1. To Close or Not to Close (the PFO)? That is the Question
Lorna Belsky, M.D.
March 31, 2004

2. Learning Objectives:
By the end of this presentation, you will be able to:
define patent foramen ovale (PFO)
define atrial septal aneurysm (ASA)
Discuss the association of PFO, ASA and migraine, TIA and stroke.
Financial disclosures – None
(I will pass the hat at the end of the talk).

3. Patients: Patient No. 1 - K.M., 44-year-old woman
3 separate episodes of visual clouding in right eye, “gray cloud”
No headache, Left eye normal
Symptoms lasted 5-8 minutes each time, occurred each evening x2, then again in the morning of the third day.
Saw her primary care doctor
PMH
migraine, started in adolescence, worsened around age 40, associated with blurred vision
Episode of vertigo 2 yrs prior, associated with sinus infection
Severe, fell out of a chair, could not drive for 4 weeks, no sequelae thereafter
Depressive disorder, treated

4. Patient No. 1 - K.M., 44-year-old woman (cont’d)
Medications – fluoxetine, MVI
Allergies – none
SH – married, 2 boys
Never smoker
Wine, 1-2/weekend
Stock broker
FH – Mother had TIA age 68, decreased vision and paresthesias, on Aspirin, no recurrence x5 years.
Sister age 36 with epilepsy
Father-HTN
No bleeding or clotting disorders

5. Patient No. 2 – A.F., 52-year-old woman
New patient to clinic to establish care
H/O left frontoparietal stroke 12 yrs ago at age 40
Treated with ASA. Residual slurred speech when tired.
No recurrent neurological symptoms.
Previous stroke workup
-No hypercoaguable disorders
-TEE showed PFO
-High suspicion of paradoxical embolism
PMH-severe migraines with aura around time of stroke
Postmenopausal, migraines remitted
Shoulder surgery
GERD

6. Patient No. 3 – R.K., 48-year-old woman
Called my office with new symptoms
While driving, she experienced:
decreased vision in left eye that followed
zig-zagging visual changes in the left eye
simultaneously, numbness of left face, arm and leg lasting 1-2 hours. Now resolved.
associated with a minor headache located over forehead

7. Patient No. 3 – R.K., 48-year-old woman
PMH
major depressive disorder,
recurrent complex regional pain syndrome right arm
Dysphagia, esophageal dysmotility
Former smoker
Migraine headaches
Hysterectomy, benign

8. Patient No. 3 - R.K., 48-year-old woman (cont’d)
Medications – Premarin
Protonix
Verapamil-for migraine
MVI
Calcium
FH – HTN, heart disease, stroke in old age

9. Patient No. 3 - R.K., 48-year-old woman (cont’d)
Admitted to hospital-stroke workup done
MRI brain-chronic infarct right caudate nucleus
Hypercoaguable workup-negative at discharge.
Factor V Leiden pending
TEE-Atrial septal aneurysm with associated PFO trivial interatrial shunt, right to left, at rest
Discharged home after two days on Aspirin 81 mg and
Plavix 75 mg (Premarin was continued)
Patient declined treatment with LMWH
Subsequently consulted Interventional Cardiology
Did not meet current FDA guidelines for percutaneous PFO closure
-failed anticoagulation with recurrent neurological symptoms
-significant contraindication to anticoagulation

10. Patient No. 3 - R.K., 48-year-old woman (cont’d)
Two weeks later-called again with recurrent left face, arm, leg numbness & mild headache, partner noted left facial droop. Patient experienced mild weakness in arm and leg this time.
Back to ER. Admitted. Completed right hemispheric sub-cortical stroke, residual left hemiplegia, (while on ASA/Plavix).
Found heterozygous for Factor V Leiden
Now-fulfills FDA criteria for PFO closure.
Undergoes percutaneous PFO closure with Amplatzer closure device.
Discharged home, disabled for her job, on Plavix, to receive physical and occupational therapy.

11. Topics for Discussion Today
What is a PFO?
What is an ASA?
What is the association between PFO, ASA, Migraine Headaches, TIA and Stroke
Who should be referred for PFO closure?
Who do you refer your pt to?
What is the role of medication treatment versus surgical interventions?

12. Embryology 101
The cardiovascular system is the first system to function in the embryo
Blood begins to circulate by the end of the third week.
Derived from angioblastic tissue (mesenchyme).
Contractions of the heart begin by Day 22.

15. Partitioning of the Primitive Atrium
Septum primum grows down from atrial roof
Foramen primum-opening in septum primum
Septum primum fuses with endocardial cushions
Foramen primum closes, concurrently:
Foramen secundum-forms in septum primum
Septum secundum grows down from atrial roof right of septum primum
The two septums overlap, incompletely, in the area of the foramen secundum-forms the foramen ovale.

