This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lamy, C. Articles by Mas, J.L. Search for Related Content PubMed PubMed Citation Articles by Lamy, C. Articles by Mas, J.L. Related Collections Echocardiography Pediatric and congenital heart disease, including cardiovascular surgery Embolic stroke Risk Factors for Stroke

(Stroke. 2002;33:706.)
© 2002 American Heart Association, Inc.

Original Contributions

Clinical and Imaging Findings in Cryptogenic Stroke Patients With and Without Patent Foramen Ovale

The PFO-ASA Study

C. Lamy, MD; C. Giannesini, MD; M. Zuber, MD; C. Arquizan, MD; J.F. Meder, MD; D. Trystram, MD; J. Coste, PhD J.L. Mas, MD for the Patent Foramen Ovale and Atrial Septal Aneurysm Study Group

From the Neurology Department (C.L., C.G., M.Z., C.A., J.L.M.) and Neuroradiology Department (J.F.M., D.T.), Sainte-Anne Hospital, and Department of Biostatistics, Cochin Hospital (J.C.), Paris V University, Paris, France.

Correspondence to Pr Jean-Louis Mas, Service de Neurologie, Hôpital Sainte-Anne, 1 Rue Cabanis, 75674 Paris Cedex 14, France. E-mail mas{at}chsa.broca.inserm.fr

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background and Purpose— Patent foramen ovale (PFO) has been identified as a potential risk factor for stroke, but the mechanisms of PFO-associated stroke remain unsettled. The aim of our study was to evaluate possible differences in stroke risk factors and stroke patterns between patients with and without PFO that may give clues to the mechanism of PFO-associated stroke.

Methods— This prospective, multicentric study involved 581 young cryptogenic stroke patients. The presence of PFO and atrial septal aneurysm was assessed by transesophageal echocardiography and reviewed independently by 2 experienced sonographers. Clinical, brain, and vascular imaging findings were reviewed by 2 neurologists and 2 neuroradiologists.

Results— Of the 581 stroke patients, 267 (45.9%) had PFO. Patients with PFO were younger (OR, 0.95; 95% CI, 0.93 to 0.97) and less likely to have traditional risk factors such as hypertension (OR, 0.49; 95% CI, 0.28 to 0.85), hypercholesterolemia (OR, 0.56; 95% CI, 0.34 to 0.93), or current smoking (OR, 0.67; 95% CI, 0.47 to 0.97). Features suggestive of paradoxical embolism, such as Valsalva-provoking activities or deep vein thrombosis, were not more frequent in patients with PFO. Migraine was more common in patients with PFO (27.3%) than in those without PFO (14.0%). PFO (OR, 1.75; 95% CI, 1.08 to 2.82), particularly when associated with atrial septal aneurysm (OR, 2.71; 95% CI, 1.36 to 5.41), was significantly associated with migraine after adjustment for age and sex.

Conclusions— Differences in stroke risk factors and stroke patterns suggest that different stroke mechanisms occur in patients with and without PFO. PFO is significantly and independently associated with migraine, and this association is even stronger in patients with PFO and atrial septal aneurysm.

Key Words: embolism, paradoxical • heart septal defects, atrial • patent foramen ovale • stroke

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Patent foramen ovale (PFO) and atrial septal aneurysm (ASA) have been identified as potential risk factors for stroke.^1–6 In a recent meta-analysis of case-control studies comparing patients <55 years of age with ischemic stroke with nonstroke control subjects, ORs of stroke were 3.1 (95% CI, 2.3 to 4.2) for PFO and 6.1 (95% CI, 2.5 to 15.2) for ASA.⁶

Whether the relationship between PFO and stroke is causal and, if so, the precise stroke mechanism are still a matter of debate.^6,7 Potential mechanisms include paradoxical embolism from a venous source,^7,8 direct embolization from thrombi formed within the PFO or an associated ASA,^9–11 and thrombus formation caused by atrial arrhythmias, such as paroxysmal atrial fibrillation.¹²

The aim of the study was to assess stroke risk factors and stroke patterns in cryptogenic stroke patients with and without PFO to provide clues to PFO-associated stroke mechanism.^13–15

	Methods

Top Abstract Introduction Methods Results Discussion References

 
This study was part of a prospective, multicentric study (the PFO-ASA study) whose methods have been reported in detail elsewhere.¹⁶ Briefly, the PFO-ASA study was designed to assess the absolute and relative risks of recurrent stroke associated with PFO, ASA, or both in young patients with an otherwise unexplained ischemic stroke. The study was conducted in 30 European neurology departments. Patients were consecutively included between May 1, 1996, and December 31, 1998.

