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

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
Downloaded from http://stroke.ahajournals.org/ by guest on May 22, 2018

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 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 tech-
nique 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
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

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 stephen.davis@mh.org.au
© 2009 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.108.536888

1325
 1326 Stroke April 2009

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 homo-
geneous density of blood. A hemorrhage arising from multi-
ple foci is more likely to present an irregular lesion edge at its
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expanding interface with the brain. A heterogeneous CT

density might reflect active hemorrhage, more variable hem-
orrhagic time course, and multifocality. Heterogeneous
bleeds are potentially fed by multiple bleeding vessels result-
ing in patches of hypoattenuating liquid blood from very
recent bleeding alongside hyperattenuating thrombus. We
therefore hypothesized that irregular shape and density het-
erogeneity 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 hy-
pothesis 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 previ-
ously, 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 neuroradiolo-
gist.25 Volume data were not recalculated for this study. Intraven-
tricular 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 pro-
gressive 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 fea-
tures 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 het-
erogeneous, 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 con-
sensus 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 within-
rater 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 dichoto-
mized 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, nonpara-
metric 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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values with interquartile ranges (IQRs). Crosstabulations were ana-
lyzed 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 re-
gression was used to model the relationships between the inde-
pendent 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 contin-
uous variable were also performed using the general linear model.
Analyses were performed using SPSS Version 15.0 software
1327
Figure 2. A, Shape category and (B) density cate-
gory histograms for the most experienced rater
(neuroradiologist), although other raters’ category
frequencies were almost identical.
(SPSS Inc, Chicago, Ill) A probability value ⬍0.05 was consid-
ered 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-
 1328 Stroke April 2009
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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 base-
line 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
Figure 4. Proportions (%) of (A) regular/irregular and (B) homo-
geneous/heterogeneous hemorrhages for each tertile of baseline
volume. Between-group differences are statistically significant
(P⬍0.001).
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 under-
went 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 rela-
tionship 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 signif-
icant 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
Table. Proportions of ICH Growth for Heterogeneous/Homogeneous Density Bleeds and Irregular/
Regular-Shaped Bleeds Using Various Growth Definitions (Percentages in Parentheses)*
ICH Characteristic Continuous Scale
Density
Heterogeneous ...
Homogeneous ...
P value 0.046
Shape
Irregular ...
Regular ...
P value 0.159
*P values are from multivariate analysis after adjustment for baseline ICH volume and time to scan.
density using new, reliable measurement scales and statistical
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adjustment for known growth predictors, baseline volume,
and time to scan. We have demonstrated that large hemato-
mas are more irregular in shape, more heterogeneous in
density, and significantly more likely to expand when con-
sidered 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 mea-
sured 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 defini-
tions and requires further validation. Irregular shape was not
identified as an independent predictor of ICH growth regard-
less 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 angio-
graphic contrast enhancement and contrast extravasation, termed
the “spot sign,” have also been shown to predict ICH expan-
sion.13–15,29 These studies were based on poor prognosis associ-
ated 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 acti-
vated 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
Density and Shape in Intracerebral Hemorrhage Growth 1329
Growth Definition
Binary Definitions
Any Growth ⱖ33% or ⱖ12.5 mL ⬎1-mm Radial Growth
43/52 (82.7) 21/52 (40.4) 27/52 (51.9)
30/38 (78.9) 11/38 (28.9) 11/38 (28.9)
0.614 0.273 0.07
60/71 (84.5) 25/71 (35.2) 30/71 (42.3)
13/19 (68.4) 7/19 (36.8) 8/19 (42.1)
0.354 0.796 0.672
(orientation).33 To date, the examination of shape character-
istics 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, multi-
nodular to separated),28 and in an analysis of ICH growth
predictors in a small study of patients undergoing hemodial-
ysis (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. More-
over, 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 concep-
tualized 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
 1330 Stroke April 2009
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 hypoat-
tenuates on CT scans relative to surrounding brain or asso-
ciated organized hyperattenuating thrombus.38 As clots re-
tract, hypoattenuating serum is released.43 Later, as thrombi
progressively liquefy into breakdown products, sites of hem-
orrhage are less dense on CT. To a varying extent, hypoat-
tenuating 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–
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brain barrier disruption.44
The heterogeneous hematoma appearances of some ac-
tively 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 retrospec-
tively 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 predic-
tive 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 phenom-
ena 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 multi-
focal contrast enhancement.13 Multifocal bleeding, occa-
sionally 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 tis-
sue.48 –51 “Satellite” hemorrhages were accommodated in our
shape scale and were deemed to represent another hemor-
rhagic 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 hetero-
geneity, according to some growth definitions, was indepen-
dently 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 Re-
search 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.
