Original Paper

Received: August 29, 2013

Accepted: November 19, 2013
Published online: February 13, 2014

Cerebrovasc Dis 2014;37:164170

DOI: 10.1159/000357397

Showing No Spot Sign Is a Strong

Predictor of Independent Living after
Intracerebral Haemorrhage
IngerHavsteen a,* ChristianOvesen b,* AndersF.Christensen a
ChristineKrarupHansen b JensKellbergNielsen a HanneChristensen b

Departments of a Radiology and b Neurology, Copenhagen University Hospital Bispebjerg and Copenhagen Stroke
Research Centre, Copenhagen, Denmark

Key Words
Spot sign Intracerebral haemorrhage Outcome
Computed tomography angiography

Abstract
Background: A spot sign on computed tomography angiography (CTA) is a potentially strong predictor of poor outcome
on ultra-early radiological imaging. The aim of this study was
to assess the spot sign as a predictor of functional outcome
at 3 months as well as long-term mortality, with a focus on
the ability to identify patients with a spontaneous, acceptable outcome. Methods: In a prospective, consecutive single-centre registry of acute stroke patients, we investigated
patients with spontaneous intracerebral haemorrhage (ICH)
admitted within 4.5 h after symptom onset from April 2009
to January 2013. The standard work-up in our centre included CTA for spot sign status, unless a contraindication was
present. Modified Rankin Scale (mRS) scores were assessed
at 3 months in the outpatient clinic or by telephone interviews. Long-term mortality was assessed by electronic chart
follow-up for up to 1,500 days. Results: Of the 128 patients,
37 (28.9%) had a spot sign on admission CTA. The presence

2014 S. Karger AG, Basel

10159770/14/03730164$39.50/0
E-Mail karger@karger.com
www.karger.com/ced

of a spot sign was associated with larger median admission

haematoma volume [38.0 ml (IQR 18.078.0) vs. 12.0 ml (5.0
24.0); p< 0.0001] and higher median National Institutes of
Health Stroke Scale score [19 (IQR 1223) vs. 12 (616); p<
0.0001]. Three months after stroke, the median functional
outcome was considerably better in patients without spot
sign [mRS score 3 (IQR 24) vs. 6 (46); p< 0.0001]. The absence of a spot sign showed a sensitivity and specificity for
good outcome (mRS scores 02) of 0.91 and 0.36, respectively. The presence of a spot sign was, in multivariate models, an independent inverse predictor of good 3-month outcome (OR 0.17; 95% CI: 0.030.88) as well as a prominent
independent predictor of poor 3-month outcome (mRS
scores 56; OR 3.40; 95% CI: 1.1010.5) and death during follow-up (HR 3.04; 95% CI: 1.456.34). Patients with a spot sign
surviving the acute phase had long-term survival comparable to patients with no spot sign. Conclusion: The absence
or presence of a spot sign is a reliable ultra-early predictor of
long-term mortality and functional outcome in patients with
spontaneous ICH.
2014 S. Karger AG, Basel

*I.H. and C.O. contributed equally to this study.

Inger Havsteen
Department of Radiology, Copenhagen University Hospital Bispebjerg and
Copenhagen Stroke Research Centre, Bispebjerg Bakke 23
DK2400 Copenhagen NV (Denmark)
E-Mail seestein@gmail.com

