Provoked Right-to-Left Shunt in Patent Foramen Ovale Associates With Ischemic Stroke in Posterior Circulation Bum Joon Kim, MD; Na-Young Kim, MD; Dong-Wha Kang, MD, PhD; Jong S. Kim, MD, PhD; Sun U. Kwon, MD, PhD Background and Purpose—Right-to-left shunt (RLS) via the patent foramen ovale is an important cause of cryptogenic stroke. The Valsalva maneuver provokes or enhances RLS, but RLS can also occur during normal respiration. This study examined whether the ischemic lesion pattern differs depending on the character of RLS. Methods—All consecutive patients with a patent foramen ovale (diagnosed by transesophageal echocardiography) who had a cryptogenic stroke and underwent transcranial Doppler–patent foramen ovale test (monitoring of microbubbles in the right middle cerebral artery by transcranial Doppler after hand-agitated saline injection) were divided according to whether RLS was constant (microbubbles detected both at baseline and after the Valsalva maneuver) or provoked (microbubbles detected only after the Valsalva maneuver). The groups were compared in terms of clinical and imaging characteristics. Results—Seventy-six patients met the eligibility criteria: 50 had constant RLS and 26 had provoked RLS. Provoked RLS patients were significantly younger. The ischemic lesions in provoked RLS patients were located predominantly in the vertebro-basilar circulation (73.1% versus 28.0%; P=0.002), whereas constant RLS patients were more likely to have multicirculatory lesions (16.0% versus 0.0%; P=0.045). After adjusting for confounders, provoked RLS associated independently with a vertebro-basilar lesion location (OR=3.306; P=0.03). Conclusions—The predominance of posterior-circulatory infarction in provoked RLS patients suggests that the Valsalva maneuver may promote RLS and paradoxical embolization to the posterior circulation. (Stroke. 2014;45:3707-3710.) Key Words: cerebral infarction ◼ patent foramen ovale ◼ Valsalva maneuver
P
aradoxical embolization through the patent foramen ovale (PFO) is considered to be one of the main mechanisms of cryptogenic stroke in patients with PFO (PFO-stroke). The mechanism relates to the incomplete closure of the intra-atrial septum, which allows right-to-left shunt (RLS). Because RLS increases when the pressure gradient between the 2 atria is increased,1 the detection of PFO by transesophageal echocardiography (TEE) or transcranial Doppler (TCD) studies is enhanced when the Valsalva maneuver is performed.2 Detection of microbubbles by TCD after agitated saline injection (TCD-PFO test) is a useful tool to detect PFO. In some patients, the microbubbles are detected only after the Valsalva maneuver, whereas in others, they are also detected during normal respiration. The response of RLS to the Valsalva maneuver may contribute to this difference in microbubble detection. Notably, it has also been shown that the Valsalva maneuver increases the blood flow in the vertebro-basilar circulation and that the predominance of posterior circulatory infarction in PFO-stroke may be explained, at least in part, by this mechanism.3
These 2 observations led us to hypothesize that patients with PFO-stroke whose RLS persists in normal respiration (ie, constant-RLS) will differ from patients with PFO-stroke whose RLS manifests only on the Valsalva maneuver (ie, provoked-RLS) in terms of ischemic lesion distribution.
Methods Subjects This study was performed in parallel with a previously published study with a slight modification of the inclusion criteria and study period.4 Briefly, all consecutive patients with PFO-stroke who were admitted to the Asan Medical Center between January 2005 and June 2014 were identified retrospectively. PFO-stroke was tentatively defined as cryptogenic stroke in patients with a PFO who lacked coexisting potential embolic sources, namely, significant stenosis at the corresponding artery, high-risk cardioembolism, or evidence of other arteriopathy. Patients classified as undetermined etiology – negative, according to the Trials of Org 10 172 in Acute Stroke Treatment classification or patients highly suspicious of cryptogenic embolic source, were regarded as cryptogenic stroke patients. Only the patients with PFO definitely observed from TEE and underwent a TCD-PFO test
Received September 17, 2014; final revision received September 17, 2014; accepted September 24, 2014. From the Department of Neurology, Asan Medical Center, Seoul, Korea. The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.007453/-/DC1. Correspondence to Sun U. Kwon, MD, PhD, Department of Neurology, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul, Korea. E-mail [email protected] © 2014 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.007453
Downloaded from http://stroke.ahajournals.org/ at University of Otago Library on July 22, 2015 3707
3708 Stroke December 2014 were included. PFO was diagnosed on the basis of TEE findings and PFO >2 mm in diameter combined with or without atrial septal aneurysm or hypermobile septum was regarded as medium- or high-risk PFO, respectively.4 The demographic and risk factors were obtained from a prospectively collected stroke registry. RoPE score which represents the possibility of PFO-stroke was also calculated.5 This study was approved by the Institutional Review Board of our center. Informed consent was not obtained because of the retrospective design of the study.
