Internal carotid artery dissection in a patient with Parkinson’s disease after COVID-19 infection

Internal carotid artery dissection in a patient with Parkinson’s disease after COVID-19 infection | 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 Internal carotid artery dissection in a patient with Parkinson’s disease after COVID-19 infection Takanobu Okubo, Hidehiro Ishikawa, Keita Matsuura, Asako Tamura, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4407014/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 Internal carotid artery (ICA) dissection is a relatively rare cause of acute ischemic stroke. Stretching and compression of the ICA owing to sudden acceleration, deceleration, and rotational forces are risk factors for ICA dissection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to trigger an inflammatory response exacerbating endothelial dysfunction leading to arterial dissection. Although levodopa-induced cervical dyskinesia in Parkinson’s disease often manifests as choreiform movement, dissection has not been reported in such patients. Case Presentation: A 51-year-old man with Parkinson’s disease (PD) presented with gradually worsening neck pain and transient aphasia one week after mild coronavirus disease 2019 (COVID-19) infection. The patient presented with levodopa-induced cervical dyskinesia. Magnetic resonance imaging revealed acute ischemic stroke in the left parietal lobe and an intramural hematoma with an area of stenosis in the left ICA. The patient was diagnosed with a left ICA artery dissection. Conclusions The quick cervical movement under COVID-19-related vessel wall vulnerability may cause ICA dissection. Although patients with PD often have neck pain, ICA dissection should be included as a differential diagnosis if the patient has COVID-19. Internal carotid artery dissection COVID-19 Parkinson’s disease dyskinesia stroke Figures Figure 1 Figure 2 Figure 3 Background Internal carotid artery (ICA) dissection has been reported to be a rare disease; however, the annual incidence rate has increased from 2.30 per 100,000 person-years to 8.93 per person-years over the past 19 years because of the evolution of vascular imaging techniques [ 1 ]. However, the actual incidence may be higher in asymptomatic patients. Prior trauma is identified in only up to 40% of cases, and most traumatic events (up to 90%) are mild or trivial insults [ 2 ]. Stretching and compression of the ICA owing to sudden acceleration, deceleration, or rotational forces can increase the risk of dissection [ 3 ] . Recently, it has been proposed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggers an inflammatory response that exacerbates endothelial dysfunction leading to dissection [ 4 ] [ 5 ] [ 6 ] [ 7 ]. Although the cause of coronavirus disease 2019 (COVID-19) and arterial dissection is uncertain, 42 patients with arterial dissection have been reported in a recent review [ 4 ]. Here, we describe a patient with Parkinson’s disease (PD) who developed levodopa-induced neck dyskinesia and cerebral infarction due to ICA dissection during COVID-19. Case presentation A 51-year-old man with levodopa-induced neck dyskinesia presented to the neurology clinic with gradually worsening neck pain 1 week after a mild COVID-19 infection. He had experienced transient motor aphasia for approximately 2–3 hours the previous day. He was clinically diagnosed with Parkinson’s disease (PD) 6 years ago based on pre-established criteria [ 8 ]. The initial signs of PD, such as bradykinesia, rigidity, and resting tremor, were observed at 44 years of age. Neuromelanin imaging, 123 I-metaiodobenzylguanidine myocardial scintigraphy, and dopamine transporter imaging supported the diagnosis (Fig. 1 , A-E) [ 9 ]. Levodopa improved his symptoms, but a dose increase and additional medication were needed because of the progression of PD. He exhibited neck dyskinesia during the on-state and complained of neck pain due to cervical spondylosis since the past year (Fig. 1 F). The site of neck pain changed slightly to left side 1 week before the presentation. He did not have any vascular risk factors such as smoking, hypertension, hyperlipidemia, or diabetes. No family history of arterial dissection, collagen vascular disease, inherited arteriopathies, fibromuscular dysplasia, extreme vessel tortuosity, moyamoya disease, or cystic medial necrosis was noted. The PD medication included levodopa/carbidopa (150/15 mg, 5 times a day), entacapone (100 mg, twice a day), selegiline (2.5 mg twice a day), and ropinirole tape (16 mg). His neurological findings were normal except for parkinsonism. The Mini-Mental State Examination score was 26 (lost 4 points in series 7). Laboratory tests including protein C, protein S, antithrombin III, ferritin, D-dimer, and autoimmune