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

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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.
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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)
P Elofuke, JM Reid, A Rana et al.
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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
Disappearance of the hyperdense MCA sign after stroke thrombolysis
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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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quantitative detection of middle cerebral artery occlusion on non-
contrast-enhanced computed tomography. Neuroradiology 2014; 56:
1063–8. http://dx.doi.org/10.1007/s00234-014-1443-y
P Elofuke, JM Reid, A Rana et al.
J R Coll Physicians Edinb 2016; 46: 81–6
© 2016 RCPE
... About 40-50% of patients with MCA infarction could present hyperdense MCA sign (HMCAs), which would disappear in 50% of patients 36 h after treatment of intravenous alteplase [27,28]. And these patients with transient HMCAs would have better outcomes [29,30]. ...
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Non-contrast computed tomography (NCCT) of the brain is critical to patients with acute ischemic stroke who receive thrombolysis and thrombectomy. It can help identify reperfusion-related hemorrhage, edema which need intervention. It also can guide the timing and intensity of antithrombotic therapy. Rapid, accurate, and automated detection and segmentation of acute ischemic lesions after endovascular therapy (EVT) are highly needed. In this work, we propose a novel encoder-decoder network for fully automatic segmentation of acute ischemic lesions after EVT on NCCT, which is named ISCT-EDN. NCCT images of AIS (acute ischemic stroke) patients who underwent EVT in a multicenter cohort study were collected in this study. ISCT-EDN takes hierarchical network as backbone. Feature pyramid network (FPN) is designed to aggregate features from multi stages of backbone. Reasonable feature fusion strategy is considered in FPN to enhance multi-level propagation. In addition, to overcome the limitation of fixed geometric structure of convolution for multi-range dependency exploitation, non-local parallel decoder is introduced with deformable convolution and self-attention. The proposed model was compared with 7 segmentation models which are commonly used in the medical domain and the performance was superior to other models in in the segmentation of post-treatment infarct lesions on NCCT images of AIS patients after EVT.
... This difference might be due to the mean of the clot length in the cardioembolic group, which is relatively longer than in the LAA and the other group, even though it had no statistical significance. From the findings of Elofuke et al. (21), a shorter thrombus is more likely to disappear postthrombolysis, a finding supporting the higher rate of disappearance in the LAA and other groups. Overall, HMCAS disappearance rate in this study (75.8%) is higher than in the Khritonova et al. (22) study, which disappeared in about half of the cases and had outcomes twice as good as in persistent HMCAS patients. ...
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Background: Identifying stroke subtypes is crucial in choosing appropriate treatment, predicting outcomes, and managing recurrent stroke prevention. Objectives: To study the association of hyperdense middle cerebral artery sign (HMCAS) on noncontrast computed tomography (NCCT) brain and subtypes of stroke etiology. Methods: This is a retrospective hypothesis testing study. Patients aged 18 or over who had middle cerebral artery occlusion symptoms with HMCAS with verification on brain NCCT and received intravenous thrombolysis between January 2016 and June 2019 were enrolled. The demographic data, clinical outcomes, stroke subtypes, and characteristics of HMCAS were collected from medical records. Results: Ninety-nine out of 299 enrolled patients presented with HMCAS. The most common stroke subtype was cardioembolism (59%). Of the baseline characteristics, hypertension was more common in cases of large-artery atherosclerosis (LAA) (86.4%), and atrial fibrillation (AF) was the highest in cardioembolism (44.8%). HMCAS disappearance in cardioembolism was lowest compared to LAA and others (63% vs. 91% vs. 94.7%, respectively). The univariable analysis found that HMCAS disappearance is significantly associated with all stroke subtypes (Odds ratio, 95% confidence interval 10.58, 1.31-85.43; P = 0.027 for other and 5.88, 1.24-27.85; P = 0.026 for LAA). Multinomial logistic regression found that body weight and hypertension were associated with the LAA subtype. AF and intracranial hemorrhage (ICH) were associated with cardioembolism. Conclusion: The most likely diagnosis from the presence of HMCAS is cardioembolism, but the definite stroke etiologic subtype can not be identified. Combining the patient risk factors, including body weight, hypertension, and AF, with HMCAS and its characteristics will predict stroke subtypes more accurately.
