Intravenous Thrombolysis for Acute Ischemic Stroke due to

Cervical Internal Carotid Artery Occlusion

Leonard L. L. Yeo, MBBS, MRCP,* Wan Yee Kong, MBBS,* Prakash Paliwal, MBBS,*
Hock L. Teoh, MBchB,* Raymond C. Seet, MBBS,*† Derek Soon, PhD,*
Rahul Rathakrishnan, MBBS,* Venetia Ong, BDS,* Tsong-Hai Lee, MBBS,‡§
Ho-Fai Wong, MBBS,§‖ Bernard P. L. Chan, MBBS,* Wee Kheng Leow, PhD,¶
Cheng Yuan, PhD,¶ Eric Ting, MBBS,# Anil Gopinathan, MBBS,#
Benjamin Y. Q. Tan, MBBS,* and Vijay K. Sharma, MBBS*†

Background: Internal carotid artery (ICA) occlusions are poorly responsive to in-
travenous thrombolysis with tissue plasminogen activator (IV-tPA) in acute ischemic
stroke (AIS). Most study populations have combined intracranial and extracra-
nial ICA occlusions for analysis; few have studied purely cervical ICA occlusions.
We evaluated AIS patients with acute cervical ICA occlusion treated with IV-tPA
to identify predictors of outcomes. Methods: We studied 550 consecutive patients
with AIS who received IV-tPA and identified 100 with pure acute cervical ICA
occlusion. We evaluated the associations of vascular risk factors, National Insti-
tutes of Health Stroke Scale (NIHSS) score, and leptomeningeal collateral vessel
status via 3 different grading systems, with functional recovery at 90 days, mor-
tality, recanalization of the primary occlusion, and symptomatic intracranial
hemorrhage (SICH). Modified Rankin Scale score 0-1 was defined as an excellent
outcome. Results: The 100 patients had mean age of 67.8 (range 32-96) and median
NIHSS score of 19 (range 4-33). Excellent outcomes were observed in 27% of the
patients, SICH in 8%, and mortality in 21%. Up to 54% of the patients achieved
recanalization at 24 hours. On ordinal regression, good collaterals showed a sig-
nificant shift in favorable outcomes by Maas, Tan, or ASPECTS collateral grading
systems. On multivariate analysis, good collaterals also showed reduced mortal-
ity (OR .721, 95% CI .588-.888, P = .002) and a trend to less SICH (OR .81, 95%
CI .65-1.007, P = .058). Interestingly, faster treatment was also associated with fa-
vorable functional recovery (OR 1.028 per minute, 95% CI 1.010-1.047, P = .001).
Conclusions: Improved outcomes are seen in patients with early acute cervical ICA
occlusion and better collateral circulation. This could be a valuable biomarker for

From the *Division of Neurology, Department of Medicine, National University Health System, Singapore; †Yong Loo Lin School of Med-
icine, National University of Singapore, Singapore; ‡Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan;
§College of Medicine and School of Medical Technology, Chang Gung University, Taoyuan, Taiwan; ‖Division of Neuroradiology, Depart-
ment of Medical Imaging and Intervention, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; ¶Department of Computer Science,
National University of Singapore, Singapore; and #Department of Diagnostic Imaging, National University Health System, Singapore.
Received March 31, 2016; revision received May 15, 2016; accepted June 8, 2016.
Ethical approval for this project was obtained from the institutional review board (IRB).
Address correspondence to Leonard Leong Litt Yeo, MBBS, MRCP, Division of Neurology, Department of Medicine, National University
Health System, 1 E Kent Ridge Road, Singapore 119228. E-mail: leonard_ll_yeo@nuhs.edu.sg.
1052-3057/$ - see front matter
© 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.06.014

Journal of Stroke and Cerebrovascular Diseases, Vol. 25, No. 10 (October), 2016: pp 2423–2429 2423

