Semin Thromb Hemost 2009; 35(5): 505-514
DOI: 10.1055/s-0029-1234146
© Thieme Medical Publishers

Patent Foramen Ovale and Cryptogenic Stroke: A Matter of Age?

Michael Handke1 , Andreas Harloff2 , Christoph Bode3 , Annette Geibel3
  • 1Department of Cardiology, University Hospital Basel, Basel, Switzerland
  • 2Department of Neurology and Neurophysiology, University Hospital Freiburg, Freiburg, Germany
  • 3Department of Cardiology and Angiology, University Hospital Freiburg, Freiburg, Germany
Further Information

Publication History

Publication Date:
08 September 2009 (online)

ABSTRACT

A patent foramen ovale (PFO) enables a right-to-left shunt in about a quarter of the population. The marked association between cryptogenic stroke and PFO supports the hypothesis that paradoxical embolism could be a relevant cause of stroke. Although this association has been described in several studies for patients <55 years of age, only limited data are available on the role of PFO in older patients. Recent studies, however, have also shown a significant association between cryptogenic stroke and PFO in patients >55 years of age. The relationship is especially marked in the presence of atrial septum aneurysm (ASA). This finding is in accordance with previous reports indicating that PFO and concomitant ASA is a high-risk feature. Factors promoting paradoxical embolism, such as deep vein thrombosis (DVT) and elevated right-heart pressure, are more frequently encountered in older than in younger patients. Independent of age, contrast-enhanced transthoracic and transesophageal echocardiography are the methods of choice for the detection and imaging of PFO and atrial septal aneurysm. Transcranial Doppler can be used as a screening method in patients with cryptogenic stroke to detect a right-to-left shunt. Proof of DVT strongly supports the suspicion of paradoxical embolism and should lead to oral anticoagulation. If paradoxical embolism is suspected without proof of DVT, both drug therapy with aspirin or warfarin and percutaneous closure of the PFO are available as therapeutic options. Recent studies have shown that percutaneous closure can be performed safely and with a low rate of recurrence both in older and younger patients. Thus far, however, there is no clear-cut evidence of superiority for either therapeutic strategy.