antibody screening were normal. C-reactive protein was slightly elevated (0.46 mg/dL, normal < 0.14 mg/dL). Brain computed tomography (CT) revealed a low-density area in the left parietal lobe (Fig. 2 A). Elongated styloid processes were not observed. Additional brain magnetic resonance imaging (MRI) detected acute infarctions in the left hemisphere (Fig. 2 , B and C), and an intramural hematoma was observed in an area of stenosis in the left ICA (Fig. 2 , D-G). The patient was admitted with left ICA dissection [ 10 ]. Dissection occurred approximately 2 cm proximal to the base of the skull (Fig. 2 , H and I). Antiplatelet therapy with 100 mg/day aspirin was initiated. Amantadine (100 mg/day) was initiated to treat the levodopa-induced dyskinesia. The patient’s dyskinesia and neck pain improved gradually. The patient was discharged 10 days later without any sequelae and returned to work. On follow-up MRI performed 6 months later, the intramural hematoma had diminished (Fig. 3 ). Antiplatelet therapy was terminated based on literature [ 2 ]. DISCUSSION To date, neck dyskinesia-induced ICA dissection has not been reported in patients with PD. A previous report described that sudden violent neck tics can cause cervical artery dissection [ 11 ]. The mechanical stress of violent jerking motions of the head and neck has been reported as a potential causative factor of ICA dissection [ 3 ]. In the present case, however, we speculated that COVID-19 was a risk factor for the onset of ICA dissection, in addition to the mechanical stress of cervical choreiform movement due to dyskinesia. According to a recent review, 42 cases of arterial dissection associated with COVID-19 were reported as of October 2021. Aortic dissection was the most common (52.3%), followed by coronary artery dissection (23.8%) and, less commonly, cerebral, vertebral and ICA dissections (7.1% each) [ 4 ]. About 50% of the patients were aged between 45 and 59 years and the period between the onset of COVID-19-like symptoms and presentation to the hospital with symptoms/signs of arterial dissection ranged from 1 day to 8 weeks [ 4 ]. The age and onset date in the present case were consistent with previous data. Common risk factors included hypertension (60%), diabetes mellitus (15%), dyslipidemia (15%), and smoking (15%). No risk factors were identified in 47.6% of the patients as with the present case. Arterial dissection in patients with COVID-19 may occur secondary to an exaggerated inflammatory response that causes endothelial dysfunction. SARS-CoV-2 infects the host using the angiotensin-converting enzyme 2 receptor, which is expressed not only in the lungs and heart but also in endothelial cells [ 6 ]. Thus, endothelium throughout the body is at risk of SARS-CoV-2 [ 12 ]. The presence of SARS-CoV-2 viral particles in the capillary endothelia of a frontal lobe specimen was confirmed in an autopsy case [ 13 ]. Cervical artery dissection is rare; however, early detection and therapeutic intervention are crucial because dissecting aneurysm rupture or stroke can be life-threatening [ 5 ]. Although the relationship between ICA dissection and COVID-19 is uncertain, a previous case report of ICA dissection after mild COVID-19 supports this causative association [ 7 ]. In that report, acute neck pain occurred when the patient’s head was hyperextended during an oropharyngeal swab test for COVID-19 during follow-up, and MRI revealed ICA dissection. Although the timing of stroke symptoms and neck pain in this case was highly suggestive of a causal link between neck extension and the onset of dissection, the site of dissection was atypical for traumatic ICA dissection. The dissection might have occurred because of mechanical stress at the site of endothelial damage due to SARS-CoV-2 in our case and the previous case. We believe that the main mechanical stress in our case was levodopa-induced dyskinesia of the neck. Coughing and sneezing might be the factors that induced dissection. Amantadine (an NMDA receptor antagonist), which is reported to be the most effective treatment for levodopa-induced dyskinesia, improved neck dyskinesia [ 14 ]. Pain is highly prevalent in patients with PD, and the neck is one of the most common sites [ 15 ]. Cervical spinal deformity and forward head posture are associated with neck pain. A CT scan for our patient might not have been performed if he had not provided information on transient aphasia, since our patient complained of neck pain for a year, and the onset of neck pain was not acute. Supportive information for ICA dissection was that the site of his neck pain was slightly left-sided. Even in patients with PD and neck pain, cervical artery dissection may be included in the differential diagnosis if the patient has COVID-19. A major limitation