Stroke

ILLUSTRATIVE TEACHING CASE

Section Editors: Sophia Sundararajan, MD, PhD and Shadi Yaghi, MD

Severe Acute Respiratory Syndrome Coronavirus

2 Infection and Ischemic Stroke
Eduard Valdes Valderrama, MD; Kelley Humbert, MD; Aaron Lord, MD; Jennifer Frontera, MD;
Shadi Yaghi , MD

CASE angiography, which demonstrated a partially occlusive

left terminal internal carotid artery thrombus extending
A 52-year-old man with essential hypertension initially
into the left anterior cerebral artery and middle cerebral
presented to a local emergency department with short-
artery with occlusion of the proximal left middle cerebral
ness of breath, cough, and fever. He was prescribed
artery. Mechanical thrombectomy was performed without
azithromycin and discharged home. On day 7, he repre-
the use of general anesthesia with restoration of flow
sented to a primary stroke center emergency department
from Thrombolysis in Cerebral Infarction 0 to Thromboly-
with sudden onset of right hemiparesis and aphasia. Upon
sis in Cerebral Infarction 2A (Figure 2).
arrival, his blood pressure was 150/94 mm Hg, and his
He was admitted to the stroke unit for further man-
National Institutes of Health Stroke Scale score was 20
agement. The reverse-transcriptase–polymerase-chain-
for global aphasia, left gaze preference, and right-sided
partial hemianopia, facial weakness, severe hemiparesis, reaction assay of a nasopharyngeal sample was positive
and hemianesthesia. He underwent a noncontrast com- for severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2). He was empirically treated with hydroxy-
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puted tomography (CT) of the brain which was reported

as negative for acute hemorrhage but showed a hyper-
density of the M1 segment of the left middle cerebral
artery. He subsequently had a CT angiography that dem-
onstrated a left intracranial internal carotid artery occlu-
sion. He was within the intravenous thrombolysis window,
and no contraindication for treatment was identified. He
received intravenous alteplase and was then transferred
to our comprehensive stroke center for consideration of
mechanical thrombectomy.
Upon arrival to the comprehensive stroke center, the
patient’s blood pressure was 146/98 mm Hg, and his
neurological deficits were persistent. A chest radiograph
was within normal and a noncontrast CT of the head was
repeated which showed early infarct signs of in the left
basal ganglia, internal capsule, caudate head, insular rib-
bon, operculum, and right posterior frontal lobe with an
Alberta Stroke Program Early CT Score of 5. CT perfusion
imaging of the brain was obtained to ensure that there
was salvageable tissue and showed a favorable mis-
match ratio of 4.1 (Figure 1). He underwent conventional
chloroquine, and his cough gradually resolved. He did
not develop complications of pneumonia, increased
work of breathing, or fever. Additional workup revealed:
BNP (B-type natriuretic peptide) 193 pg/mL, D-dimer
>10 000 ng/mL, fibrinogen 235 mg/dL, ferritin 588
µg/L, CRP (C-reactive protein) 11 mg/L, erythrocyte
sedimentation rate 37 mm/h, HIV nonreactive, and a
urine drug screen on admission was negative. Hemo-
globin A1c and LDL (low-density lipoprotein) levels
were normal. Electrocardiogram and cardiac telemetry
monitoring did not reveal any arrhythmias. Transtho-
racic echocardiography showed normal cavity size and
wall thickness of the left ventricle, an ejection fraction
of 63%, and no evidence of a cardiac source of emboli
or patent foramen ovale. A follow-up CT showed a left
MCA territory infarction with petechial hemorrhage (Fig-
ure 1). His stroke cause remained cryptogenic. Due to
the potential risk of worsening hemorrhagic transforma-
tion with anticoagulation therapy, he was discharged to
acute rehabilitation on aspirin and statin with plans for

Key Words: aspirin ◼ computed tomography angiography ◼ COVID-19 ◼ fibrinogen ◼ hydroxychloroquine

