Medicine

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Clinical Case Report

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r-tPA with loading dose of clopidogrel and
aspirin therapies for capsular warning syndrome
attributed to middle cerebral artery
atherosclerotic stenosis
A CARE-compliant case report
Jinghan Xu, MDa, Meiting Zhuang, MDa, Guanshui Bao, MD, PhDa, Yu Zhai, MDa, Guo-Yuan Yang, MD, PhDb,
∗
∗
Gang Xue, MDc,d, , Qiang Li, MD, PhDa,c,
Abstract
Rationale: The capsular warning syndrome (CWS) is a rare and special type of transient ischemic attacks (TIAs) syndrome. The

pathophysiology of CWS is very complicate, and intracranial atherosclerotic stenosis (ICAS) is rare cause. Moreover, the effective and
standard therapy has not yet been established.
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Patient concerns: A 47-year-old man experienced repeated and exacerbated TIAs of right hemiparesis and dysarthria. Fourteen
hours after the first episode of TIAs, he developed more severe right hemiparesis and dysarthria, the National Institute of Health
Stroke Scale (NIHSS) score was 12 points, and did not recover in a long time.
Diagnosis: The computed tomography (CT) angiography displayed high stenosis in the M1 segment of the left middle cerebral
artery. The patient was diagnosed as CWS with ICAS.
Interventions: Loading dose of clopidogrel and aspirin were started but were ineffective, then we used recombinant tissue
plasminogen (r-tPA) for thrombolysis therapy after repeat CT scan that showed small acute infarcts in the right putamen and no
bleeding.
Outcomes: The patient was successfully treated by r-tPA intravenous thrombolysis after loading dose of dual-anti-platelet. He

recovered rapidly, and the NIHSS score was 0 point, modified Rankin Scale score was 0 point, and Barthel Index score was 100
points at 3-month follow-up.
Lessons: r-tPA combined with loading dose of dual antiplatelet appears safe and effective in carefully selected CWS patients with
ICAS. The collection of similar cases and further randomized controlled trial research would be desirable.
Abbreviations: CT = computed tomography, CTA = computed tomography angiography, CWS = capsular warning syndrome,
ICAS = intracranial atherosclerotic stenosis, MCA = middle cerebral artery, NIHSS = National Institute of Health Stroke Scale, r-tPA =
recombinant tissue plasminogen, TIAs = transient ischemic attacks.
Keywords: capsular warning syndrome, dual anti-platelet, intracranial atherosclerotic stenosis, intravenous thrombolysis,
recombinant tissue plasminogen

Editor: N/A.
The patient has given his consents for this case report. Written informed consent was obtained from the patient for publication of this case report and accompanying
images.
This work was supported by a grant (Q.L., 17ZR1416200) from Shanghai Municipal Natural Science Foundation, a grant from Science and Technology Development
Program of Fengxian District (Q.L., 20181904).
The authors have no conflicts of interest to disclose.
a
Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, b Neuroscience and Neuroengineering Research
Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, c Department of Neurology, Fengcheng Hospital of Fengxian
District, Shanghai, d Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
∗

Correspondence: Gang Xue, Department of Neurology, Fengcheng Hospital of Fengxian District, 9983 Chuan Nan Feng Road, Shanghai 201411, China. Department
of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China (e-mail: 1050789227@qq.com), Qiang Li, Department of Neurology, Shanghai
Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China (e-mail: lqsmmu@126.com).
Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
How to cite this article: Xu J, Zhuang M, Bao G, Zhai Y, Yang GY, Xue G, Li Q. r-tPA with loading dose of clopidogrel and aspirin therapies for capsular warning
syndrome attributed to middle cerebral artery atherosclerotic stenosis: A CARE-compliant case report. Medicine 2020;99:9(e19247).
Received: 18 August 2019 / Received in final form: 8 December 2019 / Accepted: 20 January 2020
http://dx.doi.org/10.1097/MD.0000000000019247

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Xu et al. Medicine (2020) 99:9