16. Physiology/Embryology 101
Before birth-foramen ovale open-blood flows from IVC  RALA
After birth-Foramen ovale closes
Septum primum fuses with Septum Secundum

17. Atrial Septal Defects
Ostium primum ASD-failure of septum primum to fuse with endocardial cushion.
Ostium secundum ASD-inadequate development of septum secundum or excess resorption of septum primum
Patent foramen ovale-inadequate fusion of the septum primum with the septum secundum

18. Prevalence and Diagnosis of PFO
Hagen-1984-Autopsy study 965 pts
PFO in 27.3% of hearts
Varied with age
34.3% in first three decades of life
20.2% in ninth and tenth decades of life

19. Prevalence and Diagnosis of PFO
Echocardiography
PFO-echo dropout in atrial septum in more than one plane

21. Prevalence and Diagnosis of PFO
Right-to-Left Shunt-appearance of microbubbles in left atrium within 3-5 cardiac cycles after peripheral injection of agitated saline
Grading-arbitrary
10 bubbles – trivial
>10-small
intense opacification of LA-large

22. Atrial Septal Aneurysm (ASA)
Associated with PFO-Kerut, Thompson
Autopsy series – 16 ASA/1578 adults (1%)
ASA-Definition by echo
Bulging in the region of fossa ovalis
Septum membrane mobility
Sum of excursions at rest in both directions

24. Atrial Septal Aneurysm (ASA)
Hanley-suggests a sum of 15 mm or more as definition of septal excursion
Mugge pts with ASA
associated PFO with shunting 33%

25. Transesophageal Echocardiogram
TEE considered most sensitive method to detect PFO
Transcranial Doppler sonography of middle cerebral artery during contrast injection has been proposed.
PFO-microbubbles in MCA after peripheral injection
Heckman pts with stroke or TIA
Conclusion-both tests useful
Rate of detection higher when using both tests
Both tests dependent on technical expertise

26. Stroke and PFO Stroke-third leading cause of death in U.S.
700,000 new strokes/year
$50 billion in lost productivity/total health care costs
Etiology-hemorrhagic or ischemic
40% of ischemic strokes-no clear cause
Termed cryptogenic

27. Stroke and PFO Northern Manhattan Stroke Study, 1994 Sacco, et al.
Recurrence rates for all subtypes 9.4%/year
Cryptogenic stroke 10%/year
Lechal, et al First reported high prevalence of PFO in cryptogenic stroke pts.
60 adults younger than 55 years
All with ischemic stroke
Contrast surface echocardiography
PFO in 40% of study population
PFO in 10% of control group without stroke
PFO in 54% of pts with cyptogenic stroke

28. Stroke and PFO Mas, et al.-2001-New Engl J Med-598 pts
Between ages 18-35
Presented with stroke of unknown origin
PFO in 36%
ASA in 1.7%
PFO and ASA in 8.5%

29. Association between PFO and stroke stronger in certain subgroups.
Overell, et al Metanalysis of 9 studies
Rate of stroke significantly associated with:
Younger pts (< 55 years) who had:
PFO odds ratio 3.10
ASA odds ratio 6.14
PFO plus ASA odds ratio 15.59
Similar association not found in older pts

30. Despite high prevalence of PFO in general population,
Actual stroke event rate remains small
Lack of understanding of pathophysiology of PFO and cryptogenic stroke
Causal relationship between PFO, ASA, and Ischemic stroke is not established

31. Paradoxical Emboli Thrombus, fat and air all recognized
Right to left shunt occurs-
during coughing
after release phase of Valsalva
during mechanical ventilation
with elevated RA pressures from PE, COPD and RV failure
Suggested as main mechanism of stroke in PFO

32. Ranoux, et al.-1993-tested this theory
68 consecutive pts, age <55/ischemic stroke
PFO-in 32 pts (47%)
Valsalva provoking event present at stroke in 6 pts with PFO and in 8 pts without PFO
DVT present in one pt with PFO and none of the others.
Concluded—paradoxical embolization as cause of stroke in PFO—not valid.

33. Second Proposed Mechanism for Clot Embolization Primary Formation of Clot in PFO Canal
Anecdotal data only

34. Other PFO Factors Size and Shunting
Hausmann, et al Shunting is more severe and PFOs are larger in pts with strokes caused by paradoxical embolism
Homma, et al pts/ischemic stroke
Cryptogenic stroke pts had larger PFOs with more shunting than stroke pts of determined cause

35. PFO and ASA
De Castro, et al pts with acute ischemic stroke or TIA
Contrast TEE
High risk vs. low risk anatomy for subsequent stroke
PFO and ischemic stroke pts-at high risk for recurrence if—
right to left shunt at rest or
high septum membrane mobility

36. Other Proposed Mechanisms
Berthet, et al Atrial vulnerability
paroxysmal atrial arrythmia
abnormal atrial septal anatomy
studied 62 ischemic stroke pts <55 yrs
ischemic stroke/unknown cause
TEE evidence of PFO or ASA
EP study-inducible atrial fibrillation
Potential role of transient atrial arrythmias in thrombus formation in presence of ASA or PFO