... Five studies were included in the final analysis of association of HMCAS with mortality which comprised of 10,922 patients [21,25,26,28,33] (Table 1). HMCAS was not significantly associated with increased risk of mortality in patients with positive HMCAS as compared to negative HMCAS (RR 1.34; 95% CI 0.72-2.51; ...
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Pre-intervention CT imaging-based biomarkers, such as hyperdense middle cerebral artery sign (HMCAS) may have a role in acute ischaemic stroke prognostication. However, the clinical utility of HMCAS in settings of reperfusion therapy and the level of prognostic association is still unclear. This systematic review and meta-analysis investigated the association of HMCAS sign with clinical outcomes and its prognostic capacity in acute ischaemic stroke patients treated with reperfusion therapy. Prospective and retrospective studies from the following databases were retrieved from EMBASE, MEDLINE and Cochrane. Association of HMCAS with functional outcome, symptomatic intracerebral haemorrhage (sICH) and mortality were investigated. The random effect model was used to calculate the risk ratio (RR). Subgroup analyses were performed for subgroups of patients receiving thrombolysis (tPA), mechanical thrombectomy (EVT) and/or combined therapy (tPA + EVT). HMCAS significantly increased the rate of poor functional outcome by 1.43-fold in patients (RR 1.43; 95% CI 1.30–1.57; p < 0.0001) without any significant differences in sICH rates (RR 0.91; 95% CI 0.68–1.23; p = 0.546) and mortality (RR 1.34; 95% CI 0.72–2.51; p = 354) in patients with positive HMCAS as compared to negative HMCAS. In subgroup analyses, significant association between HMCAS and 90 days functional outcome was observed in patients receiving tPA (RR 1.53; 95% CI 1.40–1.67; p < 0.0001) or both therapies (RR 1.40; 95% CI 1.08–1.80; p = 0.010). This meta-analysis demonstrated that pre-treatment HMCAS increases risk of poor functional outcomes. However, its prognostic sensitivity and specificity in predicting long-term functional outcome, mortality and sICH after reperfusion therapy is poor.
... 21 Disappearance of a hyperdense artery is more likely, the shorter its length. 22 Therefore older patients with higher stroke severity, may have greater clot burden which is more resistant to IV thrombolysis, which may be more likely to recanalise following endovascular clot retrieval. ...
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Background: Thrombolysis for acute ischaemic stroke (AIS) patients aged ˜80 years is evidence based, although its use in previously dependent patients is controversial. Methods: Data from 831 thrombolysed AIS patients in our centre from 2009-2017 were used to compare demographic trends and outcomes (haemorrhage, mortality, three-month independence) in patients aged <80 and ˜80 years and with prior dependency. Comparison with UK and world registry data regarding age and pre-stroke dependency was made. Results: The percentage of treated patients aged ˜80 years increased year-on-year, doubling from 25% to 50% (p <0.01), with increasing average age and pre-stroke dependency in world centres. Patients ˜80 years had higher (p <0.001) stroke severity, symptomatic intracerebral haemorrhage (5% vs. 1.5%), mortality (35% vs. 13%) and lower three month independent survival (24% vs. 60%). Patients with pre-stroke dependency had especially higher three month mortality (57-71%, OR 3.75 [95% CI 1.97-7.15]) in both age groups. Conclusion: Patients aged ˜80 years and with dependency increasingly receive thrombolysis. Given poorer outcomes thrombolysis trials are needed in pre-stroke dependent patients.
... 16 More importantly, there is a good clinical outcome in only~25% of patients (at best) with proximal anterior circulation or basilar artery occlusion. 17 Important independent risk factors predicting poor outcome post intravenous thrombolysis are the length [18][19][20][21][22] and location 23 24 of the arterial thrombus. This lack of efficacy of the only licensed treatment led to efforts to remove larger arterial clots using intra-arterial techniques, initially using lytic but then mechanical means. ...
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Rapid, safe and effective arterial recanalisation to restore blood flow and improve functional outcome remains the primary goal of hyperacute ischaemic stroke management. The benefit of intravenous thrombolysis with recombinant tissue-type plasminogen activator for patients with severe stroke due to large artery occlusion is limited; early recanalisation is generally less than 30% for carotid, proximal middle cerebral artery or basilar artery occlusion. Since November 2014, nine positive randomised controlled trials of mechanical thrombectomy for large vessel occlusion in the anterior circulation have led to a revolution in the care of patients with acute ischaemic stroke. Its efficacy is unmatched by any previous therapy in stroke medicine, with a number needed to treat of less than 3 for improved functional outcome. With effectiveness shown beyond any reasonable doubt, the key challenge now is how to implement accessible, safe and effective mechanical thrombectomy services. This review aims to provide neurologists and other stroke physicians with a summary of the evidence base, a discussion of practical aspects of delivering the treatment and future challenges. We aim to give guidance on some of the areas not clearly described in the clinical trials (based on evidence where available, but if not, on our own experience and practice) and highlight areas of uncertainty requiring further research.
