology of ICH growth. In particular,
our findings are consistent with the CT angiographic “spot
sign” that independently predicts ICH growth and that
showed significantly greater growth in ICHs with multifocal contrast enhancement.13 Multifocal bleeding, occasionally visualized as separate “satellite” hemorrhages and
potentially as prominent bulges at the edge of a hemorrhage
may rapidly evolve from secondary bleeding in congested,
progressively edematous, hypoperfused, perilesional tissue.48 –51 “Satellite” hemorrhages were accommodated in our
shape scale and were deemed to represent another hemorrhagic focus on the density scale. Hence, hematoma growth
might be predicted by an irregular hemorrhage shape or
lesional density heterogeneity, indicative of an active and
progressively multifocal bleeding process.
This study has several limitations. The sample size of 90
patients is small, although this data set is homogeneous with
regard to time to scan and study protocol. Our findings cannot
be extrapolated to ICH patient populations scanned beyond 3
hours. Analyses were limited to the axial plane. The shape
and density scales created, although inspired by the spectrum
of variation in ICH morphology, are arbitrary, and our
conclusions are restricted to the definitions we used. The fact
that at least 50% of patients received the maximal (Category
V) shape rating suggests that the shape scale may benefit
from adjustment to reflect a wider range of irregularity, and
this may provide a different result.
In conclusion, this study has demonstrated that irregular
shape and density heterogeneity may be considered part of
the natural history or “signatures” of the expanding ICH. Two
novel categorical scales have been developed and reliably
applied to a high-quality CT data set acquired within 3 hours
of ICH onset. Irregular shape was not identified as an
independent ICH growth predictor. However, density heterogeneity, according to some growth definitions, was independently predictive of ICH growth beyond known determinants
and awaits further validation in larger sub-3-hour CT data
sets and specific examination of its relationship to the “spot
sign”, functional status and mortality.
Acknowledgments
We acknowledge the NovoSeven investigators who contributed data
to the proof-of-concept trial. We thank Bioimaging Technologies,
Newtown, Pa, for their cooperation, in particular Blaine Horvath.
Sources of Funding
C.D.B. receives funding from the National Health and Medical Research Council, Australia, a CVL Pfizer Research Grant, and support
from the Royal Melbourne Hospital Neuroscience Foundation.
Disclosures
S.A.M. received research support from Novo Nordisk. J.P.B. and
M.N.D. received consulting fees from Novo Nordisk and S.A.M.,
S.M.D., and T.S. received consulting and lecture fees from Novo
Nordisk. B.E.S. is an employee of Novo Nordisk and holds stock in
the company.
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Density and Shape as CT Predictors of Intracerebral Hemorrhage Growth
Christen D. Barras, Brian M. Tress, Soren Christensen, Lachlan MacGregor, Marnie Collins,
Patricia M. Desmond, Brett E. Skolnick, Stephan A. Mayer, Joseph P. Broderick, Michael N.
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for the Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators
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Stroke. 2009;40:1325-1331; originally published online March 12, 2009;
doi: 10.1161/STROKEAHA.108.536888
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