- Email: [email protected]
Patent foramen ovale
Perspectives in Medicine (2012) 1, 228—231
Bartels E, Bartels S, Poppert H (Editors): New Trends in Neurosonology and Cerebral Hemodynamics — an Update. Perspectives in Medicine (2012) 1, 228—231 journal homepage: www.elsevier.com/locate/permed
Patent foramen ovale Susanna Horner ∗, Kurt Niederkorn, Franz Fazekas Department of Neurology, Medical University of Graz, Austria
KEYWORDS Patent foramen ovale; Right-to-left shunt; Transcranial Doppler sonography; Ultrasound contrast agent; Transesophageal echocardiography; Cryptogenic stroke
Summary Paradoxical embolism is a possible cause of ischemic stroke, particularly in younger patients without any other cause, i.e. cryptogenic stroke, and a patent foramen ovale is the most frequently assumed cause. The contrast transcranial Doppler monitoring mode has a sensitivity that is comparable to contrast transesophageal echocardiography for detection of a right-to-left shunt, however, the contrast transesophageal echocardiography remains the ‘‘golden standard’’ for the detection of a patent foramen ovale. Diagnostic studies that can identify a patent foramen ovale may be considered for prognostic purposes. In most cases, however, it is difficult to establish a firm etiological association and the debate about medical or interventional management is ongoing. Other possible causes of right-to-left shunting leading to cerebral complications like pulmonary arteriovenous malformations have also been noted but are rarely discussed. © 2012 Elsevier GmbH. Open access under CC BY-NC-ND license.
Introduction Patients with cryptogenic stroke should be screened for possible paradoxical cerebral embolism via a cardiac or pulmonary right-to-left shunt (RLS). There is evidence for an increased prevalence of patent foramen ovale (PFO) in cryptogenic stroke, in both younger [1—5] and elderly patients [6]. An atrial septal aneurysm (ASA) may increase the stroke risk as well, whether occurring alone or combined with a PFO [2,5]. Diagnostic studies that can identify PFO with RLS or ASA may be considered for prognostic purposes [7]. Echocardiography is recommended in selected stroke and TIA patients and is particularly required in patients with suspected paradoxical embolism and no other identifiable causes of stroke [8]. Transesophageal echocardiography (TEE) is superior to transthoracic echocardiography for evaluation of the aortic arch, left atrium, and
∗ Corresponding author at: Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036 Graz, Austria. Tel.: +43 0316 385 83617; fax: +43 0316 385 3512. E-mail address: [email protected] (S. Horner).
2211-968X © 2012 Elsevier GmbH. Open access under CC BY-NC-ND license. http://dx.doi.org/10.1016/j.permed.2012.03.003
atrial septum [9] and represents the ‘‘golden standard’’ to establish the presence of a RLS and a PFO. The contrast transcranial Doppler (cTCD) monitoring mode has a sensitivity that is comparable to contrast TEE (cTEE) for detection of a PFO with RLS. Its diagnostic sensitivity ranges from 70% to 100% and the specificity is more than 95% [10,11]. Although positive cTCD studies in pulmonary RLS have been described, only cTEE allows localization of the RLS to the cardiac or pulmonary level [12—15]. The distinction between cardiac and pulmonary shunts based on the time window of contrast appearance and contrast amount shunted is unreliable by cTCD [13,16]. cTCD allows estimation of the shunt size by quantification and categorization of the contrast shunted. The results are comparable with shunt quantification using cTEE [3,11,17—21]. Large RLS assessed by cTCD have been reported to be associated with a higher risk of first and recurrent stroke, particularly with cryptogenic stroke [17,22]. In contrast, results of a study showed that massive RLS sized with TCD were not an independent risk factor for recurrent stroke [18]. Therefore, the clinical significance of cTCD shunt sizing remains unclear.