Inclusion Criteria and Initial Workup
Inclusion criteria were as follows: age 18 and 55 years; recent (3 months) ischemic stroke (neurological deficit lasting >24 hours); no definite cause of stroke after an extensive and standardized etiological workup, including cerebral CT scan (n=535) or MRI (n=428), routine blood tests, and detailed coagulation study (with protein S, protein C, antithrombin III, and antiphospholipid antibodies); 12-lead ECG and echocardiography (see below); and 1 of the following arterial investigations (within 1 month of stroke onset): catheter angiography (n=360; within 2 weeks after stroke onset in 83.2% of cases), magnetic resonance angiography (n=220), or cervical and transcranial ultrasonography (n=495). The decisions to perform additional investigations and to search for latent deep vein thrombosis or pulmonary embolism in patients with PFO were left to the investigator in charge of the patient. In 10 centers, 24-hour ECG recording was performed systematically in all patients (n=173, 84 with PFO) between days 7 and 21 after stroke onset. Twenty-four-hour ECG monitoring was performed after the acute phase of stroke to exclude arrhythmias secondary to stroke. Criteria derived from the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification¹⁷ were used to rule out definite causes of stroke.¹⁶

The clinical and imaging data of all patients were collected by the coordinating center and reviewed by 2 neurologists and 2 neuroradiologists who were blinded to the results of transesophageal echocardiography regarding the presence of PFO and ASA. Cases with potential violation of inclusion criteria were submitted to the Validation Committee.

Clinical Data
The following information was systematically recorded: (1) baseline characteristics and traditional risk factors of stroke (Table 1); (2) past vascular events, such as stroke, deep venous thrombosis, or pulmonary embolism; (3) history of migraine according to International Headache Society criteria¹⁸; (4) stroke severity assessed on a modified Rankin scale¹⁹ at the time of inclusion; (5) palpitations preceding or accompanying stroke onset; (6) neurological features reported as suggestive of cardiogenic embolism,^20,21 such as abrupt, nonprogressive onset defined as no deficit on waking from sleep, peak deficit within the first 10 minutes, no subsequent deterioration during the first 24 hours, diminished level of consciousness at onset, cortical deficits, including Wernicke’s aphasia, isolated hemianopsia, hemineglect, and apraxia; and (7) features suggesting paradoxical embolism, such as the presence of deep venous thrombosis or pulmonary embolism, Valsalva-provoking activity within the 30 minutes preceding stroke onset (sporting effort, straining at stool, intercourse, lifting a heavy weight, getting up, laughing, and coughing),⁸ and circumstances predisposing to deep venous thrombosis before stroke onset, such as immobilization, anesthesia, surgery, or pregnancy.²²

View this table: [in this window] [in a new window]   Table 1. Risk Factors for Stroke in Patients With and Without PFO

Brain and Vascular Imaging Findings
The following brain and vascular imaging features were analyzed: (1) stroke arterial territory following previously published templates^23–25; (2) imaging features of previous stroke; and (3) neuroimaging data suggestive of cardiogenic embolism,^20,26–28 such as hemorrhagic infarct on neuroimaging performed within 2 weeks of stroke onset,²⁹ superficial infarct, infarct larger than one half of the cerebral hemisphere, involvement of specific (Table 2) or multiple arterial territories, and the presence of intracranial occlusion on catheter angiography.

View this table: [in this window] [in a new window]   Table 2. Stroke Patterns in Patients With and Without PFO

Echocardiography
The presence of PFO and ASA was assessed by transesophageal echocardiography with a contrast study performed at rest and during provocative maneuvers (Valsalva and cough test) by use of 5-MHz multiplane (86.4%) or biplane (13.6%) transducers. Examinations were recorded on super VHS videotapes and independently reviewed by 2 experienced sonographers.¹⁶

The contrast study was considered positive if 3 microbubbles appeared in the left atrium, either spontaneously or after provocative maneuvers, within 3 cardiac cycles after complete opacification of the right atrium. The degree of shunting was defined as small (3 to 9 microbubbles), moderate (10 to 30 microbubbles), or large (>30 microbubbles). ASA was diagnosed when the atrial septum exhibited an excursion into the left or right atrium or both of 11 mm.

The 2 sonographers disagreed on the presence or absence of PFO in 13.9% of cases, the presence or absence of ASA in 6.6%, the degree of shunt in 26.5%, and the size of ASA in 8.4% of cases. Disagreements were resolved by unblinded consensus review.

Statistical Analysis
Clinical data, brain, and vascular imaging findings were compared between patients with and without PFO and between patients with small to moderate and those with large PFO. Comparisons between groups were performed by a ² test, Fisher’s exact test, or t test for unpaired data whenever applicable. Factors independently associated with PFO were identified by logistic regression analysis. ORs with 95% CIs were calculated.

The association between migraine and PFO was examined through logistic regression analysis with migraine as a dependent variable and age, sex, PFO, and ASA as independent variables. To assess the role of PFO and ASA in isolation from or in association with each other, we used an independent variable divided into 4 categories: no PFO or ASA, isolated PFO, isolated ASA, and PFO and ASA.

	Results

Top Abstract Introduction Methods Results Discussion References

 
This study included 581 consecutive patients. Of these, 267 patients (45.9%) had PFO and 61 (10.5%) had ASA. Of the 267 patients with PFO, 48% had small to moderate shunts and 52% had large shunts. PFO was strongly associated with ASA: 51 of the 267 patients with PFO (19.1%) also had ASA compared with 10 of 314 of those without PFO (3.2%; P<0.0001). The prevalence of ASA increased with the degree of shunt: 4.4%, 12.5%, and 25% in patients with small, moderate, and large shunts, respectively (P<0.0001).

