To Close or Not to Close (the PFO)?To Close or Not to Close (the PFO)?

That is the QuestionThat is the Question

Lorna Belsky, M.D.Lorna Belsky, M.D.

March 31, 2004March 31, 2004

Learning Objectives:Learning Objectives:

By the end of this presentation, you will be able to:1. define patent foramen ovale (PFO)

2. define atrial septal aneurysm (ASA)

3. 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).

Patients:Patients:Patient No. 1 - K.M., 44-year-old womanPatient No. 1 - K.M., 44-year-old woman

3 separate episodes of visual clouding in right eye, “gray 3 separate episodes of visual clouding in right eye, “gray cloud”cloud”No headache, Left eye normalNo headache, Left eye normalSymptoms lasted 5-8 minutes each time, occurred each Symptoms lasted 5-8 minutes each time, occurred each evening x2, then again in the morning of the third day.evening x2, then again in the morning of the third day.Saw her primary care doctorSaw her primary care doctor

PMHPMHmigraine, started in adolescence, worsened around age migraine, started in adolescence, worsened around age 40, associated with blurred vision40, associated with blurred vision

Episode of vertigo 2 yrs prior, associated with sinus Episode of vertigo 2 yrs prior, associated with sinus infectioninfectionSevere, fell out of a chair, could not drive for 4 weeks, no Severe, fell out of a chair, could not drive for 4 weeks, no sequelae thereaftersequelae thereafter

Depressive disorder, treatedDepressive disorder, treated

Patient No. 1 - K.M., 44-year-old woman Patient No. 1 - K.M., 44-year-old woman (cont’d)(cont’d)

Medications – fluoxetine, MVIMedications – fluoxetine, MVIAllergies – noneAllergies – none

SH – married, 2 boysSH – married, 2 boysNever smokerNever smokerWine, 1-2/weekendWine, 1-2/weekendStock brokerStock broker

FH – Mother had TIA age 68, decreased vision and FH – Mother had TIA age 68, decreased vision and paresthesias, on Aspirin, no recurrence x5 years.paresthesias, on Aspirin, no recurrence x5 years.Sister age 36 with epilepsySister age 36 with epilepsyFather-HTNFather-HTNNo bleeding or clotting disordersNo bleeding or clotting disorders

Patient No. 2 – A.F., 52-year-old womanPatient No. 2 – A.F., 52-year-old woman

New patient to clinic to establish careNew patient to clinic to establish careH/O left frontoparietal stroke 12 yrs ago at age 40H/O left frontoparietal stroke 12 yrs ago at age 40Treated with ASA. Residual slurred speech when Treated with ASA. Residual slurred speech when tired. tired. No recurrent neurological symptoms.No recurrent neurological symptoms.

Previous stroke workupPrevious stroke workup-No hypercoaguable disorders-No hypercoaguable disorders-TEE showed PFO-TEE showed PFO-High suspicion of paradoxical embolism-High suspicion of paradoxical embolism

PMH-severe migraines with aura around time of PMH-severe migraines with aura around time of strokestrokePostmenopausal, migraines remittedPostmenopausal, migraines remittedShoulder surgeryShoulder surgeryGERDGERD

Patient No. 3 – R.K., 48-year-old womanPatient No. 3 – R.K., 48-year-old woman

Called my office with new symptomsCalled my office with new symptoms

While driving, she experienced:While driving, she experienced:

decreased vision in left eye that followed decreased vision in left eye that followed zig-zagging visual changes in the left eye zig-zagging visual changes in the left eye

simultaneously, numbness of left face, arm simultaneously, numbness of left face, arm and leg lasting 1-2 hours. Now resolved. and leg lasting 1-2 hours. Now resolved.

associated with a minor headache located associated with a minor headache located over foreheadover forehead

Patient No. 3 – R.K., 48-year-old womanPatient No. 3 – R.K., 48-year-old woman

PMH PMH

major depressive disorder, major depressive disorder,

recurrent complex regional pain syndrome recurrent complex regional pain syndrome right armright arm

Dysphagia, esophageal dysmotilityDysphagia, esophageal dysmotility

Former smokerFormer smoker

Migraine headachesMigraine headaches

Hysterectomy, benignHysterectomy, benign

Patient No. 3 - R.K., 48-year-old woman Patient No. 3 - R.K., 48-year-old woman (cont’d)(cont’d)Medications – PremarinMedications – Premarin