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2424 L.L.L. YEO ET AL.
decision making. Key Words: Acute ischemic care—intracranial collaterals—CT
angiography—thrombolysis.
© 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Introduction hours after thrombolysis. AIS subtypes were deter-

mined by using the TOAST (Trial of Org 10172 in Acute
The major aim of intravenous thrombolysis with tissue
Stroke Treatment) classification.13 The National Insti-
plasminogen activator (IV-tPA) in acute ischemic stroke
tutes of Health Stroke Scale (NIHSS) scores were recorded
(AIS) is to achieve recanalization of the occluded intra-
for all cases by credentialed neurologists before IV-tPA
cranial artery, which in turn is an important predictor
bolus, at 2 hours, and 24 hours after treatment initiation.
of favorable clinical outcome.1,2 Various studies have proven
CTA was repeated at 24 hours. Scans were performed
that the IV-tPA-induced recanalization rates vary with the
on a 64-slice multidetector helical scanner (Philips Inc,
site of arterial occlusion.1-4 Systemic thrombolysis with
Cleveland, OH, USA) and images were acquired with
IV-tPA continues to be the primary standard of care.4 Al-
70 mL bolus injection of contrast. Scan parameters were
though endovascular therapy is an effective modality in
as follows: slice thickness 1 mm; no slice gap; field of view
patients who fail to achieve arterial recanalization with
200 mm; matrix 512 × 512, and mAs 230-250. Coverage
IV-tPA, the techniques are resource intensive and not widely
was from the base of skull to the vertex and the source
available.5
images were reformatted into 3-mm-thick axial, coronal,
Thrombotic occlusion of the internal carotid artery (ICA)
and sagittal projections. CTA images were indepen-
is associated with large infarct size and poor functional
dently reviewed by 2 experienced neuroradiologists using
outcome.6 Studies on isolated ICA occlusions are scarce,
maximum intensity projections in the axial planes. They
tend to combine intracranial and cervical ICA occlu-
were blinded to the patients’ clinical status, outcome, or
sions, and can reach contrasting conclusions.7-9 Only few
results of other neuroimaging modalities.
studies have focused on the response to IV-tPA in pa-
The recanalization status was determined by arterial
tients with primary acute occlusion of cervical ICA.10-12
occlusive lesion grading, with grades 2 and 3 consid-
These disparate populations may have different hemo-
ered as “recanalized” whereas grades 0 and 1 were
dynamic properties and response to IV-tPA.8 We identified
classified as an “occluded” artery.14 The leptomeningeal
AIS patients with primary occlusion of cervical ICA from
collateral status on the prethrombolysis CTA was as-
our thrombolysis cohort and analyzed them for the de-
sessed by 3 predefined criteria—Maas, Tan, and ASPECTS
terminants of functional outcome. We hypothesize that
collaterals, which have been previously described.15-19
there are factors that may be associated with better out-
Functional outcome was assessed by the modified Rankin
comes with IV-tPA treatment in this group.
Scale (mRS) at 3 months. An mRS score of 0-1 repre-
sented a favorable functional outcome. Symptomatic
Methods intracranial hemorrhage (SICH) was defined as the pres-
ence of new blood on the follow-up CT scan that was
Consecutive patients treated between 2010 and 2014 were
associated with an increase in NIHSS by 4 points or
included. All AIS patients presenting within the throm-
more.20,21
bolysis window of 4.5 hours undergo noncontrast
computed tomography (CT) of the brain and CT angi-
ography (CTA) of the cervico-cranial arterial tree. We
Statistical Analysis
identified all patients with primary occlusion of cervi-
cal ICA on the prethrombolysis CTA. Patients with primary We present the numerical variables as mean and stan-
intracranial ICA occlusions, tandem lesions, carotid-L oc- dard deviation (SD) or median and range. Categorical
clusions, and carotid-T occlusions (n = 27) were excluded. variables are presented as percentages. Numerical pre-
However, as the CTA scans did not have a delayed phase, dictors were assessed by using independent-samples t-test
we were unable to absolutely rule out these lesions. All or Mann–Whitney U-test where applicable. Categorical
patients received a standard dose of IV-tPA (.9 mg/kg body variables were evaluated using Pearson chi-square test
weight). Further details of the inclusion and exclusion or Fisher exact test where applicable. Variables that were
criteria are provided in the Supplementary section. found to have a significant association (P < .05) were entered
Data for demographic characteristics and vascular risk into the multivariable model using backward stepwise
factors such as hypertension, diabetes mellitus, selection procedure to perform logistic regression for de-
dyslipidemia, atrial fibrillation, and smoking were then termining the independent predictors of mortality and
extracted from the registry. Systemic blood pressure values SICH. In addition, the association of the various collat-
were recorded for all patients at presentation and at 24 eral grading with 3-month functional outcome was also

