Isolated Pulmonary Arteriovenous Fistula Related Stroke with Large Vessel Occlusions Successfully Recanalized by Recombinant Tissue Plasminogen Activator： a case report

Isolated Pulmonary Arteriovenous Fistula Related Stroke with Large Vessel Occlusions Successfully Recanalized by Recombinant Tissue Plasminogen Activator： a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Isolated Pulmonary Arteriovenous Fistula Related Stroke with Large Vessel Occlusions Successfully Recanalized by Recombinant Tissue Plasminogen Activator： a case report Meixia Zhang, Xiaoling Pan, Hongfang Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3929888/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Pulmonary arteriovenous fistula (PAVF) induced paradoxical embolism leading to stroke is rare, especially large vessel occlusions. We presented a case of a 69-year-old female with middle cerebral artery (MCA) occlusion, initially responsive to thrombolysis. Case Presentation: The patient presented with sudden-onset aphasia, resolving partially but recurring. Imaging revealed left MCA occlusion and carotid stenosis. After recombinant tissue plasminogen activator use, left MCA completely recanalized and carotid stenosis dicovered. Trans‑cranial Doppler with positive bubble test discovered a significant right-to-left shunt and chest CT angiography suggested the formation of PAVFin the lower lobe of the right lung. Discussion: Although rare, PAVF is a potentially fatal but treatable cause of stroke. Even in large vessel occlusions patients, when considering embolic stroke of undetermined source, it is crucial to consider PAVF as a rare underlying cause. Embolic Stroke of Undetermined Source Recombinant tissue plasminogen activator Pulmonary arteriovenous fistula Figures Figure 1 Figure 2 Figure 3 Introduction Pulmonary arteriovenous fistulae (PAVF) is pathologic low-resistance, high-flow conduits between a pulmonary artery and vein without intervening capillaries, which can cause paradoxical embolism and result in acute ischemic stroke (AIS). Most PAVFs (about 70%) are multiple, congenital, and recognized as an important complication of hereditary hemorrhagic telangiectasia (HHT) ( 1 ). While, isolated PAVF related ischemic strokes very rarely cause proximal large vessel occlusions. According to the British Thoracic Society Clinical Statement, the safety of thrombolysis and clinical benefit is not established. Here we present a 69-year-old female with middle cerebral artery occlusion caused by paradoxical embolism of isolated PAVF, which was successfully recanalized by recombinant tissue plasminogen activator (r-TPA). Clinical Case A 69-year-old woman arrived at neurology department of our hospital with sudden-onset aphasia. The symptom had started 1h earlier and recovered within 30 minutes. But 10 minutes later, aphasia recurred with the National Institutes of Health Stroke Scale (NIHSS) score 5. As head non-contrast computed tomography (NCCT) showed no bleeding (Fig. 1 .A) and computed tomography angiography (CTA) showed the left M2 segment of the middle cerebral artery (MCA) occlusion (Fig. 1 .B) and common carotid artery (CCA) stenosis (Fig. 1 .C). The patient received intravenous thrombolysis therapy with r-TPA, which led to complete symptom resolution with an NIHSS score of 0. No further intravascular intervention was performed. On admission, she was afebrile with normal vital signs and general examination. She did not smoke, consume use alcohol, or use illicit drugs. There was no history of other vascular risk factors, including hypertension, diabetes mellitus, hyperlipemia. She had a history of breast fibroadenoma excisiony 3 years ago, invasive adenocarcinoma treated with lung resection 2 years ago, and lower limb arterial embolization last year. The following day, a detailed head MR revealed a small infarct in the left frontal lobe (Fig. 1 .D), with magnetic resonance (MR) angiography showing complete recanalization of the M2 segment of the MCA (Fig. 1 .E). One week later, there was no filling defect in the CCA (Fig. 1 .F), but a filling defect was observed in the left extracranial carotid artery (Fig. 1 .F). Blood routine, liver and kidney function, electrolytes, coagulation function, glycosylated hemoglobin, antiphospholipid syndrome antibodies, autoimmune antibody spectrum, tumor markers, and immunoglobulins showed no abnormalities. Lipid levels and homocysteine were within normal ranges. A 24-hour dynamic electrocardiogram showed no atrial flutter or fibrillation, and doppler ultrasound