37. Other Proposed Mechanisms
Hypercoaguable States
May promote paradoxical emboli in pts with PFO and cryptogenic stroke
One small study-1998-Chaturvedi
17 pts, cryptogenic stroke and PFO
31% had hemostatic abnormalities
Need further larger series

38. Medical Treatment of Stroke Patients with PFO
Not studied extensively
No studies comparing medical, surgical and/or catheter-based treatments reported.
Medical therapy
Antiplatelet or antithrombin drugs

39. Medical Treatment of Stroke Patients with PFO
Mas, et al pts, <60, PFO/stroke
Treated with aspirin ( mg/d) or oral anticoagulation (target INR )
Average annual rate of recurrence
1.2% for stroke
3.4% for combined stroke/TIA endpoints
No difference between 2 therapies

40. Medical Treatment of Stroke Patients with PFO
Mas, et al recurrent events-prospective study
Young pts with PFO, ASA or both
Treated with aspirin (300 mg/d) for 4 years
Stroke recurrence rate
2.3% with PFO
0% with ASA
4.2% with PFO and ASA
At 4 years-risk of stroke or TIA in pts with PFO and ASA was 19.2%

41. Warfarin-Aspirin Recurrent Stroke Study (WARSS)
2206 pts with ischemic stroke
Randomized to aspirin (325 mg/d) or
warfarin (INR ) for two years
No difference between aspirin or warfarin regarding recurrent stroke or death.

42. PFO in Cryptogenic Stroke Study
Evaluated TEE findings in 630 pts with cryptogenic stroke within WARSS trial
PFO in 39% of pts with cryptogenic stroke compared to 29.9% of pts with known cause of stroke
warfarin vs. aspirin—no difference in incidence of stroke or death

43. Surgical Closure of PFO
Open thoracotomy
Mixed results
Higher recurrence of neurological events in older pts with cryptogenic stroke after open surgical repair

44. Percutaneous Closure of PFO
Braun, et al.-2002
276 consecutive pts with PFO & 1 thromboembolic event
PFO closure with a PFO-star device
Successful implantation in all 276
Complications-
Transient ST elevation 1.8%
TIA in 0.8%
15 months of follow-up
0% recurrent stroke
1.7% TIA
0% peripheral emboli

45. Percutaneous Closure of PFO
Windecker, et al.-2000
80 pts with PFO & at least 1 parodoxical embolic event
Used 1 of 5 different PFO closure devices
60 pts had PFO only
20 pts had PFO and ASA
Successful implantation in 78 pts (98%)
Complete PFO closure achieved in 57 (73%)
Residual Right to Left Shunt 21 (27%)

46. Percutaneous Closure of PFO
Five years of Followup
Actuarial annual risk for embolic event
2.5% for TIA
0% for Stroke
0.9% for Peripheral Emboli
3.4% for Combined Endpoint of TIA/Stroke and Peripheral emboli
Post-procedural shunt-predictor of recurrent event
Relative risk of 4.2%
Risk of recurrence-highest in the first year

47. PFO and Migraine Headaches
Relationship between migraine with aura and cardiac right to left shunt has been reported
Del Sette, et al Case Control Study
Conclusion-prevalence of right to left shunt in pts with migraine with aura is significantly higher than healthy controls and similar to the prevalence of RLS in young pts with stroke.

48. PFO and Migraine Headaches
Wilmshurst, et al.-2000
Of 37 pts who underwent PFO closure,
21 had migraine before procedure (57%)
30 month follow-up
10 pts-no further migraine (7 w/ aura, 3 w/o)
8 pts-decreased frequency/severity of HA
3 pts-no change in migraines

49. Patient Follow-ups
K.M.-44 y/o woman with 3 separate TIA, right eye visual loss
Found to have moderate PFO with interatrial shunting AND a cerebral aneurysm
Placed on warfarin
Developed gross hematuria
Symptomatic menorrhagia
Had percutanous PFO closure with Amplatizer Device one year ago
No recurrent neurological events
Off Warfarin
No interatrial shunting

50. Patient Follow-ups A.F.-52 y/o woman with stroke at age 40
Documented PFO
No recurrent events in 12 years on ASA alone
Not a candidate for PFO closure

51. Patient Follow-ups R.K.-48 y/o woman Recurrent TIAS, PFO with ASA
Treated with Aspirin and Plavix
Evidence of old silent caudate infarct
Heterozygous for Factor V Leiden
Subsequent right hemispheric sub-cortical stroke while taking Aspirin and Plavix
PFO closure with Amplatizer closure device on
Remains hemiplegic, undergoing rehab, with no further events, no further migraine headaches

52. UW Health Heart and Vascular Care
Interventional Cardiologist – Dr. Tim Tanke performed the first percutaneous PFO closure (K.M.) in 2002 at the University of Wisconsin.
To refer a patient-(608) or
FDA approved indications for percutaneous PFO closure
-cryptogenic stroke with PFO
-failure of medical therapy (recurrent event on “therapy”) or contraindication to medical therapy

53. Many thanks to Patty Boyle for assistance in preparing this presentation.