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INTRAVENOUS THROMBOLYSIS FOR AIS DUE TO CERVICAL ICA OCCLUSION 2425
estimated with multivariable ordinal logistic regression Table 1. Baseline patient characteristics of the study cohort
as adjusted odds ratio (OR) for a shift in the direction
of a better outcome on the mRS ranking.22 The ORs were Characteristics N = 100
adjusted by including the following baseline patient
Median age (range) (years) 69 (34-96)
characteristics in the multivariable model: diabetes, re-
Female sex (%) 35 (35.0)
canalization status, onset-to-treatment time, and baseline Hypertension (%) 73 (73.0)
NIHSS score. Associations are presented as OR with Dyslipidemia (%) 58 (58.0)
corresponding 95% confidence intervals (CI). Finally, Diabetes mellitus (%) 35 (35.0)
interobserver and intraobserver variability for assess- Smoker (%) 25 (25.0)
ment of collateral status between the 2 observers was tested Atrial fibrillation (%) 42 (42.0)
using kappa statistics. Statistical analyses were per- Mean pre-tPA systolic BP (SD) (mmHg) 154.1 (26.5)
formed using the Statistical Package for Social Sciences Median pre-tPA NIHSS score (range) 19 (4-33)
(SPSS, Armonk, NY: IBM Corp) version 20. Mean onset-to-treatment time 169.2 (42.8)
(SD) (min)
Modified Rankin Scale 0-1 at 27 (27.0)
Results 3 months (%)
Symptomatic intracranial hemorrhage (%) 12 (12.0)
In this retrospective analysis of a prospectively col- Mortality (%) 21 (21.0)
lected database, we sampled 1160 patients who were Recanalization (%) 54 (54.0)
within the 4.5-hour time window for tPA; 287 were ex- TOAST criteria
cluded for reasons of being stroke mimics or due to Large artery atherosclerosis (%) 46 (46.0)
contraindications to IV-tPA. Of the 873 patients who re- Cardioembolic (%) 46 (46.0)
ceived IV-tPA, we included in our study 100 consecutive Lacunar (%) 0 (0)
AIS patients with acute occlusion of cervical ICA treated Undetermined cause (%) 5 (5.0)
with IV-tPA. The median age of the cohort was 69 years Stroke of other etiology (%) 3 (3.0)
(range 34-96) and 65 patients were male. The mean onset-
Abbreviations: BP, blood pressure; NIHSS, National Institutes of
to-treatment time was 169.2 minutes (SD 42.8 minutes). Health Stroke Scale; SD, standard deviation; TOAST, Trial of Org
Favorable functional outcome at 3 months was achieved 10172 in Acute Stroke Treatment; tPA, tissue plasminogen activator.
in 27% of the patients, whereas 21% died and 12% de-
veloped SICH. The recanalization rate (noted on the CTA
performed at 24 hours) for acute cervical ICA occlusion Mortality and SICH
was 54% (Table 1). The degree of agreement between the Interestingly, good collaterals by ASPECTS methodol-
2 independent neuroradiologists for interpreting the ogy were the only variable that showed a trend toward
collaterals by the different systems was the following: modi- less mortality (OR .68, 95% CI .56-.82, P < .001) and SICH
fied Tan system (κ = .93, 95% CI .91-.95), Maas system (OR .74, 95% CI .60-.91, P = .004) (Tables 3 and 4).
(κ = .82, 95% CI .75-.84 for leptomeningeal collateral status;
and κ = .87, 95% CI .80-.91 for Sylvian fissure vessels),
Discussion
and ASPECTS-based grading system (κ = .77, 95% CI
.70-.81). This is perhaps the largest study of AIS due to
pure cervical ICA occlusion. Our study shows that
prethrombolysis leptomeningeal collateral status is a sig-
Good Functional Outcome
nificant determinant of functional outcome.
Arterial recanalization was a major determinant of fa- The presence of ICA occlusion is fairly common and
vorable functional outcome (OR 37.96, 95% CI 2.85- affects 1 in 4 patients who are seen within 6 hours of
505.49, P = .006). Other favorable associations were mean carotid artery territory AIS.23 AIS associated with ICA oc-
onset-to-treatment time (OR .98 per minute, 95% CI .96- clusion is often associated with a large infarct and a
.99, P = .029) and pre-tPA NIHSS score (OR .83 per point, threefold increased likelihood of poor recovery.1,2,24 Com-
95% CI .71-.96, P = .01). Interestingly, good collaterals by pared to our knowledge about the rate of recanalization
Maas methodology were also associated with favorable for intracranial arterial occlusions in IV-tPA-treated pa-
functional outcome at 3 months (OR 25.51, 95% CI 4.05- tients, the recanalization rates for cervical ICA occlusions
160.67, P = .001) (Supplementary Table S1). The adjusted are largely unknown.25,26 The little available data provide
ORs for various collateral scoring methods for an ordinal conflicting results. While some studies report lower re-
shift toward better outcome on the entire range of mRS canalization rates and poor functional outcome with IV-
grades were as follows: Maas (OR 6.03, 95% CI 2.19- tPA, other studies show that the thrombolytic therapy may
16.61, P = .001); Tan (OR 5.05, 95% CI 2.11-12.01, P < .001); be beneficial in up to 50% of AIS patients.8,9,27 We ob-
and ASPECTS collateral methodology (OR 1.24 per point, served high (54%) recanalization rates in our patients with
95% CI 1.11-1.38, P < .001) (Table 2, Fig 1). pure cervical ICA occlusion. This could be due to the late