revealed minimal regurgitation in the aortic and tricuspid valves. Abdominal ultrasound, including liver, gallbladder, pancreas, spleen, urinary system, and breast, showed no abnormalities. Thyroid ultrasound indicated a nodule in the right lobe. Pelvic examination revealed postmenopausal uterus with intracavitary fluid, a cystic lesion in the left adnexal region, and no obvious mass in the right adnexal region. Doppler ultrasound of the lower limbs on the third day of admission suggested the possibility of deep vein thrombosis in the left leg. A transcranial Doppler with positive bubble test discovered a significant right-to-left shunt whether in rest or under valsalva condition (Grade III, Fig. 2 , A, B), raising the possibility of PAVF. Then, chest CT angiography suggested the formation of PAVF in the lower right lung (Fig. 2 , C). Then we put the patient on proper anti-coagulants to prevent ischemic stroke recurrence. Three months later, the patient underwent selective right pulmonary arterial angiography and confirmed the PAVF (Fig. 3 . A). PAVF embolization surgery with coils was successfully done and shunt blood flow disappeared (Fig. 3 . B). Discussion We presented a case of new onset cryptogenic stroke in an elderly patient with finally diagnosed isolated PAVF. Initially, the thrombus in the M2 segment of the left cerebral artery in this patient was thought to originate from stenosis of the ipsilateral carotid artery. Arterial-to-arterial embolism would be the primary consideration in terms of etiology. Given the patient's age, carotid artery stenosis is often associated with atherosclerosis. However, this patient lacked conventional arterial sclerosis risk factors, and after intravenous thrombolysis treatment, both the cerebral artery and the carotid artery were completely patent, suggesting that carotid artery stenosis was not true stenosis but rather thrombi in nature. Following a series of examinations during hospitalization, we identified paradoxical embolism in the patient. There was a PAVF in the lungs, and deep vein thrombosis was present in the lower limbs. Therefore, we ultimately considered that the cause of the stroke in this patient was PAVF. PAVF is a rare vascular anomaly characterized by an abnormal connection between the pulmonary artery and vein without capillaries in the lungs ( 2 ), leading to various degrees of right-to-left shunt. A 2012 analysis of data gathered using thoracic CT scanning show a prevalence rate of 38/100,000 and its incidence is twice as common in women( 3 ). Incidence of stroke has been reported range 9.3–70% in the PAVF patients with HTT, while this cannot be report in isolated PAVF patients.( 4 , 5 ) In particular, PAVF is an important cause of stroke in young adult ( 6 ). Another retrospectively study showed that the ratio of PAVF among AIS was 0.02% and the mean age was 57.5 years ( 7 ). In other word, the initial diagnosis of PAVF is even rarer in elderly stroke patients. PAVF-related ischemic strokes may be cortical or subcortical, but very rarely cause proximal large vessel occlusions. Only one of the case reports described a proximal (M1– middle cerebral artery) large vessel occlusion( 8 ), and another reported a right M2-MCA occlusion( 9 ). Besides, a case report described a PAVF mimicking vertebral artery dissection( 10 ). In this case, both CCA and M2-MCA had thrombi, and was thought to be arterial-to-arterial embolism at first. So, PAVF-related proximal large vessel occlusion may not rare, but not detected. At present, authoritative clinical practice guidelines of Intravenous thrombolytic therapy for PAVF-related paradoxical cerebral embolism are generally lacking. According to the British Thoracic Society Clinical Statement, but the safety of thrombolysis and clinical benefit is not established ( 2 ). Moreover, no cohort studies or case series to date have described use of Intravenous thrombolytics in AIS patients with PAVF. Only a handful of case reports described the use of thrombolytics( 6 ). In the 2005–2014 NIS study ( 7 ), patients with and without PAVF received intravenous thrombolytics at a similar rate (5.9% versus 5.8%), but they didn’t compare the bleeding complications. In general, the potential for bleeding complications in PAVF is an issue with thrombolytic therapy, the high risk of fatal pulmonary bleeding, epistaxis and gastrointestinal bleeding from comorbid telangiectasia, especially in cases of HHT ( 11 ). However, PAVF often had not been diagnosed until patients presented an ischemic stroke ( 6 ), thus it is not easy to diagnose PAVF at the time of stroke onset in real world. In our case, the patient received intravenous thrombolysis achieved a really good outcome without any bleeding complications. So, thrombolytic therapy might be a choice for patients with isolated PAVF within a time window. For secondary prevention of stroke, no clear statement for optimal antithrombotic management for cerebral embolism due to PAVF. In a recent study of 4271910 AIS patients with 822 diagnosed with PAVF, patients with PAVF were ≈ 2-fold more likely to be on long-term anticoagulation after adjusted for multiple confounders( 7 ). The most recent international guidelines for HHT management recommend that, when indicated, preventive antithrombotic regimens consist of either single antiplatelet or anticoagulant therapy, avoiding double antiplatelet therapy or combined antiplatelet and anticoagulant therapy( 12 ). While, the second stroke prophylactic measure for ischemic strokes caused by large artery atherosclerosis is double antiplatelet therapy. In our case, the patient combined with deep venous thrombosis on lower extremity ultrasound, we selected Rivaroxaban as secondary prevention strategy with on recurrence before embolization therapy. Endovascular embolization therapy is the preferred treatment for PAVF ( 1 , 11 ). PAVF treatment reduces risks from paradoxical emboli and symptoms exacerbated by right-to-left shunting and haemorrhage( 2 ). Embolisation is a safe intervention in experienced hands( 2 ). In the former, embolisation is indicated, If one of the following criteria is met: any (solitary or multiple) PAVF with a feeding artery with diameter of 2 mm or larger, measurable increase in size of PAVF, and paradoxical emboli or symptomatic hypoxemia. However, currently, embolization is recommended for all treatable PAVs regardless of feeding artery size, even for asymptomatic patients ( 1 ). Conclusion PAVF is a potentially fatal but treatable disease and acute ischemic stroke may be the first symptom. Even in large vessel occlusions patients, when considering embolic stroke of undetermined source, it is crucial to consider PAVF as a rare underlying cause. Abbreviations PAVF: pulmonary arteriovenous fistula AIS: acute ischemic stroke HHT: hereditary hemorrhagic telangiectasia r-TPA: recombinant tissue plasminogen activator NIHSS:National Institutes of Health Stroke Scale NCCT: non-contrast computed tomography CTA: computed tomography angiography CCA: common carotid artery MR: magnetic resonance Declarations Ethics approval and consent to participate The protocol was approved by human ethics committee of Affiliated Jinhua Hospital, Zhejiang University School of Medicine. Clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained from the patient. Consent for publication Written informed consent is obtained from patient. Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Competing interests The authors declare that they have no competing interests Funding Medical Science and Technology Project of Zhejiang Province, China (2023KY380) Authors' contributions Meixia Zhang analyzed and interpreted the patient data and was a major contributor in writing the manuscript. Xiaoling Pan analyzed the image of the patient. Hongfang Chen revised the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable References Müller-Hülsbeck S, Marques L, Maleux G, Osuga K, Pelage J-P, Wohlgemuth WA, et al. CIRSE Standards of Practice on Diagnosis and Treatment of Pulmonary Arteriovenous Malformations. CardioVascular and Interventional Radiology. 2020;43:353-61. Shovlin CL, Condliffe R, Donaldson JW, Kiely DG, Wort SJ. British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations. Thorax. 2017;72:1154-63. Nakayama M, Nawa T, Chonan T, Endo K, Morikawa S, Bando M, et al. Prevalence of pulmonary arteriovenous malformations as estimated by low-dose thoracic CT screening. Intern Med. 2012;51:1677-81. Kjeldsen AD, Oxhøj H, Andersen PE, Green A, Vase P. Prevalence of pulmonary arteriovenous malformations (PAVMs) and occurrence of neurological symptoms in patients with hereditary haemorrhagic telangiectasia (HHT). J Intern Med. 2000;248:255-62. Faughnan ME, Lui YW, Wirth JA, Pugash RA, Redelmeier DA, Hyland RH, et al. Diffuse pulmonary arteriovenous malformations: characteristics and prognosis. Chest. 2000;117:31-8. Topiwala KK, Patel SD, Saver JL, Streib CD, Shovlin CL. Ischemic Stroke and Pulmonary Arteriovenous Malformations: A Review. Neurology. 