REFERENCES

  • 1 Lechat P, Mas J L, Lascault G et al.. Prevalence of patent foramen ovale in patients with stroke.  N Engl J Med. 1988;  318(18) 1148-1152
  • 2 Webster M W, Chancellor A M, Smith H J et al.. Patent foramen ovale in young stroke patients.  Lancet. 1988;  2(8601) 11-12
  • 3 Windecker S, Meier B. Is closure recommended for patent foramen ovale and cryptogenic stroke? Patent foramen ovale and cryptogenic stroke: to close or not to close? Closure: what else!.  Circulation. 2008;  118(19) 1989-1998
  • 4 Overell J R, Bone I, Lees K R. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies.  Neurology. 2000;  55(8) 1172-1179
  • 5 Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A. Patent foramen ovale and cryptogenic stroke in older patients.  N Engl J Med. 2007;  357(22) 2262-2268
  • 6 Force M, Massabuau P, Larrue V. Prevalence of atrial septal abnormalities in older patients with cryptogenic ischemic stroke or transient ischemic attack.  Clin Neurol Neurosurg. 2008;  110(8) 779-783
  • 7 Truelsen T, Piechowski-Jóźwiak B, Bonita R, Mathers C, Bogousslavsky J, Boysen G. Stroke incidence and prevalence in Europe: a review of available data.  Eur J Neurol. 2006;  13(6) 581-598
  • 8 Carerj L. Leonardo Botallo, the foramen ovale and the ductus arteriosus.  Minerva Med. 1955;  46 789-795
  • 9 Cohnheim J. Thrombose und Embolie. In: Cohnheim J Vorlesung über allgemeine Pathologie. Berlin, Germany; Hirschwald 1877: 134
  • 10 Zahn F W. Ueber paradoxe Embolie und ihre Bedeutung für die Geschwulstmetastase.  Virchows Arch. 1889;  115 71-80
  • 11 Gleysteen J J, Silver D. Paradoxical arterial embolism: collective review.  Am Surg. 1970;  36(1) 47-54
  • 12 Lynch J J, Schuchard G H, Gross C M, Wann L S. Prevalence of right-to-left atrial shunting in a healthy population: detection by Valsalva maneuver contrast echocardiography.  Am J Cardiol. 1984;  53(10) 1478-1480
  • 13 Chen W J, Kuan P, Lien W P, Lin F Y. Detection of patent foramen ovale by contrast transesophageal echocardiography.  Chest. 1992;  101(6) 1515-1520
  • 14 Homma S, Sacco R L. Patent foramen ovale and stroke.  Circulation. 2005;  112(7) 1063-1072
  • 15 Hagen P T, Scholz D G, Edwards W D. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts.  Mayo Clin Proc. 1984;  59(1) 17-20
  • 16 Topaz O, Feigl A, Edwards J E. Aneurysm of the fossa ovalis in infants: a pathologic study.  Pediatr Cardiol. 1985;  6(2) 65-68
  • 17 Topaz O, Edwards J E, Bojack-Mackey S, Titus J L. Aneurysm of fossa ovalis in adults: a pathologic study.  Cardiovasc Pathol. 2003;  12(4) 219-225
  • 18 Silver M D, Dorsey J S. Aneurysms of the septum primum in adults.  Arch Pathol Lab Med. 1978;  102(2) 62-65
  • 19 Mügge A, Daniel W G, Angermann C et al.. Atrial septal aneurysm in adult patients. A multicenter study using transthoracic and transesophageal echocardiography.  Circulation. 1995;  91(11) 2785-2792
  • 20 Hanley P C, Tajik A J, Hynes J K et al.. Diagnosis and classification of atrial septal aneurysm by two-dimensional echocardiography: report of 80 consecutive cases.  J Am Coll Cardiol. 1985;  6(6) 1370-1382
  • 21 Katayama H, Mitamura H, Mitani K, Nakagawa S, Ui S, Kimura M. Incidence of atrial septal aneurysm: echocardiographic and pathologic analysis [in Japanese].  J Cardiol. 1990;  20(2) 411-421
  • 22 Agmon Y, Khandheria B K, Meissner I et al.. Frequency of atrial septal aneurysms in patients with cerebral ischemic events.  Circulation. 1999;  99(15) 1942-1944
  • 23 Meissner I, Khandheria B K, Heit J A et al.. Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study.  J Am Coll Cardiol. 2006;  47(2) 440-445
  • 24 Pearson A C, Nagelhout D, Castello R, Gomez C R, Labovitz A J. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study.  J Am Coll Cardiol. 1991;  18(5) 1223-1229
  • 25 Fox E R, Picard M H, Chow C M, Levine R A, Schwamm L, Kerr A J. Interatrial septal mobility predicts larger shunts across patent foramen ovales: an analysis with transmitral Doppler scanning.  Am Heart J. 2003;  145(4) 730-736
  • 26 Schuchlenz H W, Saurer G, Weihs W, Rehak P. Persisting eustachian valve in adults: relation to patent foramen ovale and cerebrovascular events.  J Am Soc Echocardiogr. 2004;  17(3) 231-233
  • 27 Revel M P, Faivre J B, Letourneau T et al.. Patent foramen ovale: detection with nongated multidetector CT.  Radiology. 2008;  249(1) 338-345
