[ Pulmonary, Critical Care, and Sleep Pearls ]

Wake-Up Right-Sided Hemiparesis and
Dysarthria in a Heavy Snorer
Valerio Brunetti, MD; Michela Ada Noris Ferilli, MD; Catello Vollono, MD, PhD; Antonino Di Franco, MD;
and Giacomo Della Marca, MD, PhD

CASE PRESENTATION: A 57-year-old man was referred to the ED for wake-up right-sided

hemiparesis, hypoesthesia, dysarthria, and a National Institutes of Health Stroke Scale score
of 7. Urgent CT brain scanning showed an ischemic lesion of the left temporal and insular
lobes. The patient was admitted to the stroke unit, and acetylsalicylic acid 300 mg and lowmolecular-weight heparin 6,000 IU were administered.
CHEST 2018; 153(1):e13-e17

Physical Examination Findings
The patient was obese (BMI, 39.45 kg/m2) and a
heavy snorer; he reported two previous episodes of
thrombophlebitis of the lower limbs (12 years and
5 months, respectively, before the current admission).
The family medical history was suggestive for
thrombophilia: The patient’s father and nephew died of
pulmonary embolisms, and his sister had recurrent
episodes of DVT. Three days after admission, the patient
had syncope associated with severe bradycardia,
dyspnea, and severe hemoglobin desaturation, suggestive
of a pulmonary embolism.

Diagnostic Studies
CT brain imaging and CT angiography (on day 2 after
the onset of symptoms) confirmed ischemic stroke and
did not identify arterial occlusions. Urgent pulmonary
CT angiography revealed subtotal occlusion of both
pulmonary arteries (Fig 1).
Venous Doppler ultrasonography of the lower limbs
showed bilateral DVT extending to the common femoral
veins. Transcranial Doppler ultrasonography showed
microembolic signals at rest (Spencer grade 1/2), which
AFFILIATIONS: From the Istituto di Neurologia (Drs Brunetti, Ferilli,
Vollono, and Della Marca), Università Cattolica del Sacro Cuore,
Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy;
and Greenberg Cardiology Division (Dr Di Franco), Department of
Medicine, Weill Cornell Medicine, New York, NY.
CORRESPONDENCE TO: Valerio Brunetti, MD, Istituto di Neurologia,
Università Cattolica del Sacro Cuore, Fondazione Policlinico

chestjournal.org

markedly increased after a Valsalva maneuver (grade 5).
The presence of a patent foramen ovale (PFO) was
further confirmed by transesophageal echocardiography.
At transthoracic echocardiography, the left ventricular
ejection fraction was 62% and the left ventricular
telediastolic diameter was 57 mm. Both right ventricular
function (tricuspid annular plane systolic excursion,
26 mm) and dimensions were normal.
Polysomnography (PSG) on day 15 showed snoring and
prolonged apnea associated with hemoglobin
desaturation events, consistent with severe OSA. Detailed
PSG results are showed in Table 1. A 5-min recording of
the patient’s polysomnogram is shown in Figure 2.
Screening for thrombophilia showed a deficit of
antithrombin III (ATIII) (55% normal range 70-140).
Analysis of the antithrombin III gene (AT3) showed a
heterozygous mutation in exon 4, which converts
tryptophan in a stop codon at position 307. Brain
MRI could not be performed, because the patient was
claustrophobic. An extended autoimmune screening
test and 24-hour Holter ECG monitoring were
unremarkable.
Universitario Agostino Gemelli, L.go A. Gemelli, 8 - 00168 Rome, Italy;
e-mail: v.brunetti2509@gmail.com
Copyright Ó 2017 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: http://dx.doi.org/10.1016/j.chest.2017.08.006

e13

Figure 1 – Pulmonary CT angiography shows subtotal occlusion of both
pulmonary arteries.