References
1. Flaherty ML, Haverbusch M, Sekar P, Kissela B, Kleindorfer D,
Moomaw CJ, Sauerbeck L, Schneider A, Broderick JP, Woo D.
Long-term mortality after intracerebral hemorrhage. Neurology. 2006;66:
1182–1186.
2. Fogelholm R, Murros K, Rissanen A, Avikainen S. Long term survival
after primary intracerebral haemorrhage: a retrospective population based
study. J Neurol Neurosurg Psychiatry. 2005;76:1534 –1538.
3. Zahuranec DB, Brown DL, Lisabeth LD, Gonzales NR, Longwell PJ,
Smith MA, Garcia NM, Morgenstern LB. Early care limitations indepen-
dently predict mortality after intracerebral hemorrhage. Neurology. 2007;
68:1651–1657.
4. Becker KJ, Baxter AB, Cohen WA, Bybee HM, Tirschwell DL, Newell
DW, Winn HR, Longstreth WT Jr. Withdrawal of support in intracerebral
hemorrhage may lead to self-fulfilling prophecies. Neurology. 2001;56:
766 –772.
5. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA,
Begtrup K, Steiner T. Hematoma growth is a determinant of mortality and
poor outcome after intracerebral hemorrhage. Neurology. 2006;66:
1175–1181.
6. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN,
Skolnick BE, Steiner T. Recombinant activated factor VII for acute
intracerebral hemorrhage. N Engl J Med. 2005;352:777–785.
7. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN,
Skolnick BE, Steiner T. Efficacy and safety of recombinant activated
factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358:
2127–2137.
8. Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, Heeley
E, Skulina C, Parsons MW, Kim JS, Tao QL, Li YC, Jiang JD, Tai
 Barras et al Density and Shape in Intracerebral Hemorrhage Growth
LW, Zhang JL, Xu E, Cheng Y, Heritier S, Morgenstern LB, Chalmers
J. Intensive blood pressure reduction in acute cerebral haemorrhage
trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008;7:
391–399.
9. Priorities for clinical research in intracerebral hemorrhage: Report from a
National Institute of Neurological Disorders and Stroke workshop.
Stroke. 2005;36:e23– 41.
10. Stapf C, Van der Worp HB, Steiner T, Rinkel GJ, Nedeltchev K, Mast H,
Dichgans M, Cordonnier C, Arnold M, Al-Shahi R. Stroke research
priorities for the next decade-a supplement statement on intracranial
haemorrhage. Cerebrovasc Dis. 2007;23:318 –319; author reply
319 –320.
11. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of
intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day
mortality. Stroke. 1993;24:987–993.
12. Broderick JP, Diringer MN, Hill MD, Brun NC, Mayer SA, Steiner T,
Skolnick BE, Davis SM. Determinants of intracerebral hemorrhage
growth: an exploratory analysis. Stroke. 2007;38:1072–1075.
13. Wada R, Aviv RI, Fox AJ, Sahlas DJ, Gladstone DJ, Tomlinson G,
Symons SP. CT angiography ‘spot sign’ predicts hematoma expansion in
acute intracerebral hemorrhage. Stroke. 2007;38:1257–1262.
14. Goldstein JN, Fazen LE, Snider R, Schwab K, Greenberg SM, Smith EE,
Lev MH, Rosand J. Contrast extravasation on CT angiography predicts
Downloaded from http://stroke.ahajournals.org/ by guest on May 22, 2018
hematoma expansion in intracerebral hemorrhage. Neurology. 2007;68:
889 – 894.
