Correspondence

Patent Foramen Ovale, Atrial Septal Aneurysm, and Recurrent Stroke

N Engl J Med 2002; 346:1331-1332April 25, 2002

Article

To the Editor:

Mas et al. (Dec. 13 issue)1 describe multiple potential thromboembolic mechanisms that may account for the increased risk of recurrent stroke in young patients with both patent foramen ovale and atrial septal aneurysm.

The initial descriptions of paradoxical embolism with stroke provide clear evidence of a thrombotic source (e.g., deep-vein thrombosis), evidence of thrombus movement elsewhere (pulmonary embolus, ischemia in other organs, such as the kidney, or both), and a cardiac abnormality.2,3 Curiously, more recent articles have failed to identify an increased risk of deep-vein thrombosis, pulmonary embolism, or ischemia in other organs in patients with cardiac abnormalities such as patent foramen ovale and stroke. In Table 2 of their article, Mas et al. indicate that one patient had systemic embolism. Furthermore, it is unclear why the presence of both abnormalities would be necessary to account for the increased risk, rather than either one or none. Similarly, in this and numerous other studies, there has not been evidence of thrombus within the cardiac defects or an increased risk of cardiac arrhythmia among these patients.

Thus, it may be that in young patients who have had a stroke without an identifiable cause, these cardiac abnormalities are either epiphenomena of the stroke or markers of some other abnormality that confers a predisposition to stroke.

John R. Corboy, M.D.
University of Colorado School of Medicine, Denver, CO 80262
john.corboy@uchsc.edu

3 References

1. 1

   Mas J-L, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001;345:1740-1746
   Full Text | Web of Science | Medline

2. 2

   Thrombose und embolie. In: Cohnheim J. Vorlesungen uber allgemeine Pathologie. Vol. 1. Berlin, Germany: Hirschwald, 1877:134.
   

3. 3

   Thompson T, Evans W. Paradoxical embolism. QJM 1930;23:135-150
   

To the Editor:

Mas et al. used semiquantitative transesophageal echocardiography with contrast medium, a technique with pitfalls, to determine the size of a patent foramen ovale.1-3 Transesophageal echocardiography with contrast material administered through a cubital vein has a low level of accuracy for determining the size of a patent foramen ovale.2,3 Our study of patients with cryptogenic stroke and patent foramen ovale showed a significant association between the degree of interatrial septal deviation and the size of the patent foramen ovale (correlation coefficient, 0.61; P<0.001) (Figure 1Figure 1Correlation between the Size of a Patent Foramen Ovale and the Degree of Atrial Septal Deviation.). This finding suggests that an atrial septal aneurysm is an indicator of a large patent foramen ovale, which is associated with a substantial risk of recurrent stroke.3 We hypothesize that in the study by Mas et al., the high rate of recurrent stroke in the patients with both patent foramen ovale and atrial septal aneurysm was due predominantly to the presence of a large patent foramen ovale.

Herwig W. Schuchlenz, M.D.
Georg Saurer, M.D.
Wolfgang Weihs, M.D.
Landeskrankenhaus–Universitätsklinikum Graz, A-8036 Graz, Austria
herwig.schuchlenz@klinikum-graz.at

3 References

1. 1

   Agmon Y, Kandheria BK, Meissner I, et al. Comparison of frequency of patent foramen ovale by transesophageal echocardiography in patients with cerebral ischemic events versus in subjects in the general population. Am J Cardiol 2001;88:330-332
   CrossRef | Web of Science | Medline

2. 2

   Schuchlenz HW, 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;109:456-462
   CrossRef | Web of Science | Medline

3. 3

   Schuchlenz HW, Weihs W, Beitzke A, Stein JI, Gamillscheg A, Rehak P. Transesophageal echocardiography for quantifying size of patent foramen ovale in patients with cryptogenic cerebrovascular events. Stroke 2002;33:293-296
   CrossRef | Web of Science | Medline

To the Editor:

The article by Mas et al. has important implications for the management of cryptogenic stroke and patent foramen ovale. In particular, the low rate of recurrent stroke among the patients who had patent foramen ovale without an atrial septal aneurysm calls into question the use of oral anticoagulants and closure of the patent foramen ovale in patients who are not enrolled in controlled clinical trials. Paradoxical embolism is assumed to be a probable mechanism of stroke in many patients with patent foramen ovale. Hypercoagulable states may confer a predisposition to paradoxical embolism and cryptogenic stroke in patients with patent foramen ovale.1,2 Although the authors state that coagulation studies were performed in their patients, they do not report the results of these studies. Furthermore, two major hereditary hypercoagulable conditions, the factor V Leiden mutation and the G20210A factor II mutation, are not mentioned. It would be of great interest to know whether the patients with patent foramen ovale had a higher prevalence of coagulation abnormalities than those without patent foramen ovale; how many patients were tested for resistance to activated protein C, the factor V Leiden mutation, and the G20210A factor II mutation and whether the results differed between the groups; and in how many patients venous thrombosis was diagnosed (although venous thrombosis was probably not systematically investigated in this large cohort).