TABLE 1 ]

Detailed PSG Results at Baseline and During
CPAP Treatment

Sleep Macrostructure

Baseline

CPAP

TIB, min

414.0

412.5

Total sleep time, min

397.0

382.5

SPT, min

406.5

403.0

Sleep efficiency on SPT, %

97.5

94.9

Sleep efficiency on TIB, %

95.9

92.7

Sleep onset latency, min

7.0

6.5

REM/SPT, %

12.8

25.6

Stage 1/SPT, %

8.2

6.3

Stage 2/SPT, %

68.3

50.7

Stage 3/SPT, %

8.2

12.3

Wake/SPT, %

2.5

5.1

Awakenings, No.

2.0

7.0

Wake after sleep onset, min

10.5

23.5

Central AHI

1.2

3.0

Obstructive-mixed AHI

71.2

6.5

NREM AHI

75.0

3.2

REM AHI

64.6

8.2

Nonsupine AHI

67.3

2.8

Supine AHI

78.1

14.3

Longest obstructive apnea, s

66.4

15.3

ODI

73.6

4.7

t90, %

46.8

8.7

Awake SpO2, %

95.0

95.0

Lowest SpO2, %

79.4

84.0

Respiratory events

AHI ¼ apnea-hypoxia index; NREM ¼ non-rapid eye movement;
ODI ¼ oxygen desaturation index; PSG ¼ polysomnography; REM ¼ rapid
eye movement; SpO2 ¼ oxygen saturation; SPT ¼ sleep period time;
TIB ¼ time in bed; t90 ¼ percentage of sleep with hemoglobin
saturation < 90%.

e14 Pulmonary, Critical Care, and Sleep Pearls

[ 153#1 CHEST JANUARY 2018 ]

Figure 2 – Five-min polysomnography recording showing periodic obstructive apneas. ECG ¼ electrocardiogram; EMG ¼ electromyography;
EMG Chin ¼ electromyography recorded from submentalis muscle; EOGL ¼ left electrooculogram; EOGR ¼ right electrooculogram; SpO2 ¼ oxygen
saturation.

What is the diagnosis?
What three mechanisms contributed to his
stroke?
How could untreated OSA influence flow across
a PFO?

chestjournal.org

e15

Diagnosis: Ischemic stroke and pulmonary
embolism in a patient with PFO, ATIII
deficiency, and OSA.
The combination of PFO, ATIII deficiency,
and OSA concurred in the etiopathogenesis of
the ischemic stroke in the patient. ATIII
deficiency was responsible for the DVT.
During sleep, prolonged obstructive apneas
induced the Valsalva and Müller maneuvers,
which in turn caused an increase of pressure in
the right atrium and a massive right to left
shunt across the PFO, resulting in paradoxical
embolism and ischemic stroke
Discussion
PFO is a remnant of the fetal foramen ovale, a hole in the
interatrial septum, that allows blood to bypass the
pulmonary circulation, because fetal lungs do not
participate in oxygen exchange. At birth, as the lungs
begin working, pulmonary vascular resistance drops, and
there is a reversal of blood flow through the foramen ovale
as it closes. In about 25% of people it stays open as a PFO.
PFO has a high prevalence in cryptogenic stroke,
especially in younger patients. Moreover, patients with
PFO and previous cryptogenic ischemic stroke are at risk
for recurrence of cerebrovascular events. It is important to
remark that patients with a PFO who have not had a
previous stroke do not have increased cerebrovascular
risk compared with the general population. Results on
these studies are still controversial.
The most recent guidelines from the American Heart
Association/American Stroke Association on PFO
management, recommend:
1. Antiplatelet therapy for patients with ischemic stroke
or transient ischemic attack (TIA) and PFO (Class I;
Level of Evidence B)
2. Anticoagulation for patients with ischemic stroke or
TIA and both an PFO and a venous source of embolism, depending on stroke characteristics (Class I;
Level of Evidence A)
3. For patients with a cryptogenic ischemic stroke or
TIA and a PFO without evidence of DVT, available
data do not support a benefit for PFO closure (Class
III; Level of Evidence A)
4. PFO closure by a transcatheter device might be
considered, depending on the risk of recurrent DVT
(Class IIb; Level of Evidence C)