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Table 1 Summary of test procedures for detection of right-to-left shunt with ultrasound contrast agent and transcranial Doppler sonography ([16], modified). Preparation of the patient and TCD recording Supine position. Insert 18-gauge needle — preferred over a 20-gauge needle to increase the sensitivity [56] — into (right) cubital vein. A higher sensitivity is reported by using the femoral vein as injection site [43] which is, however, more uncomfortable for the patient. Insonate (if possible both) middle cerebral arteries (MCA), bilateral recordings increase the sensitivity compared with unilateral insonation [12,34]. In case of insufficient acoustic bone window, transforaminal insonation of the basilar artery might be an alternative approach [57]. Preparation of contrast agent and injection Syringe I: 9 ml saline; syringe II: 1 ml air. Connect both syringes with three-way stopcock connected with a short flexible line to an intravenous line of 18-gauge with the patient. Exchange air/saline mixture vigorously between the syringes at least ten times. Inject immediately as a bolus. In case of little or no detection of microembolic signals, repeat the examination with Valsalva maneuver. Commercially traded contrast agents should be prepared according to the manufacturer’s instructions. Application of Valsalva maneuver The patient should start with Valsalva maneuver on examiner’s command 5 s after injection of the contrast agent; the control of an adequate Valsalva maneuver will be performed by assessment of the reduction of peak flow velocity of the TCD curve. Overall Valsalva maneuver duration should be 10 s. Evaluation of test results Categorization (for unilateral testing, values for bilateral monitoring in parentheses): (1) 0 microembolic signals (negative result); (2) 1—10 (1—20) microembolic signals; (3) >10 (>20) microembolic signals, but no curtain; (4) curtain or shower of microembolic signals, where a single signal cannot be discriminated within the TCD spectra. The microembolic signal count must be documented and evaluated separately for baseline condition and Valsalva maneuver.
The impact of cTCD in RLS detection has been studied in a number of conditions other than cerebrovascular disease; however, the grade of evidence from these studies is low to moderate: a significant association was reported between the degree of cTCD sized shunting and the number of signal abnormalities on MRI in asymptomatic sport divers [23]. Divers with RLS show a higher risk of decompression sickness [24]. There is evidence of an increased prevalence of PFO in patients with migraine with aura [25], supported by cTCD studies [26,27]. Furthermore, cTCD has been described to be useful to detect residual shunting following transcatheter closure of a PFO [28]. Depending on methodological factors, cTCD results vary considerably. Therefore, criteria of the examination technique were established by an International Consensus Meeting. The goal was a standardized approach and minimal variability for RLS detection by cTCD [16]. The examination technique recommended by this Consensus Meeting is summarized in Table 1. Fig. 1 shows a video demonstration of a positive contrast study in a patient with large PFO. Additional data are available also from publications summarizing the impact and technique of cTCD for diagnosis of PFO [29,30]. cTCD uses air-containing echo contrast agents (CAs) which normally are unable to pass the pulmonary capillary bed. The diagnosis of a RLS by cTCD is established if TCD observes microembolic signals after contrast injection. However, the minimal amount of microembolic signals suggestive of a clinically relevant RLS is not established [16]. Different authors require different numbers of microembolic signals for the diagnosis of a PFO. They range from a minimum of one microembolus to more than five microemboli. In addition, the time from contrast injection to signal detection ranges from 6 to 10 cardiac cycles or from 4 s to 24 s [31—33]. Most authors used agitated saline solution as contrast agent [4,18,33—39] or D-galactose Mb solution
(Echovist® ) [12,32,34,40—46]. Only few authors used other agents such as Oxypolygelatine (Gelifundol® , Gelofusin® ) [3,31,39]. A sensitivity up to 100% was achieved by both Echovist® [42,47] and agitated saline solution [4,35,38]. The Consensus Meeting recommended using the saline/air mixture. Saline/air mixture is not subject to local approval rules and has proven as effective as Echovist® in numerous studies. However, Echovist® is out of use in most countries because this CA is not longer commercially available.
Recommendations In younger stroke patients, studies that can identify PFO or ASA may be considered for prognostic purposes (class II, level C). Echocardiography is recommended in selected stroke and TIA patients, and particularly in cryptogenic stroke and when paradoxical embolism is suspected (class III, level B). TCD is probably useful to detect cerebral microembolic signals in a wide variety of cardio- and cerebrovascular disorders or procedures (classes II—IV, level B). Standardized technique cTCD has a sensitivity similar to cTEE for detection of a PFO with RLS (class II, level A) but does not provide information of the anatomic location of the shunt or the presence of an ASA. The examination should be performed according to the instructions of the International Consensus Conference [16] (class II, level A). Although cTCD provides information about the size of the shunt, the clinical usefulness remains to be determined (level C). cTEE remains the ‘‘golden standard’’ for the detection of PFO. However, cTCD can be used as a minimally invasive screening test before cTEE or as an alternative method if cTEE is not available (classes III—IV, level C). Uncertainties exist regarding optimal treatment of paradoxical cerebral embolism and therapeutic considerations have focussed primarily on the management of
230 PFO. Although international guidelines [48,49] recommend antiplatelet therapy as first line strategy for treating stroke patients with PFO, transcatheter closure has become common practice in many centres and is one of the most frequent interventional procedures performed in adult congenital heart disease [50]. Unfortunately, results from large randomized trials [51—54] that compare interventional closure of a PFO with medical therapy regarding the prevention of further cerebral ischemic events do not yet exist or have just been reported at meetings [55]. Therefore individual counselling is variable and the benefit of either strategy largely unknown.