TCD-PFO Test and Neuroimaging The TCD-PFO test, diffusion-weighted image, and magnetic resonance angiography were performed within 2 weeks of symptom onset. Normal saline that had been agitated with 1 cc of room air was injected into the antecubital vein and the microbubbles in the right middle cerebral artery were monitored by the M-Mode of TCD (ST3 TCD; Spencer Technologies, WA). The numbers of microbubbles at baseline and after the Valsalva maneuver (40 mm Hg calibrated respiratory strain for 10 seconds) were counted. A patient was deemed to have constant RLS or provoked RLS if microbubbles were detected both at baseline and after the Valsalva maneuver or only after the Valsalva maneuver, respectively. The diffusion-weighted image lesion pattern was classified similarly as in the previous study.4 The pertinent vascular territory of the ischemic lesions was classified as right-carotid, left-carotid, vertebro-basilar, or multicirculatory considering the results of magnetic resonance angiography.
Statistical Analysis The constant RLS and provoked RLS groups were compared in terms of clinical and imaging variables by chi-square, Fisher exact test, or
Student’s t test, depending on the nature of the variable. Binary logistic multivariate analysis was performed to test whether provoked RLS associated independently with lesions in the vertebro-basilar circulatory after adjustment for potential confounders (P
P
aradoxical embolization through the patent foramen ovale (PFO) is considered to be one of the main mechanisms of cryptogenic stroke in patients with PFO (PFO-stroke). The mechanism relates to the incomplete closure of the intra-atrial septum, which allows right-to-left shunt (RLS). Because RLS increases when the pressure gradient between the 2 atria is increased,1 the detection of PFO by transesophageal echocardiography (TEE) or transcranial Doppler (TCD) studies is enhanced when the Valsalva maneuver is performed.2 Detection of microbubbles by TCD after agitated saline injection (TCD-PFO test) is a useful tool to detect PFO. In some patients, the microbubbles are detected only after the Valsalva maneuver, whereas in others, they are also detected during normal respiration. The response of RLS to the Valsalva maneuver may contribute to this difference in microbubble detection. Notably, it has also been shown that the Valsalva maneuver increases the blood flow in the vertebro-basilar circulation and that the predominance of posterior circulatory infarction in PFO-stroke may be explained, at least in part, by this mechanism.3
These 2 observations led us to hypothesize that patients with PFO-stroke whose RLS persists in normal respiration (ie, constant-RLS) will differ from patients with PFO-stroke whose RLS manifests only on the Valsalva maneuver (ie, provoked-RLS) in terms of ischemic lesion distribution.
Methods Subjects This study was performed in parallel with a previously published study with a slight modification of the inclusion criteria and study period.4 Briefly, all consecutive patients with PFO-stroke who were admitted to the Asan Medical Center between January 2005 and June 2014 were identified retrospectively. PFO-stroke was tentatively defined as cryptogenic stroke in patients with a PFO who lacked coexisting potential embolic sources, namely, significant stenosis at the corresponding artery, high-risk cardioembolism, or evidence of other arteriopathy. Patients classified as undetermined etiology – negative, according to the Trials of Org 10 172 in Acute Stroke Treatment classification or patients highly suspicious of cryptogenic embolic source, were regarded as cryptogenic stroke patients. Only the patients with PFO definitely observed from TEE and underwent a TCD-PFO test
Received September 17, 2014; final revision received September 17, 2014; accepted September 24, 2014. From the Department of Neurology, Asan Medical Center, Seoul, Korea. The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.007453/-/DC1. Correspondence to Sun U. Kwon, MD, PhD, Department of Neurology, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul, Korea. E-mail [email protected] © 2014 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.007453
Downloaded from http://stroke.ahajournals.org/ at University of Otago Library on July 22, 2015 3707
3708 Stroke December 2014 were included. PFO was diagnosed on the basis of TEE findings and PFO >2 mm in diameter combined with or without atrial septal aneurysm or hypermobile septum was regarded as medium- or high-risk PFO, respectively.4 The demographic and risk factors were obtained from a prospectively collected stroke registry. RoPE score which represents the possibility of PFO-stroke was also calculated.5 This study was approved by the Institutional Review Board of our center. Informed consent was not obtained because of the retrospective design of the study.
TCD-PFO Test and Neuroimaging The TCD-PFO test, diffusion-weighted image, and magnetic resonance angiography were performed within 2 weeks of symptom onset. Normal saline that had been agitated with 1 cc of room air was injected into the antecubital vein and the microbubbles in the right middle cerebral artery were monitored by the M-Mode of TCD (ST3 TCD; Spencer Technologies, WA). The numbers of microbubbles at baseline and after the Valsalva maneuver (40 mm Hg calibrated respiratory strain for 10 seconds) were counted. A patient was deemed to have constant RLS or provoked RLS if microbubbles were detected both at baseline and after the Valsalva maneuver or only after the Valsalva maneuver, respectively. The diffusion-weighted image lesion pattern was classified similarly as in the previous study.4 The pertinent vascular territory of the ischemic lesions was classified as right-carotid, left-carotid, vertebro-basilar, or multicirculatory considering the results of magnetic resonance angiography.
Statistical Analysis The constant RLS and provoked RLS groups were compared in terms of clinical and imaging variables by chi-square, Fisher exact test, or
Student’s t test, depending on the nature of the variable. Binary logistic multivariate analysis was performed to test whether provoked RLS associated independently with lesions in the vertebro-basilar circulatory after adjustment for potential confounders (P
