Lesion patterns in patients with cryptogenic stroke with and without right-to-left-shunt

European Journal of Neurology 2009, 16: 1077 1082 CME ARTICLE doi:10.1111/j.1468-1331.2009.02692.x Lesion patterns in patients with cryptogenic stroke with and without right-to-left-shunt R. Feurer a, S. Sadikovic a, L. Esposito a, J. Schwarze b, A. Bockelbrink c, B. Hemmer a, D. Sander a and H. Poppert a a Department of Neurology, Technische Universitaet Muenchen, Klinikum Rechts der Isar, Muenchen, Germany; b Department of Neurology, Klinikum Chemnitz, Chemnitz, Germany; and c Department of Social Medicine, Epidemiology and Health Economics, Charite, University Medicine Berlin, Berlin, Germany Keywords: crytogenic stroke, diffusion weighted imaging, multiple ischaemic lesions, patent foramen ovale Received 3 October 2008 Accepted 18 February 2009 Background and purpose: Despite numerous studies, the role of patent foramen ovale (PFO) as a risk factor for stroke due to paradoxical embolism is still controversial. On the assumption that specific lesion patterns, in particular multiple acute ischaemic lesions on diffusion-weighted magnetic resonance imaging, indicate a cardioembolic origin, we compared the MRI findings in stroke patients with right-to-left shunt (RLS) and those without. Methods: The records of 486 patients with diagnosis of cerebral ischaemia were reviewed. For detection of RLS, contrast-enhanced transcranial Doppler (c-tcd) was carried out in all patients. An MRI scan of the brain was performed in all patients. Affected vascular territories were divided into anterior cerebral artery, middle cerebral artery, vertebrobasilar artery system including posterior cerebral artery, brain stem and cerebellar stroke, and strokes occurring in more than one territory. Results: We did not find a specific difference in neuroradiological lesion patterns in patients with RLS compared with patients without RLS. In particular, 23 of 165 patients (13.9%) with RLS showed multiple ischaemic lesions on MRI in comparison with 45 of 321 patients (14.0%) without RLS (P = 0.98). These findings also applied for the subgroup of cryptogenic strokes with and without RLS. Conclusion: We found no association between an ischaemic lesion pattern that is considered as being typical for stroke due to cardiac embolism and the existence of PFO. Therefore, our findings do not provide any support for the common theory of paradoxical embolism as a major cause of stroke in PFO carriers. Introduction In 1877, the pathologist Julius Cohnheim indicated a causal relationship between patent foramen ovale (PFO) and stroke when analyzing the case of a young woman [1]. However, foramen ovale can be found in about 30% of autopsies [2]. The development of contrast transesophageal echocardiography (TEE) in the 1970s enabled the detection of PFO in vivo with high sensitivity. In 1988, Lechat and colleagues [3] reported PFO detected by TEE to be significantly more frequent in stroke patients than Correspondence: Dr. Regina Feurer, Department of Neurology, Klinikum rechts der Isar, Technische Universitaet Muenchen, Ismaningerstr. 22, 81675 Muenchen, Germany (tel.: +49 89 4140 7680; fax.: +49 89 4140 4867; e-mail: regina.feurer@gmx.de). This is a Continuing Medical Education article, and can be found with corresponding questions on the Internet at http://www.efns.org/content.php?pid=132. Certificates for correctly answering the questions will be issued by the EFNS. in controls. They suggested that clinically latent venous thrombosis and paradoxical embolism through a PFO might be responsible for the ischaemic event in a considerable proportion of patients. Other TEE-based studies agreed with these findings and contributed to the theory of paradoxical brain embolism [4,5]. However, two prospective population-based studies have yielded controversial results about the causal relationship of PFO and paradoxical embolism [6,7]. Another study found that PFO alone was not a significant independent predictor of cerebrovascular events after adjustment for age and comorbid conditions [8]. A potential mechanism of stroke in patients with PFO is thought to be paradoxical embolism from a venous source like deep vein thrombosis, causing neuroradiological features of cerebral embolism such as large infarctions with a diameter >3.0 cm, cortical infarctions, and multiple ischaemic lesions occurring in more than one territory. In particular, the presence of multiple ischaemic lesions on MRI is thought to be Journal compilation Ó 2009 EFNS 1077