2022;98:188-98. Topiwala KK, Patel SD, Pervez M, Shovlin CL, Alberts MJ. Ischemic Stroke in Patients With Pulmonary Arteriovenous Fistulas. Stroke. 2021;52:e311-e5. Inoue S, Fujita A, Kurihara E, Sasayama T. Mechanical thrombectomy for acute paradoxical cerebral embolism due to pulmonary arteriovenous malformation: A case report and review of literature. Surg Neurol Int. 2023;14:13. Yassi N, Yan B, Dowling R, Mitchell PJ. A rare cause of embolic stroke in hereditary hemorrhagic telangiectasia. J Stroke Cerebrovasc Dis. 2014;23:1245-6. Isogai M, Suzuki T, Kato S, Taniguchi Y, Hasegawa H, Oishi M, et al. A Case of Paradoxical Cerebral Embolism Due to Pulmonary Arteriovenous Fistula Mimicking Vertebral Artery Dissection With Wallenberg Syndrome. Cureus. 2023;15:e34564. Lin G, Jiang P, Lou M. Thrombolysis in Ischemic Stroke Patients with Isolate Pulmonary Arteriovenous Malformations. J Stroke Cerebrovasc Dis. 2019;28:e68-e70. Faughnan ME, Mager JJ, Hetts SW, Palda VA, Lang-Robertson K, Buscarini E, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 2020;173:989-1001. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3929888","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":272703673,"identity":"90552e72-dd7f-4509-af5c-693b0ffb90c3","order_by":0,"name":"Meixia Zhang","email":"","orcid":"","institution":"Affiliated Jinhua Hospital, Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Meixia","middleName":"","lastName":"Zhang","suffix":""},{"id":272703674,"identity":"0a546273-3417-4ea1-ac24-721dafc775f0","order_by":1,"name":"Xiaoling Pan","email":"","orcid":"","institution":"Affiliated Jinhua Hospital, Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xiaoling","middleName":"","lastName":"Pan","suffix":""},{"id":272703675,"identity":"dce48e90-ecd9-4a1a-9732-09c23d381944","order_by":2,"name":"Hongfang Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIie3RPUvEMBjA8acU0uXRrg8U8SsUAuFAuX6VlkJdggqC3NAhcHBTwbXgp3BxPghkOvcbuh10sUMncbjB1MOxvXMTzB/yQsiPDAFwuf5iBOAPa6Ds1AMb9vFpBNcAXv1r4uPhbJqEz0uzu1808yp40+/X+/NMBctXgrIZf6QxN7zetHmFt8WVRJYpNI8Eph0lMUkRna10noAUXJIl9oQ8pSfI3cc3wbATfBZbctkdI5INZI4k+Q7S4RWcJrQtRIQbnSJ1wqvWjK+weJilZpyEdd5GuNAJhpL3n3tz8RTol21fjpOfMgXA7B+Zw2emRwFAYoffA5Qn3HW5XK7/1hfkWE6nMcQYJwAAAABJRU5ErkJggg==","orcid":"","institution":"Affiliated Jinhua Hospital, Zhejiang University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hongfang","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-02-05 04:30:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3929888/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3929888/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51181750,"identity":"f9ad3744-8a4b-439b-af86-1a031231e909","added_by":"auto","created_at":"2024-02-15 15:03:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":880356,"visible":true,"origin":"","legend":"\u003cp\u003eNon-contrast computed tomography showed no bleeding (A), computed tomography angiography showed the left M2 segment of the middle cerebral artery occlusion (B, blue arrow) and common carotid artery (CCA) stenosis (C, red arrow) before r-TPA use. MR diffusion-weighted imaging showed a small ischemic lesion in the front lobe (D, red circle), MR angiography showed the occlusion of left MCA (E, blue arrowhead) and the stenosis of left CCA (F, red arrowhead) were successfully recanalized. A filling defect was observed in the left extracranial carotid artery (F, yellow arrowhead).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3929888/v1/c2c6a199c6287cb0a2176b75.png"},{"id":51181749,"identity":"d62c604a-35a0-4f84-ad2a-0cc50af7b2eb","added_by":"auto","created_at":"2024-02-15 15:03:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":716877,"visible":true,"origin":"","legend":"\u003cp\u003eTrans‑cranial Doppler with positive bubble test discovered a significant right-to-left shunt whether in rest or under valsalva condition (A, B). Chest CT angiography (C, red circle) suggested the formation of pulmonary arteriovenous fistula (PAVF) in the lower lobe of the right lung.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3929888/v1/9a854de675ab4ca26e9d34db.png"},{"id":51181748,"identity":"20260233-8157-4eb0-9bf9-7883a6413c68","added_by":"auto","created_at":"2024-02-15 15:03:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":632543,"visible":true,"origin":"","legend":"\u003cp\u003ePretreatment angiography (A) suggested the formation of pulmonary arteriovenous fistula (PAVF) in the lower lobe of the right lung. The PAVF was embolized with coils and shunt blood flow disappeared (B).