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The aim of our study was to compare the rapid neurological improvement after intravenous recombinant tissue-type plasminogen activator (rtPA) in patients with proximal hyperdense middle cerebral artery sign (p-HMCAS) to those without the sign and those with the distal hyperdense middle cerebral artery sign (d-HMCAS). Admission and 24 hour non-contrast CT scans of 120 patients with middle cerebral artery (MCA) territory stroke who were treated with intravenous rtPA were assessed for the presence of p-HMCAS and d-HMCAS. The sign was classified according to the site of occlusion. Rapid neurological improvement was defined as $50% improvement in the NIHSS score at 24 hours after thrombolysis. Rapid neurological recovery after thrombolysis was assessed and compared between the subgroups. Rapid neurological recovery was less common in the pooled group of patients with either p-HMCAS or d-HMCAS than those without the sign (p,0.01). Patients with p-HMCAS were less likely to have rapid neurological recovery than those with d-HMCAS (p,0.01). However, there was no difference in early neurological recovery between patients with d-HMCAS and those without any hyperdense sign. Our study showed that poor neurological recovery post rtPA was confined to p-HMCAS and not to d-HMCAS, indicating that these signs have quite different prognostic significance.
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Objective: To investigate whether the location and extent of the CT hyperdense artery sign (HAS) at presentation affects response to IV alteplase in the randomized controlled Third International Stroke Trial (IST-3). Methods: All prerandomization and follow-up (24-48 hours) CT brain scans in IST-3 were assessed for HAS presence, location, and extent by masked raters. We assessed whether HAS grew, persisted, shrank, or disappeared at follow-up, the association with 6-month functional outcome, and effect of alteplase. IST-3 is registered (ISRCTN25765518). Results: HAS presence (vs absence) independently predicted poor 6-month outcome (increased Oxford Handicap Scale [OHS]) on adjusted ordinal regression analysis (odds ratio [OR] 0.66, p < 0.001). Outcome was worse in patients with more (vs less) extensive HAS (OR 0.61, p = 0.027) but not in proximal (vs distal) HAS (p = 0.420). Increasing age was associated with more HAS growth at follow-up (OR 1.01, p = 0.013). Treatment with alteplase increased HAS shrinkage/disappearance at follow-up (OR 0.77, p = 0.006). There was no significant difference in HAS shrinkage with alteplase in proximal (vs distal) or more (vs less) extensive HAS (p = 0.516 and p = 0.580, respectively). There was no interaction between presence vs absence of HAS and benefit of alteplase on 6-month OHS (p = 0.167). Conclusions: IV alteplase promotes measurable reduction in HAS regardless of HAS location or extent. Alteplase increased independence at 6 months in patients with and without HAS. Classification of evidence: This study provides Class I evidence that for patients within 6 hours of ischemic stroke with a CT hyperdense artery sign, IV alteplase reduced intra-arterial hyperdense thrombus.