  • 28 Nusser T, Höher M, Merkle N et al.. Cardiac magnetic resonance imaging and transesophageal echocardiography in patients with transcatheter closure of patent foramen ovale.  J Am Coll Cardiol. 2006;  48(2) 322-329
  • 29 Dubourg O, Bourdarias J P, Farcot J C et al.. Contrast echocardiographic visualization of cough-induced right to left shunt through a patent foramen ovale.  J Am Coll Cardiol. 1984;  4(3) 587-594
  • 30 Homma S, Sacco R L, Di Tullio M R, Sciacca R R, Mohr J P. PFO in Cryptogenic Stroke Study (PICSS) Investigators . Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study.  Circulation. 2002;  105(22) 2625-2631
  • 31 Cheng T O. The proper conduct of Valsalva maneuver in the detection of patent foramen ovale.  J Am Coll Cardiol. 2005;  45(7) 1145-1146
  • 32 Devuyst G, Piechowski-Józwiak B, Karapanayiotides T et al.. Controlled contrast transcranial Doppler and arterial blood gas analysis to quantify shunt through patent foramen ovale.  Stroke. 2004;  35(4) 859-863
  • 33 Siostrzonek P, Zangeneh M, Gössinger H et al.. Comparison of transesophageal and transthoracic contrast echocardiography for detection of a patent foramen ovale.  Am J Cardiol. 1991;  68(11) 1247-1249
  • 34 Di Tullio M, Sacco R L, Venketasubramanian N, Sherman D, Mohr J P, Homma S. Comparison of diagnostic techniques for the detection of a patent foramen ovale in stroke patients.  Stroke. 1993;  24(7) 1020-1024
  • 35 Belkin R N, Pollack B D, Ruggiero M L, Alas L L, Tatini U. Comparison of transesophageal and transthoracic echocardiography with contrast and color flow Doppler in the detection of patent foramen ovale.  Am Heart J. 1994;  128(3) 520-525
  • 36 Kühl H P, Hoffmann R, Merx M W et al.. Transthoracic echocardiography using second harmonic imaging: diagnostic alternative to transesophageal echocardiography for the detection of atrial right to left shunt in patients with cerebral embolic events.  J Am Coll Cardiol. 1999;  34(6) 1823-1830
  • 37 Daniëls C, Weytjens C, Cosyns B et al.. Second harmonic transthoracic echocardiography: the new reference screening method for the detection of patent foramen ovale.  Eur J Echocardiogr. 2004;  5(6) 449-452
  • 38 Pearson A C, Labovitz A J, Tatineni S, Gomez C R. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology.  J Am Coll Cardiol. 1991;  17(1) 66-72
  • 39 Hofmann T, Kasper W, Meinertz T, Geibel A, Just H. Echocardiographic evaluation of patients with clinically suspected arterial emboli.  Lancet. 1990;  336(8728) 1421-1424
  • 40 Schuchlenz H W, Weihs W, Beitzke A, Stein J I, Gamillscheg A, Rehak P. Transesophageal echocardiography for quantifying size of patent foramen ovale in patients with cryptogenic cerebrovascular events.  Stroke. 2002;  33(1) 293-296
  • 41 Mügge A, Daniel W G, Klöpper J W, Lichtlen P R. Visualization of patent foramen ovale by transesophageal color-coded Doppler echocardiography.  Am J Cardiol. 1988;  62(10 Pt 1) 837-838
  • 42 Schuchlenz H W, Weihs W, Horner S, Quehenberger F. The association between the diameter of a patent foramen ovale and the risk of embolic cerebrovascular events.  Am J Med. 2000;  109(6) 456-462
  • 43 Homma S, Di Tullio M R, Sacco R L, Mihalatos D, Li Mandri G, Mohr J P. Characteristics of patent foramen ovale associated with cryptogenic stroke. A biplane transesophageal echocardiographic study.  Stroke. 1994;  25(3) 582-586
  • 44 Schneider B, Zienkiewicz T, Jansen V, Hofmann T, Noltenius H, Meinertz T. Diagnosis of patent foramen ovale by transesophageal echocardiography and correlation with autopsy findings.  Am J Cardiol. 1996;  77(14) 1202-1209
  • 45 Hamann G F, Schätzer-Klotz D, Fröhlig G et al.. Femoral injection of echo contrast medium may increase the sensitivity of testing for a patent foramen ovale.  Neurology. 1998;  50(5) 1423-1428
  • 46 Daniel W G, Erbel R, Kasper W et al.. Safety of transesophageal echocardiography. A multicenter survey of 10,419 examinations.  Circulation. 1991;  83(3) 817-821
  • 47 Hüttemann E, Schelenz C, Kara F, Chatzinikolaou K, Reinhart K. The use and safety of transoesophageal echocardiography in the general ICU—a minireview.  Acta Anaesthesiol Scand. 2004;  48(7) 827-836
  • 48 Zabalgoitia M, Gandhi D K, Evans J, Mehlman D J, McPherson D D, Talano J V. Transesophageal echocardiography in the awake elderly patient: its role in the clinical decision-making process.  Am Heart J. 1990;  120(5) 1147-1153
  • 49 Stoddard M F, Longaker R A. The safety of transesophageal echocardiography in the elderly.  Am Heart J. 1993;  125(5 Pt 1) 1358-1362
