The causality of PFO,

cryptogenic embolism, and stroke

J. David Spence M.D.
Stroke Prevention & Atherosclerosis Research Centre
Robarts Research Institute
London, Canada

dspence@robarts.ca www.robarts.ca/sparc
 Paradoxical embolism
Far commoner than you may think
Paradoxical embolism
4% of ischemic stroke

Hankinson and Hutcheson 1978

 Large thrombus through PFO
Thrombi in both
atria and
ventricles

Thrombus in
PFO on echo with contrast
left atrium and
aortic valve
20 cm thrombus from embolectomy
from left iliac and superficial femoral a.

Thrombus has
embolized to
the left leg

Maier LS et al. Eur J Echocardiogr. 2007;8:158-60

Patching sounds like a good idea,
but…
PFO Closure: Statistical power issue
• 25% of the population have a PFO
• 4-5.5% of strokes are due to paradoxical
embolism1,2
•  ~ 80% of PFO’s in stroke patients are incidental
• ~ 50% incidental in cryptogenic stroke3

1. Hutchinson,EC and Acheson, EJ. Strokes: natural history, pathology and

surgical treatment. (4). 1975. London, W.B. Saunders.
2. Ozdemir AO, et al. J Neurol Sci 2008; 275: 121–127
3. Kent D, Thaler D. Stroke 2010; 41(10 Suppl):S26-S30
Complications of percutaneous closure
• Atrial fibrillation
• Embolization of the device
– Fatal aortic valve occlusion
– Femoral artery occlusion
• Thrombus on the device
Surgical removal of Cardioseal device with thrombus 6 years after closure
Stroke in 2000 age 54; closure
2003; 2008 thrombus on
device
6 months intensive
anticoagulation failed
Device removed 2009

Courtesy of Dr. Bob Kiaii and Dr. Bryan Dias

 Meta-analysis 2018: Stroke reduction

Ahmad Y et al. Eur Heart J. 2018;39:1638-1649

 Meta-analysis 2018: increased AF

Ahmad Y et al. Eur Heart J. 2018;39:1638-1649

Retinal embolus of platelet aggregates

Fisher CM. Neurology. 1959 May;9(5):333-47

 White thrombus vs red thrombus

White thrombus: platelet aggregates;

- fast flow, arteries
Treatment: antiplatelet agents

Red thrombus: fibrin polymer with entrapped RBCs

-stasis, veins, AF, recent MI, ventricular aneurysm
Treatment: anticoagulants
Deykin D. New Engl J Med 1967; 276: 622-628
Caplan L. Rev Neurol Dis 2007; 4: 113-121
 Anticoagulation is better than aspirin

Proportion
with
recurrent
ischemic
stroke

• Kasner S et al. Lancet Neurology, In press, 2018

Anticoagulation is better than antiplatelet
for PFO stroke prevention

Kasner S. et al. Lancet Neurology, In press, 2018

PFO closure does not prevent
Pulmonary Emboli

Kasner S et al. Lancet Neurology, In press, 2018

 Some patients will be better
anticoagulated
• PFO closure mandates antiplatelet therapy
• So patients at risk of PE may be better treated
with anticoagulants
• New DOACs are not more likely than aspirin to
cause severe hemorrhage
 So:
We need to identify which
PFO patients are more likely
to have paradoxical
embolism and benefit from
closure
 Clinical Clues to Paradoxical Embolism
5.5% of new TIA/stroke patients
Suspect if:
• Young patient without other cause
• Dyspnoea*, tachycardia at onset
• ↓ O2, ↓ pCO2 (pulmonary embolus)
• Loud P2, Pulmonic regurge
• Loss of consciousness at onset of carotid stroke
• Long ride in a car, airplane or sitting at computer*
• Swollen leg, previous DVT, varicose veins*
• Pulmonary emboli in past*
• Valsalva maneuver*
• Waking up with stroke*
• Sleep apnea* *p<0.05
Ozdemir AO, et al. J Neurol Sci 2008; 275: 121–127
 Better tools needed
“Additional tools to describe PFOs
may be useful in helping to
determine whether an observed
PFO is incidental or pathogenically
related to (cryptogenic stroke).”1
1. Di Tullio MR et al. J Am Coll Cardiol 2013; 62:35-41.
 Dangerous PFO?

Meier B, Nietlispach F. European Heart

Journal 2018; 39: 1650–1652
 TCD more sensitive than TEE 1

• Inadequate Valsalva2
• ? Eustachian valve3
• One small study (n=59) suggested shunt grade
predicted events4
1.Bogousslavsky J et al. Neurology 1996; 46:1301-1305.
2. Rodrigues AC et al. J Am Soc Echocardiogr. 2013; 26:1337-1343.
3. Anzola GP. Stroke 2004; 35:e137.
4. Anzola,GP et al. Eur J Neurol 2003; 10:129-135.
 Our study
• Patients referred to the Urgent TIA Clinic in 2000 - 2013
• Cryptogenic stroke
• Suspected of having paradoxical embolism
• All had TCD saline studies
• 340 patients with RLS confirmed on TCDSS
• 61.5% female, age 53 + 14 years
• Median followup 420 days, max 3240 days
• 85 had a recurrent ischemic stroke or TIA
• 284 cases had TEE available
• Atrial septal aneurysm or mobile septum in 54 cases
(19.3%)
• TE Echo failed to show RLS in 43 (15.1%)
Tobe J, … Spence JD. Can J Cardiol. 2016;32:986 e9- e16.
 TCD shunt grades
• Grade 0: no microemboli detected
• Grade I: 1-10 microemboli
• Grade II: 11-30 microemboli
• Grade III: 31-100 microemboli
• Grade IV:101-300 microemboli
• Grade V: > 300 microemboli

Spencer MP et al. J Neuroimaging 2004; 14:342-349.

 Shunt grades on TCD

Tobe J, … Spence JD. Can J Cardiol. 2016;32:986 e9- e16.

Bubbles are not subtle; they are definite

Before injection Without Valsalva maneuver

Besides the visual output and

bubble count, there is an audio
signal that is unmistakeable – on
video clip

With Valsalva maneuver

Ozdemir AO, et al. J Neurol Sci 2008; 275: 121–127
Grade V shunt missed on TEE
 TCD better than Echocardiogram
Echo missed 15% of right-to-left shunts
Echo misses
even large
shunts n = 43/284

41.7%
Grade 3 or
higher
Tobe J, … Spence JD. Can J Cardiol. 2016;32:986 e9- e16.
Survival free of stroke/TIA by TCD shunt grade

Tobe J, … Spence JD. Can J Cardiol. 2016;32:986 e9- e16.

 Survival free of stroke/TIA by RLS on TEE

Right-left
shunt on TEE
did not predict
recurrent
events

Tobe J, … Spence JD. Can J Cardiol. 2016;32:986 e9- e16.

 Conclusions
• Clinical clues can identify patients more likely to
have paradoxical embolism
• Larger shunt size more likely to benefit from closure
• TCD better for assessing shunt size
• Some patients may be better anticoagulated
 Acknowledgements
TCD bubble studies:
Arturo Tamayo, Claudio Munoz

Data:
Sheldon Tobe, Chrysi Bogiatzi
http://www.imaging. robarts.ca/sparc dspence@robarts.ca