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Background: Brain scans are essential to exclude haemorrhage in patients with suspected acute ischaemic stroke before treatment with alteplase. However, patients with early ischaemic signs could be at increased risk of haemorrhage after alteplase treatment, and little information is available about whether pre-existing structural signs, which are common in older patients, affect response to alteplase. We aimed to investigate the association between imaging signs on brain CT and outcomes after alteplase. Methods: IST-3 was a multicentre, randomised controlled trial of intravenous alteplase (0·9 mg/kg) versus control within 6 h of acute ischaemic stroke. The primary outcome was independence at 6 months (defined as an Oxford Handicap Scale [OHS] score of 0-2). 3035 patients were enrolled to IST-3 and underwent prerandomisation brain CT. Experts who were unaware of the random allocation assessed scans for early signs of ischaemia (tissue hypoattenuation, infarct extent, swelling, and hyperattenuated artery) and pre-existing signs (old infarct, leukoaraiosis, and atrophy). In this prespecified analysis, we assessed interactions between these imaging signs, symptomatic intracranial haemorrhage (a secondary outcome in IST-3) and independence at 6 months, and alteplase, adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score, and time to randomisation. This trial is registered at ISRCTN.com, number ISRCTN25765518. Findings: 3017 patients were assessed in this analysis, of whom 1507 were allocated alteplase and 1510 were assigned control. A reduction in independence was predicted by tissue hypoattenuation (odds ratio 0·66, 95% CI 0·55-0·81), large lesion (0·51, 0·38-0·68), swelling (0·59, 0·46-0·75), hyperattenuated artery (0·59, 0·47-0·75), atrophy (0·74, 0·59-0·94), and leukoaraiosis (0·72, 0·59-0·87). Symptomatic intracranial haemorrhage was predicted by old infarct (odds ratio 1·72, 95% CI 1·18-2·51), tissue hypoattenuation (1·54, 1·04-2·27), and hyperattenuated artery (1·54, 1·03-2·29). Some combinations of signs increased the absolute risk of symptomatic intracranial haemorrhage (eg, both old infarct and hyperattenuated artery, excess with alteplase 13·8%, 95% CI 6·9-20·7; both signs absent, excess 3·2%, 1·4-5·1). However, no imaging findings-individually or combined-modified the effect of alteplase on independence or symptomatic intracranial haemorrhage. Interpretation: Some early ischaemic and pre-existing signs were associated with reduced independence at 6 months and increased symptomatic intracranial haemorrhage. Although no interaction was noted between brain imaging signs and effects of alteplase on these outcomes, some combinations of signs increased some absolute risks. Pre-existing signs should be considered, in addition to early ischaemic signs, during the assessment of patients with acute ischaemic stroke. Funding: UK Medical Research Council, Health Foundation UK, Stroke Association UK, Chest Heart Stroke Scotland, Scottish Funding Council SINAPSE Collaboration, and multiple governmental and philanthropic national funders.
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Background and purpose: Atrial fibrillation (AF) increases the risk of stroke and is associated with poor stroke outcomes. Limited tools are available to evaluate clinical outcomes and response to thrombolysis in stroke patients with AF. Methods: We applied the iScore (http://www.sorcan.ca/iscore), a validated risk score, to consecutive patients with an acute ischemic stroke admitted to stroke centers in the Registry of the Canadian Stroke Network. The main outcome considered was a favorable outcome (defined as a modified Rankin scale 0-2) at discharge after thrombolysis. Secondary outcomes included intracerebral hemorrhage, death at 30 days, and at 1 year stratified by terciles of the iScore. Results: Among 12 686 patients with an acute ischemic stroke, 2185 (17.2%) had AF. Overall, AF patients had higher risk of death at 30 days (22.3% versus 10.2%; P<0.0001), 1 year (37.1% versus 19.5%; P<0.0001) and death or disability at discharge (69.7% versus 54.7%; P<0.0001) compared with non-AF patients. After adjustment, thrombolysis was associated with a favorable outcome for patients without AF (relative risk, 1.18; 95% CI, 1.10-1.27), but no benefit was observed for patients with AF (relative risk, 0.91; 95% CI, 0.71-1.17). There was a modestly increased risk of intracranial hemorrhage (any type) (16.5% versus 11.6%; relative risk, 1.42; 95% CI, 1.05-1.91) after thrombolysis among AF compared with non-AF patients. In the logistic regression analysis, there was an interaction between tPA and iScore for a favorable outcome (P-value interaction <0.001). The interaction also was significant (P<0.0012) among patients without AF, but did not reach significance (P=0.17) in patients with AF. Conclusions: Stroke patients with AF have higher mortality, greater risk of intracerebral hemorrhage, and a similar response trend to thrombolysis compared with non-AF patients.