S. Horner et al.
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[13]
[14]
Appendix A. Supplementary data [15]
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.permed.2012.03.003.
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231 [44] Klötzsch C, Janssen G, Berlit P. Transesophageal echocardiography and contrast-TCD in the detection of a patent foramen ovale: experiences with 111 patients. Neurology 1994;44:1603—6. [45] Schminke U, Ries S, Daffertshofer M, Staedt U, Hennerici M. Patent foramen ovale: a potential source of cerebral embolism. Cerebrovascular Diseases 1995;5:133—8. [46] Droste DW, Jekentaite R, Stypmann J, Grude M, Hansberg T, Ritter M, et al. Contrast transcranial Doppler ultrasound in the detection of right-to-left shunts: comparison of Echovist® 200 and Echovist® -300, timing of the Valsalva maneuver, and general recommendations for the performance of the test. Cerebrovascular Diseases 2002;13:235—41. [47] Uzuner N, Horner S, Pichler G, Svetina D, Niederkorn K. Right-to-left shunt assessed by contrast transcranial Doppler sonography. Journal of Ultrasound in Medicine 2004;23:1475—82. [48] European Stroke Organisation (ESO) Executive Committee, ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovascular Diseases 2008;25(5):457—507 [Epub 2008 May 6]. [49] Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42(January (1)):227—76. [50] Kenny D, Turner M, Martin R. When to close a patent foramen ovale. Archives of Disease in Childhood 2008;93(March (3)):255—9. [51] PC-Trial. Patent foramen ovale and cryptogenic embolism. http://clinicaltrials.gov/ct2/show/NCT00166257?term=Patent +foramen+ovale+and+Cryptogenic+embolism&rank=1. [52] RESPECT. Randomized evaluation of recurrent stroke comparing PFO closure to established current standard of care treatment. http://www.amplatzer.com/clinical trials/ tabid/94/default.aspx. [53] CLOSE. Patent foramen ovale closure or anticoagulants versus antiplatelet therapy to prevent stroke recurrence. ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/ NCT00562289?term=NCT00562289&rank=1. [54] CARDIA STARTM Trial: A United States Randomized Clinical Trial of the CARDIA STARTM Patent Foramen Ovale Closure System (The CARDIA STARTM Trial). http://www.mplsheart.com/ Publications/Research/InterventionalCardiologyResearch/ CARDIASTAR.aspx. [55] Furlan AMJ, Mauri L, Adams H, Albers G, Felberg R, Herrmann H, et al. Late breaking clinical trial and science abstracts from the American Heart Association’s scientific session 2010; abstract 21752: CLOSURE I: A prospective, multicenter, randomized, controlled trial to evaluate the safety and efficacy of the Starflex septal closure system versus best medical therapy in patients with a stroke or transient ischemic attack due to presumed paradoxical embolism through a patent foramen ovale. Circulation 2010;122:2218. [56] Khan KA, Yeung M, Shuaib A. Comparative study of 18 gauge and 20 gauge intravenous catheters during transcranial Doppler ultrasonography with saline solution contrast. Journal of Ultrasound in Medicine 1997;16:341—4. [57] Perren F, Savva E, Landis T. Transforaminal Doppler: an alternative to transtemporal approach for right-to-left cardiac shunt assessment. Journal of the Neurological Sciences 2008;273(1—2):49—50.