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3929888/v1/bc36646d33bcabbe32c43d46.png"},{"id":57701504,"identity":"845177e3-0ad6-4ad3-ac08-e77addfc9b6e","added_by":"auto","created_at":"2024-06-04 14:01:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3043673,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3929888/v1/f2a8b90d-4dbb-4e5d-81f9-ed936772a5d7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Isolated Pulmonary Arteriovenous Fistula Related Stroke with Large Vessel Occlusions Successfully Recanalized by Recombinant Tissue Plasminogen Activator： a case report","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePulmonary arteriovenous fistulae (PAVF) is pathologic low-resistance, high-flow conduits between a pulmonary artery and vein without intervening capillaries, which can cause paradoxical embolism and result in acute ischemic stroke (AIS). Most PAVFs (about 70%) are multiple, congenital, and recognized as an important complication of hereditary hemorrhagic telangiectasia (HHT) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). While, isolated PAVF related ischemic strokes very rarely cause proximal large vessel occlusions. According to the British Thoracic Society Clinical Statement, the safety of thrombolysis and clinical benefit is not established. Here we present a 69-year-old female with middle cerebral artery occlusion caused by paradoxical embolism of isolated PAVF, which was successfully recanalized by recombinant tissue plasminogen activator (r-TPA).\u003c/p\u003e"},{"header":"Clinical Case","content":"\u003cp\u003eA 69-year-old woman arrived at neurology department of our hospital with sudden-onset aphasia. The symptom had started 1h earlier and recovered within 30 minutes. But 10 minutes later, aphasia recurred with the National Institutes of Health Stroke Scale (NIHSS) score 5. As head non-contrast computed tomography (NCCT) showed no bleeding (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.A) and computed tomography angiography (CTA) showed the left M2 segment of the middle cerebral artery (MCA) occlusion (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.B) and common carotid artery (CCA) stenosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.C). The patient received intravenous thrombolysis therapy with r-TPA, which led to complete symptom resolution with an NIHSS score of 0. No further intravascular intervention was performed.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOn admission, she was afebrile with normal vital signs and general examination. She did not smoke, consume use alcohol, or use illicit drugs. There was no history of other vascular risk factors, including hypertension, diabetes mellitus, hyperlipemia. She had a history of breast fibroadenoma excisiony 3 years ago, invasive adenocarcinoma treated with lung resection 2 years ago, and lower limb arterial embolization last year.\u003c/p\u003e \u003cp\u003eThe following day, a detailed head MR revealed a small infarct in the left frontal lobe (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.D), with magnetic resonance (MR) angiography showing complete recanalization of the M2 segment of the MCA (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.E). One week later, there was no filling defect in the CCA (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.F), but a filling defect was observed in the left extracranial carotid artery (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.F).\u003c/p\u003e \u003cp\u003eBlood routine, liver and kidney function, electrolytes, coagulation function, glycosylated hemoglobin, antiphospholipid syndrome antibodies, autoimmune antibody spectrum, tumor markers, and immunoglobulins showed no abnormalities. Lipid levels and homocysteine were within normal ranges. A 24-hour dynamic electrocardiogram showed no atrial flutter or fibrillation, and doppler ultrasound revealed minimal regurgitation in the aortic and tricuspid valves. Abdominal ultrasound, including liver, gallbladder, pancreas, spleen, urinary system, and breast, showed no abnormalities. Thyroid ultrasound indicated a nodule in the right lobe. Pelvic examination revealed postmenopausal uterus with intracavitary fluid, a cystic lesion in the left adnexal region, and no obvious mass in the right adnexal region. Doppler ultrasound of the lower limbs on the third day of admission suggested the possibility of deep vein thrombosis in the left leg.