Article
Purpose Thin-section (≤2.5 mm) NCCT is a dependable method for measurement of clot length in documented anterior circulation occlusions. A majority of clots in the proximal anterior circulation are ≥8 mm, which have low probability of revascularization with IV rtPA alone. Nevertheless, past studies have had sampling restrictions, and correlations of clot length continue to be classified. Methods Data was captured to investigate potential correlates of clot length from an ongoing multicenter review. Patients were eligible if presented within 8 h of onset, had thin-section NCCT admission imaging, and evidence of ICA-T, M1, or M2 MCA occlusion. All patients had their occlusions documented by CTA, angiography, or MRI. Patients did not necessarily have thrombectomy performed. Baseline characteristics of interest included age, sex, baseline NIHSS, ASPECTS, occlusion level, IV rtPA dose pre vs. post scan, time from stroke onset to imaging, and IA recanalization. Univariate analyzes were implemented with clot length as a dichotomized variable (≥8 mm vs <8 mm), and multivariate logistic regression was used to define predictors. Results Consecutive stroke admissions were reviewed at 3 US centers between August 2011 and March 2013 for eligibility, and 175 patients met criteria. Mean age was 70 years old; 56% were female. Median baseline NIHSS score was 17 (IQR 12–22). The level of occlusion was distributed such that 23% were ICA-T, 54% M1, and 23% M2 MCA. Of the 175 confirmed occlusions, hyperdense clot was visible in 89% (156/175) of cases. Visible clot ranged from 2 mm to 65 mm, while mean length was 14 mm. There were 66% (115/175) patients with clot lengths ≥8 mm. In comparing clot length to occlusion level, 90% of ICA-T, 69% of M1, and 34% of M2 occlusions were ≥8 mm (p < 0.001), with median clot lengths of 20.5, 14.1, and 7.2, respectively. The only significant multivariate predictor of clot length was the occlusion level (OR, 95% CI =3.9 (2.2–6.9) per step from M2 to M1 to ICA-T, p < 0.0001). Conclusion This analysis further supports the idea of measuring hyperdense thrombus by use of thin-section NCCT. Occlusion site is a key predictor of clot length, which may explain the relative ineffectiveness of IV rtPA in more proximal anterior circulation large vessels. These findings suggest a sizeable population who may benefit from a bridging approach. Disclosures D. Frei: 3; C; Penumbra Inc. 4; C; Penumbra Inc. D. Heck: None. A. Yoo: 1; C; National Institutes of Health, Penumbra Inc., Remedy Pharmaceuticals. D. Loy: None. H. Buell: 5; C; Penumbra Inc. S. Kamalian: 1; C; GE Healthcare, Department of Defense, CIMIT. L. Morais: None. A. Bitner: 3; C; Penumbra Inc. D. Meyer: 5; C; Penumbra Inc. S. Kuo: 5; C; Penumbra Inc. A. Bose: 4; C; Penumbra Inc. 5; C; Penumbra Inc. S. Sit: 4; C; Penumbra Inc. 5; C; Penumbra Inc.
Article
Introduction: This study aims to investigate diagnostic sensitivity and reliability for the detection of middle cerebral artery occlusion (MCAO) on non-contrast-enhanced computed tomography (NECT) by visual assessment (VA), Hounsfield unit (HU) measurement, calculation of the Hounsfield unit/hematocrit (HU/Hct) ratio, and combination of visual assessment and attenuation measurement (VA + HU). Methods: NECT of 18 patients with angiographically proven MCAO and 18 patients without MCAO were reviewed by two blinded observers. Visual assessment of presence or absence of a hyperdense sign was followed by HU measurement of both middle cerebral arteries (MCA). Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for VA, HU measurement, HU/Hct ratio, and VA + HU measurement. Receiver operating characteristic curve analysis (ROC) was performed to determine the optimal cut-off values for MCAO using attenuation measurements or HU/Hct ratio. Results: Diagnostic sensitivity/specificity was 63%/91% for VA, 56%/88% for attenuation measurement, 68 %/81 % for HU/Hct ratio, and 75%/78% for VA + HU. ROC curve analysis revealed cut-off values of >42.5 HU for attenuation measurements and >1.12 HU/Hct for HU/Hct ratio. Conclusion: Combination of visual assessment with additional attenuation measurement with a cut-off value of 42.5 HU is recommended for most sensitive and reliable detection of MCAO on NECT.