 
Correspondence to: Shadi Yaghi, MD, Department of Neurology, New York University School of Medicine, 150 55th St, Brooklyn, NY 11220. Email shadiyaghi@
yahoo.com
IRB approval: Since this is a case report, study approval and informed consent were waived by the Institutional Review Board.
© 2020 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

e124   July 2020 Stroke. 2020;51:e124–e127. DOI: 10.1161/STROKEAHA.120.030153

 Valderrama et al
Figure 1. Left, computed tomography (CT) perfusion study with 51 mL of core infarction and mismatch volume of 122 mL.
Right, Follow-up CT scan at 24 h with a middle cerebral artery infarction and petechial hemorrhage.
outpatient cardiac monitoring. At the time of discharge,
he had moderate aphasia and improved strength (Medi-
cal Research Council grade 3/5) in the right arm and leg.
DISCUSSION
Coronavirus disease 2019 (COVID-19) is an infectious
respiratory disease caused the novel coronavirus, SARS-
CoV-2. There is limited data on the co-occurrence of stroke
and COVID-19 infection. Our article highlights acute man-
agement, prevention, and recovery in patients with COVID-
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19 and stroke. Our patient was screened for COVID-19,
received alteplase and mechanical thrombectomy, and
underwent a diagnostic evaluation to determine the potential
mechanism. He was also discharged to acute rehabilitation.
Given that COVID-19 confirmed cases are over 1 million
globally and continue to rise, understanding the relation-
ship between COVID-19 and ischemic stroke will be criti-
cal for stroke prevention, surveillance, and management.
A recent retrospective study from Wuhan, China began
to address the potential relationship between COVID-19
and neurological conditions, including stroke.1 These may
occur in up to 50% of patients and include headache,
dysautonomia, anosmia and ageusia, stroke (ischemic or
Stroke. 2020;51:e124–e127. DOI: 10.1161/STROKEAHA.120.030153
Stroke in COVID-19
Illustrative Teaching Case
hemorrhagic), seizures, encephalopathy, and necrotizing
encephalitis. The exact mechanism(s) of central nervous
system involvement with COVID-19 remain unclear but
are possibly due to direct central nervous system invasion
through the systemic circulation or a retrograde neuronal
route through the cribriform plate. Alternatively, systemic
processes of such as a cytokine storm/immune or hypox-
emia may contribute to neurological injury.2
Stroke is one of the complications reported in patients
with COVID-19 infection, occurring in ≈2% of patients dur-
ing their hospitalization.1 This, however, does not provide evi-
dence of causality between the 2. This is particularly the case
since hospitalized patients with COVID-19 and ischemic
stroke share overlapping risk factors.3 Alternatively, there is
some indirect evidence that in some patients with COVID-
19 and ischemic stroke, COVID-19 may be the culprit.
The relationship between infection and ischemic stroke
is well-established. Infection increases the odds of stroke
by 1.4-fold particularly early in convalescence.4 A similar
relationship might be expected from infection by the novel
coronavirus SARS-CoV-2, which causes COVID-19.
On top of the general association between infection and
stroke, there are potential links between COVID-19 and
stroke that may be more specific to COVID-19. SARS-CoV-2
Figure 2. Left, initial cerebral
angiogram showing thrombus in the
middle and anterior cerebral arteries.
Right, post-treatment cerebral angiogram
showing Thrombolysis in Cerebral
Infarction 2A reperfusion of the affected
territory.
July 2020   e125
 Valderrama et al Stroke in COVID-19
Illustrative Teaching Case
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Figure 3. Pathophysiology of stroke in patients with severe acute respiratory syndrome coronavirus 2 infection.
ACE-2 indicates angiotensin-converting enzyme II; COVID-19, coronavirus disease 2019; DIC, disseminated intravascular coagulation; ESUS,
embolic stroke of undetermined source; and SIRS, systemic inflammatory response syndrome.

can enter myocardial cells via the ACE2 (angiotensin-
converting enzyme II) receptor, which is heavily expressed
in myocardium, vascular endothelium, and arterial smooth
muscle.5 This distribution could make these organ sys-
tems focally susceptible to SARS-CoV-2 infection, causing
inflammation and injury to the myocardium, predisposing to
thrombogenesis and stroke risk. In addition, COVID-19 has
been shown to create a prothrombotic state associated with
increased D-dimer levels, thus increasing the risk of throm-
botic complications including stroke.6 In fact, in one study,
25% of patients with severe SARS infection had evidence
of venous thromboembolism, this is particularly the case
with D-dimer levels >1.5 µg/mL.7 Moreover, SARS-CoV-2
appears to be associated with a hyperinflammatory state, or
cytokine storm associated with increased IL-6 (interleukin-6)
levels8 resulting in hyperviscosity and stroke risk. Finally, as
with other coronavirus,9 SARS-CoV-2 can potentially cause
vascular endothelial damage and increased risk for spon-
taneous intracerebral hemorrhage and microthrombosis
of small penetrating arteries and cervical artery dissection
of larger arteries. Furthermore, SARS-CoV-2 is associated
with a fibrinogen consumption coagulopathy either from
metabolic acidosis or disseminated intravascular coagulation
increasing the risk of intracranial hemorrhage.
SARS-CoV-2 is widely spread in the community includ-
ing those at increased risk of ischemic stroke. Therefore, a

