Case Report

Paradoxical Cerebral Embolism as Initial Manifestation of
Chronic Thromboembolic Pulmonary Hypertension: A Case
Report
Akira Machida, MD, PhD,* Itsuki Soejima, MD,* Takeshi Bo, MD,*
Eiichiro Amano, MD,* Kiyobumi Ota, MD, PhD,* Yoshinori Kanno, MD,† and
Tsunekazu Kakuta, MD, PhD†
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by
chronic thrombi in the pulmonary arteries, causing pulmonary hypertension and
right heart failure. Early and accurate diagnosis are essential for successful treatment
but are often difficult because clinical signs and symptoms can be nonspecific and
risk factors, such as history of venous thromboembolism, may not always be present.
Here, we report a case involving a 76-year-old woman who demonstrated paradoxical cerebral embolism as the initial manifestation of CTEPH. She developed right
hemiplegia without dyspnea or edema. Brain magnetic resonance imaging revealed
multiple fresh infarctions, while transesophageal echocardiography revealed a patent
foramen ovale. Based on these findings, she was diagnosed as having paradoxical
cerebral embolism. During the search for the embolic source, right heart catheterization showed significant pulmonary hypertension and pulmonary angiography
revealed chronic thrombi in the peripheral pulmonary arteries, consistent with a
diagnosis of CTEPH. To our knowledge, this is the first case of CTEPH to be diagnosed with the onset of paradoxical cerebral embolism. Because CTEPH is the only
potentially curable form of pulmonary hypertension, clinicians should consider paradoxical cerebral embolism as a possible initial manifestation of CTEPH.
Key Words: Cryptogenic stroke—chronic thromboembolic pulmonary hypertension—
patent foramen ovale—paradoxical cerebral embolism
© 2019 Elsevier Inc. All rights reserved.

Introduction
Chronic thromboembolic pulmonary hypertension
(CTEPH) is characterized by chronic thrombi in the

From the *Department of Neurology, Tsuchiura Kyodo General
Hospital, Tsuchiura, Japan; and †Department of Cardiovascular
Medicine, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan.
Received April 16, 2019; revision received May 23, 2019; accepted
June 2, 2019.
Grant support: This report received no specific grant from any
funding agency in the public, commercial, or not-for-profit sector.
Address correspondence to Akira Machida, MD, PhD, Department
of Neurology, Tsuchiura Kyodo General Hospital, 4-1-1 Otsuno,
Tsuchiura-shi, Ibaraki 300-0028, Japan. E-mail: akinuro@tmd.ac.jp.
1052-3057/$ - see front matter
© 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.06.006

pulmonary arteries, causing pulmonary hypertension and
right ventricular dysfunction1 and is associated with significant morbidity and mortality.2 However, patients with
CTEPH may have no history of pulmonary embolism
(PE),3,4 and CTEPH can develop with nonspecific and
insidious clinical symptoms.

Case Report
A 76-year-old woman was referred for dizziness and
right-hand clumsiness, which occurred after urination on
the previous night. Although she reported slight dyspnea
while cycling, ordinary physical activities were not limited and her New York Heart Association Functional Classification was I. She had no history of PE, deep venous
thrombosis (DVT), or atrial fibrillation.

Journal of Stroke and Cerebrovascular Diseases, Vol. 28, No. 9 (September), 2019: pp e135 e138

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A. MACHIDA ET AL.

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On admission, her blood pressure was 131/85
mmHg, heart rate was 74 beats/min, and respiratory
rate was 18 breaths/min. No pathologic breath sounds
or heart murmurs were heard and no pitting edema
was observed in her lower extremities. Neurologic
examination revealed right hemiplegia and right-hand

numbness. Her National Institutes of Health Stroke
Scale score was 2.
Brain magnetic resonance imaging revealed sporadic
fresh cerebral infarctions in the left insular cortex and
bilateral parietal cortices (Fig 1A). No significant stenosis
was observed on brain and carotid magnetic resonance

B

A

Rt

Lt

C

D

Rt

E

Lt

F

Rt

Lt

G

Rt

Lt

H

Rt

Lt

Figure 1. (A) Axial diffusion-weighted magnetic resonance image on admission showing sporadic acute cerebral infarctions in the left insular cortex and bilateral parietal cortices (arrows). (B) Short-axis transthoracic echocardiogram on admission showing a D-shaped left ventricle due to compression by a markedly
dilated right ventricle. (C) Contrast-enhanced computed tomography (CT) scan showing a mosaic perfusion pattern, patchy areas of decreased attenuation intermingled with areas of increased attenuation in bilateral lung fields. (D) Coronal CT pulmonary angiogram showing mural thrombi in the left peripheral pulmonary arteries (arrow). (E) Color Doppler transesophageal echocardiography (TEE) showing color-flow communication (open arrowhead) through a patent
foramen ovale (PFO). (F) Contrast-enhanced TEE showing translocation of microbubbles from the right atrium to the left atrium after a Valsalva maneuver, indicating a right-to-left shunt through a PFO. (G) Anterior ventilation/perfusion scan showing unmatched perfusion defects in bilateral lung fields. (H) Pulmonary
angiogram showing intimal irregularities and abrupt narrowing of the right pulmonary arteries in addition to pouch defects in the left pulmonary arteries (closed
arrowhead), consistent with chronic thromboembolic pulmonary hypertension.