15. Kim J, Smith A, Hemphill JC III, Smith WS, Lu Y, Dillon WP, Win-
termark M. Contrast extravasation on CT predicts mortality in primary
intracerebral hemorrhage. AJNR Am J Neuroradiol. 2008;29:520 –525.
16. Demchuk AM, Kosior J, Tymchuk S, Molina C, Dzialowski I, Boulanger
JM, Roy J, Gladstone D, Aviv R. Multicentre prospective study demon-
strates validity of CTA ‘spot sign’ for hematoma expansion prediction in
noncoagulopathic primary ICH patients [Abstract]. Cerebrovasc Dis.
2008;25(suppl 2):52.
17. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L,
Spilker J, Duldner J, Khoury J. Early hemorrhage growth in patients with
intracerebral hemorrhage. Stroke. 1997;28:1–5.
18. Portenoy RK, Lipton RB, Berger AR, Lesser ML, Lantos G. Intracerebral
haemorrhage: a model for the prediction of outcome. J Neurol Neurosurg
Psychiatry. 1987;50:976 –979.
19. Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular
blood is an important determinant of outcome in supratentorial intrace-
rebral hemorrhage. Crit Care Med. 1999;27:617– 621.
20. Helweg-Larsen S, Sommer W, Strange P, Lester J, Boysen G. Prognosis
for patients treated conservatively for spontaneous intracerebral
hematomas. Stroke. 1984;15:1045–1048.
21. Zazulia AR, Diringer MN, Derdeyn CP, Powers WJ. Progression of mass
effect after intracerebral hemorrhage. Stroke. 1999;30:1167–1173.
22. Diringer MN, Edwards DF, Zazulia AR. Hydrocephalus: a previously
unrecognized predictor of poor outcome from supratentorial intracerebral
hemorrhage. Stroke. 1998;29:1352–1357.
23. Hemphill JC III, Bonovich DC, Besmertis L, Manley GT, Johnston SC.
The ICH score: a simple, reliable grading scale for intracerebral hemor-
rhage. Stroke. 2001;32:891– 897.
24. Ruiz-Sandoval JL, Chiquete E, Romero-Vargas S, Padilla-Martinez JJ,
Gonzalez-Cornejo S. Grading scale for prediction of outcome in primary
intracerebral hemorrhages. Stroke. 2007;38:1641–1644.
25. Zimmerman RD, Maldjian JA, Brun NC, Horvath B, Skolnick BE.
Radiologic estimation of hematoma volume in intracerebral hemorrhage
trial by CT scan. AJNR Am J Neuroradiol. 2006;27:666 – 670.
26. Landis JR, Koch GG. The measurement of observer agreement for cate-
gorical data. Biometrics. 1977;33:159 –174.
27. Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuc-
carello M, Khoury J. The ABCs of measuring intracerebral hemorrhage
volumes. Stroke. 1996;27:1304 –1305.
28. Huttner HB, Steiner T, Hartmann M, Kohrmann M, Juettler E, Mueller S,
Wikner J, Meyding-Lamade U, Schramm P, Schwab S, Schellinger PD.
Comparison of ABC/2 estimation technique to computer-assisted plani-
metric analysis in warfarin-related intracerebral parenchymal hemor-
rhage. Stroke. 2006;37:404 – 408.
1331
29. Becker KJ, Baxter AB, Bybee HM, Tirschwell DL, Abouelsaad T, Cohen
WA. Extravasation of radiographic contrast is an independent predictor of
death in primary intracerebral hemorrhage. Stroke. 1999;30:2025–2032.
30. Kowada M, Yamaguchi K, Matsuoka S, Ito Z. Extravasation of angio-
graphic contrast material in hypertensive intracerebral hemorrhage.
J Neurosurg. 1972;36:471– 473.
31. Mizukami M, Araki G, Mihara H, Tomita T, Fujinaga R. Arterio-
graphically visualized extravasation in hypertensive intracerebral hemor-
rhage. Report of seven cases. Stroke. 1972;3:527–537.
32. Murai Y, Ikeda Y, Teramoto A, Tsuji Y. Magnetic resonance imaging-
documented extravasation as an indicator of acute hypertensive intrace-
rebral hemorrhage. J Neurosurg. 1998;88:650 – 655.