Wolfgang Lalouschek, M.D.
University of Vienna Medical School, 1097 Vienna, Austria
wolfgang.lalouschek@univie.ac.at

for the Vienna Stroke Study Group

2 References

1. 1

   Chaturvedi S. Coagulation abnormalities in adults with cryptogenic stroke and patent foramen ovale. J Neurol Sci 1998;160:158-160
   CrossRef | Web of Science | Medline

2. 2

   Nabavi DG, Junker R, Wolff E, et al. Prevalence of factor V Leiden mutation in young adults with cerebral ischaemia: a case-control study on 225 patients. J Neurol 1998;245:653-658
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Statistical association does not necessarily imply causality, since it may result from selection or information bias, chance, or confounding factors.1 Although bias and chance are unlikely to explain the findings of numerous studies linking patent foraman ovale and atrial septal aneurysm to stroke,2 it is more difficult to exclude the presence of an as yet unknown confounding factor that is associated with these septal disorders and that affects the outcome (stroke). The criteria that support causality include a temporal sequence, a strong and consistent association, a dose–response relation, biologic plausibility, and experimental evidence.1,2 The association of stroke with the above-mentioned cardiac disorders meets the first three criteria.2

Large shunts have been reported to be more strongly associated with stroke than smaller ones, suggesting a dose–response relation. However, since atrial septal aneurysm has not usually been taken into account, stroke may be associated with the two lesions in combination, rather than with patent foramen ovale alone. Potential mechanisms of stroke include paradoxical embolism and in situ thrombosis, but we agree that these mechanisms have rarely been documented. Causality will eventually be confirmed if randomized trials demonstrate that endovascular or surgical “removal” of these septal disorders substantially reduces the risk of subsequent stroke, in the same way that the clinical relevance of carotid stenosis has been confirmed by the finding that carotid endarterectomy substantially reduces the risk of subsequent ipsilateral stroke.

We agree that future studies should include direct evaluation of the size of the foramen.3 However, whether the measurement of a morphologic characteristic (the size of the foramen) rather than a functional characteristic (the degree of shunting) results in a more accurate assessment of the risk of recurrent stroke remains to be determined. With regard to atrial septal aneurysm, we also found that its prevalence increased with the degree of shunting, but the degree of shunting was not a significant predictor of recurrent stroke in an analysis adjusted for atrial septal aneurysm.4

Our study was not designed to assess the role of a hypercoagulable state. Patients with a definite cause of stroke, including those with a coagulation disorder, were excluded from the study. (Among the patients who were excluded because of a definite cause of stroke, less than 5 percent had a coagulation disorder as the definite cause.) Tests for factor V Leiden and the G20210A factor II mutation were not available at the time the study was designed. About 50 percent of the patients with patent foramen ovale were evaluated for latent venous thrombosis within four weeks of the onset of stroke, mainly with the use of Doppler ultrasonography. Latent venous thrombosis was found in only 4 percent of these patients, a rate consistent with that in our previous study with the use of phlebography.5

Jean-Louis Mas, M.D.
Sainte-Anne Hospital, 75674 Paris CEDEX 14, France

Laure Cabanes, Ph.D.
Joël Coste, Ph.D.
Cochin Hospital, 75679 Paris CEDEX 14, France

for the Patent Foramen Ovale and Atrial Septal Aneurysm Study Group

5 References

1. 1

   Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet 2002;359:248-252
   CrossRef | Web of Science | Medline

2. 2

   Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000;55:1172-1179
   Web of Science | Medline

3. 3

   Schuchlenz HW, Weihs W, Beitzke A, Stein JI, Gamillscheg A, Rehak P. Transesophageal echocardiography for quantifying size of patent foramen ovale in patients with cryptogenic cerebrovascular events. Stroke 2002;33:293-296
   CrossRef | Web of Science | Medline

4. 4

   Mas J-L, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001;345:1740-1746
   Full Text | Web of Science | Medline

5. 5

   Ranoux D, Cohen A, Cabanes L, Amarenco P, Bousser MG, Mas JL. Patent foramen ovale: is stroke due to paradoxical embolism? Stroke 1993;24:31-34
   CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   R. Charles Callison, Harold P. Adams. (2008) Use of Antiplatelet Agents for Prevention of Ischemic Stroke. Neurologic Clinics 26:4, 1047-1077
   CrossRef

2. 2

   Steven C. Cramer. (2005) Patent Foramen Ovale and Stroke: Prognosis and Treatment in Young Adults. Journal of Thrombosis and Thrombolysis 20:2, 85-91
   CrossRef

3. 3

   Stephan Windecker, Andreas Wahl, Krassen Nedeltchev, Marcel Arnold, Markus Schwerzmann, Christian Seiler, Heinrich P. Mattle, Bernhard Meier. (2004) Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke. Journal of the American College of Cardiology 44:4, 750-758
   CrossRef

4. 4

   Steven C. Cramer, Jeffrey H. Maki, Gayle M. Waitches, Neisha D'Souza, James C. Grotta, W. Scott Burgin, Larry A. Kramer. (2003) Paradoxical Emboli from Calf and Pelvic Veins in Cryptogenic Stroke. Journal of Neuroimaging 13:3, 218-223
   CrossRef