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Spontaneous intracerebral haemorrhage (ICH) is regarded as the worst presentation of stroke, as 40% of patients die within the first month [1, 2], and only 20% of
patients achieve independent living at 6 months [3]. For
a long period of time, no new treatment options proven
effective in reducing mortality and morbidity in randomized clinical trials have emerged for ICH. Consequently,
the standard of care remains stroke unit rehabilitation
and prevention of medical complications. However, recently, blood pressure reduction has shown a small but
clinically significant benefit (INTERACT 2) [4], while
conclusive positive evidence is still lacking in surgical
treatment (STICH II) [5].
The spot sign is defined as contrast-enhancing foci within the haematoma observed on computed tomography angiography (CTA) source images [6]. This promising biomarker is an independent predictor of early haematoma
expansion and neurological deterioration [79] within the
first 6 h after symptom onset [1012]. Recent single-centre
case series [1315] and a multicentre study [16] have confirmed the spot sign to be an independent predictor of early haematoma expansion. However, the ability of spot sign
presence or absence to predict 3-month beneficial functional outcome and long-term mortality remains less established, and disagreement between studies exists [14, 16].
Robust and broadly validated biomarkers predicting outcome are essential in clinical decision-making as well as to
provide reliable information for patients and relatives.
Aim
The aim of this study was to assess the ability of the
spot sign to serve as a biomarker to predict 3-month functional outcome and long-term mortality in a consecutive,
prospective single-centre cohort of patients with ICH.

Subjects and Methods

This analysis was based on a prospectively planned inception
cohort study of acute stroke patients admitted within 4.5 h from
onset and worked up by CTA. In this analysis, we included the
subgroup of patients with a final diagnosis of spontaneous ICH,
defined as patients with non-traumatic ICH, in which no underlying focal causes as, for instance, tumour or vessel malformations
were identified during diagnostic work-up.

ants) who present symptoms of acute stroke on even dates. On

uneven dates, patients are received in another Copenhagen University Hospital. Consequently, patients who suffer from acute
stroke symptoms of a duration of no more than 4.5 h in this
catchment area are referred directly to the acute stroke service
by paramedics, general practitioners or other hospitals. On arrival, patients undergo a standardized work-up including CTA
unless no clinical suspicion of acute stroke or contraindications
to intravenous iodine contrast (allergy or significant kidney failure) are present.
Patients with ICH are treated according to Danish guidelines,
which are in accordance with existing European and North
American guidelines. In our institution, patients have continuous monitoring and recording of vital signs every 2 h in the first
24 h. Neurosurgeons in a neighbouring hospital (distance: 3 km)
are informed of patients with acute ICH by telephone, and CT
images are accessed electronically. Patients are referred to neurosurgery at the surgeons discretion. Patients on vitamin K antagonist treatment or with an international normalized ratio of >1.7
are treated with coagulation factors II, VII, IX and X in combination (Octaplex) and vitamin K in accordance with clinical
guidelines.
We excluded patients (n = 9) with surgical haematoma evacuation from outcome analysis. These patients were selected by the
surgeons for individual reasons due to expected surgical treatment
benefit. In these cases, the results from STICH I [17] and STICH
II [5] cannot be extrapolated. Patients with ventricular drainage
stayed in the analysis as this has no documented effect on outcome
[18]. All hospitals comply with the National Indicator Project criteria for rehabilitation and patient follow-up [19]. Local hospitals
have the same level of care except for hyperacute services such as
intravenous thrombolysis.
Definitions of Patient Characteristics and Risk Factors
Data on risk factors were extracted prospectively from the admission chart. Hypertension was defined as prestroke use of antihypertensive medication or a diagnosis of hypertension in the outpatient clinic. Hyperlipidaemia was defined as total plasma cholesterol above 5.0 mmol/l or statin treatment. Coronary heart disease
was defined as either a history of myocardial infarction, coronary
bypass surgery, percutaneous coronary intervention or angina
pectoris. Diabetes was defined as previous diagnosis of diabetes or
HbA1c >6.5%. Excessive use of alcohol was defined as weekly consumption of more than 21 units (252 g) alcohol for men and 14
units (168 g) for women. History of smoking was defined as present use of tobacco in any form or previous tobacco use of at least
3 pack years.