Patients Characteristics and Stroke Patterns
Baseline characteristics and risk factors of stroke, according to the presence of a PFO, are shown in Table 1. Patients with PFO were younger and less likely to have traditional risk factors of stroke than those with no PFO. In logistic regression analysis (with age, sex, stroke risk factors, and ASA as independent variables), age (OR, 0.95; 95% CI, 0.93 to 0.97), hypertension (OR, 0.49; 95% CI, 0.28 to 0.85), hypercholesterolemia (OR, 0.56; 95% CI, 0.34 to 0.93), and current smoking (OR, 0.67; 95% CI, 0.47 to 0.97) were inversely associated with PFO, whereas ASA (OR, 7.4; 95% CI, 3.6 to 15.2) was positively associated with PFO.

Table 2 shows the characteristics of stroke. Patients with PFO had on average a less severe stroke as assessed by the Rankin scale at the time of inclusion, and this remained significant after adjustment for age, sex, vascular risk factors, and presence of ASA (P=0.01). Overall, no difference was found regarding arterial territories. Neuroimaging features of previous stroke were less frequent in patients with PFO, but this association was not significant after adjustment for age and risk factors for stroke. No significant difference was found between small to moderate and large shunts in terms of patient and stroke characteristics.

Mechanism of PFO-Associated Stroke
Clinical and imaging features suggestive of cardiogenic embolism did not differ significantly between groups, except for a higher frequency of cortical signs and of infarcts in the superior cerebellar artery territory in the PFO group. Features consistent with the diagnosis of paradoxical embolism were not found more frequently in patients with PFO than in patients without PFO, except for a higher frequency of circumstances predisposing to deep venous thrombosis (Table 3). Features suggesting cardioembolism or paradoxical embolism were not associated with the degree of shunt.

View this table: [in this window] [in a new window]   Table 3. Arguments Suggesting Paradoxical Embolism

Of the 267 patients with PFO, 122 (45.7%) had a search for latent deep venous thrombosis or pulmonary embolism within 4 weeks after stroke onset (43% within 8 days). Investigations consisted of Doppler ultrasonography (n=112), phlebography (n=3), and pulmonary scintigraphy (n=43). A latent deep venous thrombosis or pulmonary embolism was found in 5 patients (4.1%) 4 to 12 days after stroke onset.

Palpitations preceding or accompanying stroke onset were rare and even less common in patients with PFO (0.7% versus 3.5% in those without PFO; P=0.06). Twenty-four-hour ECG recording did not reveal emboligenic arrhythmias in the 84 consecutive patients with PFO in whom it was performed.

Migraine
Migraine was more common in patients with PFO (27.3%) than in patients without PFO (14.0%; P<0.0001). No significant relation was found between migraine and the degree of shunt: 22.2%, 29.2%, and 28.1% in patients with small, moderate, and large shunts, respectively (P=0.7). Migraine was also more frequent in patients with ASA (34.4%) than in those without ASA (18.5%; P=0.003). Logistic regression analysis showed that younger age, female sex, and PFO were significantly associated with migraine (Table 4). The association of PFO with migraine was stronger in patients with both PFO and ASA.

View this table: [in this window] [in a new window]   Table 4. Association Between Migraine, PFO, and ASA as given by Logistic Regression Analysis

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This is the first prospective, multicentric study comparing stroke risk factors and stroke patterns in a large population of young cryptogenic stroke patients with or without PFO. We selected patients 55 years of age because the higher prevalence of large-vessel atherosclerosis or small-artery disease in the elderly makes the diagnosis of cryptogenic stroke less frequent than in the young. In addition, the association of PFO and cryptogenic stroke has been consistently reported in this age group, whereas this association in those >55 years of age remains unconfirmed.⁶ Independent review of transesophageal echocardiography examinations by 2 experienced sonographers provided prevalences of PFO and ASA that were in the range of reported rates.⁶ To minimize information biases, clinical and imaging data were reviewed by 2 neurologists and 2 neuroradiologists who were blinded to the presence of PFO.

The first finding of our study is that cryptogenic stroke patients with PFO were younger and less likely to have traditional risk factors for stroke than patients without PFO. They also had on average a less severe stroke. These differences in stroke risk factors and stroke severity have not been stressed previously and suggest different stroke mechanisms in patients with and without PFO.

Some features suggestive of cardiogenic embolism were more frequent in the PFO group, which also suggests different stroke mechanisms in patients with and without PFO. These features, however, have a limited positive or negative predictive value for the diagnosis of cardioembolism.³⁰ In contrast to the study by Steiner et al,¹⁵ we did not find embolic features to be more common in patients with large shunts than in patients with small to moderate shunts. On the whole, features suggesting paradoxical embolism were not more frequent in patients with PFO than in those without PFO, suggesting that paradoxical embolism might not be the prevalent mechanism of PFO-associated stroke, a finding consistent with our previous experience.⁸ These features, however, may be insufficient or inaccurate and therefore not useful in clinical practice. In the present study, investigators were not blinded to the presence of PFO when recording features suggesting paradoxical embolism. However, if this unblinded recording had introduced a bias, a higher prevalence of these features in patients with PFO would have been expected. The frequency of latent deep venous thrombosis in stroke patients with PFO^8,31,32 was not an objective of our study, and the search for deep venous thrombosis was left to the investigator in charge of the patient. It was performed in fewer than half of the patients with PFO by use of various diagnostic techniques. This low rate of search for deep venous thrombosis suggests that many investigators either are not convinced that paradoxical embolism is a prevalent mechanism of PFO-associated stroke or are concerned about the low yield and pitfalls of a systematic search for deep venous thrombosis.⁷ Indeed, the source of emboli may remain undetected because of its location or the size of the thrombus. Venous thrombi may disappear either spontaneously or after anticoagulation before investigations are performed. Finally, venous thrombosis may be a mere consequence of immobilization resulting from stroke rather than a cause of stroke. The low rate of latent deep venous thrombosis found in the present study is consistent with the result of our previous study in young stroke patients.⁸ The role of a hypercoagulable state in the pathophysiology of PFO-associated stroke cannot be evaluated from this study because patients with a definite coagulopathy were not included in the study.