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1. Introduction

therapy, and the attack duration extended longer time (Fig. 1).
Fourteen hours after the first episode of TIAs, he developed more
severe right hemiparesis and dysarthria, and the NIHSS score was
12 points (Fig. 1). The computed tomography angiography
(CTA) results showed that M1 segment of the left MCA was
highly stenosis, but the distal end of the M2 segment was well
clear (Fig. 2). Repeat CT scan showed small acute infarcts in the
right putamen and no bleeding. The loading dose of dual
antiplatelet treatments seemed to be ineffective in the acute phase,
and the patient declined to proceed for digital subtraction
angiography. We administered r-tPA (46.8 mg, 0.6 mg/kg) at 76
minutes after final unrecovered attack of right hemiparesis and
dysarthria. His NIHSS score immediately decreased to 10 points at
1 hour after r-tPA administration and further decreased to 2 points
at 24 hours post r-tPA administration. Brain CT at 24 hours post rtPA thrombolysis shows larger acute infarcts in the right putamen
and no bleeding, and then we continued aspirin, clopidogrel, and
statins treatment. He gradually recovered, the NIHSS score was 0
point, modified Rankin Scale score was 0 point, and Barthel Index
score was 100 points at 3-month follow-up.

The capsular warning syndrome (CWS) is a rare and special type
of transient ischemic attacks (TIAs) syndrome with a recurrent
stereotypical motor or sensory deficits (such as aphasia, aversion,
neglect) and no cortical signs.[1] The pathophysiology of CWS
has been suggested, such as hemodynamic impairment, microembolism from artery to artery or from the heart, vasospasm.[2]
Only few cases reported CWS was attributed to large artery
atherosclerotic stenosis.[1] About 40% to 60% of CWS patients
finally developed cerebral infarction within 10 days, but effective
and standard therapy has not yet been established.[1,2] Here we
reported a CWS patient attributed to middle cerebral artery
(MCA) atherosclerotic stenosis, and the patient was treated by
recombinant tissue plasminogen (r-tPA) intravenous thrombolysis after loading dose of dual antiplatelet with a good clinical
outcome.

2. Case presentation
A 47-year-old man with hypertension suddenly developed right
hemiparesis and dysarthria at 9 o’clock in the morning, and his
symptoms disappeared within a few minutes. He had a long
history of smoking and hypertension and was treated with
amlodipine 5 mg once a day in the past 2 years. He experienced
hemiparesis and dysarthria attack once again and also rapidly
recovered. He had a third stereotypical episode at around 4 PM,
and then was taken to our hospital immediately. He has
completely recovered when arriving at the emergency department
and the National Institute of Health Stroke Scale (NIHSS) score
was 0 point. No abnormalities such as bleeding or tumor were
found in the examination of brain computed tomography (CT)
scan. We treated him with clopidogrel 300 mg and aspirin tablets
300 mg immediately. Another 3 similar attacks occurred for 5
hours after administration of loading dose of the dual antiplatelet

3. Discussion
The prevalence of intracranial atherosclerotic stenosis (ICAS) is
higher in Oriental and Asian populations than in Western
populations, but there are few studies on the treatment and
mechanism of ICAS in patients with CWS. This study is the first
to report a CWS patient attributed to ICAS treated with r-tPA
thrombolysis and loading dose of dual antiplatelet with the good
clinical effect.
As regards the mechanisms of CWS, the atherosclerotic
stenosis of penetrating artery has been widely accepted by most
researchers at present.[3,4] The lenticulostriate arteries originating
from the MCA are the most commonly affected artery in CWS.

Figure 1. The clinical course of the patient. The horizontal bar shows the time course (hour); the vertical bar shows the National Institute of Health Stroke Scale
(NIHSS) score. CT = computed tomography, CTA = computed tomography angiography, NIHSS = National Institute of Health Stroke Scale, r-tPA = recombinant
tissue plasminogen.