Bartels E, Bartels S, Poppert H (Editors): New Trends in Neurosonology and Cerebral Hemodynamics — an Update. Perspectives in Medicine (2012) 1, 228—231 journal homepage: www.elsevier.com/locate/permed
Patent foramen ovale Susanna Horner ∗, Kurt Niederkorn, Franz Fazekas Department of Neurology, Medical University of Graz, Austria
KEYWORDS Patent foramen ovale; Right-to-left shunt; Transcranial Doppler sonography; Ultrasound contrast agent; Transesophageal echocardiography; Cryptogenic stroke
Summary Paradoxical embolism is a possible cause of ischemic stroke, particularly in younger patients without any other cause, i.e. cryptogenic stroke, and a patent foramen ovale is the most frequently assumed cause. The contrast transcranial Doppler monitoring mode has a sensitivity that is comparable to contrast transesophageal echocardiography for detection of a right-to-left shunt, however, the contrast transesophageal echocardiography remains the ‘‘golden standard’’ for the detection of a patent foramen ovale. Diagnostic studies that can identify a patent foramen ovale may be considered for prognostic purposes. In most cases, however, it is difficult to establish a firm etiological association and the debate about medical or interventional management is ongoing. Other possible causes of right-to-left shunting leading to cerebral complications like pulmonary arteriovenous malformations have also been noted but are rarely discussed. © 2012 Elsevier GmbH. Open access under CC BY-NC-ND license.
Introduction Patients with cryptogenic stroke should be screened for possible paradoxical cerebral embolism via a cardiac or pulmonary right-to-left shunt (RLS). There is evidence for an increased prevalence of patent foramen ovale (PFO) in cryptogenic stroke, in both younger [1—5] and elderly patients [6]. An atrial septal aneurysm (ASA) may increase the stroke risk as well, whether occurring alone or combined with a PFO [2,5]. Diagnostic studies that can identify PFO with RLS or ASA may be considered for prognostic purposes [7]. Echocardiography is recommended in selected stroke and TIA patients and is particularly required in patients with suspected paradoxical embolism and no other identifiable causes of stroke [8]. Transesophageal echocardiography (TEE) is superior to transthoracic echocardiography for evaluation of the aortic arch, left atrium, and
∗ Corresponding author at: Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036 Graz, Austria. Tel.: +43 0316 385 83617; fax: +43 0316 385 3512. E-mail address: [email protected] (S. Horner).
2211-968X © 2012 Elsevier GmbH. Open access under CC BY-NC-ND license. http://dx.doi.org/10.1016/j.permed.2012.03.003
atrial septum [9] and represents the ‘‘golden standard’’ to establish the presence of a RLS and a PFO. The contrast transcranial Doppler (cTCD) monitoring mode has a sensitivity that is comparable to contrast TEE (cTEE) for detection of a PFO with RLS. Its diagnostic sensitivity ranges from 70% to 100% and the specificity is more than 95% [10,11]. Although positive cTCD studies in pulmonary RLS have been described, only cTEE allows localization of the RLS to the cardiac or pulmonary level [12—15]. The distinction between cardiac and pulmonary shunts based on the time window of contrast appearance and contrast amount shunted is unreliable by cTCD [13,16]. cTCD allows estimation of the shunt size by quantification and categorization of the contrast shunted. The results are comparable with shunt quantification using cTEE [3,11,17—21]. Large RLS assessed by cTCD have been reported to be associated with a higher risk of first and recurrent stroke, particularly with cryptogenic stroke [17,22]. In contrast, results of a study showed that massive RLS sized with TCD were not an independent risk factor for recurrent stroke [18]. Therefore, the clinical significance of cTCD shunt sizing remains unclear.
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Table 1 Summary of test procedures for detection of right-to-left shunt with ultrasound contrast agent and transcranial Doppler sonography ([16], modified). Preparation of the patient and TCD recording Supine position. Insert 18-gauge needle — preferred over a 20-gauge needle to increase the sensitivity [56] — into (right) cubital vein. A higher sensitivity is reported by using the femoral vein as injection site [43] which is, however, more uncomfortable for the patient. Insonate (if possible both) middle cerebral arteries (MCA), bilateral recordings increase the sensitivity compared with unilateral insonation [12,34]. In case of insufficient acoustic bone window, transforaminal insonation of the basilar artery might be an alternative approach [57]. Preparation of contrast agent and injection Syringe I: 9 ml saline; syringe II: 1 ml air. Connect both syringes with three-way stopcock connected with a short flexible line to an intravenous line of 18-gauge with the patient. Exchange air/saline mixture vigorously between the syringes at least ten times. Inject immediately as a bolus. In case of little or no detection of microembolic signals, repeat the examination with Valsalva maneuver. Commercially traded contrast agents should be prepared according to the manufacturer’s instructions. Application of Valsalva maneuver The patient should start with Valsalva maneuver on examiner’s command 5 s after injection of the contrast agent; the control of an adequate Valsalva maneuver will be performed by assessment of the reduction of peak flow velocity of the TCD curve. Overall Valsalva maneuver duration should be 10 s. Evaluation of test results Categorization (for unilateral testing, values for bilateral monitoring in parentheses): (1) 0 microembolic signals (negative result); (2) 1—10 (1—20) microembolic signals; (3) >10 (>20) microembolic signals, but no curtain; (4) curtain or shower of microembolic signals, where a single signal cannot be discriminated within the TCD spectra. The microembolic signal count must be documented and evaluated separately for baseline condition and Valsalva maneuver.