Patients
Copenhagen University Hospital Bispebjerg receives all patients from a well-defined catchment area consisting of the entire Capital Region of Denmark (approx. 1.7 million inhabit-

CT and CTA Imaging and Analysis

Imaging was obtained using a 64-section multidetector CT
(Brilliance 64; Philips Medical Systems, Best, The Netherlands).
Helical CTA was performed from the aortic arch to the vertex
with 120 kVp, 400 mAs/slice, collimation 64 0.625 mm (isotropic voxel resolution) and 70-ml iodine intravenous contrast injection (iohexol 350 mg/ml) followed by 50 ml saline at 5 ml/s via an
antecubital vein monitored by automated contrast tracking. After
24 h, a control non-contrast CT was performed if the patient remained in our institution. The majority of patients was referred
to local hospitals as soon as worked up and considered clinically
stable.

No Spot Sign: Predictor of Independent

Living after ICH

Cerebrovasc Dis 2014;37:164170

DOI: 10.1159/000357397

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Introduction

Follow-Up
A follow-up interview was conducted 3 months after stroke and
included modified Rankin Scale (mRS) scores evaluated via a faceto-face interview or a telephone interview by a stroke neurologist
or a trained nurse [22]. For deceased patients, information was
retrieved from the national electronic patient chart system. Patients were prospectively followed up regarding mortality via the
national electronic patient chart system for up to 1,500 days after
admission.
Ethics Statement
This observational study of the long-term effects of best clinical
care and with no interventions was approved by the Danish Data
Protection Agency (file No. 2010-41-5205) in accordance with
Danish law.
Statistics
Endpoints were defined as (1) functional outcome measured
using the mRS 3 months after stroke onset, and (2) death from any
cause between the date of inclusion and July 1, 2013. Good functional outcome was defined as 3-month mRS scores of 02. Poor
outcome was defined as 3-month mRS scores of 56. Group differences in baseline characteristics were compared using Students
t test for continuous variables after testing for normality using the
Kolmogorov-Smirnov test. Non-normally distributed data were
analysed using the Mann-Whitney U test. Ordinal scale data were
analysed using the Mann-Whitney U test, and categorical variables
using the 2 test. Cohens was used to grade interrater agreement.
Predictors of good and poor outcome 3 months after stroke
were analysed using multivariable stepwise logistical regression.
Besides the spot sign, we entered consistent predictors of functional outcome and mortality from the literature into the models:
age [23], prestroke mRS score, admission ICH volume [1], intraventricular extension [23], subarachnoid extension [24], admission plasma glucose level [25], admission National Institutes of
Health Stroke Scale (NIHSS) score [12] and warfarin treatment
[26]. Areas under the receiver operating characteristic curve (c statistics) were assessed to determine the calibration and discriminative ability of the models.
Non-adjusted survival (death) analysis of patients with and
without spot sign was undertaken using Kaplan-Meier curves
stratified for the presence of a spot sign. Difference between survival curves was tested for using the log rank test. Factors related
to survival during the entire follow-up time were assessed using the
Cox proportional hazards model. The proportional hazards assumptions were evaluated using Schoenfeld residuals. A general
significance level of p < 0.05 was employed. Statistical analyses
were performed by SPSS statistical software version 20 (IBM Corp.,
Armonk, N.Y., USA).