  • 50 Nedeltchev K, Mattle H P. Contrast-enhanced transcranial Doppler ultrasound for diagnosis of patent foramen ovale.  Front Neurol Neurosci. 2006;  21 206-215
  • 51 Belvís R, Leta R G, Martí-Fàbregas J et al.. Almost perfect concordance between simultaneous transcranial Doppler and transesophageal echocardiography in the quantification of right-to-left shunts.  J Neuroimaging. 2006;  16(2) 133-138
  • 52 Devuyst G, Despland P A, Bogousslavsky J, Jeanrenaud X. Complementarity of contrast transcranial Doppler and contrast transesophageal echocardiography for the detection of patent foramen ovale in stroke patients.  Eur Neurol. 1997;  38(1) 21-25
  • 53 Messé S R, Kasner S E. Is closure recommended for patent foramen ovale and cryptogenic stroke? Patent foramen ovale in cryptogenic stroke: not to close.  Circulation. 2008;  118(19) 1999-2004
  • 54 Di Tullio M R, Sacco R L, Sciacca R R, Jin Z, Homma S. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population.  J Am Coll Cardiol. 2007;  49(7) 797-802
  • 55 Tillett A, Hartley B, Simpson J. Paradoxical embolism causing fatal myocardial infarction in a newborn infant.  Arch Dis Child Fetal Neonatal Ed. 2001;  85 F137-F138
  • 56 Kessel-Schaefer A, Lefkovits M, Zellweger M J et al.. Migrating thrombus trapped in a patent foramen ovale.  Circulation. 2001;  103(14) 1928
  • 57 Fraticelli A, Gambini C, Iannoni E, Paciaroni E. Impending paradoxical embolism through a patent foramen ovale in an octogenarian with pulmonary embolism: detection by transesophageal echocardiography and successful treatment by anticoagulation.  Arch Gerontol Geriatr. 1998;  27(1) 41-47
  • 58 Cabanes L, Mas J L, Cohen A et al.. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography.  Stroke. 1993;  24(12) 1865-1873
  • 59 Di Tullio M, Sacco R L, Gopal A, Mohr J P, Homma S. Patent foramen ovale as a risk factor for cryptogenic stroke.  Ann Intern Med. 1992;  117(6) 461-465
  • 60 Hausmann D, Mügge A, Becht I, Daniel W G. Diagnosis of patent foramen ovale by transesophageal echocardiography and association with cerebral and peripheral embolic events.  Am J Cardiol. 1992;  70(6) 668-672
  • 61 Job F P, Ringelstein E B, Grafen Y et al.. Comparison of transcranial contrast Doppler sonography and transesophageal contrast echocardiography for the detection of patent foramen ovale in young stroke patients.  Am J Cardiol. 1994;  74(4) 381-384
  • 62 Jones E F, Calafiore P, Donnan G A, Tonkin A M. Evidence that patent foramen ovale is not a risk factor for cerebral ischemia in the elderly.  Am J Cardiol. 1994;  74(6) 596-599
  • 63 Yeung M, Khan K A, Shuaib A. Transcranial Doppler ultrasonography in the detection of venous to arterial shunting in acute stroke and transient ischaemic attacks.  J Neurol Neurosurg Psychiatry. 1996;  61(5) 445-449
  • 64 Silverstein M D, Heit J A, Mohr D N, Petterson T M, O’Fallon W M, Melton III L J. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.  Arch Intern Med. 1998;  158(6) 585-593
  • 65 Stöllberger C, Slany J, Schuster I, Leitner H, Winkler W B, Karnik R. The prevalence of deep venous thrombosis in patients with suspected paradoxical embolism.  Ann Intern Med. 1993;  119(6) 461-465
  • 66 Belcaro G, Geroulakos G, Nicolaides A N, Myers K A, Winford M. Venous thromboembolism from air travel: the LONFLIT study.  Angiology. 2001;  52(6) 369-374
  • 67 Heckmann J G, Stadter M, Reulbach U, Duetsch M, Nixdorff U, Ringwald J. Increased frequency of cardioembolism and patent foramen ovale in patients with stroke and a positive travel history suggesting economy class stroke syndrome.  Heart. 2006;  92(9) 1265-1268
  • 68 Meister S G, Grossman W, Dexter L, Dalen J E. Paradoxical embolism. Diagnosis during life.  Am J Med. 1972;  53(3) 292-298
  • 69 Konstantinides S, Geibel A, Kasper W, Olschewski M, Blümel L, Just H. Patent foramen ovale is an important predictor of adverse outcome in patients with major pulmonary embolism.  Circulation. 1998;  97(19) 1946-1951
  • 70 Ueda R, Yokouchi M, Andou H et al.. Pulmonary artery systolic pressure is elevated in the elderly: relationships between echocardiographic and pathological findings.  Intern Med. 2004;  43(5) 374-378
  • 71 Mas J L, Arquizan C, Lamy C Patent Foramen Ovale and Atrial Septal Aneurysm Study Group et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both.  N Engl J Med. 2001;  345(24) 1740-1746