1078 R. Feurer et al. highly suggestive of an embolic source [9]. Additionally, Jauss et al. reported that multiple ischaemic lesions in the posterior circulation are associated with the presence of PFO [10]. Yasaka et al. confirmed with this finding and argued that small emboli passing through the PFO may enter the vertebral arteries more easily than the common carotid arteries [11]. However, numerous patients with PFO show neither deep vein thrombosis nor multiple acute ischaemic lesion patterns on MRI. Thus, the contribution of paradoxical embolism through PFO to the causation of stroke may be smaller than previously assumed. In our study, we searched for specific MRI lesion patterns that might support the theory of underlying paradoxical embolism in stroke patients with right-toleft shunt (RLS). Therefore, we examined the prevalence of affected vascular territories and multiple lesions in particular. As different prevalences of further known causes of cardiac embolism such as atrial fibrillation (AF) in the two groups would bias our results, these data were also taken into account for the analysis. As our study relies on contrast-enhanced transcranial Doppler (ctcd) for the detection of RLS, other septal abnormalities such as atrial septal aneurysm (ASA) which can be seen in echocardiography should be disregarded. Subjects and methods Subjects The records of consecutive patients examined between January 1995 and August 2005 at our institution the Neurovascular Laboratory of the Klinikum rechts der Isar, Technische Universita t Mu nchen, were reviewed. Subjects with the diagnosis of stroke or transient ischaemic attack (TIA) at discharge without artificial heart valves were included. Complete clinical neurological examination, electrocardiogram, and Doppler and color coded duplex ultrasound of the extracranial arteries and Doppler ultrasound of the intracranial arteries were carried out in all patients, cerebral CT or MRI or both was performed in all patients. All patients received a 4-lead 24-h ECG at admission. All baseline strokes were classified according to the criteria of The Trial of Org 10172 in Acute Stroke Therapy (TOAST) [12], with one modification: Strokes of unknown origin were subdivided into stroke with conflicting mechanisms and cryptogenic stroke. Stroke with conflicting mechanisms was then subsumed under Ôother etiologyõ. The subtype of stroke due to cardioembolism included strokes with a high-risk cardiac source such as AF, rheumatic mitral or aortic valve disease, atrial or ventricular thrombus, sick sinus syndrome, sustained atrial flutter, recent myocardial infarction, chronic myocardial infarction together with ejection fraction <28%, symptomatic congestive heart failure with ejection fraction <30%, dilated cardiomyopathy, fibrous non-bacterial endocarditis as found in patients with systemic lupus, infective endocarditis, papillary fibroelastoma, left atrial myxoma and coronary artery bypass graft surgery. Additional diagnostic investigations such as echocardiography or angiography were taken into account if available. The TOAST subtyping was performed by a physician who was blinded to knowledge of the TCD findings. TCD methodology For microembolic monitoring, a 2-MHz pulsed-wave transcranial Doppler device (Multi-DOP; DWL Elektronische Systeme, Sipplingen, Germany) was used for simultaneous long-term insonation of both middle cerebral arteries (MCA) using simultaneous 64-point fast Fourier transformation and bigate technique. All embolic signals (ES) were automatically saved on computer hard disk and were analyzed offline. Later all data were archived on magnetic optical disk. All analyses were performed blinded to individual patient details. ES were accepted that appeared within 20 s after the injection of contrast medium, were unidirectional from the baseline, and occurred randomly throughout the cardiac cycle. They lasted 10 50 ms and had an intensity 11 db higher than that of surrounding blood. The subject was placed in supine position. The transducer was fixed in position with the use of a standard headset. The ES were recorded after bolus injection of galactose (Echovist Ò ; Schering AG, Berlin, Germany) via the right antecubital vein followed by a flush injection of 5 ml of normal saline. Five seconds after start of the injection, patients had to perform a Valsalva maneuver. This was monitored by means of a pressure gauge, which was connected to a flexible tube with a snorkel mouthpiece. The patients were asked to maintain a pressure of 4000 Pa (40 mbar) for 5 s. Simultaneous monitoring of the Doppler spectrum allowed us to demonstrate increased intrathoracic pressure as shown by a reduction in the mean velocity in the MCA of at least 25%. In case of a positive finding, the examination was repeated at rest to discriminate large versus small functional shunts. All the parameters mentioned were chosen according to our previously published protocol [13]. Except for the choice of contrast medium, all parameters conform to the Consensus conference of Venice [14]. To ensure a maximum degree of standardization, we used commercially available galactose instead of agitated saline.

