1. A patent foramen ovale (PFO) is present in 25% of the population but is more common in younger people. 2. Stroke and PFO as well as migraine and PFO have a proven or suspected causal relationship. 3. Catheter based PFO closure is considered the safest therapeutic intervention for cardiology but randomized studies comparing it to drug therapy are still ongoing and results are not expected until at least 2010.

1. Professor Bernhard Meier, Department of Cardiology,
University Hospital Bern, 3010 Bern,
Switzerland; bernhard.meier@insel.ch

2. A patent foramen ovale (PFO) is present in 25% of the
population with decreasing prevalence with age.

A PFO with ominous anatomical features such as atrial septal
aneurysm or Eustachian valve is present in about 4% of the
population.
Stroke and PFO have a proven and migraine and PFO a suspected
causal relationship.
To call a stroke in a patient with a PFO cryptogenic is an
historical oxymoron.
Catheter based PFO closure is the safest and most simple
therapeutic intervention in cardiology.
The protective power against paradoxical stroke of PFO closure is
probably better than that of oral anticoagulation and certainly
better than that of antiplatelet therapy.
First results of randomised studies comparing PFO closure in
patients with stroke or migraine cannot be expected before 2010,
and first positive results may take even longer.

4. Transthoracic echocardiography depicting a highly mobile septum primum
(arrows), a sign making a patent foramen ovale highly probable. LA, left atrium;
LV, left ventricle; RA, right atrium; RV, right ventricle.

5.  A field study in northern Manhatten found no
difference in the incidence of ischaemic stroke among
1100 subjects (with an average age of about 70 years)
during an observation period of about 7 years with
respect to their PFO status; 15% were diagnosed by
non-specialised transthoracic echocardiography to
have a PFO and 3% to also have an associated
ASA(Atrial Septal Aneurysm)

6.  A meta-analysis on individuals below 55 years of age
identified a threefold risk of a PFO carrier suffering a
stroke (16-fold if an ASA was also present) compared to
controls.
 The respective risk of suffering a cryptogenic stroke
was estimated at fivefold and 24-fold, respectively.

7.  Using standard means for detection, a PFO is found in
about 50% of patients with a cryptogenic stroke.
 This is most likely an underestimation due to many
missed PFOs with the somewhat crude screening
techniques used.

8.  Even when most of the so-called cryptogenic strokes
are put on the account of the PFO, its risk may still be
underestimated. It appears logical that the potential of
a PFO to mediate stroke is independent of associated
problems.
 Venous thrombosis, a sine qua non of paradoxical
embolism, is exquisitely rare in children (although
PFO mediated juvenile strokes have been
observed), but starts to rise steeply after the age of 50
years to reach about 600 afflicted people per year
among 100 000 octogenarians.

9.  A sub-analysis of WARSS (Warfarin Aspirin Recurrent
Stroke Study) found a positive correlation between the 2
year ischaemic stroke recurrence rate in patients with an
initial cryptogenic stroke only in those 65 years or older.
 A much smaller Spanish study on about 500 patients with
cryptogenic stroke and 2 years of follow-up did not find any
increased hazard with the presence of a PFO, not even in
younger patients with a massive right-to-left shunt.

10.  A 20 year population based field study on middle-aged
people with venous thromboembolism proved a high
concomitant incidence of stroke and myocardial infarction.
 Over the subsequent 20 years the risk never completely
returned to normal.
 The authors hypothesised about general pro-coagulant
factors begetting simultaneous venous thrombosis and
arterial plaque rupture. They did not even mention the
PFO,

11.  Patients (average age 60 years) presenting with a
clinically significant pulmonary embolism had a mortality
of 33% if they had a PFO and 14% if they had none.
 The respective risks of a simultaneous peripheral embolism
such as a stroke were 28% and 2%, respectively.
 This conspicuous display of danger posed by the PFO
published 10 years ago has all but fallen into obscurity.

12. Situations where preventive PFO closure can be considered
Embolism prone surgery:

major orthopaedic surgery

brain surgery in sitting position

 Planned pregnancy
 Vocational or recreational hazards:
deep sea divers

brass musicians

glass blowers

professions requiring squatting position

military jet pilots

astronauts

commercial drivers or pilots


13. Diseases putatively blamed on the
PFO among other causes
 Ischaemic stroke
Transient ischaemic attacks
Transitory (global) amnesia
Retinal infarction
Myocardial infarction
Visceral infarction
Limb ischaemia
Economy class stroke syndrome
Migraine (with and without aura)
Decompression illness in deep sea divers
High altitude pulmonary oedema
Platypnoea orthodeoxia
Sleep apnoea syndrome
Excessive snoring

14.  A study reported an improvement after PFO closure
only in patients with migraine and aura or with
migraine and documented embolic brain defects, but
not in patients with migraine alone.
 The correlation with migraine was shown to be more
conspicuous in females than in males and in people
with a PFO and an ASA, as opposed to people with a
simple PFO.