Our study does not provide argument for transient arrhythmia as a mechanism of PFO-associated stroke. Palpitations preceding or accompanying stroke onset were rare, and 24-hour ECG recording did not reveal emboligenic arrhythmias. It should be stressed, however, that arrhythmias are often clinically silent¹² and that a single 24-hour Holter monitoring is not the optimal method to detect potentially more spaced-out episodes of transient arrhythmias.

Another interesting finding of our study is that migraine was more common in cryptogenic stroke patients with PFO (27.3%) than in those without PFO (14.0%). This result is consistent with recent studies in stroke patients and nonstroke individuals that showed an association between migraine with aura and PFO as detected by transcranial Doppler^33,34 or transthoracic echocardiography.³⁵ At the time of the present study, the relation between migraine with aura and PFO had not emerged in the literature. Therefore, investigators were not asked to differentiate migraine with and without aura and were not blinded to the presence of PFO. However, because investigators were not aware of a potential relation between migraine and PFO, an information bias seems unlikely. The present study is the first to confirm the association between PFO and migraine with contrast transesophageal echocardiography as the diagnostic procedure with independent review of transesophageal echocardiographies by 2 sonographers who were blinded to the presence of migraine. In addition, our study, based on a large population of young stroke patients, shows that PFO is independently associated with migraine and that this association is stronger when PFO is associated with ASA. We did not find an increasing prevalence of migraine with the degree of shunt. No statistically significant association was found between migraine and isolated ASA, but the number of patients with isolated ASA was small. The link between migraine, PFO, and ASA is unclear. A particular genetic substrate might determine both atrial septal abnormalities³⁶ and migraine.³³ Another hypothesis, recently suggested by Wilmshurst et al,³⁵ is that PFO might allow trigger substances of migraine (such as vasoactive chemicals) in the venous blood to bypass the pulmonary filter and to reach the systemic circulation in amounts large enough to induce a migraine attack. Further studies are needed to elucidate the relationships between migraine and atrial septal abnormalities.

Coordinating Center
J.L. Mas, C. Arquizan, C. Lamy, M. Zuber, C. Gianesini, D. Trystram, and J.F. Méder, Sainte-Anne Hospital, Paris, France.

Scientific Committee
J.L. Mas (chairman), Y. Bernard, B. Bertrand, J. Bogousslavsky, F. Chollet, L. Cabanes, A. Cohen, J.M. Ferro, H. Kwiecinski, J.P. Lesbre, D. Leys, T. Moulin, J.F. Pinel, R. Roudaut, D. Saudeau, and F. Woimant.

TEE Committee
L. Cabanes, G. Derumeaux, X. Jeanrenaud, and A. Cohen.

Validation Committee
P. Césaro, M. Giroud, F. Nicoli, and S. Weber.

Participating Institutions and Investigators
Centre Hospitalier Universitaire (CHU), Besançon, France. Neurology: T. Moulin and L. Tatu. Cardiology: A. Vuillemenot, D. Magnin, M.F. Seronde, F. Apffel, N. Meneveau, and Y. Bernard.

CHU Lariboisière and Saint-Antoine, Paris, France. Neurology: F. Woimant, P. Amarenco, N. Kubis, K. Vahedi, I. Crassard, G. Ast, H. Chabriat, M. Sarazin, and M. Haguenau. Cardiology: J.M. de Kermadec, A. N’Guyen Van Cao, S. Mazouz, B. Benhalima, C. Albo, A. Cohen, M. Khireddine, and N. Lamisse.

Sainte-Anne Hospital and CHU Cochin Port-Royal, Paris, France. Neurology: Coordinating Center. Cardiology: L. Cabanes, I. Cornuejols, and E. Lombard.

CHU, Nancy, France. Neurology: X. Ducrocq and J.C. Lacour. Cardiology: J.F. Bruntz and I. Magnin-Poull.

CHU, Tours, France. Neurology: D. Saudeau. Cardiology: A. Sirinelli.

CHU, Rennes, France. Neurology: J.F. Pinel. Cardiology: C. de Place, M. Laurent, and C. Bossee-Pilon.

Medical University of Warsaw, Warsaw, Poland. Neurology: H. Kwiecinski, B. Szyluk, A. Opuchlik, and J. Mieszkowski. Cardiology: A. Torbicki, P. Pruszczyk, and A. Kuch-Wocial.

CHU, Poitiers, France. N: J.P. Neau and C. Couderq. Cardiology: D. Coisne, G. Bacque, L. Christiaens, C. Couderq, and P. Raud-Raynier.