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2426 L.L.L. YEO ET AL.
Table 2. Ordinal analysis of variables for shift of mRS by 1 category

Odds ratios 95% CI P value Wald d.f.

Diabetes .218 .088-.541 .001 10.805 1

Good collaterals by Maas methodology 6.025 2.186-16.609 .001 12.053 1
Good collaterals by Tan methodology 5.054 2.111-12.099 <.001 13.229 1
Mean collaterals score by ASPECTS methodology 1.240 per point 1.112-1.382 <.001 14.993 1
Recanalization 4.111 1.654-10.219 .002 9.259 1
Onset-to-treatment time .987 per min .978-.997 .09 6.897 1
Mean NIHSS score at onset .864 per point .794-.918 <.001 18.292 1

Abbreviations: CI, confidence interval; d.f., degrees of freedom; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke
Scale.

evaluation on the day-2 CTA, which would have in-
cluded even the patients with delayed and spontaneous
recanalization. However, there may also be racial differ-
ences in coagulation and fibrinolysis factors.28
Most of the previous studies have focused on a mix
of intracranial and extracranial occlusions in acute stroke
using various modalities to confirm the occlusion.7-12 Few
have given sufficient details to differentiate the effect of
recanalization therapies on a single group of patients, such
as what we have done (extracranial ICA occlusions only).
Large vessel occlusion is associated with increased mor-
tality and there appear to be worse outcomes with ICA
occlusions, compared with other anterior circulation
occlusions.7 In the large vessel occlusion study, only 19%
of the patients with ICA occlusions had a good clinical
outcome, whereas 34% of M1 and 40% of M2 occlu-
sions had a good outcome. In a similar vein, 35% of ICA
occlusion patients died within 3 months compared with
24% for M1 and M2 occlusions.7 Our study, with a larger
number of extracranial ICA occlusion patients studied com-
pared to the large vessel occlusion series, had a slightly
higher incidence of better functional outcomes (27%) and
less mortality (21%), and this proportion improved with
good collaterals.
Overall, there seems to be a consensus that IV-tPA does
not produce good functional outcomes in ICA occlusion

Figure 1. The distribution of scores on the modified Rankin Scale for patients according to collateral grading by Maas methodology.

