Disappearance of the Hyperdense Mca Sign after Stroke Thrombolysis: Implications for Prognosis and Early Patient Selection for Clot Retrieval

Abstract

Disappearance of the hyperdense middle cerebral artery sign (HMCAS) following intravenous thrombolysis for ischaemic stroke is associated with improved outcome. Debate exists over which radiological thrombus characteristics can predict disappearance of the HMCAS after thrombolysis such as vessel attenuation or extent of thrombus length.

Methods
Ischaemic stroke patients treated with intravenous thrombolysis from our hospital were entered into a European registry. Patient demographics, stroke severity pre- and 24 hours post-thrombolysis were recorded. Patients with HMCAS were identified from the registry using records from 2010–2013. Images from the pre and post-thrombolysis computed tomography scan were measured. Thrombus characteristics (length and attenuation), extent of ischaemic change and clinical outcome (stroke severity and 3 month survival) were compared between patients with and without HMCAS disappearance. Logistic regression analysis was performed to identify predictors of HMCAS disappearance.

Results
HMCAS was present in 88/315 (28%) of thrombolysed ischaemic stroke patients. 36/88 (41%) of patients had thrombus disappearance 24 hours after thrombolysis. HMCAS disappearance was associated with reduced stroke severity, less radiological ischaemic change, and higher 3 month survival (87% vs 56%). Median thrombus length was shorter in the HMCAS disappearance group (11 vs 17 mm, p = 0.0004), but no significant difference in vessel attenuation was observed (48 vs 51 Hounsfield Units, p = 0.25). HMCAS disappearance occurred in 73% of cases where HMCAS length was < 10 mm, 38% when length was 10–20 mm, and 21% if > 20 mm. Thrombus length was the only independent predictor of HMCAS disappearance (odds ratio 0.90 per mm; 95% CI 0.84-0.96, p = 0.01).

Conclusion
Disappearance of HMCAS is associated with better clinical and radiological outcomes. A shorter thrombus is more likely to disappear post-thrombolysis. The data highlight the limitation of intravenous thrombolysis in patients with longer hyperattenuated vessels, and the potential role for clot retrieval in such patients.

Full text

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http://dx.doi.org/10.4997/JRCPE.2016.203
© 2016 Royal College of Physicians of Edinburgh
INTRODUCTION
The hyperdense middle cerebral artery sign (HMCAS)
seen on non-contrast computed tomography of the
brain is a highly specific marker of thrombotic vascular
occlusion and therefore middle cerebral artery (MCA)
territory stroke.1 In one large multicentre study (IST-3)2
hyperdense arteries were seen in about a quarter of
ischaemic strokes, predominantly in the anterior
circulation. The presence of HMCAS was associated
with worse outcomes but no increased risk of
symptomatic haemorrhage following intravenous
thrombolysis (IVT). Disappearance of the HMCAS is
more likely following intravenous thrombolysis3 and is
associated with improved outcome.4 Recent studies
suggest that occlusion site,5 clot length,6,7 and thrombus
Hounsfield Unit (HU) quantification1,8,9 are all candidates
to predict vessel recanalisation after intravenous
thrombolysis. It has also been suggested that HMCAS
due to cardio-embolism has higher vessel attenuation
and is more likely to recanalise post-thrombolysis.1
Previous angiographic studies show that HMCAS
disappearance post-thrombolysis indicates recanalisation
of occluded vessels.10,11 Using HMCAS disappearance as
a surrogate for MCA recanalisation, this study aimed to
assess predictors of HMCAS disappearance in a real-
world group of thrombolysed stroke patients. This could
potentially inform selection of clot retrieval therapies
for patients likely to have persistence of HMCAS.