CHU Vaudois, Lausanne, Switzerland. Neurology: P. Arnold, M. Altieri, and J. Bogousslavsky. Cardiology: M. Nasratullah, N. Aebischer, and X. Jeanrenaud.

CHU, Rouen, France. Neurology: E. Guégan-Massardier and B. Mihout. Cardiology: D. Thomas, G. Derumeaux, and J.L. Gauthier.

CHU Pitié-Salpêtrière, Paris, France. Neurology: R. Manai, Y. Samson, and G. Rancurel. Cardiology: E. Coignard and R. Isnard.

CHU La Timone, Marseille, France. Neurology: L. Milandre. Cardiology: G. Habib.

Centre Hospitalier Général, Meaux, France. Neurology: F. Chedru and A. Ameri. Cardiology: J.F. Lefort.

CHU, Lille, France. Neurology: D. Leys and C. Lucas. Cardiology: C. Savoye, L. Goullard, and E. Chammas.

CHU, Saint-Etienne, France. Neurology: P. Garnier and D. Michel. Cardiology: C. Comtet and I. Cusey.

Santa Maria Hospital, University of Lisbon, Portugal. Neurology: T. Pinho e Melo, J.M. Ferro, P. Canhao, and F. Falcao. Cardiology: F. Pais, I. Dionisio, and M. Fiuza.

CHU Purpan, Toulouse, France. Neurology: J.F. Albucher. Cardiology: M. Andrieu, N. Blot-Souletie, M. Elbaz, and E. Maupas.

CHU, Bordeaux, France. Neurology: P. Gaïda and F. Rouanet. Cardiology: M. Marazanof, R. Roudaut, and P. Laffort.

CHU, Grenoble, France. Neurology: G. Besson, A. Jaillard, and M. Hommel. Cardiology: B. Bertrand and J.P. Baguet.

Klinikum Grossharden, Ludwig Maximiliams University, München, Germany. Neurology: T. Pfefferkorn and G. Hamann. Cardiology: W. von Scheidt.

Dr Schaffner Hospital, Lens, France. Neurology: F. Mounier-Véhier. Cardiology: R. Deturck.

CHU Rangueil, Toulouse, France. Neurology: V. Larrue. Cardiology: P. Massabuau.

CHU, Brest, France. Neurology: Y. Mocquard, F. Rouhart, and P. Diraison. Cardiology: Y. Jobic.

CHU, Nice, France. Neurology: M.H. Mahagne. Cardiology: P. Gibelin.

CHU, Angers, France. Neurology: H. Brugeilles, C. Moreau. Cardiology: J. Laporte.

Jolimont Hospital, Haine-Saint-Paul, Belgium. Neurology: G. Devuyst, P. Bara, M. Vandooren. Cardiology: R. Luwaert.

CHU Saint-Antonie. Tenon Hospital, Paris, France. Neurology: S. Alamowitch, C. Roos. Cardiology: E. Carbarz, B. Cormier.

E. Muller Hospital, Mulhouse, France. Neurology: G. Rodier. Cardiology: S. Hass.

Université libre de Bruxelles, Hôpital Erasme, Bruxelles, Belgium. Neurology: S. Blecic. Cardiology: P. Unger.

CHU, Clermont-Ferrant, France. Neurology: A. Coustes-Durieux. Cardiology: P. Marcollet.

	Acknowledgments

 
This work was supported by grants from the Program Hospitalier de Recherche Clinique of the French Ministry of Health (AOM95059). The Assistance Publique-Hôpitaux de Paris had legal responsibility for the study.

	Footnotes

 
Study members are listed in the Appendix.

Received October 2, 2001; revision received November 15, 2001; accepted November 21, 2001.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Lechat P, Mas JL, Lascault G, Loron P, Theard M, Klimczac M, Drobinski G, Thomas D, Grosgogeat Y. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med. 1988; 318: 1148–1152.[Abstract]

2. Webster MWI, Chancellor AM, Smith HJ, Swift DL, Sharpe DN, Bass NM. Patent foramen ovale in young stroke patients. Lancet. 1988; 2: 11–12.[Medline] [Order article via Infotrieve]

3. Pearson AC, Nagelhout D, Castello R, Gomez CR, Labovitz A. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol. 1991; 18: 1223–1229.[Abstract]

4. Di Tullio M, Sacco RL, Gopal A, Mohr JP, Homma S. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med. 1992; 117: 461–465.

5. Cabanes L, Mas JL, Cohen A, Amarenco P, Cabanes PA, Oubary P, Chedru F, Guérin F, Bousser MG, de Recondo J. 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: 1865–1873.[Abstract/Free Full Text]

6. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology. 2000; 55: 1172–1179.[Abstract/Free Full Text]

7. Mas JL. Patent foramen ovale, atrial septal aneurysm and ischaemic stoke in young adults. Eur Heart J. 1994; 15: 446–449.[Free Full Text]

8. 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.[Abstract/Free Full Text]

9. Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med. 1978; 102: 62–65.[Medline] [Order article via Infotrieve]

10. Schneider B, Hanrath P, Vogel P, Meinertz T. Improved morphologic characterization of atrial septal aneurysm by transesophageal echocardiography: relation to cerebrovascular events. J Am Coll Cardiol. 1990; 16: 1000–1009.[Abstract]