of this study is that we conducted only physical/neurological examinations, blood tests, and imaging studies to rule out alternative mechanisms of ICA dissection, such as collagen vascular disease, inherited arteriopathies, fibromuscular dysplasia, extreme vessel tortuosity, or cystic medial necrosis. However, considering previous reports regarding SARS-CoV-2 and arterial dissection, further studies are needed to clarify the effect of COVID-19 infection on the vulnerability of the endothelium and arterial dissection. Abbreviations ICA Internal carotid artery SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 PD Parkinson’s disease NMDA N-methyl-d-aspartate Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of Mie University Hospital (H2018-032). Written informed consent and permission to publish the case report anonymously were obtained from the patient. Consent for publication Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Availability of data and materials The datasets generated during the current study are available from the corresponding author upon reasonable request. Competing interests None declared. Funding This work was supported by JSPS KAKENHI (grant number 21K15678). The role of the funding body; English editing of the manuscript. Author’s contributions TO provided and cared for the study patient, collected data; HI served as scientific advisors, collected data, reviewed the study proposal; KM, AT, and KM served as scientific advisors; MU and MM collected and interpreted data; AS served as scientific advisors, critically reviewed the study proposal. TO and HI equally contributed to this work. Acknowledgements We thank Dr N. Toma of the neurosurgery department for providing critical advice. References Griffin KJ, Harmsen WS, Mandrekar J, Brown RD, Jr., Keser Z: Epidemiology of Spontaneous Cervical Artery Dissection: Population-Based Study . Stroke 2024, 55 (3):670-677. Keser Z, Chiang CC, Benson JC, Pezzini A, Lanzino G: Cervical Artery Dissections: Etiopathogenesis and Management . Vasc Health Risk Manag 2022, 18 :685-700. Akbaş Y, Arhan E, Serdaroglu A, Nazlıel B: Intracranial internal carotid artery dissection following waterslide use: the first case report . Childs Nerv Syst 2016, 32 (3):411-413. Abraham B, Mathew SD, Sridharan K: A Systematic Review of Arterial Dissections in COVID-19 Patients . Curr Cardiol Rev 2023, 19 (1):e280622206435. Sato T, Miura Y, Yasuda R, Toma N, Suzuki H: Vertebral artery dissecting aneurysm rupture under severe COVID-19 . Brain Hemorrhages 2022, 3 (4):210-213. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H: Endothelial cell infection and endotheliitis in COVID-19 . Lancet (London, England) 2020, 395 (10234):1417-1418. Asan L, Deuschl C, Forsting M, Kleinschnitz C, Köhrmann M: Oropharyngeal swab for SARS-CoV-2 test causing atypical internal carotid artery dissection and stroke in a patient after mild COVID-19 . Therapeutic advances in neurological disorders 2021, 14 :17562864211033521. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE et al : MDS clinical diagnostic criteria for Parkinson's disease . Movement disorders : official journal of the Movement Disorder Society 2015, 30 (12):1591-1601. Matsuura K, Ii Y, Maeda M, Tabei KI, Satoh M, Umino M, Miyashita K, Ishikawa H, Shindo A, Tomimoto H: Neuromelanin-sensitive magnetic resonance imaging in disease differentiation for parkinsonism or neurodegenerative disease affecting the basal ganglia . Parkinsonism & related disorders 2021, 87 :75-81. Bond KM, Krings T, Lanzino G, Brinjikji W: Intracranial dissections: A pictorial review of pathophysiology, imaging features, and natural history . J Neuroradiol 2021, 48 (3):176-188. Lehman LL, Gilbert DL, Leach JL, Wu SW, Standridge SM: Vertebral artery dissection leading to stroke caused by violent neck tics of Tourette syndrome . Neurology 2011, 77 (18):1706-1708. Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S: Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review . JAMA Neurol 2020, 77 (8):1018-1027. Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM, Fowkes M: Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) . J Med Virol 2020, 92 (7):699-702. Kwon DK, Kwatra M, Wang J, Ko HS: Levodopa-Induced Dyskinesia in Parkinson's Disease: Pathogenesis and Emerging Treatment Strategies . Cells 2022, 11 (23). Tueth LE, Duncan RP: Musculoskeletal pain in Parkinson's disease: a narrative review . Neurodegener Dis Manag 2021, 11 (5):373-385. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-4407014","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":303411544,"identity":"83c802a5-6ad7-4e23-99f1-1831c3f76ced","order_by":0,"name":"Takanobu Okubo","email":"","orcid":"","institution":"Mie University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takanobu","middleName":"","lastName":"Okubo","suffix":""},{"id":303411545,"identity":"6a64f690-c43a-4198-b1e7-e65e71466f7d","order_by":1,"name":"Hidehiro Ishikawa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIiWNgGAWjYBACA2YwArKYmQ8wMLCBEQQwNhDUwpZApBawLjDgMUBSjweYszNvfFxQcE+OgZ3n64YPZQzRfOwNbBIMNXYMzLOxW2PZzFZsPMOg2JiBmXfbzRnnGHLbeA4AtRxLZmCccwC7ww7zmEnzGCQk7j/Mu+02bxtQi0T+NwkGtgMMjDMScGkx/w3S0sDM8+z2X5AW+QdAW/7h1WLGDNXCdpsRbAsDmwRjGz4tbMUghwH9wmZ2s+ecBNAvCcwWiX3JPDj9cv7wxs88fxLkGPgPP7vxo8wmd377AcYbH77ZyRniCDF0IAGhgE7iMZxBlA5kIC9BspZRMApGwSgYngAAIdFQS5Pa1xwAAAAASUVORK5CYII=","orcid":"","institution":"Mie University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hidehiro","middleName":"","lastName":"Ishikawa","suffix":""},{"id":303411546,"identity":"4db27ec5-2c09-43eb-a21a-db046d9c2314","order_by":2,"name":"Keita Matsuura","email":"","orcid":"","institution":"Mie University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Keita","middleName":"","lastName":"Matsuura","suffix":""},{"id":303411547,"identity":"2f1eead0-f0d4-42f7-ba50-07d8105097c4","order_by":3,"name":"Asako Tamura","email":"","orcid":"","institution":"Mie University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Asako","middleName":"","lastName":"Tamura","suffix":""},{"id":303411548,"identity":"54e0dd29-8e94-4e21-966b-5206d974d7c2","order_by":4,"name":"Koichi Miyashita","email":"","orcid":"","institution":"Mie University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Miyashita","suffix":""},{"id":303411549,"identity":"d8a5ac47-a470-46ef-9dea-50e3076f1ffa","order_by":5,"name":"Maki Umino","email":"","orcid":"","institution":"Mie University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Maki","middleName":"","lastName":"Umino","suffix":""},{"id":303411550,"identity":"9653495f-ef9a-4fd9-a2da-edfd7e0b7b2a","order_by":6,"name":"Masayuki Maeda","email":"","orcid":"","institution":"Mie University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Maeda","suffix":""},{"id":303411551,"identity":"ca3e1c79-1f6b-4d5c-9f3c-ced016de9bf6","order_by":7,"name":"Akihiro Shindo","email":"","orcid":"","institution":"Mie University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Akihiro","middleName":"","lastName":"Shindo","suffix":""}],"badges":[],"createdAt":"2024-05-12 02:53:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4407014/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4407014/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57452442,"identity":"6bba5e8e-29cd-4f09-a6f0-8b6e28b7b2d5","added_by":"auto","created_at":"2024-05-30 21:00:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":939838,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFindings related to Parkinson’s disease and cervical spondylosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNeuromelanin-sensitive magnetic resonance imaging (NMI) revealed reduced intensity in the substantia nigra pars compacta (A).The intensity of the locus coeruleus is normal (B). The pulse sequence used for NMI was the T1-weighted turbo spin-echo technique. A cardiac \u003csup\u003e123\u003c/sup\u003eI-metaiodobenzylguanidine myocardial scintigraphy (MIBG) shows decreased MIBG uptake in early phase [Heart-to-mediastinum (H/M) ratio of 1.99, normal \u0026gt; 2.2) (C), delayed phase (H/M ratio of 1.41, normal \u0026gt; 2.2) (D), and washout rate of 69.2% (normal \u0026lt; 34%), that indicated cardiac sympathetic denervation. Dopamine transporter imaging (DAT) reveals decreased DAT uptake (Specific Binding Ratio; right: 2.06, left: 2.80, average: 51 years old=8.17 (S.D.=1.35]) in both basal ganglia regions (E). Cervical MRI-T2-weighted imaging reveals cervical spondylosis with stenosis in C4–6 and hyperintensity on the right side at the C5/6 level of the spine (F).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4407014/v1/72b8b3dd16c51bdc93503936.png"},{"id":57451621,"identity":"a574a0c1-a8d4-4fa6-a7e5-bfac809ca0d4","added_by":"auto","created_at":"2024-05-30 20:52:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":528144,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMagnetic resonance imaging (MRI) of internal carotid artery dissection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComputed tomography (CT) reveals a low-density area in the left parietal lobe (A). The low-density area on CT is hyperintense on MRI diffusion-weighted imaging (DWI), indicating an acute infarction (B). Small hyperintensities are observed in the left hemisphere (C). The MR angiography (MRA) source image reveals stenosis of the left internal carotid artery (yellow arrow, D). In the area of stenosis, the intramural hematoma is detected as hyperintense on DWI (yellow arrow, E) and 3D-fluid attenuated inversion recovery (yellow arrow, F) and hypointense on susceptibility-weighted imaging (yellow arrow, G). These findings are compatible with those of ICA dissection. Stenosis due to dissection observed on MRA (yellow arrow, H) occurs approximately 2 cm proximal to the base of the skull (yellow arrow, I).