Lesion patterns in patients with cryptogenic stroke 1079 Brain imaging An MRI scan of the brain was performed using a superconducting magnet at a field strength of either 1.0 or 1.5 T. Tissue abnormality was defined as an area of high signal intensity on isotropic diffusion-weighted imaging (DWI) reflecting an acute ischaemic lesion. Affected vascular territories were divided into anterior cerebral artery, middle cerebral artery, vertebrobasilar artery system including posterior cerebral artery, brain stem and cerebellar stroke, and strokes occurring in more than one territory. In addition, strokes were divided into anterior circulation stroke, which includes ischaemic lesions occurring in areas supplied by the anterior cerebral artery and the middle cerebral artery, and posterior circulation stroke, which refers to ischaemic lesions occurring in areas supplied by the vertebrobasilar artery system. A total of 698 patients underwent c-tcd and MRI. Of this total, 486 patients showed acute ischaemic lesions on MRI. Patients without acute ischaemic lesions were not evaluated. Patients with ischaemic lesions in both middle and posterior cerebral artery territory affecting the same hemisphere were additionally checked for having a fetal circle of Willis by searching typical morphological signs in magnetic resonance angiogram (MRA), as patients with an embryonic derivation of the posterior cerebral artery from the internal carotid artery and ischaemic lesions in both middle and posterior cerebral artery would not satisfy our definition of multiple ischaemic lesions referring to different vascular territories. Statistical analysis Continuous data are shown as mean and SD; categorical variables are expressed as absolute and relative frequencies. Differences in frequencies were tested by chi-squared test, those in continuous data by t-test. A two-tailed significance level of 0.05 was applied. All calculations were performed using the statistical software package SPSS version 15.0 (SPSS Inc., Chicago, IL, USA). Results A total of 698 patients were retrospectively included in the study over a period of 11 years (January 1995 to December 2005). A total of 212 patients were excluded because they did not show acute ischaemic lesions on MRI. The remaining 486 stroke patients were analyzed. Baseline characteristics of the study population are shown in Table 1. Frequency of different stroke subtypes and stroke patterns in patients with and without RLS is shown in Table 2. A RLS was detected by c-tcd in 165 patients (34.0%) with acute ischaemic lesions on MRI. Patients with RLS were younger than patients without RLS (P < 0.01). Groups did not differ in the prevalence of AF (P = 0.93). Stroke due to cardioembolism, which occurred in 107 of 486 patients and was rated according to the TOAST criteria, was highly associated with multiple ischaemic lesions on MRI (P < 0.01). Nine of 486 patients had ipsilateral ischaemic lesions in both middle and posterior cerebral artery territory and were therefore checked for an embryonic derivation of the posterior cerebral artery from the internal carotid artery. Three of these nine patients did not receive an MRA. Only one patient of the remaining five patients showed evidence of a fetal circle of Willis in MRA (0.02%). Exclusion of this patient and of three patients without MRA did not change our statistical results (Data shown in Table 3). Between the two groups of patients with and without RLS, differences in the occurrence of ischaemic lesions in areas supplied by the anterior cerebral artery (P = 0.33), middle cerebral artery (P = 0.53), and vertebrobasilar artery system (P = 0.67) did not reach statistical significance. In particular, there was no difference in the occurrence of multiple ischaemic lesion pattern in patients with RLS compared with stroke patients without RLS (P = 0.98). Additionally, we did not find a significant association between RLS and posterior circulation stroke (P = 0.67). Table 1 Baseline characteristics of the study population Study population (n = 486) Age (mean ± SD), years 64.2 ± 14.5 Atrial fibrillation, n (%) 57 (11.7) TOAST classification Large-artery atherosclerosis, n (%) 72 (14.8) Cardioembolism, n (%) 107 (22.0) Small-vessel occlusion, n (%) 118 (24.3) Stroke of other determined etiology, n (%) 38 (7.8) Stroke of undetermined etiology, n (%) 151 (31.8) Brain imaging features Circulation Anterior cerebral artery, n (%) 8 (1.6) Middle cerebral artery, n (%) 260 (53.5) Vertebrobasilar, n (%) 150 (30.9) Multiple ischaemic lesions, n (%) 68 (14.0) Anterior circulation stroke a, n (%) 268 (55.1) Posterior circulation stroke b, n (%) 150 (30.9) Fetal circle of Willis, n (%) 1 (0.2) a Anterior circulation stroke refers to ischaemic lesions occurring in areas supplied by the anterior cerebral artery and the middle cerebral artery. b Posterior circulation stroke refers to ischaemic lesions occurring in areas supplied by the vertebrobasilar artery system.

