Re: Clinical and Imaging Findings in Cryptogenic Stroke Patients With and Without Patent Foramen Ovale
To the Editor:
We read with interest the article by Lamy et al1 in which they felt that their data did not support paradoxical embolism as the mechanism of stroke in patients with a patent foramen ovale (PFO). Their study excluded patients with a thrombophilia, which is the group most at risk for venous thromboembolism and hence paradoxical embolism. They therefore excluded the stroke patients most likely to have suffered paradoxical embolism. How many such patients were excluded?
They also argued that as deep vein thrombosis (DVT) was rarely detected in their stroke patients, it was unlikely that paradoxical embolism had occurred. However, in patients with a confirmed pulmonary embolism, which must have arisen from a DVT, the causative DVT usually cannot be detected despite extensive investigation.2,3⇓ Considering that the origin of a paradoxical embolus may be a very small DVT, even a valve cusp thrombus, failure to document a DVT after a stroke does not exclude paradoxical embolism any more than it would exclude the diagnosis of pulmonary embolism.
We were interested to see that migraine was again found to be more common in cryptogenic stroke patients with a PFO than in those without a PFO. This association has been reported previously.4 It is biologically plausible that showers of microemboli crossing a PFO may cause cerebral vasospasm and migraine. Sztajzel et al4 demonstrated that surgical closure or anticoagulant treatment in stroke patients with a PFO may cure migraine symptoms. Lamy et al do not seem to have considered the possibility that paradoxical embolism may cause migraine in some individuals.
What a shame that the authors chose to investigate subjects up to the age of 55 years in whom atherosclerosis is clearly the predominant cause of stroke.5 Do their data show a greater frequency of PFO in their stroke patients aged under 40? It is not clear whether aortic arch atheroma was assessed during the transesophageal echocardiography investigation.6
- ↵Lamy C, Giannesini C, Zuber M, Arquizan C, Meder JF, Trystam D, Coste J, Mas JL. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA study. Stroke. 2002; 33: 706–711.
- ↵Hull DH, Hirsh J, Carter CJ, Jay RM, Dodd PE, Ockelford PA, Coates G, Gill GJ, Turpie AG, Doyle DJ, Buller HR, Raskob GE. Pulmonary angiography, ventilation lung scanning and venography for clinically suspected pulmonary embolism and abnormal perfusion lung scan. Ann Intern Med. 1983; 98: 891–899.
- ↵Prati P, Vanuzzo D, Casaroli M, Di Chiara A, De Biasi F, Feruglio GA, Touboul PJ. Prevalence and determinants of carotid atherosclerosis in a general population. Stroke. 1992; 23: 1705–1711.
We agree with Dr Khiani et al that a coagulation disorder may theoretically predispose to paradoxical embolism in patients with a PFO,1 although this remains to be proven. Patients with a definite cause of stroke (including coagulation disorders) were not included in the PFO-ASA study, but we kept a register of all consecutive patients (<55 years) with ischemic stroke who were screened for possible inclusion in the study.2 Of the patients who were not included because of the presence of a definite cause of stroke (whether or not associated with PFO), <5% had a coagulation or hematological disorder. Therefore, the vast majority of patients with PFO-associated stroke have no (currently identifiable) coagulation disorder.
As regards the prevalence of DVT, we only concluded that the low rate of search for DVT in our study 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 DVT.3 We agree that DVT may remain undetected because of its location or the size of the thrombus, but it would be “paradoxical” to use the low yield of a systematic search for DVT as an argument for paradoxical embolism.
The relationship between PFO and migraine is unclear. Assuming cause-effect is a matter of speculation. Statistical association as determined by case-control studies does not necessarily imply causality, because it may result from bias, chance, or confounding.4 Given that the pathophysiology of migraine is poorly known, biological plausibility cannot be put forward to suggest a causal link. The relevance of PFO in the cause of migraine (or stroke) will be confirmed when randomized controlled trials will demonstrate that “removal” of this septal disorder, by means of endovascular or surgical techniques, substantially reduces the risk of subsequent migraine attacks (or stroke), in the same way, the relevance of carotid stenosis has been confirmed by the finding that carotid endarterectomy substantially reduces the risk of ipsilateral ischemic stroke.
We selected patients who were <55 years of age because the association of PFO with cryptogenic stroke has been consistently reported in this age group.5 One of the conclusions of our study is precisely that stroke patients with PFO are significantly younger and less likely to have traditional risk factors for stroke than patients without PFO. These differences suggest different stroke mechanisms in patients with and without PFO but do not imply that the mechanism of stroke is paradoxical embolism. Aortic arch atheroma was systematically assessed during transesophageal investigation, and patients with complex atheroma of the aortic arch were not included in the PFO-ASA study.
- ↵Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J, for the Patent Foramen Ovale and Atrial Septal Aneurysm Study Group. Recurrent cerebrovascular events in young adults with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001; 345: 1740–1746.
- ↵Lamy C, Giannesini C, Zuber M, Arquizan C, Meder JF, Trystram D, Coste J, Mas JL, for the Patent Foramen Ovale and Atrial Septal Aneurysm Study Group. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Stroke. 2002; 33: 706–711.
- ↵Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology. 2000; 55: 1172–1179.