Neurology -- Correspondence for Messé et al., 62 (7) 1042-1050

Correspondence published:

Practice Parameter: Recurrent stroke with patent foramen ovale and atrial septal aneurysm: Report of: Heinrich P. Mattle, Bernhard Meier, Stephan Windecker for the PC Trial Group (6 July 2004)

Practice Parameter: Recurrent stroke with patent foramen ovale and atrial septal aneurysm: Report of: Mehmet Akif Topcuoglu (6 July 2004)

Reply to Topcuoglu and Mattle: Steven R. Messe, Shunichi Homma, Scott E. Kasner (6 July 2004)

Practice Parameter: Recurrent stroke with patent foramen ovale and atrial septal aneurysm: Report of 6 July 2004

Heinrich P. Mattle,
Department of Neurology
Inselspital, 3010 Bern, Switzerland,
Bernhard Meier, Stephan Windecker for the PC Trial Group
Send Correspondence to journal:
Re: Practice Parameter: Recurrent stroke with patent foramen ovale and atrial septal aneurysm: Report of

heinrich.mattle{at}insel.ch Heinrich P. Mattle, et al.

We thank Messe et al for their analysis of data regarding recurrent stroke with patent foramen ovale (PFO) and atrial septal aneurysm (ASA). [1] They addressed an issue which is highly controversial. Opinions supported with valid arguments range from "closure is the best option" to "is there an association of PFO and cryptogenic stroke (CS) at all?”. [2,3]
The evidence that PFO and CS are associated is well established. [4,5] However, the risk of recurrence and the best secondary prevention strategy in such patients is still unclear.
Messe et al conclude that PFO alone is not associated with increased risk of subsequent stroke or death among medically treated patients with CS compared to those without PFO. They found a possible increased stroke risk only in medically-treated patients who had an ASA and who were less than 55 years old. In patients with PFO or ASA, there was no proven benefit of warfarin over aspirin in preventing recurrent stroke or death; only minor bleeding was more frequent with warfarin.
In addition, they consider the evidence to evaluate PFO closure as insufficient. The authors allude to a potentially severe limitation of their analysis. Their recommendation is based on studies which compared CS patients with PFO, ASA or both to CS patients with neither PFO nor ASA. However, cryptogenic does not mean that a stroke has no cause. It only means that it was impossible to identify it. The stroke risk represented by PFO, ASA or both may be balanced by the risk represented by the cryptogenic etiology that caused the stroke in CS patients without PFO or ASA.
The conclusion that there is no recurrent risk attributable to PFO alone may be inaccurate; only randomized trials will resolve it. Such trials are under way (e.g., PC- Trial with the Amplatzer® device in Europe, Canada and Australia; CLOSURE with Cardioseal®, RESPECT with Amplatzer® and CARDIA with PFO-star® in the USA). In the PC Trial, more than 180 patients have been randomized, yet all trials seem to struggle with a slow randomization. Slow recruitment will be exacerbated if readers misguidedly conclude that current data provide the answers.
References
1. Messe SR, Silverman IE, Kizer JR, Homma S, Zahn C, Gronseth G, Kasner SE. 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: 1042-1050.
2. Furlan AJ. Patent foramen ovale and stroke: Closure is the best option: yes. Stroke 2004; 35: 803-804.
3. Tong DC, Becker KJ. Patent foramen ovale and stroke: Closure is the best option: No. Stroke 2004; 35: 804-805.
4. Webster MW, Chancellor, Smith HJ et al. Patent foramen ovale in young stroke patients. Lancet 1988; 2: 11-12.
5. Lechat P, Mas JL, Lascault G et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1998; 318: 1148-1152. Disclosure: Bernhard Meier, Dept of Cardiology, Inselspital, 3010 Bern, and Heinrich P. Mattle, Department of Neurology, Inselspital, 3010 Bern, Switzerland, are the principal investigators of the PC-Trial, which is sponsored by AGA Medical Incorporation, Golden Valley, MN, USA.

Practice Parameter: Recurrent stroke with patent foramen ovale and atrial septal aneurysm: Report of 6 July 2004

Mehmet Akif Topcuoglu,
Akdeniz University
Department of Neurology, Dumlupinar Bulvari, 07059, Antalya, Turkey
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Re: Practice Parameter: Recurrent stroke with patent foramen ovale and atrial septal aneurysm: Report of