1080 R. Feurer et al. RLS (n = 165) No RLS (n = 321) P Age (mean ± SD), years 53.1 ± 15.7 61.4 ± 12.6 <0.01 Atrial fibrillation, n (%) 19 (11.5) 38 (11.8) 0.95 TOAST classification Large-artery atherosclerosis, n (%) 22 (13.3) 50 (15.6) 0.51 Cardioembolism, n (%) 35 (21.2) 72 (22.4) 0.76 Small-vessel occlusion, n (%) 31 (18.8) 87 (27.1) 0.04 Stroke of other determined etiology, n (%) 12 (7.3) 26 (8.1) 0.75 Stroke of undetermined etiology, n (%) 65 (39.4) 86 (26.8) < 0.01 Brain imaging features Circulation Anterior cerebral artery, n (%) 4 (2.4) 4 (1.2) 0.33 Middle cerebral artery, n (%) 85 (51.5) 175 (54.5) 0.53 Vertebrobasilar, n (%) 53 (32.1) 97 (30.2) 0.67 Multiple ischaemic lesions, n (%) 23 (13.9) 45 (14.0) 0.98 Anterior circulation stroke, n (%) 89 (53.9) 179 (55.8) 0.70 Posterior circulation stroke, n (%) 53 (32.1) 97 (30.2) 0.67 Table 2 Frequency of different stroke subtypes and stroke patterns in patients with and without RLS RLS, right-to-left-shunt. RLS (n = 164) No RLS (n = 318) P Brain imaging features circulation Anterior cerebral artery, n (%) 4 (2.4) 4 (1.2) 0.34 Middle cerebral artery, n (%) 85 (51.8) 175 (55.0) 0.50 Vertebrobasilar, n (%) 53 (32.3) 97 (30.5) 0.68 Multiple ischaemic lesions, n (%) 22 (13.4) 42 (13.2) 0.95 Anterior circulation stroke, n (%) 89 (54.3) 179 (56.3) 0.67 Posterior circulation stroke, n (%) 53 (32.3) 97 (30.5) 0.68 Table 3 Stroke patterns in patients with and without RLS after exclusion of four patients with possible fetal circle of Willis RLS, right-to-left-shunt. We then compared the subgroups of patients with the diagnosis of stroke with undetermined etiology with and without RLS and still did not find any association between an ischaemic lesion pattern that is considered as being typical for stroke due to cardiac embolism and the existence of RLS (P = 0.23). These data are shown in Table 4. Discussion We report on an unselected group of 486 stroke patients including 165 patients with RLS. Such patients often present with the problem of undetermined stroke etiology. To the best of our knowledge, this study describes ischaemic lesions on MRI in combination with RLS detection in the largest population of stroke patients to date. We did not find an association between a lesion pattern on MRI that is considered as being typical for stroke due to cardiac embolism and the existence of RLS. Different patterns on MRI have often been associated with stroke etiology [9,11] and the presence of multiple ischaemic lesions is highly suggestive of cardiac embolism. But despite extensive work-up, there RLS (n = 65) No RLS (n = 86) P Brain imaging features Circulation Anterior cerebral artery, n (%) 3 (4.6) 2 (2.3) 0.45 Middle cerebral artery, n (%) 33 (50.8) 50 (58.1) 0.37 Vertebrobasilar, n (%) 25 (38.5) 32 (37.2) 0.86 Multiple ischaemic lesions, n (%) 4 (6.2) 2 (2.3) 0.23 Anterior circulation stroke, n (%) 36 (55.4) 52 (60.5) 0.53 Posterior circulation stroke, n (%) 25 (38.5) 32 (37.2) 0.86 Table 4 Stroke patterns in patients with stroke of undetermined etiology with and without RLS RLS, right-to-left-shunt.