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4407014/v1/dae0c593d8e85565c4d61dc0.png"},{"id":57451623,"identity":"af88c3b6-bbe0-4221-bbc1-be7cf6f47712","added_by":"auto","created_at":"2024-05-30 20:52:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":967234,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFollow-up magnetic resonance imaging (MRI)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStenosis on MR angiography and intramural hematoma on T1-weighted black blood imaging (yellow arrow) (A) shows improvement on follow-up imaging 6 months after onset (B).\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4407014/v1/aafb11ae2b85fc487551ff8c.png"},{"id":57877536,"identity":"0e8d2562-091c-4c7d-aa9f-34d803afcf18","added_by":"auto","created_at":"2024-06-06 21:01:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5015329,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4407014/v1/388fbe29-ff03-444d-97a9-0ff4a6413fad.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Internal carotid artery dissection in a patient with Parkinson’s disease after COVID-19 infection","fulltext":[{"header":"Background","content":"\u003cp\u003eInternal carotid artery (ICA) dissection has been reported to be a rare disease; however, the annual incidence rate has increased from 2.30 per 100,000 person-years to 8.93 per person-years over the past 19 years because of the evolution of vascular imaging techniques [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, the actual incidence may be higher in asymptomatic patients. Prior trauma is identified in only up to 40% of cases, and most traumatic events (up to 90%) are mild or trivial insults [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Stretching and compression of the ICA owing to sudden acceleration, deceleration, or rotational forces can increase the risk of dissection [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eRecently, it has been proposed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggers an inflammatory response that exacerbates endothelial dysfunction leading to dissection [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Although the cause of coronavirus disease 2019 (COVID-19) and arterial dissection is uncertain, 42 patients with arterial dissection have been reported in a recent review [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Here, we describe a patient with Parkinson\u0026rsquo;s disease (PD) who developed levodopa-induced neck dyskinesia and cerebral infarction due to ICA dissection during COVID-19.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 51-year-old man with levodopa-induced neck dyskinesia presented to the neurology clinic with gradually worsening neck pain 1 week after a mild COVID-19 infection. He had experienced transient motor aphasia for approximately 2\u0026ndash;3 hours the previous day. He was clinically diagnosed with Parkinson\u0026rsquo;s disease (PD) 6 years ago based on pre-established criteria [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The initial signs of PD, such as bradykinesia, rigidity, and resting tremor, were observed at 44 years of age. Neuromelanin imaging, \u003csup\u003e123\u003c/sup\u003eI-metaiodobenzylguanidine myocardial scintigraphy, and dopamine transporter imaging supported the diagnosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, A-E) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Levodopa improved his symptoms, but a dose increase and additional medication were needed because of the progression of PD. He exhibited neck dyskinesia during the on-state and complained of neck pain due to cervical spondylosis since the past year (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). The site of neck pain changed slightly to left side 1 week before the presentation. He did not have any vascular risk factors such as smoking, hypertension, hyperlipidemia, or diabetes. No family history of arterial dissection, collagen vascular disease, inherited arteriopathies, fibromuscular dysplasia, extreme vessel tortuosity, moyamoya disease, or cystic medial necrosis was noted. The PD medication included levodopa/carbidopa (150/15 mg, 5 times a day), entacapone (100 mg, twice a day), selegiline (2.5 mg twice a day), and ropinirole tape (16 mg).