e16 Pulmonary, Critical Care, and Sleep Pearls

The most widely accepted mechanism of PFO-related
stroke being considered is the paradoxical embolism.
A massive right to left shunt across a PFO is normally
prevented by the higher pressures in the left-sided heart
chambers; all conditions that increase pressure in the
right side of the heart exceeding left atrial pressure (such
as coughing, exercise, heavy lifting, Valsalva maneuvers)
determine a right to left shunt, causing paradoxical
embolism through a PFO. OSA is one of the conditions in
which pressure can rise in the right-sided chambers.
In fact, during obstructive apneas, patients breathe
against resistance, thus performing Müller and Valsalva
maneuvers. Direct evidence of the occurrence of a right to
left shunt during OSA has been provided by Beelke et al.
On transcranial Doppler ultrasonography, these authors
observed that right to left shunting was present in nine of
10 patients and appeared during obstructive apneas
longer than 17 s. The number of microembolic signals
detected during apneas was directly related to the number
detected during Valsalva maneuvers in wakefulness. In a
large cohort of 100 patients, Guchlerner et al. observed
that the prevalence of PFO is high in OSA and that right
to left shunting occurs frequently in these patients.
On these grounds, it could be hypothesized that OSA
contributes to the reopening of a patent, but formerly
closed, foramen. The repeated transient episodes
of hypoxemia caused by OSA cause pulmonary
vasoconstriction and eventually pulmonary
hypertension. The result is a permanent increase in rightsided cardiac pressures and in turn an increased risk of
paradoxical embolism. An Italian multicenter trial
(DARIA [Detection of Sleep Apnea as Risk Factor in
Acute Stroke]) evaluated the association among OSA,
PFO, and wake-up cerebrovascular accidents (stroke and
TIA). The results of this study suggested that even
single long-lasting (20 s or more) obstructive events can
facilitate a right to left shunt and that the combination
of long episodes of apnea and PFO could be a risk
factor for cerebrovascular ischemic events. More recently,
Siarnik et al reported that wake-up stroke is associated
with higher apnea/hypopnea and desaturation indexes.
The suspicion of paradoxical embolism also implies a
venous source. ATIII is a natural anticoagulant. It is a
serine protease inhibitor, acting on factor IIa, factor Xa,
and other serine proteases in the coagulation cascade.
Deficiency of ATIII can be inherited or acquired.
Inheritance of ATIII deficiency is in an autosomal
dominant fashion with variable penetrance. The
resulting phenotypes are divided into type I and type II
deficiencies, corresponding to reduced levels of ATIII

[ 153#1 CHEST JANUARY 2018 ]

antigen and activity or to functionally defective ATIII
presenting at normal levels, respectively. In the patient,
there was a type I phenotype caused by a single base
substitution (mutation) in exon 4 that determined a
deficiency of ATIII. This deficiency is associated with an
increased risk of DVT and pulmonary embolism; arterial
thrombosis has been reported but is not characteristic of
ATIII deficiency.

Clinical Course
The patient was treated with IV heparin and ATIII
replacement (50 IU/kg), because heparin is an indirect
inhibitor of thrombin and factor Xa and requires
adequate levels of circulating ATIII to be effective. When
heparin was replaced with an oral anticoagulant, ATIII
implementation was interrupted. Oral anticoagulation
(target international normalized ratio, 2.5; range, 2.03.0) and CPAP (10 cm H2O) were initiated, and
percutaneous closure of the PFO was performed.
Detailed PSG results during CPAP treatment are shown
in Table 1. The patient progressively recovered, and at
discharge on day 25, the National Institutes of Health
Stroke Scale score was 0.
In conclusion, the combination of these three risk
factors concurred in the etiopathogenesis of ischemic
stroke in the patient: ATIII deficiency was responsible
for DVT; during sleep, prolonged sleep apnea induced a
massive right to left shunt across the PFO, and this in
turn resulted in paradoxical embolism and ischemic
stroke. This pathogenic mechanism suggested a peculiar
therapeutic strategy, consisting of a combination of
anticoagulation treatment, nocturnal positive-pressure
ventilation, and surgical closure of the PFO.