PARADOXICAL CEREBRAL EMBOLISM IN CTEPH

angiography. Cervical color Doppler ultrasound showed
normal arterial morphology and blood flow velocity in
the bilateral carotid and vertebral arteries.
Laboratory tests revealed high levels of high-sensitivity
troponin I (494 ng/L) and N-terminal pro-brain natriuretic peptide (3009 pg/mL). Although protein C, protein
S, antithrombin III, lupus anticoagulant, and anticardiolipin antibodies were within normal limits, her D-dimer
level was moderately elevated (4.2 mg/mL). Twelve-lead
electrocardiography showed a normal sinus rhythm.
Chest radiography revealed an increase in the size of the
cardiac shadow, with a cardiothoracic ratio of 54%.
Results of pulmonary function tests were within normal
limits, but results of arterial blood gas analysis (room air)
were consistent with respiratory alkalosis with hypoxia
(PaO2, 52.7 mmHg; PaCO2, 29.2 mmHg; pH, 7.484).
Transthoracic echocardiography revealed a normal ejection fraction (70%) without a patent foramen ovale (PFO).
Neither spontaneous echo contrast nor thrombus was
detected. However, right heart cavity dilation was
observed with a D-shaped left ventricle (Fig 1B) with high
tricuspid regurgitation peak gradient (72 mmHg), suggestive of pulmonary hypertension. Twenty-four-hour electrocardiographic monitoring showed a normal sinus
rhythm throughout with no atrial fibrillation episodes.
Chest contrast-enhanced computed tomography (CT)
demonstrated a mosaic perfusion pattern in bilateral lung
fields (Fig 1C), while CT pulmonary angiography
revealed mural thrombi in the left peripheral pulmonary
arteries (Fig 1D).
Color Doppler transesophageal echocardiography
revealed a right-to-left shunt at the interatrial septum
(Fig 1E), while 2-dimensional transesophageal echocardiography showed right-to-left microbubbles in the left
atrium after a Valsalva maneuver (Fig 1F), indicating the
existence of a PFO. Ultrasound and contrast-enhanced CT
of the lower extremities showed no evidence of DVT;
however, a ventilation/perfusion scan revealed unmatched
perfusion defects in bilateral lung fields (Fig 1G). Right
heart catheterization confirmed significant pulmonary
hypertension, with mean pulmonary artery pressure
(mPAP) of 38 mmHg, while pulmonary artery wedge pressure was normal (3 mmHg). Furthermore, pulmonary angiography showed intimal irregularities and abrupt
narrowing of the right pulmonary arteries in addition to
pouch defects in the left pulmonary arteries (Fig 1H).
Finally, a diagnosis of CTEPH complicated by paradoxical
cerebral embolism was made.
The patient had no indication for pulmonary endarterectomy or balloon pulmonary angioplasty and was
administered warfarin and riociguat (3 mg/d) for the
treatment of pulmonary hypertension. She had no recurrence of cerebral infarction within 6 months of follow-up
and her pulmonary hypertension gradually improved.
Her tricuspid regurgitation peak gradient decreased to
52 mmHg and she felt no dyspnea on exertion.

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Discussion
To our knowledge, this is the first case of CTEPH to
be diagnosed with the onset of paradoxical cerebral
embolism.
Venous thrombosis may cause embolism in both the
lungs and brain if a PFO exists.5-7 Unlike those with acute
PE, however, approximately half of patients with CTEPH
have no history of DVT, and D-dimer levels are increased
in only about one-quarter of cases.8 Therefore, pulmonary
hypertension is the key echocardiographic finding for
CTEPH diagnosis. Without appropriate treatment,
CTEPH has an estimated 5-year survival rate of 30% in
patients with mPAP >40 mmHg and 10% in patients with
mPAP >50 mmHg.3 Although rare, it is necessary to consider CTEPH as a comorbidity that causes paradoxical
cerebral embolism.
CTEPH is the only potentially curable form of pulmonary hypertension.3 Pulmonary endarterectomy is considered curative for CTEPH with central pulmonary
thrombi, while balloon pulmonary angioplasty is available for more distal thrombi. In addition, riociguat, a
novel pulmonary vasodilator that acts via stimulation of
soluble guanylate cyclase, is approved for patients with
inoperative CTEPH. Considering the prevention of paradoxical cerebral embolism in patients with CTEPH and a
PFO, correction of pulmonary hemodynamics is important in addition to anticoagulation.
It has been reported that the prevalence of new ischemic
brain lesions in patients with PE is related to the presence
of a PFO and right-to-left shunt, suggesting a higher risk
of paradoxical embolism in those patients despite effective
oral anticoagulation.9 As a possible explanation, it is
assumed that higher right-sided pressure and dysfunction
may predispose to more right-to-left shunting owing to a
previously closed foramen ovale becoming stretched
open with disease progression.10 Confirmation via largescale studies is necessary.

Conclusions
It is important to recognize that paradoxical cerebral
embolism can develop as a rare initial manifestation of
CTEPH. Furthermore, in terms of secondary cerebral
embolism prevention, simultaneous correction of pulmonary hemodynamics and anticoagulation is important.

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