11. Mügge A, Daniel WG, Angermann C, Spes C, Khandheria BK, Kronzon I, Freeberg RS, Keren A, Dennig K, Engberding R, Sutherland GR, Vered Z, Erbel R, Visser CA, Lindert O, Hausmann D, Wenzlaff P. Atrial septal aneurysm in adults patients: a multicenter study using transthoracic and transesophageal echocardiography. Circulation. 1995; 91: 2785–2792.[Abstract/Free Full Text]

12. Berthet K, Lavergne T, Cohen A, Guize L, Bousser MG, Le Heuzey JY, Amarenco P. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke. 2000; 31: 398–403.[Abstract/Free Full Text]

13. Lucas C, Goullard L, Marchau M, Godefroy O, Rondepierre P, Chamas E, Mounier-Vehier F, Leys D. Higher prevalence of atrial septal aneurysms in patients with ischemic stroke of unknown origin. Acta Neurol Scand. 1994; 89: 210–213.[Medline] [Order article via Infotrieve]

14. Bogousslavsky J, Garazi S, Jeanrenaud X, Aebischer N, Van Melle G, for the Lausanne Stroke With Paradoxical Embolism Study Group. Stroke recurrence in patients with patent foramen ovale. Neurology. 1996; 46: 1301–1305.[Abstract/Free Full Text]

15. Steiner MM, Di Tullio MR, Rundek T, Gan R, Chen X, Liguori C, Brainin M, Homma S, Sacco RL. Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke. 1998; 29: 944–948.[Abstract/Free Full Text]

16. Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J. Recurrent cerebrovascular events in young adults with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001; 345: 1740–1746.[Abstract/Free Full Text]

17. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Lowe BB, Gordon DL, Marsh EE, for the TOAST Investigators. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke. 1993; 24: 35–41.[Abstract/Free Full Text]

18. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988; 8: 19–28.[CrossRef]

19. Van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJA, Van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988; 19: 604–607.[Abstract/Free Full Text]

20. Kittner SJ, Sharkness CM, Price TR, Plotnick GD, Dambrosia JM, Wolf PA, Mohr JP, Hier DB, Kase CS, Tuhrim S. Infarcts with a cardiac source of embolism in the NINCDS Stroke Data Bank: historical features. Neurology. 1990; 40: 281–284.[Abstract/Free Full Text]

21. Bogousslavsky J, Cachin C, Regli F, Despland PA, Van Melle G, Kappenberger L. Cardiac sources of embolism and cerebral infarction: clinical consequences and vascular concomitants: the Lausanne Stroke Registry. Neurology. 1991; 41: 855–859.[Abstract/Free Full Text]

22. Weimann EE, Salzman W. Deep-vein thrombosis. N Engl J Med. 1994; 331: 1630–1641.[Free Full Text]

23. Damasio H. A computed tomographic guide to the identification of cerebral vascular territories. Arch Neurol. 1983; 40: 138–142.[Abstract/Free Full Text]

24. Tatu L, Moulin T, Bogousslavsky J, Duvernoy H. Arterial territories of the human brain: brainstem and cerebellum. Neurology. 1996; 47: 1125–1135.[Abstract/Free Full Text]

25. Tatu L, Moulin T, Bogousslavsky J, Duvernoy H. Arterial territories of the human brain: cerebral hemispheres. Neurology. 1998; 50: 1699–1708.[Abstract]

26. Caplan LR, Hier DB, D’Cruz I. Cerebral embolism in the Michael Reese Stroke Registry. Stroke. 1983; 14: 530–536.[Abstract/Free Full Text]

27. Kittner SJ, Sharkness CM, Sloan MA, Price TR, Dambrosia JM, Tuhrim S, Wolf PA, Mohr JP, Hier DB. Features on initial computed tomography scan of infarcts with a cardiac source of embolism in the NINDS Stroke Data Bank. Stroke. 1992; 23: 1748–1751.[Abstract/Free Full Text]

28. Amarenco P, Hauw JJ. Cerebellar infarction in the territory of the superior cerebellar artery: a clinicopathological study of 33 cases. Neurology. 1990; 40: 1383–1390.[Abstract/Free Full Text]

29. Motto C, Aritzu E, Boccardi E, De Grandi C, Piana A, Candelise L. Reliability of hemorrhagic transformation diagnosis in acute ischemic stroke. Stroke. 1997; 28: 302–306.[Abstract/Free Full Text]

30. Cerebral Embolism Task Force. Cardiogenic brain embolism: the second report of the Cerebral Embolism Task Force. Arch Neurol. 1989; 46: 727–743.[Abstract/Free Full Text]

31. Stöllberger C, Slany, Schuster I, Leitner H, Winkler WB, Karnik R. The prevalence of deep venous thrombosis in patients with suspected paradoxical embolism. Ann Intern Med. 1993; 119: 461–465.[Abstract/Free Full Text]

32. Lethen H, Flachskampf FA, Schneider R, Sliwka U, Köhn G, Noth J, Hanrath P. Frequency of deep vein thrombosis in patients with patent foramen ovale and ischemic stroke or transient ischemic attack. Am J Cardiol. 1997; 80: 1066–1069.[CrossRef][Medline] [Order article via Infotrieve]