15.  To confound the issue further, an analysis of the cross
sectional Northern Manhatten Study (NOMAS) found
absolutely no correlation between PFO and migraine,
 and another study found the closest correlation
between PFO and migraine in patients with an
ASA but no PFO

16.  Lastly, a study in 75 adults on device closure of an ASD
showed that migraine disappeared in 12 (16%)and
newly appeared in 10 (13%). Migraine without aura was
reduced from 19 to 12 patients but migraine with aura
increased from 11 to 15 patients.

17. Before PFO Devise Closure
No echocardiographic guidance required
Local anaesthesia
Access: right femoral vein
Heparin bolus 5000 units
0.0035 inch (exchange) wire
Multipurpose catheter to pass defect unless wire crossed
spontaneously
No balloon gauging
9 French sheath fits most PFO occluder sizes
Right atrial dye injections for position control (with device in
perfect profile)
Antibiotics (1–3 doses)

18. After PFO Devise treatment
 Unrestricted physical activity after a few hours
 Aspirin 100 mg for 5 months
 Clopidogrel 75 mg for 1 month
 Prophylaxis against endocarditis (for 3–6 months)
 Transoesophageal echocardiography at about 6 months (1 month
after stopping platelet inhibitors)

19. Recurrent ischaemic events in patients treated for patent foramen ovale (PFO)
with three different modalities at a centre for 4 years (top panel)and another
centre for 10 years(bottom panel). The numbers in parenthesis

20. conclusion of a panel of the US Food and
Drug Administration on 2 March 2007
 Advocating patients abstain from percutaneous PFO
closures except for those willing to participate in
randomised trials

21.  Another View

24. Increased prevalence of PFO in
cryptogenic stroke?
 SPARC – Olmsted County Study (JACC
2006;47:440-5): Prospektive (5,1years) population
based study of 585 randomly sampled persons age
45+ yrs with TEE:
PFO not a risk factor for stroke or TIA (hazard
ratio 1,28 (0,65-2,50),
after adjustment for comorbidity HR1,46 (0,74-
2,88) , both non significant

25. Increased prevalence of PFO in
Cryptogenic Stroke?
 NOMAS-study: Prospektive study (6,5 yrs) of
incidence, risk factors and clinical outcome of
stroke in 1.100 individuals (39+ yrs) without
previous stroke, evaluated by TTE (JACC
2007;49:797-802):
Stroke incidence 12,2 (+PFO) vs 8,9 (no PFO) pr
1.000 person yrs (p= 0,5).
Hazard Ratio after risk-factor adjustment 1,46 (CI
0.87-3.09)

26. PFO and Cryptogenic Stroke
Present knowledge
 Retrospektive case control studies show a
significantly increased prevalence of PFO with
cryptogenic stroke, and a reduced recurrence rate
following PFO closure
 Newer prospektive population based sudies report
a minor and non-significantly higher prevalence
of PFO in individuals who subsequently had a
stroke.
 The stroke recurrence rate on antithrombotics is
independent of PFO

27. Stroke undergo Catheter
Closure?
 A low risk procedure, but small risk of:
Periprocedure stroke, arrhytmias,catheter perforation or
occluder erosion with pericardial tamponade, infection,
thrombus formation on atrial discs, occluder embolisation
(open heart surgery). Catheter Cardiovasc Interv
2004;62:512-16: 272 PFO-closures, 8 centers Complication
frequency 6,6% ! (?)
Long term (15+ yrs) side effects of implant unknown
Estimated Costs: USD 10.000, in DK 5.000

30. USA FDA 2000
humanitarian device
exemption
” is indicated for closure of PFO in
patients with recurrent cryptogenic
stroke due to presumed embolism
through a PFO and who have failed
conventional drug therapy” (warfarin)
This exemption withdrawn in 2006 .
Since then only available at selected
institutions with institutional protocols

31. Guidelines for Prevention of Stroke in Patients with Ischemic
Stroke or TIA. A Statement for Healthcare Professionals from
AHA, Am Stroke Ass Council on Stroke, Co-sponsored by
Council of Cardiovasc Rad. and Interv. and affirmed by Am
Ac of Neurol: Circulation 2006;113:409-49
 ”Insufficient data exist to make a recommendation about
PFO closure in patients with a first stroke and a PFO. PFO
closure may be considered for patients with recurrent
cryptogenic stroke despite optimal medical treatment (Class
IIb, Level of Evidence C)”

32. Conclusions
 For patients with an ischemic stroke or TIA and a
PFO antiplatelet therapy is reasonably to prevent a
recurrent event
 Warfarin is reasonable for high-risk patients who
have other indications for oral anticoagulation
 It is truely unknown whether patients benefit from
catheter closure of PFO, which therefore can only
be recommended in controlled clinical trials