e126   July 2020 Stroke. 2020;51:e124–e127. DOI: 10.1161/STROKEAHA.120.030153

 Valderrama et al
Take-Home Points
• An important question that remains unanswered
is whether coronavirus disease 2019 (COVID-19)
affects the likelihood of ischemic stroke independent
of stroke risk factors.
• This risk of stroke may be increased in patients with
COVID-19 due to direct damage to the heart and vas-
cular endothelium, markedly elevated inflammation,
and elevation of prothrombotic factors.
• Understanding the neurotropic mechanisms of corona-
viruses that have caused disease outbreaks in the past
certain proportion of patients with ischemic stroke in setting
of SARS-CoV-2 may have a well-established non-SARS-
CoV-2 stroke mechanism. Thus, patients with COVID-19
with ischemic stroke should undergo a diagnostic evalu-
ation to look for non-COVID related stroke mechanisms,
as illustrated with our patient and this includes a brain
imaging, intracranial and extra-cranial vascular imaging,
echocardiography, cardiac telemetry, and outpatient car-
diac monitoring in those whose stroke is cryptogenic.10 In
addition to the standard diagnostic evaluation, checking
coagulation markers such as D-dimer and fibrinogen lev-
els and inflammatory markers such as CRP and IL-6 levels
may help determine whether the patient has an underly-
ing prothrombotic or inflammatory response and may help
guide treatment. Our patient received a complete diagnos-
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tic evaluation, and his stroke remained cryptogenic upon
discharge. It is noteworthy that our patient had an elevated
D-dimer suggesting acquired hypercoagulability in the
setting of SARS-CoV-2 as potential mechanism.
Understanding the factors associated with stroke in
COVID-19 can lead to identifying therapeutic targets and
reducing stroke risk. Studies thus far have failed to a ben-
efit of anticoagulation in patients with cryptogenic stroke,
those with cryptogenic stroke in the setting of SARS-
CoV-2 infection may be a subgroup who may where
anticoagulation versus antiplatelet therapy can be tested.
This is particularly the case in those whose D-dimer level
is elevated. In addition, more research is needed to bet-
ter understand the impact of inflammation on stroke risk
in patients with COVID-19 and whether novel treatment
options such as IL-6 inhibitors can reduce this risk.
Finally, while it is challenging to perform acute reha-
bilitation in patients with COVID-19 infection due to the
need for isolation and the potential for infection spread,
patients with COVID-19 may benefit from acute rehabili-
tation. Our patient was discharged to acute rehabilitation
and on last follow-up, his aphasia and motor strength had
significantly improved.
CONCLUSIONS
Stroke can be seen in patients with SARS-CoV-2 infec-
tion and the mechanisms of stroke could be related to
Stroke. 2020;51:e124–e127. DOI: 10.1161/STROKEAHA.120.030153
Stroke in COVID-19
Illustrative Teaching Case
can provide valuable knowledge to reduce the morbid-
ity of COVID-19.
• Patients with COVID-19 and ischemic stroke should
undergo standard diagnostic evaluation. Additionally, we
recommend checking coagulation markers such as D-dimer
and fibrinogen levels and inflammatory markers such as
CRP (C-reactive protein) and IL-6 (interleukin-6).
• Future research is needed to study the effect of
rehabilitation strategies on outcomes in patients with
COVID-19 infection.
conventional mechanisms or related directly to SARS-
CoV-2 infection (Figure 3). Studies are needed to under-
stand those mechanisms and potential treatments such
as anticoagulation therapy to decrease stroke risk in this
vulnerable population.
ARTICLE INFORMATION
Affiliation
Department of Neurology, NYU Langone Health, New York, NY.
Acknowledgments
Drs Yaghi and Valdez contributed to study design and drafting article. Drs Hum-
bert, Frontera, and Lord contributed to article revision.
Disclosures
Dr Yaghi reports funding from Medtronic. The other authors report no conflicts.
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