Lesion patterns in patients with cryptogenic stroke 1081 is frequent failure to detect an embolic source of stroke in patients with an embolic lesion pattern on MRI. The lack of an association in our findings between an ischaemic lesion pattern that is considered as being typical for stroke due to cardiac embolism and the existence of RLS may suggest that the contribution of stroke due to paradoxical embolism through PFO is overestimated. However, the sensitivity of this highly specific finding has not been defined precisely in large studies and therefore might be overrated. Furthermore, it has to be pointed out that many patients with cardioembolic stroke have single lesions, and the absence of multiple lesions does not necessarily argue against paradoxical embolism as the stroke mechanism. It is possible that paradoxical embolism is more probably to produce single lesions than, for example, endocarditis where the embolic material is being liberated with some frequency. A previous study of Yasaka et al. reported that only 3.24% of 136 PFO carriers fitted the criteria for definite paradoxical brain embolism, which were defined as the presence of deep vein thrombosis; the presence of neuroradiological features indicating embolic stroke, defined as large (>3.0 cm diameter) or cortical infarction; and the absence of other sources of emboli. They found that a considerable number of PFO carriers exhibited other sources of emboli such as a cardiac source, cerebral artery stenosis or aortic atheroma. Furthermore, they also reported that PFO carriers with concomitant AF shared clinical and neuroradiological features with stroke patients suffering only from AF without right-to-left-shunting [11]. This underlines the importance of other embolic mechanism besides paradoxical embolism in patients with PFO. Another study by Santamarina et al., which studied stroke pattern on DWI in cryptogenic stroke (N = 126) with respect to septal abnormalities, found that only the presence of PFO with concomitant ASA, but not isolated PFO, is associated with an embolic pattern on DWI, which was defined as the presence of scattered lesions or a cortical subcortical territorial lesion on MRI [9]. An embolic lesion pattern was more frequently seen in PFO with concomitant ASA (n = 37, 44%) as compared with PFO alone (n = 22, 26.2%). Therefore, PFO alone is less probably to cause stroke of cardioembolic origin, whereas the presence of PFO with ASA can be considered as being a risk for stroke of embolic mechanism. The relevance of PFO as embolic source has been further weakened by Mas et al. [6] who pointed out that PFO alone was not a predictor of recurrent cerebrovascular events. Our data did not provide support for the common theory of paradoxical embolism as a major cause of stroke in PFO carriers. Another often-cited argument for the theory of stroke due to paradoxical embolism is the frequently found association between RLS and cryptogenic stroke [5,7,15]. In a previous publication, we also found a significant association between RLS and cryptogenic stroke [16]. Also in accordance with other studies, patients with RLS were younger and were less probably to have traditional risk factors. A higher prevalence of PFO in young subjects has also been reported in the general population [2]. The association of RLS and cryptogenic stroke might therefore be coincidence. When adjusting for age, there was no longer a significant correlation between RLS and cryptogenic stroke in our study, which reduced the suggested statistical association between cryptogenic stroke and PFO. This is in line with a recently published population-based study which also describes a much weaker association between PFO and cryptogenic stroke than has been reported earlier [8,17]. As mentioned above, our study relies on ctcd for detection of RLS. Accordingly, other septal abnormalities such as ASA that can be detected on echocardiography should not be taken into account in our study. It has to be pointed out that ASA is a rare septal abnormality that has been found in only 1% of necropsies [18], whilst PFO occurs in approximately 25% of adults. In the PFO ASA study, which included 581 stroke patients, the incidence of ASA was much higher in the 267 patients with PFO as in the 314 patients without PFO (19.1% vs. 3.2% in those without PFO), showing on the one hand that PFO is strongly associated with ASA but on the other that the combination of both cardiac abnormalities does not occur very frequently (8.8%). Therefore, it seems to be important to focus on the contribution of PFO alone to paradoxical embolism. Conclusion Although our study was performed retrospectively, because of the large number of patients included our findings are very relevant to the common theory of paradoxical embolism as a major cause of stroke in PFO carriers. In particular, we did not find any association between a lesion pattern on MRI that is considered as being typical for stroke due to cardiac embolism and the existence of PFO. Our findings also underline the importance of excluding other causes of stroke in PFO carriers. Questions concerning secondary stroke prevention and the disputable benefit of PFO closure should be further investigated by prospective randomized clinical trials.

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