33. Del Sette M, Angeli S, Leandri M, Ferriero G, Bruzzone GL, Finocchi C, Gandolfo C. Migraine with aura and right-to-left shunt on transcranial Doppler: a case-control study. Cerebrovasc Dis. 1998; 8: 327–330.[CrossRef][Medline] [Order article via Infotrieve]

34. Anzola GP, Magoni M, Guindani M, Rozzini L, Dalla Volta G. Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study. Neurology. 1999; 52: 1622–1625.[Abstract/Free Full Text]

35. Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet. 2000; 356: 1648–1651.[CrossRef][Medline] [Order article via Infotrieve]

36. Arquizan C, Coste J, Touboul PJ, Mas JL. Is patent foramen ovale a family trait? A transcranial Doppler sonographic study. Stroke. 2001; 32: 1563–1566.[Abstract/Free Full Text]

This article has been cited by other articles:

				P. T. O'Gara, S. R. Messe, E. M. Tuzcu, G. Catha, and J. C. Ring Percutaneous Device Closure of Patent Foramen Ovale for Secondary Stroke Prevention: A Call for Completion of Randomized Clinical Trials A Science Advisory From the American Heart Association/American Stroke Association and the American College of Cardiology Foundation The American Academy of Neurology affirms the value of this science advisory J. Am. Coll. Cardiol., May 26, 2009; 53(21): 2014 - 2018. [Abstract] [Full Text] [PDF]

				P. T. O'Gara, S. R. Messe, E. M. Tuzcu, G. Catha, and J. C. Ring Percutaneous Device Closure of Patent Foramen Ovale for Secondary Stroke Prevention: A Call for Completion of Randomized Clinical Trials: A Science Advisory From the American Heart Association/American Stroke Association and the American College of Cardiology Foundation The American Academy of Neurology affirms the value of this science advisory. Circulation, May 26, 2009; 119(20): 2743 - 2747. [Abstract] [Full Text] [PDF]

				B. Meier Stroke and migraine: a cardiologist's headache Heart, April 1, 2009; 95(7): 595 - 602. [Full Text] [PDF]

				J. Putaala, A. J. Metso, T. M. Metso, N. Konkola, Y. Kraemer, E. Haapaniemi, M. Kaste, and T. Tatlisumak Analysis of 1008 Consecutive Patients Aged 15 to 49 With First-Ever Ischemic Stroke: The Helsinki Young Stroke Registry Stroke, April 1, 2009; 40(4): 1195 - 1203. [Abstract] [Full Text] [PDF]

				J. Rodes-Cabau, M. Noel, A. Marrero, D. Rivest, A. Mackey, C. Houde, E. Bedard, E. Larose, S. Verreault, M. Peticlerc, et al. Atherosclerotic Burden Findings in Young Cryptogenic Stroke Patients With and Without a Patent Foramen Ovale Stroke, February 1, 2009; 40(2): 419 - 425. [Abstract] [Full Text] [PDF]

				J. Serena, J. Marti-Fabregas, E. Santamarina, J. J. Rodriguez, M. J. Perez-Ayuso, J. Masjuan, T. Segura, J. Gallego, A. Davalos, on Behalf of the CODICIA (Right-to-Left Shunt in C, et al. Recurrent Stroke and Massive Right-to-Left Shunt: Results From the Prospective Spanish Multicenter (CODICIA) Study Stroke, December 1, 2008; 39(12): 3131 - 3136. [Abstract] [Full Text] [PDF]

				R. K. Mareedu, M. S. Shah, J. E. Mesa, and C. S. McCauley Percutaneous Closure of Patent Foramen Ovale: A Case Series and Literature Review Clin. Med. Res., December 1, 2007; 5(4): 218 - 226. [Abstract] [Full Text] [PDF]

				H. Sievert, E. Fischer, C. Heinisch, N. Majunke, A. Roemer, and N. Wunderlich Transcatheter Closure of Patent Foramen Ovale Without an Implant: Initial Clinical Experience Circulation, October 9, 2007; 116(15): 1701 - 1706. [Abstract] [Full Text] [PDF]

				L. R. MacClellan, W. Giles, J. Cole, M. Wozniak, B. Stern, B. D. Mitchell, and S. J. Kittner Probable Migraine With Visual Aura and Risk of Ischemic Stroke: The Stroke Prevention in Young Women Study Stroke, September 1, 2007; 38(9): 2438 - 2445. [Abstract] [Full Text] [PDF]

				D J H McCabe and R D Rakhit Antithrombotic and interventional treatment options in cardioembolic transient ischaemic attack and ischaemic stroke J. Neurol. Neurosurg. Psychiatry, January 1, 2007; 78(1): 14 - 24. [Abstract] [Full Text] [PDF]

				L. H. Bonati, A. Kessel-Schaefer, A. Z. Linka, P. Buser, S. G. Wetzel, E.-W. Radue, P. A. Lyrer, and S. T. Engelter Diffusion-Weighted Imaging in Stroke Attributable to Patent Foramen Ovale: Significance of Concomitant Atrial Septum Aneurysm Stroke, August 1, 2006; 37(8): 2030 - 2034. [Abstract] [Full Text] [PDF]

				G. P. Anzola, E. Morandi, F. Casilli, and E. Onorato Different degrees of right-to-left shunting predict migraine and stroke: Data from 420 patients Neurology, March 14, 2006; 66(5): 765 - 767. [Abstract] [Full Text] [PDF]