The impact of cTCD in RLS detection has been studied in a number of conditions other than cerebrovascular disease; however, the grade of evidence from these studies is low to moderate: a significant association was reported between the degree of cTCD sized shunting and the number of signal abnormalities on MRI in asymptomatic sport divers [23]. Divers with RLS show a higher risk of decompression sickness [24]. There is evidence of an increased prevalence of PFO in patients with migraine with aura [25], supported by cTCD studies [26,27]. Furthermore, cTCD has been described to be useful to detect residual shunting following transcatheter closure of a PFO [28]. Depending on methodological factors, cTCD results vary considerably. Therefore, criteria of the examination technique were established by an International Consensus Meeting. The goal was a standardized approach and minimal variability for RLS detection by cTCD [16]. The examination technique recommended by this Consensus Meeting is summarized in Table 1. Fig. 1 shows a video demonstration of a positive contrast study in a patient with large PFO. Additional data are available also from publications summarizing the impact and technique of cTCD for diagnosis of PFO [29,30]. cTCD uses air-containing echo contrast agents (CAs) which normally are unable to pass the pulmonary capillary bed. The diagnosis of a RLS by cTCD is established if TCD observes microembolic signals after contrast injection. However, the minimal amount of microembolic signals suggestive of a clinically relevant RLS is not established [16]. Different authors require different numbers of microembolic signals for the diagnosis of a PFO. They range from a minimum of one microembolus to more than five microemboli. In addition, the time from contrast injection to signal detection ranges from 6 to 10 cardiac cycles or from 4 s to 24 s [31—33]. Most authors used agitated saline solution as contrast agent [4,18,33—39] or D-galactose Mb solution
(Echovist® ) [12,32,34,40—46]. Only few authors used other agents such as Oxypolygelatine (Gelifundol® , Gelofusin® ) [3,31,39]. A sensitivity up to 100% was achieved by both Echovist® [42,47] and agitated saline solution [4,35,38]. The Consensus Meeting recommended using the saline/air mixture. Saline/air mixture is not subject to local approval rules and has proven as effective as Echovist® in numerous studies. However, Echovist® is out of use in most countries because this CA is not longer commercially available.
Recommendations In younger stroke patients, studies that can identify PFO or ASA may be considered for prognostic purposes (class II, level C). Echocardiography is recommended in selected stroke and TIA patients, and particularly in cryptogenic stroke and when paradoxical embolism is suspected (class III, level B). TCD is probably useful to detect cerebral microembolic signals in a wide variety of cardio- and cerebrovascular disorders or procedures (classes II—IV, level B). Standardized technique cTCD has a sensitivity similar to cTEE for detection of a PFO with RLS (class II, level A) but does not provide information of the anatomic location of the shunt or the presence of an ASA. The examination should be performed according to the instructions of the International Consensus Conference [16] (class II, level A). Although cTCD provides information about the size of the shunt, the clinical usefulness remains to be determined (level C). cTEE remains the ‘‘golden standard’’ for the detection of PFO. However, cTCD can be used as a minimally invasive screening test before cTEE or as an alternative method if cTEE is not available (classes III—IV, level C). Uncertainties exist regarding optimal treatment of paradoxical cerebral embolism and therapeutic considerations have focussed primarily on the management of
230 PFO. Although international guidelines [48,49] recommend antiplatelet therapy as first line strategy for treating stroke patients with PFO, transcatheter closure has become common practice in many centres and is one of the most frequent interventional procedures performed in adult congenital heart disease [50]. Unfortunately, results from large randomized trials [51—54] that compare interventional closure of a PFO with medical therapy regarding the prevention of further cerebral ischemic events do not yet exist or have just been reported at meetings [55]. Therefore individual counselling is variable and the benefit of either strategy largely unknown.
S. Horner et al.
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Appendix A. Supplementary data [15]
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.permed.2012.03.003.
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