Article
Quantitative and qualitative evaluation of middle cerebral artery (MCA) density, together with extent of thrombi, was assessed on plain computerized tomography (CT) to delineate better the prognostic value of the hyperdense MCA sign (HMCAS) in a cohort of patients who underwent intravenous or intra-arterial thrombolysis. Density of MCA was quantified by maximum pixel-sized measurement of Hounsfield unit (HU) in 105 patients with acute MCA proximal segment occlusion, 15 patients with vertebrobasilar circulation stroke (VBS) and 44 nonstroke control subjects. Predictive value of HMCAS, absolute HU value of within MCA, side-to-side HU ratio, and difference along with a newly introduced hyperdense MCA burden score in early dramatic recovery (EDR) and third-month favorable prognosis were determined with multivariate adjustment for age, baseline stroke severity, and thrombus length as measured on CT angiography. Receiver operator characteristics (ROC) curves were used to determine the cutoffs of quantitative indices to determine HMCAS and their prognostic significance. Higher HU was present in the ipsilateral MCA of the patients compared with their contralateral side and basilar tip and any MCA of VBS stroke and control subjects (area under the curve [AUC] of ROC curves was .753). Symptomatic-to-asymptomatic HU difference and ratio of MCA stroke were also significantly higher than side-to-side difference calculated in VBS stroke and control groups (AUC of ROC curves: .770 and .764, respectively). Optimal thresholds of absolute HU (44), side-to-side HU difference (2), and ratio (1.0588) showed borderline sensitivity and specificity. HMCAS and its quantitative indices were not significantly associated with EDR and favorable third-month outcome. Furthermore, there was no difference in terms of cardioembolic and atherothrombotic thrombi HU. Utility of the HMCAS as a prognostic marker in stroke thrombolysis is not high in the CT angiography era. Previous observation regarding its positive prognostic role can be attributed to its association with proximal location and extent of clot burden, which are detectable reliably with current CT angiography techniques. Neither quantification nor extent of increased density seems to have clinical utility for treatment decision making in MCA strokes and prediction of emboli composition and response to recanalization attempt.
Article
Background: We sought to assess the hypothesis that length and volumes of middle cerebral artery (MCA) thrombus were associated with disappearance of the hyperdense middle cerebral artery sign (HMCAS) in acute ischemic stroke. Methods: This is a retrospective cohort study of acute ischemic stroke patients with MCA occlusion admitted to the University Hospital in Canada. The length and volumes of the HMCAS was measured on the plain CT by placing CTA images (CTA source images or MIP images) side-by-side. Results: Seventy-six patients with acute stroke having HMCAS on noncontrast CT (NCCT) with M1 MCA occlusion confirmed by CT angiography or digital subtraction angiography and received tPA. The treatments received were: IV tPA 41(53.9%) and endovascular treatment ± IV tPA 35 (46.1%). In the IV tPA group, the rate of disappearance varied depending on the baseline HMCAS length. Short length HMCAS (<10 mm) disappeared in 6/7 (85.7%) (P < .001). Medium length HMCAS (10-20 mm) disappeared in 9/24 (37.5%). No cases of long length HMCAS (>20 mm) disappeared (0/10) (P = .05). Rate of disappearance of HMCAS was found to be volume dependent (P < .002). Conclusion: HMCAS length >10 mm infrequently disappears with IV tPA suggesting a potential need for ancillary therapy in this group.
Article
Background and purpose: Can lysability of large vessel thrombi in acute ischemic stroke be predicted by measuring clot density on admission nonenhanced CT (NECT), postcontrast enhanced CT, or CT angiogram (CTA)? Methods: We retrospectively studied 90 patients with acute large vessel ischemic strokes treated with intravenous (IV) tPA, intra-arterial (IA) tPA, and/or mechanical thrombectomy devices. Clot density [in Hounsfield unit (HU)] was measured on NECT, postcontrast enhanced CT, and CTA. Recanalization was assessed by the Thrombolysis in Cerebral Infarction grading system (TICI) on digital subtraction angiography. Results: Thrombus density on preintervention NECT correlated with postintervention TICI grade regardless of pharmacological (IV tPA r=0.69, IA tPA r=0.72, P<0.0001) or mechanical treatment (r=0.73, P<0.0001). Patients with TICI≥2 demonstrated higher HU on NECT (mean corrected HU IV tPA=1.58, IA tPA=1.66, mechanical treatment=1.7) compared with patients with TICI<2 (IV tPA=1.39, IA tPA=1.4, mechanical treatment=1.3) (P=0.01, 0.006, <0.0001 respectively). There was no association between recanalization and age, sex, baseline National Institute of Health Stroke Scale, treatment method, time to treatment, or clot volume. Conclusions: Thrombi with lower HU on NECT appear to be more resistant to pharmacological lysis and mechanical thrombectomy. Measuring thrombus density on admission NECT provides a rapid method to analyze clot composition, a potentially useful discriminator in selecting the most appropriate reperfusion strategy for an individual patient.