Disappearance of the hyperdense MCA sign after
stroke thrombolysis: implications for prognosis
and early patient selection for clot retrieval
Paper
1P Elofuke,2JM Reid, 4A Rana, 3M-J Macleod
1ST6 Acute and Stroke Medicine, 2Consultant Neurologist, 3Senior Clinical Lecturer, Acute Stroke Unit, Aberdeen Royal Infirmary, Aberdeen,
UK; 4Consultant Neuroradiologist, Department of Neuroradiology, Aberdeen Royal Infirmary, Aberdeen, UK
ABSTRACT Disappearance of the hyperdense middle cerebral artery sign
(HMCAS) following intravenous thrombolysis for ischaemic stroke is associated
with improved outcome. Debate exists over which radiological thrombus
characteristics can predict disappearance of the HMCAS after thrombolysis such
as vessel attenuation or extent of thrombus length.
Methods Ischaemic stroke patients treated with intravenous thrombolysis from
our hospital were entered into a European registry. Patient demographics, stroke
severity pre- and 24 hours post-thrombolysis were recorded. Patients with
HMCAS were identified from the registry using records from 2010–2013. Images
from the pre and post-thrombolysis computed tomography scan were measured.
Thrombus characteristics (length and attenuation), extent of ischaemic change
and clinical outcome (stroke severity and 3 month survival) were compared
between patients with and without HMCAS disappearance. Logistic regression
analysis was performed to identify predictors of HMCAS disappearance.
Results HMCAS was present in 88/315 (28%) of thrombolysed ischaemic stroke
patients. 36/88 (41%) of patients had thrombus disappearance 24 hours after
thrombolysis. HMCAS disappearance was associated with reduced stroke
severity, less radiological ischaemic change, and higher 3 month survival (87% vs
56%). Median thrombus length was shorter in the HMCAS disappearance group
(11 vs 17 mm, p = 0.0004), but no significant difference in vessel attenuation was
observed (48 vs 51 Hounsfield Units, p = 0.25). HMCAS disappearance occurred
in 73% of cases where HMCAS length was < 10 mm, 38% when length was 10–20
mm, and 21% if > 20 mm. Thrombus length was the only independent predictor
of HMCAS disappearance (odds ratio 0.90 per mm; 95% CI 0.84-0.96, p = 0.01).
Conclusion Disappearance of HMCAS is associated with better clinical and
radiological outcomes. A shorter thrombus is more likely to disappear post-
thrombolysis. The data highlight the limitation of intravenous thrombolysis in
patients with longer hyperattenuated vessels, and the potential role for clot
retrieval in such patients.
KeywORDS acute ischaemic stroke, computed tomography, hyperdense vessel,
thrombolysis, outcome prediction
DeClARATION Of INTeReSTS No conflict of interest declared
Correspondence to JM Reid
Acute Stroke Unit
Aberdeen Royal Infirmary
Foresterhill
Aberdeen AB25 2ZN
UK
e-mail johnreid1@nhs.net

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MeTHODS
Participants
We identified patients who received intravenous
thrombolysis for acute ischaemic stroke at Aberdeen
Royal Infirmary between January 2010 and May 2013,
using the Treatment in Stroke-International Stroke
Thrombolysis Register (SITS-ISTR). This acute stroke
unit serves a population of 523,000 in the north-east of
Scotland and 42,000 in Orkney and the Shetland Isles,
and admits approximately 700 patients per annum. This
study had local Caldicott approval as an audit for the
purposes of quality assurance and monitoring of practice.
We adhered to the NHS Code of Practice on Protecting
Patient Confidentiality.12 Data recorded included blood
pressure, serum glucose, atrial fibrillation and stroke
severity (National Institute of Health Stroke Scale
[NIHSS])13 at 0, 2, 24 hours and 7 days after thrombolysis,
which was performed using tissue plasminogen activator.
Early neurological improvement or deterioration was
defined as an increase or decrease of 4 points on the
NIHSS scale 24 hours post-thrombolysis. Survival at 3
months is recorded in the registry; this information was
derived from the patient’s electronic record.