166

Cerebrovasc Dis 2014;37:164170

DOI: 10.1159/000357397

Results

From April 2009 to January 2013, 186 patients were

admitted to our stroke unit with acute spontaneous
ICH. Of these, 138 patients were admitted within 4.5 h
after ictus and worked up by CTA on admission (34 patients were admitted >4.5 h after ictus and 14 did not
undergo CTA). Surgical evacuation of the haematoma
was undertaken in 9 patients (6.5%). These were excluded from the outcome analysis. No patients or relatives
refused the surgical intervention offered. One patient
was, as a visitor to Denmark, lost to follow-up. The final
cohort consisted of 128 patients. External intraventricular drainage was placed in 5 patients (3.9%) without haematoma evacuation. These patients stayed in the analysis. Vitamin K antagonist-related ICH was observed in
14 patients (11%).
A spot sign was observed in 37 patients without haematoma evacuation (28.9%) and in 3 patients who underwent early haematoma evacuation. The baseline characteristics of the spot sign-positive and -negative groups are
presented in table1.
The time from onset to initial scanning was similar between the groups (means SD: 117 49 min vs. 112
48min; p= 0.70). Patients with a spot sign had clinically
more severe strokes [median NIHSS score 19 (IQR 12
23) vs. 12 (616); p < 0.0001] on admission and larger
initial median haematoma volumes [38.0 ml (IQR 18.0
78.0) vs. 12.0 ml (5.024.0); p< 0.0001]. Intraventricular
haemorrhage was present in 43% of the spot sign-positive, and in 27% of the spot sign-negative patients (p=
0.10). The spot sign-positive patients had slightly higher
median prestroke disability scores [mRS score 0 (IQR
01) vs. 0 (00); p= 0.02], and a non-significant trend
towards higher rates of alcohol abuse as well as antiplatelet and anticoagulant treatment before admission. Other
stroke risk factors were evenly distributed between the
patients. No differences were observed regarding admission blood pressure or blood glucose levels.
The median 3-month outcome was an mRS score of 3
(IQR 24; moderate disability) for patients without a spot
sign, and an mRS score of 6 (IQR 46; death) for patients
with a spot sign (p< 0.0001). Good outcome at 3 months
(mRS scores 02) was achieved by 36 patients (40%) in
the spot sign-negative group and by 2 patients (5.4%) in
the spot sign-positive group. Compared with this, 25
(68%) of the spot sign-positive patients suffered a poor
outcome (mRS scores 56) along with 17 patients (19%)
from the spot sign-negative group. Absence of a spot sign
yielded 95% sensitivity (specificity: 39%) for good outHavsteen/Ovesen/Christensen/Hansen/
Nielsen/Christensen

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A consultant neuroradiologist (A.F.C.) and a senior neuroradiological fellow (I.H.) blinded to all clinical data systematically
reviewed all images. Disagreement was resolved by consensus.
Agreement between the observers was substantial ( = 0.72). A
spot sign was defined as 1 or more 1- to 2-mm foci of enhancement
within the haematoma on CTA source images [6]. The CTA images were analysed in bone window (width 2,0002,500, level 400
500) and spot window settings (width 200, level 110) [20] to differentiate between spot sign and calcification. Haematoma volumes were calculated using the ABC/2 method [21].

Table 1. Baseline patient characteristics

Spot sign
Number of patients
Gender male, n
Mean age SD, years
Medical history
Median prestroke mRS score
Prior stroke, n
Atrial fibrillation, n
Hypertension, n
Coronary heart disease, n
Diabetes, n
Hyperlipidaemia, n
History of smoking, n
Excessive use of alcohola, n
Antiplatelet treatment, n
Warfarin treatment, n
Admission values
Mean time from onset to CT scanning SD, min
Median admission NIHSS score
Mean BP SD, mm Hg
Systolic
Diastolic
Mean blood glucose SD, mmol/l
Mean platelet count SD, 109/l
Mean INR SD
Mean APTT SD, s
Haematoma characteristics
Median initial volume, ml
IVH, n
SAH, n
Lobar, n
Basal ganglia, n
Posterior fossa, n

No spot sign

37
22 (60%)
7212

91
52 (58%)
6912

0.71
0.09

0 (01)
9 (25%)
8 (22%)
28 (78%)
1 (2.8%)
3 (8.3%)
17 (74%)
12 (41%)
7 (23%)
11 (31%)
8 (22%)

0 (00)
11 (12%)
10 (11%)
68 (76%)
4 (4.4%)
7 (7.8%)
49 (70%)
34 (45%)
7 (8.9%)
15 (17%)
9 (10%)

0.01
0.11
0.28
0.81
0.66
1.00
1.00
0.83
0.06
0.09
0.08

11749
19 (1223)

11248
10 (616)