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA transcranial Doppler with positive bubble test discovered a significant right-to-left shunt whether in rest or under valsalva condition (Grade III, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, A, B), raising the possibility of PAVF. Then, chest CT angiography suggested the formation of PAVF in the lower right lung (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, C). Then we put the patient on proper anti-coagulants to prevent ischemic stroke recurrence. Three months later, the patient underwent selective right pulmonary arterial angiography and confirmed the PAVF (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. A). PAVF embolization surgery with coils was successfully done and shunt blood flow disappeared (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. B).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe presented a case of new onset cryptogenic stroke in an elderly patient with finally diagnosed isolated PAVF. Initially, the thrombus in the M2 segment of the left cerebral artery in this patient was thought to originate from stenosis of the ipsilateral carotid artery. Arterial-to-arterial embolism would be the primary consideration in terms of etiology. Given the patient's age, carotid artery stenosis is often associated with atherosclerosis. However, this patient lacked conventional arterial sclerosis risk factors, and after intravenous thrombolysis treatment, both the cerebral artery and the carotid artery were completely patent, suggesting that carotid artery stenosis was not true stenosis but rather thrombi in nature. Following a series of examinations during hospitalization, we identified paradoxical embolism in the patient. There was a PAVF in the lungs, and deep vein thrombosis was present in the lower limbs. Therefore, we ultimately considered that the cause of the stroke in this patient was PAVF.\u003c/p\u003e \u003cp\u003ePAVF is a rare vascular anomaly characterized by an abnormal connection between the pulmonary artery and vein without capillaries in the lungs (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), leading to various degrees of right-to-left shunt. A 2012 analysis of data gathered using thoracic CT scanning show a prevalence rate of 38/100,000 and its incidence is twice as common in women(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Incidence of stroke has been reported range 9.3\u0026ndash;70% in the PAVF patients with HTT, while this cannot be report in isolated PAVF patients.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) In particular, PAVF is an important cause of stroke in young adult (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Another retrospectively study showed that the ratio of PAVF among AIS was 0.02% and the mean age was 57.5 years (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In other word, the initial diagnosis of PAVF is even rarer in elderly stroke patients.\u003c/p\u003e \u003cp\u003ePAVF-related ischemic strokes may be cortical or subcortical, but very rarely cause proximal large vessel occlusions. Only one of the case reports described a proximal (M1\u0026ndash; middle cerebral artery) large vessel occlusion(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), and another reported a right M2-MCA occlusion(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Besides, a case report described a PAVF mimicking vertebral artery dissection(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In this case, both CCA and M2-MCA had thrombi, and was thought to be arterial-to-arterial embolism at first. So, PAVF-related proximal large vessel occlusion may not rare, but not detected.\u003c/p\u003e \u003cp\u003eAt present, authoritative clinical practice guidelines of Intravenous thrombolytic therapy for PAVF-related paradoxical cerebral embolism are generally lacking. According to the British Thoracic Society Clinical Statement, but the safety of thrombolysis and clinical benefit is not established (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Moreover, no cohort studies or case series to date have described use of Intravenous thrombolytics in AIS patients with PAVF. Only a handful of case reports described the use of thrombolytics(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In the 2005\u0026ndash;2014 NIS study (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), patients with and without PAVF received intravenous thrombolytics at a similar rate (5.9% versus 5.8%), but they didn\u0026rsquo;t compare the bleeding complications. In general, the potential for bleeding complications in PAVF is an issue with thrombolytic therapy, the high risk of fatal pulmonary bleeding, epistaxis and gastrointestinal bleeding from comorbid telangiectasia, especially in cases of HHT (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, PAVF often had not been diagnosed until patients presented an ischemic stroke (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), thus it is not easy to diagnose PAVF at the time of stroke onset in real world. In our case, the patient received intravenous thrombolysis achieved a really good outcome without any bleeding complications. So, thrombolytic therapy might be a choice for patients with isolated PAVF within a time window.