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Figure 2. Brain CT and CTA of the patient. (A) Brain CT at 5 hours after the first episode of TIAs (the third TIAs) shows normal. (B) Brain CT at 14 hours after the first
episode of TIAs (repeat CT before r-tPA thrombolysis) shows small acute infarcts in the right putamen (white arrow). (C) Brain CT at 39 hours after the first episode of
TIAs (24 hours post r-tPA thrombolysis) shows larger acute infarcts in the right putamen (white arrow) and no bleeding. (D) Brain CTA shows M1 segment stenosis of
the left middle cerebral artery (white arrow). (E) The higher magnification of M1 segment stenosis(white arrow, Fig.2 E is the boxed area in Fig. 2D). CT = computed
tomography, CTA = computed tomography angiography, r-tPA = recombinant tissue plasminogen, TIAs = transient ischemic attacks.

were significantly prevented and the frequent TIAs episodes were
terminated. In previously reported cases of CWS, the recurring
episode was stabilized with plural antiplatelet therapy.[7] When
clopidogrel is started at a conventional doses, it takes several days
to get their antiplatelet effects, while a loading dose of them can
reach effective levels within 2 hours after administration.[8] So we
started loading dose of dual antiplatelet therapy (clopidogrel 300
mg + aspirin 300 mg) at the early stage for the patient. However,
initially loading dual antiplatelet therapy was not effective in our
case. For the first time, we gave an extra intravenous r-tPA
therapy after loading dose of dual antiplatelet for CWS with
ICAS.
The most crucial goal is the prevention of infarction for CWS.
The case showed that progressive symptoms were unresponsive
to loading dose of dual antiplatelet. Theoretically, r-tPA is
effective for not only dissolving fibrin thrombus in the stenosis
region of MCA but also microthrombus at the origin of the
lenticulostriate artery. Vivanco-Hidalgo et al[9] treated 4 CWS
patients with intravenous thrombolysis, and 3 of them made a full
recovery with no lesion presented in DWI. Camps-Renom et al[10]
reported that 8 of 12 patients with r-tPA had a good prognosis.
There was a case of CWS without ICAS that was successfully
treated with r-tPA and other antithrombotic therapies.[11]
However, there were also some discrepancies in the current

Although multiple studies have confirmed the penetrating artery
mechanism of CWS,[3,4] the pathophysiology of large vascular
atherosclerosis has not yet been fully elucidated. The perfusion
deficits of large intracranial artery may lead to CWS, but the case
is rare. Donnan et al’s[1] study reported only 1 patient with
ipsilateral MCA stenosis among 50 CWS patients, which was
caused by the stenosis of the left MCA and the hypoperfusion of
the penetrating artery area. In this case, the M1 segment stenosis
of the left MCA leads to the hypoperfusion and the formation of
thrombosis which blocks the origin of the penetrating artery,
which results in recurrent TIAs. The pathogenesis of CWS caused
by ICAS is mainly due to the obstruction of the proximal portions
of penetrating artery and the microembolism from artery to
artery.
The lack of effective and standard therapy for CWS is a
potential dilemma to the future study, especially for the CWS
patient with ICAS. Several reports have showed loading dose of
dual antiplatelet therapy for CWS patients had a good clinical
effect. Kawano et al[5] reported that a loading dose of clopidogrel
was given for CWS patient when the 10th episode appeared after
initially treating with aspirin, argatroban, and cilostazol, and
finally the symptoms did not recur. Asil et al[6] developed a
loading dose of double antiplatelet strategy (clopidogrel and
aspirin 300 mg each) for 2 patients with CWS, and the symptoms
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reports of IV r-tPA therapy for CWS patient. Tassi et al[12]
reported that intravenous thrombolysis did not prevent the
evolution of CWS, and didn’t demonstrate higher efficacy than
other treatments at 3-month follow-up. All reports confirmed
that r-tPA thrombolysis for CWS patients did not significantly
increase the probability of any symptomatic intracranial
hemorrhages. In our case, the pathogenesis of CWS was
associated with highly atherosclerotic stenosis of MCA. This
patient suffered the frequent and extended TIAs duration, and
has a high risk of cerebral infarctions. We supposed r-tPA may be
an effective and safe treatment in our case. Our result also
actually showed r-tPA was effective and safe on CWS patient with
ICAS. This is the first case of CWS patient attributed to
atherosclerotic stenosis of intracranial artery, who was treated
with loading dose of dual antiplatelet combination with r-tPA.
The presence of left MCA atherosclerotic stenosis was
confirmed by CTA diagnosis, but endovascular intervention
therapy was not performed because of informed consent
problem. Lee et al[13] reported a case of CWS patient with
MCA stenosis, who got a favorable prognosis after receiving
intravascular intervention treatment to improve the perfusion of
the perforating artery. However, we recommend to early r-tPA
combined with loading dose of dual antiplatelet treatment for
CWS patients with ICAS in a primary hospital lack of
neurointervention condition. Furthermore, previous CWS
thrombolysis cases showed that the prognosis was closely related
to r-tPA treatment time window.[7,11,12,14] The time window
always was delayed because r-tPA thrombolysis usually was used
in the patients with high-frequency TIAs, long duration, and high
NIHSS score at onset. Therefore, CWS patients who have 3 times
TIAs episodes or any ischemic symptoms lasting more than 30
minutes, should be evaluated according to the acute ischemic
stroke guidelines.