Imaging
Non-contrast computed tomography of the brain was
performed using a Siemens 128 slice CT scanner. Images
in continuous axial sections parallel to the orbitomeatal
line from the skull base to the vertex were acquired in 1
mm section thickness. The extent of ischaemic change
(Alberta Stroke Program Early CT score – ASPECTS)14 on
images at baseline and 24 hours post-thrombolysis was
recorded. This score evaluates ten anatomical sites within
the MCA territory for signs of ischaemic change and
produces a normal maximum score of 10 (no ischaemic
changes), minus one point for each area with ischaemic
changes. In all non-enhanced images, thrombus in the
MCA was defined by the following criteria: spontaneous
visibility of the whole horizontal part of the MCA,
attenuation of the MCA higher than that of the surrounding
brain, disappearance on bone windows and unilaterality.1
The M2 dot sign was defined as hyperattenuation of an
arterial structure in the Sylvian fissure relative to the
contralateral side. Patients found to have HMCAS by the
stroke physician had this recorded in the registry. This was
reassessed and confirmed on reviewing the images by two
stroke physicians (JMR and PE). The neuroradiologist (AR)
then confirmed the presence of HMCAS in all cases.
Angiography was not routinely performed. The MCA
vessel hyperattenuation, vessel length and estimated
occlusion site were obtained by two independent
assessors (a consultant neuroradiologist and neurologist).
All radiological variables were measured blinded to
outcome and clinical data.
The HU measurements were obtained on the basis of 3
mm computed tomography slices as previously
described.1 Regions of interest were manually placed on
the thrombus (HMCAS) and on the contralateral MCA.
The ratio of the ipsilateral to contralateral HU defined
as rHU was calculated to correct for haematocrit; rHU
= [iHU] MCA symptomatic side/[cHU] MCA
asymptomatic side. Thrombus length was measured as
previously described7 using the HMCAS detected in
images with slice thicknesses of 1.25 mm. Examples of
FIGURE 1A Estimation of hyperdense and contralateral
middle cerebral artery vessel attenuation (ipsilateral
Hounsfield unit [HU]-49.0, contralateral HU-35.3, ratio of
ipsilateral/contralateral HU-1.39)
FIGURE 1B Estimation of hyperdense middle cerebral
artery vessel thrombus length (= 20.9 mm)
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calculations of the regions of interest of contralateral
and ipsilateral MCA HU, and clot length are shown in
Figure 1.
Statistical analysis
Baseline data were analysed using the Student’s t-test for
continuous variables and the Chi-squared test to
compare proportions between groups. Significance was
taken as p < 0.05 for all analyses. Mean values are shown
with standard deviations. For analysis, vessel length and
HU estimation were taken as the mean value between
the two assessors. Four variables were selected a priori
to perform stepwise logistic regression analysis to
predict HMCAS-D to avoid an event to variable ratio <
10.15 Based on prior published studies and biological
plausibility;1 age, baseline NIHSS, HU ratio and HMCAS
length were chosen. Regression analysis was also tested
using all clinical and radiological variables in case any
other variables could have been significant independent
predictors. Analyses were performed using SPSS version
22 (IBM, NY, USA).
ReSUlTS
Eighty-eight (28%) of 315 patients receiving intravenous
thrombolysis for ischaemic stroke between January
2010 and April 2013 were identified as having HMCAS.
Patients with HMCAS had worse stroke severity, higher
rates of atrial fibrillation, a greater degree of ischaemic
change on the pre and post-thrombolysis CT scans,
higher rates of intracerebral haemorrhage after
thrombolysis, and lower survival at 3 months (Table 1).
Thirty-six (41%) patients had disappearance of HMCAS
(HMCAS-D) on the 24 hour post thrombolysis CT scan.
The mean attenuation measured was 3.6 HU higher
(95% confidence intervals -16.1 to +9.3) when measured
by the neurologist (average 44 HU, range 19–134 HU),
compared to the radiologist (41 HU, range 17–141 HU,
p = 0.004). The mean radiologist measured HMCAS
length was 1.6 mm shorter (mean 16.7 mm, range 5–74
mm) compared to the neurologist (mean 18.3 mm, range
5–55 mm, p = 0.32).