Clinical Pearls
1. OSA is a well-known risk factor for stroke and has a
high prevalence in stroke; in particular, OSA is associated with wake-up cerebrovascular events.
2. OSA can induce paradoxical embolism in patients with
PFO because obstructive apneas can increase right
atrial pressure and facilitate right to left shunting.
3. PFO alone is not a risk factor for ischemic stroke.
Instead the risk of ischemic stroke is increased in patients with PFO and a previous cryptogenic stroke. The

chestjournal.org

paradoxical embolism is the most reliable mechanism
but probably not the only one.
4. The best medical treatment for secondary prevention in
patients with PFO and ischemic stroke is antiplatelet
therapy. Anticoagulation can be taken into consideration when there is a venous source of the embolism,
depending on the stroke characteristics. PFO closure
has to be taken into consideration when there is a high
risk of recurrence of DVT.

Acknowledgments
Author contributions: V. B. contributed to the study concept and
design, drafting of the manuscript, and interpretation of data and
accepts responsibility for the conduct of research and acquisition of
data. M. A. N. F., C. V., and A. D. contributed to the interpretation of
data and accept responsibility for the conduct of research and
acquisition of data. G. D. M. contributed to the interpretation of data
and accepts responsibility for the conduct of research, study
supervision, revising the manuscript, and final approval.
Financial/nonfinancial disclosures: None declared.
Other contributions: CHEST worked with the authors to ensure that
the Journal policies on patient consent to report information were met.
The patient’s mother (in consultation with the patient) consented to
the publication of this Clinical Pearl.

Suggested Readings
Shanoudy H, Soliman A, Raggi P, Liu JW, Russell DC, Jarmukli NF.
Prevalence of patent foramen ovale and its contribution to hypoxemia
in patients with obstructive sleep apnea. Chest. 1998;113(1):91-96.
Beelke M, Angeli S, Del Sette M, et al. Obstructive sleep apnea can be
provocative for right-to-left shunting through a patent foramen ovale.
Sleep. 2002;25(8):856-862.
De Stefano V, Simioni P, Rossi E, et al. The risk of recurrent venous
thromboembolism in patients with inherited deficiency of natural
anticoagulants antithrombin, protein C and protein S. Haematologica.
2006;91(5):695-698.
Guchlerner M, Kardos P, Liss-Koch E, et al. PFO and right-to-left
shunting in patients with obstructive sleep apnea. J Clin Sleep Med.
2012;8(4):375-380.
Ciccone A, Proserpio P, Roccatagliata DV, et al. Wake-up stroke and TIA
due to paradoxical embolism during long obstructive sleep apnoeas: a
cross-sectional study. Thorax. 2013;68(1):97-104.
Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention
of stroke in patients with stroke and transient ischemic attack: a guideline
for healthcare professionals from the American Heart Association/
American Stroke Association. Stroke. 2014;45(7):2160-2236.
Mojadidi MK, Bokhoor PI, Gevorgyan R, et al. Sleep apnea in patients
with and without a right-to-left shunt. J Clin Sleep Med. 2015;11(11):
1299-1304.
Siarnik P, Kollar B, Carnicka Z, et al. Association of sleep disordered
breathing with wake-up acute ischemic stroke: a full polysomnographic
study. J Clin Sleep Med. 2016;12(4):549-554.
Sun YP, Homma S. Patent foramen ovale and stroke. Circ J. 2016;80(8):
1665-1673.
Tur S, de la Pena M, Vives B, et al. Sleep apnea syndrome and patent
foramen ovale: a dangerous association in ischemic stroke? Sleep Med.
2016;25:29-33.

e17