0.70
<0.0001

192.029.6
99.920.0
7.43.0
225.279.5
1.40.8
28.15.5
38.0 (18.078.0)
16 (43%)
14 (38%)
16 (43%)
19 (51%)
2 (5.4%)

185.729.6
103.023.8
7.12.0
225.171.1
1.20.7
28.06.4
12.0 (5.024.0)
24 (27%)
19 (21%)
28 (31%)
58 (64%)
4 (4.4%)

0.25
0.53
0.58
0.91
0.10
0.70
<0.0001
0.10
0.08
0.23
0.17
0.81

come and a negative predictive value (NPV) of 95% (positive predictive value, PPV, 40%). Spot sign presence
showed 86% specificity (sensitivity: 60%) and an NPV of
81% (PPV 68%) for poor outcome.
The median follow-up time was 594 days (range:
01,500 days). During the entire follow-up period, 22
spot sign-positive patients (59.5%) and 15 spot sign-negative patients (16.5%) died. The Kaplan-Meier curves
show significantly different survival patterns between
groups (p< 0.0001; fig.1). The presence of a spot sign
yielded an NPV of 88% and a PPV of 57% for 3-month
mortality (sensitivity and specificity: 66 and 83%, respectively).

In a stepwise regression model, a spot sign independently predicted poor 3-month functional outcome (OR
3.40; 95% CI: 1.1010.5; table2). Finally, a spot sign was
inversely associated with good 3-month functional outcome (OR 0.17; 95% CI: 0.030.88). Both final models
derived from the logistic regression analysis provided excellent discriminative ability towards good and poor outcome (c statistics; table2). Significant predictors of death
during the follow-up period were spot sign (HR 3.04; 95%
CI: 1.456.34), admission NIHSS score (HR 1.11; 95% CI:
1.061.17 per unit) and increasing age (HR 1.30; 95% CI:
1.131.51 per 5 years). The same parameters as in table2
were entered in the Cox regression analysis.

No Spot Sign: Predictor of Independent

Living after ICH

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Values in parentheses denote IQR unless specified otherwise. BP= Blood pressure; INR= international normalized ratio; APTT= activated partial thromboplastin time; IVH= intraventricular haemorrhage; SAH= subarachnoid haemorrhage.
aWeekly alcohol consumption of more than 168 g for females and 252 g for males.

100
p < 0.0001

Cumulative mortality (%)

80

60

40

20

0
0

300

600

Fig. 1. Kaplan-Meier curves ( SE) for ICH

Spot sign
37
No spot sign 91

Table 2. Determinants of functional outcome after 3 months

OR

95% CI

0.82
0.68
0.21
0.17

0.740.90
0.530.87
0.050.83
0.030.88

1.21
1.70
1.02
3.40

1.101.32
1.262.31
1.001.04
1.1010.5

Gender, age, haematoma location, admission NIHSS score, admission ICH volume, prestroke mRS score, subarachnoid haemorrhage, intraventricular haemorrhage, warfarin treatment, plasma
glucose level and spot sign were entered in both models. First model (mRS scores 02): c statistics= 0.88 (95% CI: 0.820.94); second
model (mRS scores 56): c statistics= 0.92 (95% CI: 0.870.97); c
statistics indicate a good discriminative power for both models.

Discussion

The main finding of this study was that having no spot

sign entailed an acceptable long-term outcome with independent living after ICH, while the presence of a spot sign
in early imaging increased the odds for poor outcome 3.4fold adjusted for age, haematoma volume and NIHSS
score. We further report that patients with a spot sign suf168