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INTRAVENOUS THROMBOLYSIS FOR AIS DUE TO CERVICAL ICA OCCLUSION 2427
Table 3. Determinants of mortality in patients with cervical ICA AIS after thrombolysis

Univariate analysis Multivariate analysis

Survived Death Odds ratio

(n = 79) (n = 21) P value (95% CI) P value

Female sex (%) 27 (34.2) 8 (38.1) .738

Mean age (year) (SD) 67.1 (13.9) 70.8 (11.8) .228
Hypertension (%) 56 (70.9) 17 (81.0) .356
Dyslipidemia (%) 45 (57.0) 13 (61.9) .683
Diabetes (%) 23 (29.1) 12 (57.1) .017
Smoker (%) 21 (26.6) 4 (19.0) .478
AF (%) 31 (39.2) 11 (52.4) .278
Good collaterals by Maas (%) 23 (29.1) 2 (9.5) .065
Good collaterals by Tan (%) 50 (63.3) 4 (19.0) <.001
Mean collaterals score by ASPECTS methodology (range) 7.8 (3.9) 3.1 (2.6) <.001 .68 (.56-.82) <.001
Recanalization (%) 48 (60.8) 6 (28.6) .062
ASPECTS ≤ 7 36 (45.6) 16 (76.2) .014
Mean onset-to-treatment time (min) (SD) 164.7 (44.2) 186.0 (33.0) .020
Mean NIHSS score at onset (range) 17.7 (6.3) 21.3 (4.8) .018
Mean SBP pre TPA (mmHg) (SD) 152.7 (24.6) 159.3 (32.6) .399

Abbreviations: AF, atrial fibrillation; AIS, acute ischemic stroke; CI, confidence interval; ICA, internal carotid artery; NIHSS, National
Institutes of Health Stroke Scale; SBP, systolic blood pressure; SD, standard deviation; tPA, tissue plasminogen activator.
Bold numbers is statistically significant variables.

patients; however, there appears to still have a benefit
albeit a modest one, in comparison to other anterior cir-
culation occlusions.7,8,10 Our study demonstrates that the
factors predicting favorable functional outcome in extra-
cranial ICA lesions appear to be similar to other anterior
circulation strokes, including lower pre-TPA NIHSS score,
faster onset-to-treatment time, arterial recanalization, and
the presence of good leptomeningeal collateral status.15,16,19
Our findings are consistent with recent studies which re-
ported that faster initiation of thrombolysis and early

Table 4. Determinants of SICH in patients with cervical ICA AIS after thrombolysis

Univariate analysis Multivariate analysis

No SICH With SICH Odds ratio

(n = 88) (n = 12) P value (95% CI) P value

Female sex (%) 27 (30.7) 8 (66.7) .014

Mean age (year) (SD) 68.5 (12.5) 62.8 (19.4) .165
Hypertension (%) 64 (72.7) 9 (75.0) .868
Dyslipidemia (%) 50 (56.8) 8 (66.7) .517
Diabetes (%) 28 (31.8) 7 (58.3) .071
Smoker (%) 22 (25.0) 3 (25.0) 1.000
AF (%) 37 (42.0) 5 (41.7) .980
Good collaterals by Maas (%) 24 (27.3) 1 (8.3) .155
Good collaterals by Tan (%) 52 (59.1) 2 (16.7) .006
Mean collaterals score by ASPECTS methodology (range) 7.3 (4.0) 3.3 (3.1) .001 .74 (.60-.91) .004
Recanalization (%) 49 (55.7) 5 (41.7) .433
ASPECTS ≤ 7 42 (47.7) 10 (83.3) .023
Mean onset-to-treatment time (min) (SD) 168.1 (43.0) 177.5 (42.6) .483
Mean NIHSS score at onset (range) 18.4 (6.4) 19.0 (5.1) .717
Mean SBP pre TPA (mmHg) (SD) 153.2 (26.3) 160.8 (28.0) .387