Details of baseline characteristics of those patients with
disappearance and persistence of HMCAS are given in
Table 2. There were no significant differences in baseline
clinical variables between patients with and without
disappearance of HMCAS. The only significantly different
radiological variables at baseline were HMCAS vessel
length, which was shorter in the HMCAS-D group
(median 11 [interquartile range, IQR 8-16] vs 17 [IQR,
11-24] mm, p = 0.004), and the fact that no patient with
involvement of the terminal internal carotid artery
achieved HMCAS disappearance.
The probability of HMCAS disappearance was 73%
(16/22) if HMCAS length was < 10 mm, 38% (14/37) if
10–20 mm, and 21% (6/29) > 20 mm. Analysis of patients
with and without atrial fibrillation did not demonstrate
any difference in rates of HMCAS disappearance (36 vs
44%, respectively, p = 0.45), vessel length or HU
quantification. In stepwise logistic regression analysis
limited to four a priori selected variables, only HMCAS
vessel length was an independent predictor of HMCAS
disappearance (odds ratio 0.90 per mm, 95% confidence
interval 0.84–0.96, p = 0.01).
Characteristics No HMCAS HMCAS p value
n (%) 227 (72) 88 (28) -
Mean age (years) (SD) 69 (12) 71 (11) 0.19
Female sex (%) 97 (43) 35 (40) 0.63
Atrial fibrillation (%) 48/213 (23) 46/86 (53) <0.001
Independent pre-stroke (%) 196/208 (94) 70/75 (93) 0.78
Mean glucose (mmol/l) (SD) 6.7 (0.3) 6.5 (1.0) 0.74
Baseline mean systolic BP (mmHg) (SD) 151 (25) 149 (20) 0.62
Baseline mean diastolic BP (mmHg) (SD) 80 (15) 83 (12) 0.34
Mean NIHSS pre-IVT (SD) 9.8 (7.8) 15.7 (7.2) <0.001
Mean NIHSS 24 hrs post-IVT (SD) 7.7 (8.3) 12.5 (9.3) 0.001
3 month survival (%) 179/211 (85) 60 (68) 0.01
Mean ASPECTS pre-IVT (SD) 9.5 (0.9) 8.4 (1.7) <0.001
Mean ASPECTS 24 hrs post-IVT (SD) 8.3 (2.4) 5.4 (2.9) <0.001
Any intracerebral haemorrhage (%) 24/222 (11) 21 (24) 0.003
Parenchymal haemorrhage (Type 1 or 2) (%) 12/222 (5) 11 (13) 0.03
Symptomatic intracerebral haemorrhage (%) 13/222 (6) 5 (6) 0.95
NIHSS: National Institutes of Health Scale; BP: blood pressure; IVT: intravenous thrombolysis; ASPECTS: Alberta Stroke Program
Early CT score.
TABLE 1 Clinical characteristics of patients with or without a hyperdense middle cerebral artery sign (HMCAS). The new
denominator is specified where the data are incomplete
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DISCUSSION
This study demonstrates that HMCAS disappearance is
associated with improvement in the stroke severity
score, lower parenchymal haemorrhage rates and better
survival after intravenous thrombolysis. HMCAS
disappearance may not guarantee neurological
improvement as only HMCAS features at 24 hours are
measured, which may be because only vessel
recanalisation within the first few hours may allow
salvage of ischaemic tissue at risk of infarction.
There was a clear relationship between HMCAS length
and HMCAS disappearance. One study suggested that
HMCAS disappearance post-thrombolysis occurs only in
hyperdense arteries with a thrombus length of 8 mm or
less,7 whereas 83% of those we observed in whom
HMCAS disappeared had a HMCAS length greater than
8 mm. Another study of 41 thrombolysed patients with
HMCAS also suggested that HMCAS disappearance is
length dependent, occurring in 86% with lengths <
10mm, 38% if 10–20 mm, and in no cases > 20 mm.6 Our
results, obtained in a larger patient group, broadly
concur. Determination of thrombus length and estimated
occlusion site is not cumbersome and shows promise as
a predictor of HMCAS disappearance post-thrombolysis.