ProtonixProtonixVerapamil-for migraineVerapamil-for migraineMVIMVICalciumCalcium

FH – HTN, heart disease, stroke in old FH – HTN, heart disease, stroke in old ageage

Patient No. 3 - R.K., 48-year-old woman Patient No. 3 - R.K., 48-year-old woman (cont’d)(cont’d)Admitted to hospital-stroke workup doneAdmitted to hospital-stroke workup done

MRI brain-chronic infarct right caudate nucleusMRI brain-chronic infarct right caudate nucleusHypercoaguable workup-negative at discharge. Hypercoaguable workup-negative at discharge. Factor V Leiden pendingFactor V Leiden pending

TEE-Atrial septal aneurysm with associated PFO trivial TEE-Atrial septal aneurysm with associated PFO trivial interatrial shunt, right to left, at restinteratrial shunt, right to left, at rest

Discharged home after two days on Aspirin 81 mg andDischarged home after two days on Aspirin 81 mg andPlavix 75 mg (Premarin was continued)Plavix 75 mg (Premarin was continued)

Patient declined treatment with LMWHPatient declined treatment with LMWH

Subsequently consulted Interventional CardiologySubsequently consulted Interventional CardiologyDid not meet current FDA guidelines for percutaneous Did not meet current FDA guidelines for percutaneous

PFO PFO closureclosure-failed anticoagulation with recurrent neurological -failed anticoagulation with recurrent neurological

symptomssymptoms-significant contraindication to anticoagulation-significant contraindication to anticoagulation

Patient No. 3 - R.K., 48-year-old woman Patient No. 3 - R.K., 48-year-old woman (cont’d)(cont’d)Two weeks later-called again with recurrent left face, Two weeks later-called again with recurrent left face, arm, leg numbness & mild headache, partner noted left arm, leg numbness & mild headache, partner noted left facial droop. Patient experienced mild weakness in arm facial droop. Patient experienced mild weakness in arm and leg this time.and leg this time.

Back to ER. Admitted. Completed right hemispheric sub-Back to ER. Admitted. Completed right hemispheric sub-cortical stroke, residual left hemiplegia, (while on cortical stroke, residual left hemiplegia, (while on ASA/Plavix).ASA/Plavix).

Found heterozygous for Factor V LeidenFound heterozygous for Factor V Leiden

Now-fulfills FDA criteria for PFO closure.Now-fulfills FDA criteria for PFO closure.

Undergoes percutaneous PFO closure with Amplatzer Undergoes percutaneous PFO closure with Amplatzer closure device.closure device.

Discharged home, disabled for her job, on Plavix, to Discharged home, disabled for her job, on Plavix, to receive physical and occupational therapy.receive physical and occupational therapy.

Topics for Discussion TodayTopics 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?

Embryology 101Embryology 101

The cardiovascular system is the first The cardiovascular system is the first system to function in the embryosystem to function in the embryo

Blood begins to circulate by the end of Blood begins to circulate by the end of the third week.the third week.

Derived from angioblastic tissue Derived from angioblastic tissue (mesenchyme).(mesenchyme).

Contractions of the heart begin by Day Contractions of the heart begin by Day 22.22.

Partitioning of the Primitive Partitioning of the Primitive AtriumAtrium1. Septum primum grows down from atrial roof

2. Foramen primum-opening in septum primum

3. Septum primum fuses with endocardial cushions

4. Foramen primum closes, concurrently:

5. Foramen secundum-forms in septum primum

6. Septum secundum grows down from atrial roof right of septum primum

7. The two septums overlap, incompletely, in the area of the foramen secundum-forms the foramen ovale.

Physiology/Embryology 101Physiology/Embryology 101

Before birth-foramen ovale open-blood flows from IVC RALA

After birth-Foramen ovale closes

Septum primum fuses with Septum Secundum

Atrial Septal DefectsAtrial 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

Prevalence and Diagnosis of Prevalence and Diagnosis of PFOPFO

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

Prevalence and Diagnosis of Prevalence and Diagnosis of PFOPFO

Echocardiography

PFO-echo dropout in atrial septum in more than one plane

Prevalence and Diagnosis of Prevalence and Diagnosis of PFOPFO

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

Atrial Septal Aneurysm (ASA)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