Investigation: Jinghan Xu, Guanshui Bao.
Project administration: Gang Xue, Qiang Li.
Resources: Qiang Li.
Software: Guanshui Bao.
Supervision: Gang Xue, Qiang Li.
Validation: Gang Xue, Qiang Li.
Visualization: Jinghan Xu.
Writing – original draft: Jinghan Xu, Meiting Zhuang.
Writing – review & editing: Yu Zhai, Guo-Yuan Yang, Qiang Li.
Qiang Li orcid: 0000-0003-1350-4008.

References
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syndrome: pathogenesis and clinical features. Neurology 1993;43:
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[2] Paul NL, Simoni M, Chandratheva A, Rothwell PM. Population-based
study of capsular warning syndrome and prognosis after early recurrent
TIA. Neurology 2012;79:1356–62.
[3] Staaf G, Geijer B, Lindgren A, Norrving B. Diffusion-weighted MRI
findings in patients with capsular warning syndrome. Cerebrovasc Dis
2004;17:1–8.
[4] Caplan LR. Intracranial branch atheromatous disease: a neglected,
understudied, and underused concept. Neurology 1989;39:1246–50.
[5] Kawano H, Nakajima M, Inatomi Y, et al. Loading dose of clopidogrel in
combination with other antithrombotic therapy for capsular warning
syndrome. J Stroke Cerebrovasc Dis 2014;23:1265–6.
[6] Asil T, Ir N, Karaduman F, et al. Combined antithrombotic treatment
with aspirin and clopidogrel for patients with capsular warning
syndrome: a case report. Neurologist 2012;18:68–9.
[7] Kamo H, Miyamoto N, Otani H, et al. The importance of combined
antithrombotic treatment for capsular warning syndrome. J Stroke
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[8] Diener HC, Bogousslavsky J, Brass LM, et al. MATCH investigatorsAspirin and clopidogrel compared with clopidogrel alone after recent
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(MATCH): randomised, double-blind, placebo-controlled trial. Lancet
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[9] Vivanco-Hidalgo RM, Rodriguez-Campello A, Ois A, et al. Thrombolysis in capsular warning syndrome. Cerebrovasc Dis 2008;25:508–10.
[10] Camps-Renom P, Delgado-Mederos R, Martinez-Domeno A, et al.
Clinical characteristics and outcome of the capsular warning syndrome: a
multicenter study. Int J Stroke 2015;10:571–5.
[11] Fuseya Y, Kawamura M, Matsuda E, et al. rt-PA with antithrombotic
therapies in a case with capsular warning syndrome. Intern Med
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[12] Tassi R, Cerase A, Acampa M, et al. Stroke warning syndrome: 18 new
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[13] Lee J, Albers GW, Marks MP, Lansberg MG. Capsular warning
syndrome caused by middle cerebral artery stenosis. J Neurol Sci
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[14] Gonzalez Hernandez A, Fabre Pi O, Cabrera Naranjo F, et al.
Intravenous thrombolysis with recombinant tissue plasminogen activator in vascular warning syndromes. Neurologia 2014;29:334–8.

4. Conclusion
CWS with ICAS is rare, and this case suggests r-tPA combined
with loading dose of dual antiplatelet appears safe and effective
on carefully selected CWS patients with ICAS. The collection of
similar cases and further randomized controlled trial research
would be desirable.

Author contributions
Conceptualization: Gang Xue, Qiang Li.
Data curation: Jinghan Xu, Meiting Zhuang.
Funding acquisition: Qiang Li.

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