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHis neurological findings were normal except for parkinsonism. The Mini-Mental State Examination score was 26 (lost 4 points in series 7). Laboratory tests including protein C, protein S, antithrombin III, ferritin, D-dimer, and autoimmune antibody screening were normal. C-reactive protein was slightly elevated (0.46 mg/dL, normal\u0026thinsp;\u0026lt;\u0026thinsp;0.14 mg/dL). Brain computed tomography (CT) revealed a low-density area in the left parietal lobe (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Elongated styloid processes were not observed. Additional brain magnetic resonance imaging (MRI) detected acute infarctions in the left hemisphere (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, B and C), and an intramural hematoma was observed in an area of stenosis in the left ICA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, D-G). The patient was admitted with left ICA dissection [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Dissection occurred approximately 2 cm proximal to the base of the skull (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, H and I).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAntiplatelet therapy with 100 mg/day aspirin was initiated. Amantadine (100 mg/day) was initiated to treat the levodopa-induced dyskinesia. The patient\u0026rsquo;s dyskinesia and neck pain improved gradually. The patient was discharged 10 days later without any sequelae and returned to work. On follow-up MRI performed 6 months later, the intramural hematoma had diminished (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Antiplatelet therapy was terminated based on literature [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTo date, neck dyskinesia-induced ICA dissection has not been reported in patients with PD. A previous report described that sudden violent neck tics can cause cervical artery dissection [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The mechanical stress of violent jerking motions of the head and neck has been reported as a potential causative factor of ICA dissection [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In the present case, however, we speculated that COVID-19 was a risk factor for the onset of ICA dissection, in addition to the mechanical stress of cervical choreiform movement due to dyskinesia.\u003c/p\u003e \u003cp\u003eAccording to a recent review, 42 cases of arterial dissection associated with COVID-19 were reported as of October 2021. Aortic dissection was the most common (52.3%), followed by coronary artery dissection (23.8%) and, less commonly, cerebral, vertebral and ICA dissections (7.1% each) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. About 50% of the patients were aged between 45 and 59 years and the period between the onset of COVID-19-like symptoms and presentation to the hospital with symptoms/signs of arterial dissection ranged from 1 day to 8 weeks [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The age and onset date in the present case were consistent with previous data. Common risk factors included hypertension (60%), diabetes mellitus (15%), dyslipidemia (15%), and smoking (15%). No risk factors were identified in 47.6% of the patients as with the present case. Arterial dissection in patients with COVID-19 may occur secondary to an exaggerated inflammatory response that causes endothelial dysfunction. SARS-CoV-2 infects the host using the angiotensin-converting enzyme 2 receptor, which is expressed not only in the lungs and heart but also in endothelial cells [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Thus, endothelium throughout the body is at risk of SARS-CoV-2 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The presence of SARS-CoV-2 viral particles in the capillary endothelia of a frontal lobe specimen was confirmed in an autopsy case [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Cervical artery dissection is rare; however, early detection and therapeutic intervention are crucial because dissecting aneurysm rupture or stroke can be life-threatening [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although the relationship between ICA dissection and COVID-19 is uncertain, a previous case report of ICA dissection after mild COVID-19 supports this causative association [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In that report, acute neck pain occurred when the patient\u0026rsquo;s head was hyperextended during an oropharyngeal swab test for COVID-19 during follow-up, and MRI revealed ICA dissection. Although the timing of stroke symptoms and neck pain in this case was highly suggestive of a causal link between neck extension and the onset of dissection, the site of dissection was atypical for traumatic ICA dissection. The dissection might have occurred because of mechanical stress at the site of endothelial damage due to SARS-CoV-2 in our case and the previous case. We believe that the main mechanical stress in our case was levodopa-induced dyskinesia of the neck. Coughing and sneezing might be the factors