No patient with terminal internal carotid artery
involvement showed disappearance of the HMCAS.
Some studies excluded patients with internal carotid
artery involvement on angiography,1 but as we did not
routinely perform angiography we included this group
so as to be representative of our whole population of
treated patients. The International Stroke Trial-3
randomised trial has recently reported that intravenous
thrombolysis improves the odds that the hyperdense
artery regresses or disappears with odds ratios
between 0.51–0.66 if limited to single segment, proximal
or distal arteries.3 However this study did not report
vessel length or attenuation. Of the non-thrombolysed
TABLE 2 Characteristics of patients with disappearance (HMCAS-D) and persistence (HMCSA-P) of hyperdense MCA sign
Characteristic HMCAS disappearance HMCAS persistence p value
n (%) 36 (41) 52 (59) –
Mean age (years) 75 (10) 72 (11) 0.11
Female sex (%) 16 (42) 19 (37) 0.46
Atrial fibrillation (%) 22 (61) 24/51 (47) 0.20
Independent pre-stroke (%) 30/32 (94) 40/43 (93) 0.90
Mean glucose (mmol/l) (SD) 6.3 (1.4) 6.7 (2.0) 0.34
Baseline mean systolic BP (mmHg) (SD) 152 (22) 147 (19) 0.26
Baseline mean diastolic BP (mmHg) (SD) 83 (11) 82 (12) 0.29
Mean symptom onset to treatment (min) (SD) 148 (63) 158 (72) 0.53
Mean NIHSS pre-IVT (SD) 14.8 (5.7) 16.9 (6.3) 0.11
Mean NIHSS 2 hrs post-IVT (SD) 13.3 (7.5) 16.1 (6.7) 0.08
Mean NIHSS 24 hrs post-IVT (SD) 10.0 (8.0) 17.5 (8.1) <0.001
Mean NIHSS 7 days post-IVT (SD) 9.3 (7.7) 13.8 (7.0) 0.03
24 hr NIHSS improved ≥ 4 points (%) 20 (56) 12 (23) 0.002
24 hr NIHSS worsened ≥ 4 points (%) 3 (8) 12 (23) 0.013
3 month survival (%) 31 (87) 29 (56) 0.009
Radiological characteristics
Mean ipsilateral HU (SD) 48.3 (5.4) 51.0 (13.9) 0.25
Mean contralateral HU (SD) 34.2 (5.7) 35.5 (5.1) 0.23
Mean HU ratio (SD) 1.44 (0.28) 1.45 (0.38) 0.91
Left MCA involved (%) 18 (50) 21 (40) 0.16
M1 involved (%) 24 (75) 43 (83) 0.39
M2 or more distal only (%) 16 (44) 19 (37) 0.46
Terminal internal carotid involved (%) 0 (0) 7 (13) 0.02
Mean ASPECTS pre-IVT (SD) 8.9 (1.4) 8.4 (1.3) 0.16
Mean ASPECTS 24 hrs post-IVT (SD) 6.4 (2.3) 3.8 (2.6) <0.001
Median HMCAS length (mm) (IQR) 11 (8–16) 17 (11–24) 0.004
Any intracerebral haemorrhage (%) 8 (22) 13 (25) 0.77
Parenchymal haemorrhage (Type 1 or 2) (%) 3 (8) 8 (15) 0.02
Symptomatic intracerebral haemorrhage (%) 1 (3) 4 (8) 0.32
NIHSS: National Institutes of Health Scale; BP: blood pressure; IVT: intravenous thrombolysis; HU: Hounsfield Unit; HU ratio
(ratio of ipsilateral to contralateral HU); ASPECTS: Alberta Stroke Program Early CT score; IQR: interquartile range.
Symptomatic ICH is any ICH with worse NIHSS score at 24 hrs post thrombolysis.