33. Crum W. Shape and texture. In: Tofts P, ed. Quantitative MRI of the
Brain—Measuring Changes Caused by Disease. West Sussex: John
Wiley and Sons Pty, Ltd; 2004:559 –579.
34. Fujii Y, Tanaka R, Takeuchi S, Koike T, Minakawa T, Sasaki O.
Hematoma enlargement in spontaneous intracerebral hemorrhage.
J Neurosurg. 1994;80:51–57.
35. Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate
analysis of predictors of hematoma enlargement in spontaneous intrace-
rebral hemorrhage. Stroke. 1998;29:1160 –1166.
36. Zhan RY, Tong Y, Shen JF, Lang E, Preul C, Hempelmann RG, Hugo
HH, Buhl R, Barth H, Klinge H, Mehdorn HM. Study of clinical features
of amyloid angiopathy hemorrhage and hypertensive intracerebral hem-
orrhage. J Zhejiang Univ Sci. 2004;5:1262–1269.
37. Miyahara K, Murata H, Abe H. Predictors of intracranial hematoma
enlargement in patients undergoing hemodialysis. Neurol Med Chir
(Tokyo). 2007;47:47–51; discussion 51–52.
38. New PF, Aronow S. Attenuation measurements of whole blood and blood
fractions in computed tomography. Radiology. 1976;121:635– 640.
39. Norman D, Price D, Boyd D, Fishman R, Newton TH. Quantitative
aspects of computed tomography of the blood and cerebrospinal fluid.
Radiology. 1977;123:335–338.
40. Pierce JN, Taber KH, Hayman LA. Acute intracranial hemorrhage sec-
ondary to thrombocytopenia: CT appearances unaffected by absence of
clot retraction. AJNR Am J Neuroradiol. 1994;15:213–215.
41. Ito H, Maeda M, Uehara T, Yamamoto S, Tamura M, Takashima T.
Attenuation values of chronic subdural haematoma and subdural effusion
in CT scans. Acta Neurochir (Wien). 1984;72:211–217.
42. Wolverson MK, Crepps LF, Sundaram M, Heiberg E, Vas WG, Shields
JB. Hyperdensity of recent hemorrhage at body computed tomography:
incidence and morphologic variation. Radiology. 1983;148:779 –784.
43. Zimmerman RA, Bilaniuk LT. Computed tomographic staging of
traumatic epidural bleeding. Radiology. 1982;144:809 – 812.
44. Hua Y, Keep RF, Hoff JT, Xi G. Brain injury after intracerebral hemor-
rhage: the role of thrombin and iron. Stroke. 2007;38:759 –762.
45. Helmer FA, Sukoff MH, Plaut MR. Angiographic extravasation of
contrast medium in an epidural hematoma. Case report. J Neurosurg.
1968;29:652– 654.
46. Greenberg J, Cohen WA, Cooper PR. The ‘hyperacute’ extraaxial intra-
cranial hematoma: computed tomographic findings and clinical signif-
icance. Neurosurgery. 1985;17:48 –56.
47. Al-Nakshabandi NA. The swirl sign. Radiology. 2001;218:433.
48. Zazulia AR, Diringer MN, Videen TO, Adams RE, Yundt K, Aiyagari V,
Grubb RL Jr, Powers WJ. Hypoperfusion without ischemia surrounding
acute intracerebral hemorrhage. J Cereb Blood Flow Metab. 2001;21:
804 – 810.
49. Mayer SA, Lignelli A, Fink ME, Kessler DB, Thomas CE, Swarup R,
Van Heertum RL. Perilesional blood flow and edema formation in
acute intracerebral hemorrhage: a SPECT study. Stroke. 1998;29:
1791–1798.
50. Butcher KS, Baird T, MacGregor L, Desmond P, Tress B, Davis S.
Perihematomal edema in primary intracerebral hemorrhage is plasma
derived. Stroke. 2004;35:1879 –1885.
51. Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S,
Spilker J, Tomsick TA, Duldner J, Broderick JP. Relative edema volume
is a predictor of outcome in patients with hyperacute spontaneous intra-
cerebral hemorrhage. Stroke. 2002;33:2636 –2641.
 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.
Diringer, Thorsten Steiner and Stephen M. Davis
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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