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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.
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