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patients with distal or proximal HMCAS, 51% had no
regression/disappearance compared to 32% in the
thrombolysis arm.3 The low level of HMCAS
disappearance we observed, particularly for lengths >
10 mm, highlights the need for additional treatments
such as clot retrieval for patients with large vessel
occlusive stroke. Early recognition of the HMCAS may
help to identify patients eligible for clot retrieval in a
timely fashion, although the absence of the HMCAS
does not exclude a large vessel occlusion.1,3
We could not replicate the findings of Puig et al.1 who
found that the ratio of contralateral to ipsilateral HU
ratio <1.382 (i.e. ratio of ipsilateral to contralateral
vessel attenuation) predicted persistent occlusion after
intravenous tissue plasminogen activator with high
sensitivity and specificity.1 A further study found that for
intravenous thrombolysis, intra-arterial thrombolysis
and mechanical revascularisation, patients with vessel
recanalisation had on average higher hyperdense vessel
attenuation.8 It may be that methodological differences
explain the variability of these findings; one study1 used
transcranial Doppler monitoring which is known to be
associated with higher rates of recanalisation.16 The
aforementioned study also included a minority of
patients with vessel occlusion identified by CT
angiography without HMCAS, and vessel recanalisation
was confirmed by angiographic or ultrasonic methods.1
One study8 found no relationship between clot volume
and recanalisation, whether using thrombolysis or
mechanical approaches.
HMCAS clot length is dependent on the site of the
occlusion, with more proximal clots being longer.17
Patients with more proximal HMCAS are less likely to
improve clinically, and HMCAS disappearance is less
likely than those with a distally located HMCAS.1,18
Furthermore, our population age is older than those
included in previous studies.1,8 Some studies suggest
patients with cardioembolic stroke or atrial fibrillation
are more likely to recanalise with intravenous
thrombolysis.1, 5 However we found no evidence for this,
in keeping with larger studies demonstrating no
differential effect of thrombolysis on cardioembolic
compared to non-cardioembolic strokes.19,20 Similar to
our findings, a recent study found no difference in HU
ratio or early recovery depending on whether the
aetiology of thrombus was thought to be cardioembolic
or atherothrombotic.9
The significant trend towards reduced parenchymal
haemorrhage we observed in patients with HMCAS
disappearance is likely due to the smaller ischaemic
volume, represented by higher ASPECTS scores and
reduced stroke severity. Indeed HMCAS disappearance
is associated with striatocapsular infarcts, in keeping
with ASPECTS scores of 6 or higher seen in the HMCAS
disappearance group.21
There are limitations to our study that mandate cautious
interpretation of the results. The sample size is small and
the data were collected retrospectively, though blinded
to clinical outcome. Disappearance of HMCAS may not
necessarily equate to vessel recanalisation as we had not
confirmed this with transcranial Doppler or angiography.
Ernst et al.22 described slightly better inter-rater
evaluation of HU (mean difference of 2.1), perhaps
because we included assessment by a neurologist,
whereas the aforementioned study used two neuro-
radiologists. Since the overall number of patients with
HMCAS is small, this study may be underpowered to
detect other variables to predict HMCAS disappearance.
In view of the challenge of attempting to implement clot
retrieval services in the UK with limited provision of
neuro-interventional services our findings are a
justification for more prospective studies to develop a
model for predicting HMCAS disappearance as a
surrogate for vessel recanalisation. This could influence
patient selection for clot retrieval, particularly in a
resource-limited health system, although ideally all
patients with large vessel occlusive stroke should be
considered for clot retrieval.
CONClUSION
The presence of a HMCAS is associated with higher
stroke severity and worse outcome; however
disappearance of the HMCAS is associated with
improved clinical and radiological outcomes. Only
HMCAS vessel length predicted HMCAS disappearance.
The persistence of HMCAS particularly with longer
thrombus length highlights a potential role for clot
retrieval in these patients.
ACKNOwleDgeMeNTS
We are grateful to Dr Carl Counsell for assistance with
statistical analysis.
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