				R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, 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. Circulation, March 14, 2006; 113(10): e409 - e449. [Abstract] [Full Text] [PDF]

				R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, 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, February 1, 2006; 37(2): 577 - 617. [Abstract] [Full Text] [PDF]

				G. P. Anzola, G. B. Frisoni, E. Morandi, F. Casilli, and E. Onorato Shunt-Associated Migraine Responds Favorably to Atrial Septal Repair: A Case-Control Study Stroke, February 1, 2006; 37(2): 430 - 434. [Abstract] [Full Text] [PDF]

				M. Schwerzmann, K. Nedeltchev, F. Lagger, H. P. Mattle, S. Windecker, B. Meier, and C. Seiler Prevalence and size of directly detected patent foramen ovale in migraine with aura Neurology, November 8, 2005; 65(9): 1415 - 1418. [Abstract] [Full Text] [PDF]

				H. Hara, R. Virmani, E. Ladich, S. Mackey-Bojack, J. Titus, M. Reisman, W. Gray, M. Nakamura, M. Mooney, A. Poulose, et al. Patent Foramen Ovale: Current Pathology, Pathophysiology, and Clinical Status J. Am. Coll. Cardiol., November 1, 2005; 46(9): 1768 - 1776. [Abstract] [Full Text] [PDF]

				S. Kumar, I. Khan, R. Milton, A. A. Ali, and D. J. O'Regan Pulmonary and Paradoxical Embolism in Protein C and S Deficient Patient Ann. Thorac. Surg., July 1, 2005; 80(1): 324 - 326. [Abstract] [Full Text] [PDF]

				A. T. Lovering, M. K. Stickland, and M. W. Eldridge Contrast Ultrasound Techniques in the Detection and Quantification of Patent Foramen Ovale: Myth Versus Reality--A Clarification Stroke, June 1, 2005; 36(6): 1109 - 1109. [Full Text] [PDF]

				B. Azarbal, J. Tobis, W. Suh, V. Chan, C. Dao, and R. Gaster Association of interatrial shunts and migraine headaches: Impact of transcatheter closure J. Am. Coll. Cardiol., February 15, 2005; 45(4): 489 - 492. [Abstract] [Full Text] [PDF]

				J. E. Sousa, M. A. Costa, E. M. Tuzcu, J. S. Yadav, and S. Ellis New Frontiers in Interventional Cardiology Circulation, February 8, 2005; 111(5): 671 - 681. [Full Text] [PDF]

				O. K. Mohrs, S. E. Petersen, D. Erkapic, C. Rubel, R. Schrader, B. Nowak, W. A. Fach, H.-U. Kauczor, and T. Voigtlaender Diagnosis of Patent Foramen Ovale Using Contrast-Enhanced Dynamic MRI: A Pilot Study Am. J. Roentgenol., January 1, 2005; 184(1): 234 - 240. [Abstract] [Full Text] [PDF]

				M. D. Price, P. Kanake, and D. Talmor Paradoxical Embolus After Multiple Trauma Resulting in a Cerebrovascular Accident Anesth. Analg., April 1, 2004; 98(4): 1121 - 1123. [Abstract] [Full Text] [PDF]

				G. Devuyst, B. Piechowski-Jozwiak, T. Karapanayiotides, J.-W. Fitting, V. Kemeny, L. Hirt, L. A. Urbano, P. Arnold, G. van Melle, P.-A. Despland, et al. Controlled Contrast Transcranial Doppler and Arterial Blood Gas Analysis to Quantify Shunt Through Patent Foramen Ovale Stroke, April 1, 2004; 35(4): 859 - 863. [Abstract] [Full Text] [PDF]

				H. P. Adams Jr Patent Foramen Ovale: Paradoxical Embolism and Paradoxical Data Mayo Clin. Proc., January 1, 2004; 79(1): 15 - 20. [PDF]

				R. D Rakhit Learning on the Web. Case 2: patent foramen ovale (PFO) and paradoxical embolism. Heart, November 1, 2003; 89(11): 1362 - 1362. [Full Text]

				R. Castello and T. G. Brott Patent foramen ovale: friend or foe? J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1073 - 1075. [Full Text] [PDF]

				C. Lamy, V. Domigo, F. Semah, C. Arquizan, D. Trystram, J. Coste, and J.L. Mas Early and late seizures after cryptogenic ischemic stroke in young adults Neurology, February 11, 2003; 60(3): 400 - 404. [Abstract] [Full Text] [PDF]

				B. Meier and J. E. Lock Contemporary Management of Patent Foramen Ovale Circulation, January 7, 2003; 107(1): 5 - 9. [Full Text] [PDF]

				R. Khiani, K. Daly, C. McCollum, C. Lamy, and J.-L. Mas Re: Clinical and Imaging Findings in Cryptogenic Stroke Patients With and Without Patent Foramen Ovale * Response Stroke, September 1, 2002; 33(9): 2149 - 2150. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lamy, C. Articles by Mas, J.L. Search for Related Content PubMed PubMed Citation Articles by Lamy, C. Articles by Mas, J.L. Related Collections Echocardiography Pediatric and congenital heart disease, including cardiovascular surgery Embolic stroke Risk Factors for Stroke