  • 72 Berthet K, Lavergne T, Cohen A et al.. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause.  Stroke. 2000;  31(2) 398-403
  • 73 Cianciulli T F, Chejtman D, Lipshitz S B, Saccheri M C, Dethinne S L, Prezioso H A. Atrial septal aneurysm and spontaneous echo contrast: an association with higher embolic risk?.  Eur J Echocardiogr. 2006;  7(3) 243-246
  • 74 Homma S, DiTullio M R, Sacco R L, Sciacca R R, Mohr J P. PICSS Investigators . Age as a determinant of adverse events in medically treated cryptogenic stroke patients with patent foramen ovale.  Stroke. 2004;  35(9) 2145-2149
  • 75 Messé S R, Silverman I E, Kizer J R Quality Standards Subcommittee of the American Academy of Neurology et al. Practice parameter: recurrent stroke with patent foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of Neurology.  Neurology. 2004;  62(7) 1042-1050
  • 76 Sacco R L, Adams R, Albers G American Heart Association et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline.  Stroke. 2006;  37(2) 577-617
  • 77 Wahl A, Meier B, Haxel B et al.. Prognosis after percutaneous closure of patent foramen ovale for paradoxical embolism.  Neurology. 2001;  57(7) 1330-1332
  • 78 Hung J, Landzberg M J, Jenkins K J et al.. Closure of patent foramen ovale for paradoxical emboli: intermediate-term risk of recurrent neurological events following transcatheter device placement.  J Am Coll Cardiol. 2000;  35(5) 1311-1316
  • 79 Martín F, Sánchez P L, Doherty E et al.. Percutaneous transcatheter closure of patent foramen ovale in patients with paradoxical embolism.  Circulation. 2002;  106(9) 1121-1126
  • 80 Braun M, Gliech V, Boscheri A et al.. Transcatheter closure of patent foramen ovale (PFO) in patients with paradoxical embolism. Periprocedural safety and mid-term follow-up results of three different device occluder systems.  Eur Heart J. 2004;  25(5) 424-430
  • 81 Windecker S, Wahl A, Nedeltchev K et al.. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke.  J Am Coll Cardiol. 2004;  44(4) 750-758
  • 82 Schuchlenz H W, Weihs W, Berghold A, Lechner A, Schmidt R. Secondary prevention after cryptogenic cerebrovascular events in patients with patent foramen ovale.  Int J Cardiol. 2005;  101(1) 77-82
  • 83 Khairy P, O’Donnell C P, Landzberg M J. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review.  Ann Intern Med. 2003;  139(9) 753-760
  • 84 Wahl A, Krumsdorf U, Meier B et al.. Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high-risk patients.  J Am Coll Cardiol. 2005;  45(3) 377-380
  • 85 Spies C, Khandelwal A, Timmemanns I, Kavinsky C J, Schräder R, Hijazi Z M. Recurrent events following patent foramen ovale closure in patients above 55 years of age with presumed paradoxical embolism.  Catheter Cardiovasc Interv. 2008;  72(7) 966-970
  • 86 Kiblawi F M, Sommer R J, Levchuck S G. Transcatheter closure of patent foramen ovale in older adults.  Catheter Cardiovasc Interv. 2006;  68(1) 136-142, discussion 143–144
  • 87 Harloff A, Handke M, Reinhard M, Geibel A, Hetzel A. Therapeutic strategies after examination by transesophageal echocardiography in 503 patients with ischemic stroke.  Stroke. 2006;  37(3) 859-864
  • 88 Saver J L. Cryptogenic stroke in patients with patent foramen ovale.  Curr Atheroscler Rep. 2007;  9(4) 319-325
  • 89 Thaler D E, Saver J L. Cryptogenic stroke and patent foramen ovale.  Curr Opin Cardiol. 2008;  23(6) 537-544
  • 90 Lethen H, Flachskampf F A, Schneider R et al.. Frequency of deep vein thrombosis in patients with patent foramen ovale and ischemic stroke or transient ischemic attack.  Am J Cardiol. 1997;  80(8) 1066-1069
  • 91 Cramer S C, Rordorf G, Maki J H et al.. Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) study.  Stroke. 2004;  35(1) 46-50
  • 92 Primary and Secondary Prevention of Cerebral Ischemia .Joint guidelines issued by the German Neurological Society (Deutsche Gesellschaft für Neurologie; DGN) and the German Stroke Society (Deutsche Schlaganfallgesellschaft; DSG). Published in German, September 2005. Available at: http://www.dgn.org/
  • 93 Wahl A, Praz F, Stinimann J et al.. Safety and feasibility of percutaneous closure of patent foramen ovale without intra-procedural echocardiography in 825 patients.  Swiss Med Wkly. 2008;  138(39-40) 567-572

Michael HandkeM.D. 

University Hospital Basel, Department of Cardiology

Petersgraben 4, 4031 Basel, Switzerland

Email: HandkeM@uhbs.ch

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