\u003c/p\u003e \u003cp\u003eFor secondary prevention of stroke, no clear statement for optimal antithrombotic management for cerebral embolism due to PAVF. In a recent study of 4271910 AIS patients with 822 diagnosed with PAVF, patients with PAVF were \u0026asymp;\u0026thinsp;2-fold more likely to be on long-term anticoagulation after adjusted for multiple confounders(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The most recent international guidelines for HHT management recommend that, when indicated, preventive antithrombotic regimens consist of either single antiplatelet or anticoagulant therapy, avoiding double antiplatelet therapy or combined antiplatelet and anticoagulant therapy(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). While, the second stroke prophylactic measure for ischemic strokes caused by large artery atherosclerosis is double antiplatelet therapy. In our case, the patient combined with deep venous thrombosis on lower extremity ultrasound, we selected Rivaroxaban as secondary prevention strategy with on recurrence before embolization therapy.\u003c/p\u003e \u003cp\u003eEndovascular embolization therapy is the preferred treatment for PAVF (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). PAVF treatment reduces risks from paradoxical emboli and symptoms exacerbated by right-to-left shunting and haemorrhage(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Embolisation is a safe intervention in experienced hands(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In the former, embolisation is indicated, If one of the following criteria is met: any (solitary or multiple) PAVF with a feeding artery with diameter of 2 mm or larger, measurable increase in size of PAVF, and paradoxical emboli or symptomatic hypoxemia. However, currently, embolization is recommended for all treatable PAVs regardless of feeding artery size, even for asymptomatic patients (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePAVF is a potentially fatal but treatable disease and acute ischemic stroke may be the first symptom. Even in large vessel occlusions patients, when considering embolic stroke of undetermined source, it is crucial to consider PAVF as a rare underlying cause.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePAVF: pulmonary arteriovenous fistula\u003c/p\u003e\n\u003cp\u003eAIS: acute ischemic stroke\u003c/p\u003e\n\u003cp\u003eHHT: hereditary hemorrhagic telangiectasia\u003c/p\u003e\n\u003cp\u003er-TPA: recombinant tissue plasminogen activator\u003c/p\u003e\n\u003cp\u003eNIHSS:National Institutes of Health Stroke Scale\u003c/p\u003e\n\u003cp\u003eNCCT: non-contrast computed tomography\u003c/p\u003e\n\u003cp\u003eCTA: computed tomography angiography\u003c/p\u003e\n\u003cp\u003eCCA: common carotid artery\u003c/p\u003e\n\u003cp\u003eMR: magnetic resonance\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The protocol was approved by human ethics committee of Affiliated Jinhua Hospital, Zhejiang University School of Medicine. Clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Consent for publication\u003c/p\u003e\n\u003cp\u003eWritten informed consent is obtained from patient.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Availability of data and materials\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Competing interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Funding\u003c/p\u003e\n\u003cp\u003eMedical Science and Technology Project of Zhejiang Province, China (2023KY380)\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eMeixia Zhang analyzed and interpreted the patient data and was a major contributor in writing the manuscript. Xiaoling Pan analyzed the image of the patient. Hongfang Chen revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Acknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eM\u0026uuml;ller-H\u0026uuml;lsbeck S, Marques L, Maleux G, Osuga K, Pelage J-P, Wohlgemuth WA, et al. CIRSE Standards of Practice on Diagnosis and Treatment of Pulmonary Arteriovenous Malformations. CardioVascular and Interventional Radiology. 