matopcuoglu{at}akdeniz.edu.tr Mehmet Akif Topcuoglu

In their article, Messe et al state that patent foramen ovale (PFO) in patients with cryptogenic stroke is not associated with increased risk of subsequent stroke or death. [1]
Based on the results of French PFO/atrial septal aneurysm (ASA) study , they also report a possible increase of subsequent stroke (but not death) risk in those with PFO associated with ASA. Although the authors mention that certain features of PFO might raise stroke risk including amount of trans-PFO shunting in the middle of the manuscript, the lack of clear statements in the abstract and conclusion sections can be misleading for casual readers not only from an etiopathogenic view but also a practical view.
There is an association between PFO size and its clinical manifestations. However, both French PFO/ASA and Patent Foramen Ovale In Cryptogenic Stroke Study (PICSS) studies did not find an association between shunting degree and stroke recurrence risk perhaps because transesophageal echocardiography (TEE) technique was used. There is enough data indicating that TEE with contrast medium is a semiquantitative technique with pitfalls to define PFO size [2], even though it is the gold standard for its diagnosis.
It is difficult to quantify small bright spots visually on B-mode images. In contrast, it is a dependable method to determine PFO size by transcranial Doppler ultrasound (TCD). Accordingly, studies used TCD for shunt quantification found a clear association between large PFO and subsequent stroke risk. [3]
Moreover, high recurrent stroke rate reported in the patients with both PFO and ASA in the French study can simply be a representation of association between large PFO and increased stroke risk, because coexistence of ASA indicates high degree of right-to-left shunts across PFO. [4] Furthermore, the role of ASA in stroke etiology can only be attributable to the associated trans-septal shunt size. [4] There is also evidence indicating that ASA does not have a role of its own in embolic stroke etiopathogenesis. [5]
There may be no need to detect presence of ASA in patients with PFO for the subsequent stroke risk stratification. That is, we need not do TEE for this purpose. Primarily relying on a single study data [1] implies that TEE to detect ASA is required. TCD is a readily available, noninvasive and bed-side diagnostic which cannot detect ASA but is highly accurate in PFO diagnosis and grading and seems to be sufficient as a screening test in stroke patients. TEE is better to be reserved for those with large PFO scheduled to invasive treatment.
References
1. Messé SR, Silverman IE, Kizer JR, Homma S, Zahn C, Gronseth G, Kasner SE. 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: 1042-1050.
2. 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.
3. Anzola GP, Zavarize P, Morandi P, Rozzini P, Parrinello G. Transcranial Doppler and risk of recurrence in patients with stroke and patent foramen ovale. Eur J Neurol 2003; 10: 129-135.
4. Fox ER, Picard MH, Chow CH, Levine RA, Schwamm L, Kerr AJ. Interatrial septal mobility predicts larger shunts across patent foramen ovales: An analysis with transmitral Doppler scanning. Am Heart J 2003; 145: 730-736.
5. Burger AJ, Sherman HB, Charlamb MJ. Low incidence of embolic strokes with atrial septal aneurysms: A prospective, long-term study. Am Heart J 2000; 139; 149-52.

Reply to Topcuoglu and Mattle 6 July 2004

Steven R. Messe,
Department of Neurology (Drs. Messé and Kasner), University of Pennsylvania, Philadelphia
3400 Spruce Street,
Shunichi Homma, Scott E. Kasner
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Re: Reply to Topcuoglu and Mattle

srmesse{at}hotmail.com Steven R. Messe, et al.

Practice parameters are developed according to a strict protocol insuring that recommendations will be evidence based. This parameter addressed prognosis and therapy for patients with PFO and stroke; we did not specifically address diagnosis. Since the evidence to date suggests that PFO alone does not increase the risk of future stroke or death, but the combination of PFO and ASA may increase risk in younger patients, we concluded that “studies which can identify PFO or ASA may be considered for prognostic purposes.” We did not state that such studies were required, nor do we mention which is best. However, only TEE can reliably detect ASA.
Dr. Topcuoglu argues that the association between ASA and the risk of recurrent stroke in patients with PFO may be erroneous, since the degree of right-to-left shunting is likely the critical determinant of future risk. ASA may be a marker for greater right-to-left shunt. However, strokes in patients with PFO and ASA may not always be due to paradoxical embolism, as in situ atrial thrombosis and atrial arrhythmia may occur as well.1, 2 Thus, right-to-left shunt may not be the only mechanism of stroke associated with ASA. Quantification of right-to-left shunt can be measured with either TCD or TEE, though it remains controversial which, if either, is superior. Many studies suggest that they are complementary.3 Small studies using either tool have suggested that degree of shunting predicts future stroke risk,4, 5 but this was not borne out in the larger trials.6 TEE is the gold standard for evaluation of the atrial septum. Unlike TCD, TEE is capable of distinguishing PFO from atrial septal defect, which may impact therapy. Further, TEE is the best method to identify other potential cardiac sources of embolism, such as left atrial appendage thrombus, valvular vegetation, aortic atheroma, spontaneous echo contrast, or atrial myxoma. We appreciate Dr. Mattle’s comments on the practice parameter, though he made one statement which is not entirely accurate. He states that we found no benefit of warfarin over aspirin, implying that the two medicines are equally effective. Unfortunately, the evidence is insufficient to make any conclusions about these medications and their relative efficacy. In our survey of the current literature we found that the largest prospective studies of PFO in stroke patients did not support an association between degree of shunt and stroke recurrence. This result may be unsatisfying and may defy clinical intuition, but is unfortunately the evidence available to us. As noted in the practice parameter, and echoed by Dr. Mattle above, further study of stroke patients with PFO is greatly needed.
References
1. Mugge A, Daniel WG, Angermann C, et al. Atrial septal aneurysm in adult patients. Circulation 1995;91:2785-2792.
2. 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;31:398.
3. Droste DW, Schmidt-Rimpler C, Wichter T, et al. Right-to-Left-Shunts Detected by Transesophageal Echocardiography and Transcranial Doppler Sonography. Cerebrovasc Dis 2004;17(2-3):191-196. Epub 2003 Dec 2029.
4. Anzola GP, Zavarize P, Morandi E, Rozzini L, Parrinello G. Transcranial Doppler and risk of recurrence in patients with stroke and patent foramen ovale. Eur J Neurol 2003;10(2):129-135.
5. Stone DA, Godard J, Corretti MC, et al. Patent foramen ovale: association between the degree of shunt by contrast transesophageal echocardiography and the risk of future ischemic neurologic events. American Heart Journal 1996;131(1):158-161.
6. Messe SR, Silverman IE, Kizer JR, 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.