1,200

1,500

Cerebrovasc Dis 2014;37:164170

DOI: 10.1159/000357397

14
75

9
57

7
35

4
16

1
2

fered an increased risk of death during the initial process;

however, survivors of the first months had a similar survival pattern to that of patients without a spot sign on
admission scans.
The strengths of this study were unselected and consecutive patient inclusion, as admission to our acute
stroke unit is strictly based on catchment area, and routine CTA performance on admission. This ensured very
early inclusion and a reduced risk of selection bias. Comprehensive national registers and electronic patient files
ensured quality in the follow-up, with very few patients
lost to follow-up. This emphasizes the everyday usefulness of the spot sign as a reliable biomarker in unselected
patients admitted early to the hospital for thrombolytic
assessment.
On the other hand, this was a single-centre study, and
the majority of patients were referred to local hospitals as
soon as possible and often before a planned 24-hour control non-contrast CT. Consequently, radiological followup cannot support the clinical follow-up. Our imaging
was performed slightly earlier than reported in most other studies [15, 20, 27, 28]; however, our population rates
of spot sign and 3-month mortality were similar to those
in earlier reports [29]. The proportions of spot signpositive and -negative patients with good outcome at
3months were similar to data earlier reported [6].
A significantly larger initial haematoma volume was
encountered in spot sign-positive patients. This is in accordance with previously published studies [14, 16]. It is
Havsteen/Ovesen/Christensen/Hansen/
Nielsen/Christensen

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patients stratified for the presence of a spot

sign on admission CTA. The numbers of
patients at risk at a given time are listed below. Log rank test: p< 0.0001.

Good outcome (mRS scores 02)

Increasing NIHSS score (per unit)
Increasing age (per 5 years)
Intraventricular haemorrhage
Spot sign
Poor outcome (mRS scores 56)
Increasing NIHSS score (per unit)
Increasing age (per 5 years)
Admission volume (per millilitre)
Spot sign

900

Time (days)

possible that haematomas with larger initial volumes

will originate from larger initial vessel ruptures or compress surrounding tissue more, causing secondary vascular damage responsible for haematoma expansion. We
further encountered a highly significant difference in
3-month functional outcome between patients with and
those without a spot sign. A large proportion of the difference in functional outcome can be readily explained
by the higher median haematoma volume in patients
with a spot sign, even if an independent effect of the spot
sign was found (table2). This is most likely due to the
spot sign being a mediator of haematoma expansion.
The median 3-month outcome among spot sign-positive
patients was slightly more beneficial in the multicentre
study population described by Demchuk et al. [16], i.e.
an mRS score of 5, versus an mRS score of 6 in our population. This may be explained by their selection criteria
limiting haematoma volumes to 100 ml in contrast to
our unselected population. In a more recent prospective
study elaborated by Rizos et al. [14], no difference was
found between 90-day functional outcome in spot signpositive and -negative patients. The discrepancy between the neutral finding reported by Rizos et al. [14]
and our data is not readily explained. Even though our
cohorts were similar, both groups in our study had larger initial haematoma sizes, and the patients in the spot
sign-negative group suffered milder neurological deficits on admission.
Haemostatic agents have been shown to reduce haematoma growth [30, 31], but their effect on outcome has
so far not been documented in randomized controlled

trials [31]. However, the use of spot sign diagnostics may

improve patient selection in clinical trials as this group
represents the large majority of patients at risk of significant deterioration based on continuous bleeding. Ongoing trials with either tranexamic acid (STOP-AUST) or
recombinant factor VII (STOP-IT and SPOTLIGHT) will
show whether a spot sign is able to select patients who
may benefit from thrombostatic therapy. A spot sign may
also influence the effects of aggressive blood pressure
lowering and haematoma evacuation, as it is hypothesized that these patients are in a process of deterioration
that may be affected by treatment. A puzzling question is
the timing of haematoma expansion. We need observational studies with serial measurements to describe the
natural cause of haematoma expansion in order to answer
the question whether a treatment window exists to limit
haematoma expansion and hopefully improve clinical
outcome.

Conclusion

The spot sign discriminates well between patients with

an acceptable functional outcome and patients prone to
poor outcome. This study shows that the absence of a spot
sign is a robust predictor of independent living after ICH.

Disclosure Statement
No conflicts of interest declared.

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No Spot Sign: Predictor of Independent

Living after ICH

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