Abbreviations: AF, atrial fibrillation; AIS, acute ischemic stroke; CI, confidence interval; ICA, internal carotid artery; NIHSS, National
Institutes of Health Stroke Scale; SBP, systolic blood pressure; SD, standard deviation; SICH, symptomatic intracranial hemorrhage; tPA,
tissue plasminogen activator.
Bold numbers is statistically significant variables.

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2428
clinical improvement due to arterial recanalization re-
sulted in improved outcomes in AIS patients. 29,30
Importantly, we found that the pretreatment collateral status
plays a major role in determining functional outcome,
mortality, and SICH. Probably, the collaterals provide
alternative channels for the blood supply of ischemic pen-
umbra while awaiting recanalization. Furthermore,
intracranial collaterals may help in bringing higher amount
of tPA to the site of occlusion resulting in improved
recanalization.31 Regardless of the mechanism, our study
shows that the pretreatment collateral status could
serve as a potential surrogate marker in selecting AIS
patients with ICA occlusions for recanalization therapy,
and this should be further studied in patients undergo-
ing endovascular recanalization.
A consistent mode of imaging via pre-tPA and
24-hour CTA is one of the major strengths of our study.
This ensures a more reproducible determination of the
collateral status and recanalization status than previous
studies. In those studies, duplex sonography was uti-
lized to assess the ICA which is more operator dependent;
at other times, different modalities were used to scan
the ICA pre tPA and post tPA.24,32,33 This all can lead to
inconsistency in the analysis of the recanalization status.
Although this is perhaps the largest study for pure
cervical ICA occlusion, our conclusions need to be
proven in a larger prospective study. Our study is
limited by the moderate number of patients. In our
study, we also did not take into account the subset of
patients where significant stenosis persisted after IV-
tPA and who may have required an endarterectomy or
carotid stenting at a later date.
Recent studies have reinforced the suggestion that
endovascular treatment may be beneficial for cervical ICA
occlusion, especially for AIS patients who fail to respond
to the conventional thrombolytic therapy.34,35 Several of
these studies show that endovascular therapy appears to
convey a benefit over IV-tPA alone in acute strokes in-
volving the ICA.8,10,11 With the advent of endovascular
therapy used in combination with IV-tPA, the careful pre-
selection of suitable patients is crucial in maximizing clinical
outcomes. Our study findings propose important factors
to consider in selecting extracranial ICA occlusion pa-
tients for revascularization treatment using IV-tPA. We
believe that these factors, in particular the leptomenin-
geal collateral status, could potentially be extended to
extracranial ICA occlusion patients undergoing
endovascular therapy, but will definitely need to be evalu-
ated further in prospective studies. Currently, only a limited
proportion of stroke centers are able to provide acute
endovascular treatment. Moreover, time to recanaliza-
tion, whatever the therapeutic modality used, is a major
factor that can influence the patient’s long-term func-
tional outcome. In areas where neurointerventional facilities
are lacking, it is still vital to know the effect that IV-tPA
has on cervical ICA occlusions.
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L.L.L. YEO ET AL.
Conclusion
Intravenous thrombolysis should be rapidly adminis-
tered as first-line treatment in patients with acute cervical
ICA occlusion. Improved outcomes are seen in patients
with better collateral circulation and the collateral status
may serve as a valuable biomarker for further therapeu-
tic decision making.
Acknowledgment: This research was sponsored by the Na-
tional Medical Research Council (NMRC), Singapore (Grant
number: CNIG12nov001).
Appendix: Supplementary Material
Supplementary data to this article can be found online
at doi:10.1016/j.jstrokecerebrovasdis.2016.06.014.
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