2020;43:353-61.\u003c/li\u003e\n\u003cli\u003eShovlin CL, Condliffe R, Donaldson JW, Kiely DG, Wort SJ. British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations. Thorax. 2017;72:1154-63.\u003c/li\u003e\n\u003cli\u003eNakayama M, Nawa T, Chonan T, Endo K, Morikawa S, Bando M, et al. Prevalence of pulmonary arteriovenous malformations as estimated by low-dose thoracic CT screening. Intern Med. 2012;51:1677-81.\u003c/li\u003e\n\u003cli\u003eKjeldsen AD, Oxh\u0026oslash;j H, Andersen PE, Green A, Vase P. Prevalence of pulmonary arteriovenous malformations (PAVMs) and occurrence of neurological symptoms in patients with hereditary haemorrhagic telangiectasia (HHT). J Intern Med. 2000;248:255-62.\u003c/li\u003e\n\u003cli\u003eFaughnan ME, Lui YW, Wirth JA, Pugash RA, Redelmeier DA, Hyland RH, et al. Diffuse pulmonary arteriovenous malformations: characteristics and prognosis. Chest. 2000;117:31-8.\u003c/li\u003e\n\u003cli\u003eTopiwala KK, Patel SD, Saver JL, Streib CD, Shovlin CL. Ischemic Stroke and Pulmonary Arteriovenous Malformations: A Review. Neurology. 2022;98:188-98.\u003c/li\u003e\n\u003cli\u003eTopiwala KK, Patel SD, Pervez M, Shovlin CL, Alberts MJ. Ischemic Stroke in Patients With Pulmonary Arteriovenous Fistulas. Stroke. 2021;52:e311-e5.\u003c/li\u003e\n\u003cli\u003eInoue S, Fujita A, Kurihara E, Sasayama T. Mechanical thrombectomy for acute paradoxical cerebral embolism due to pulmonary arteriovenous malformation: A case report and review of literature. Surg Neurol Int. 2023;14:13.\u003c/li\u003e\n\u003cli\u003eYassi N, Yan B, Dowling R, Mitchell PJ. A rare cause of embolic stroke in hereditary hemorrhagic telangiectasia. J Stroke Cerebrovasc Dis. 2014;23:1245-6.\u003c/li\u003e\n\u003cli\u003eIsogai M, Suzuki T, Kato S, Taniguchi Y, Hasegawa H, Oishi M, et al. A Case of Paradoxical Cerebral Embolism Due to Pulmonary Arteriovenous Fistula Mimicking Vertebral Artery Dissection With Wallenberg Syndrome. Cureus. 2023;15:e34564.\u003c/li\u003e\n\u003cli\u003eLin G, Jiang P, Lou M. Thrombolysis in Ischemic Stroke Patients with Isolate Pulmonary Arteriovenous Malformations. J Stroke Cerebrovasc Dis. 2019;28:e68-e70.\u003c/li\u003e\n\u003cli\u003eFaughnan ME, Mager JJ, Hetts SW, Palda VA, Lang-Robertson K, Buscarini E, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 2020;173:989-1001.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Embolic Stroke of Undetermined Source, Recombinant tissue plasminogen activator, Pulmonary arteriovenous fistula","lastPublishedDoi":"10.21203/rs.3.rs-3929888/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3929888/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Pulmonary arteriovenous fistula (PAVF) induced paradoxical embolism leading to stroke is rare, especially large vessel occlusions. We presented a case of a 69-year-old female with middle cerebral artery (MCA) occlusion, initially responsive to thrombolysis.\u003c/p\u003e\n\u003cp\u003eCase Presentation: The patient presented with sudden-onset aphasia, resolving partially but recurring. Imaging revealed left MCA occlusion and carotid stenosis. After recombinant tissue plasminogen activator use, left MCA completely recanalized and carotid stenosis dicovered. Trans‑cranial Doppler with positive bubble test discovered a significant right-to-left shunt and chest CT angiography suggested the formation of PAVFin the lower lobe of the right lung.\u003c/p\u003e\n\u003cp\u003eDiscussion: Although rare, PAVF is a potentially fatal but treatable cause of stroke. Even in large vessel occlusions patients, when considering embolic stroke of undetermined source, it is crucial to consider PAVF as a rare underlying cause.\u003c/p\u003e","manuscriptTitle":"Isolated Pulmonary Arteriovenous Fistula Related Stroke with Large Vessel Occlusions Successfully Recanalized by Recombinant Tissue Plasminogen Activator： a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-15 15:03:14","doi":"10.21203/rs.3.rs-3929888/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bc1a9830-3cf7-451b-9635-9208ec57527d","owner":[],"postedDate":"February 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-04T13:53:44+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-15 15:03:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3929888","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3929888","identity":"rs-3929888","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}