Atrial Septal Aneurysm (ASA)Atrial Septal Aneurysm (ASA)

Hanley-suggests a sum of 15 mm or more as definition of septal excursion

Mugge-1995-195 pts with ASA

associated PFO with shunting 33%

Transesophageal Transesophageal EchocardiogramEchocardiogramTEE 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-1999-45 pts with stroke or TIA

Conclusion-both tests useful

Rate of detection higher when using both tests

Both tests dependent on technical expertise

Stroke and PFOStroke 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

Stroke and PFOStroke 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.-1988-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

Stroke and PFOStroke 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%

Association between PFO and stroke stronger in certain subgroups.

Overell, et al.-2000-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

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

Paradoxical EmboliParadoxical EmboliThrombus, 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

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.

Second Proposed Mechanism Second Proposed Mechanism for Clot Embolizationfor Clot Embolization

Primary Formation of Clot in PFO CanalPrimary Formation of Clot in PFO Canal

Anecdotal data only

Other PFO FactorsOther PFO Factors

Size and Shunting

Hausmann, et al.-1995-Shunting is more severe and PFOs are larger in pts with strokes caused by paradoxical embolism

Homma, et al.-1994-74 pts/ischemic stroke

Cryptogenic stroke pts had larger PFOs with more shunting than stroke pts of determined cause

PFO and ASAPFO and ASA

De Castro, et al.-2000-350 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

Other Proposed MechanismsOther Proposed Mechanisms

Berthet, et al.-1999-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

Other Proposed MechanismsOther 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

Medical Treatment of Stroke Medical Treatment of Stroke Patients with PFOPatients with PFO

Not studied extensively

No studies comparing medical, surgical and/or catheter-based treatments reported.

Medical therapy

Antiplatelet or antithrombin drugs

Medical Treatment of Stroke Medical Treatment of Stroke Patients with PFOPatients with PFO

Mas, et al.-1995-132 pts, <60, PFO/stroke

Treated with aspirin (250-500 mg/d) or oral anticoagulation (target INR 2.0-3.0)

Average annual rate of recurrence

1.2% for stroke

3.4% for combined stroke/TIA endpoints

No difference between 2 therapies

Medical Treatment of Stroke Medical Treatment of Stroke Patients with PFOPatients with PFO

Mas, et al.-2001-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%

Warfarin-Aspirin Recurrent Warfarin-Aspirin Recurrent Stroke Study (WARSS)Stroke Study (WARSS)

2206 pts with ischemic stroke

Randomized to aspirin (325 mg/d) or

warfarin (INR 1.4-2.8) for two years

No difference between aspirin or warfarin regarding recurrent stroke or death.

PFO in Cryptogenic Stroke PFO in Cryptogenic Stroke StudyStudy

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

Surgical Closure of PFOSurgical Closure of PFO

Open thoracotomy

Mixed results

Higher recurrence of neurological events in older pts with cryptogenic stroke after open surgical repair

Percutaneous Closure of PFOPercutaneous 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

Percutaneous Closure of PFOPercutaneous Closure of PFOWindecker, 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%)

Percutaneous Closure of PFOPercutaneous Closure of PFOFive years of FollowupActuarial annual risk for embolic event

2.5% for TIA0% for Stroke0.9% for Peripheral Emboli3.4% for Combined Endpoint of TIA/Stroke and Peripheral emboli

Post-procedural shunt-predictor of recurrent eventRelative risk of 4.2%Risk of recurrence-highest in the first year

PFO and Migraine HeadachesPFO and Migraine Headaches

Relationship between migraine with aura and cardiac right to left shunt has been reported

Del Sette, et al.-1998 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.

PFO and Migraine HeadachesPFO 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

Patient Follow-upsPatient Follow-ups1. 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

Patient Follow-upsPatient Follow-ups

2. 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

Patient Follow-upsPatient Follow-ups3. 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

1-7-04.

Remains hemiplegic, undergoing rehab, with no further events, no further migraine headaches

UW Health Heart and UW Health Heart and Vascular CareVascular 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)263-1530 or tet@medicine.wisc.edu

FDA approved indications for percutaneous PFO closure

-cryptogenic stroke with PFO

-failure of medical therapy (recurrent event on “therapy”) or contraindication to medical

therapy

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