that induced dissection. Amantadine (an NMDA receptor antagonist), which is reported to be the most effective treatment for levodopa-induced dyskinesia, improved neck dyskinesia [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePain is highly prevalent in patients with PD, and the neck is one of the most common sites [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Cervical spinal deformity and forward head posture are associated with neck pain. A CT scan for our patient might not have been performed if he had not provided information on transient aphasia, since our patient complained of neck pain for a year, and the onset of neck pain was not acute. Supportive information for ICA dissection was that the site of his neck pain was slightly left-sided. Even in patients with PD and neck pain, cervical artery dissection may be included in the differential diagnosis if the patient has COVID-19. A major limitation of this study is that we conducted only physical/neurological examinations, blood tests, and imaging studies to rule out alternative mechanisms of ICA dissection, such as collagen vascular disease, inherited arteriopathies, fibromuscular dysplasia, extreme vessel tortuosity, or cystic medial necrosis. However, considering previous reports regarding SARS-CoV-2 and arterial dissection, further studies are needed to clarify the effect of COVID-19 infection on the vulnerability of the endothelium and arterial dissection.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternal carotid artery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSARS-CoV-2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esevere acute respiratory syndrome coronavirus 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eParkinson\u0026rsquo;s disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNMDA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eN-methyl-d-aspartate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of Mie University Hospital (H2018-032). Written informed consent and permission to publish the case report anonymously were obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by JSPS KAKENHI (grant number 21K15678). The role of the funding body; English editing of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor’s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTO provided and cared for the study patient, collected data; HI served as scientific advisors, collected data, reviewed the study proposal; KM, AT, and KM served as scientific advisors; MU and MM collected and interpreted data; AS served as scientific advisors, critically reviewed the study proposal. TO and HI equally contributed to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Dr N. Toma of the neurosurgery department for providing critical advice.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGriffin KJ, Harmsen WS, Mandrekar J, Brown RD, Jr., Keser Z: \u003cstrong\u003eEpidemiology of Spontaneous Cervical Artery Dissection: Population-Based Study\u003c/strong\u003e. \u003cem\u003eStroke \u003c/em\u003e2024, \u003cstrong\u003e55\u003c/strong\u003e(3):670-677.\u003c/li\u003e\n\u003cli\u003eKeser Z, Chiang CC, Benson JC, Pezzini A, Lanzino G: \u003cstrong\u003eCervical Artery Dissections: Etiopathogenesis and Management\u003c/strong\u003e. \u003cem\u003eVasc Health Risk Manag \u003c/em\u003e2022, \u003cstrong\u003e18\u003c/strong\u003e:685-700.\u003c/li\u003e\n\u003cli\u003eAkbaş Y, Arhan E, Serdaroglu A, Nazlıel B: \u003cstrong\u003eIntracranial internal carotid artery dissection following waterslide use: the first case report\u003c/strong\u003e. \u003cem\u003eChilds Nerv Syst \u003c/em\u003e2016, \u003cstrong\u003e32\u003c/strong\u003e(3):411-413.\u003c/li\u003e\n\u003cli\u003eAbraham B, Mathew SD, Sridharan K: \u003cstrong\u003eA Systematic Review of Arterial Dissections in COVID-19 Patients\u003c/strong\u003e. \u003cem\u003eCurr Cardiol Rev \u003c/em\u003e2023, \u003cstrong\u003e19\u003c/strong\u003e(1):e280622206435.\u003c/li\u003e\n\u003cli\u003eSato T, Miura Y, Yasuda R, Toma N, Suzuki H: \u003cstrong\u003eVertebral artery dissecting aneurysm rupture under severe COVID-19\u003c/strong\u003e. \u003cem\u003eBrain Hemorrhages \u003c/em\u003e2022, \u003cstrong\u003e3\u003c/strong\u003e(4):210-213.\u003c/li\u003e\n\u003cli\u003eVarga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H: \u003cstrong\u003eEndothelial cell infection and endotheliitis in COVID-19\u003c/strong\u003e. \u003cem\u003eLancet (London, England) \u003c/em\u003e2020, \u003cstrong\u003e395\u003c/strong\u003e(10234):1417-1418.\u003c/li\u003e\n\u003cli\u003eAsan L, Deuschl C, Forsting M, Kleinschnitz C, K\u0026ouml;hrmann M: \u003cstrong\u003eOropharyngeal swab for SARS-CoV-2 test causing atypical internal carotid artery dissection and stroke in a patient after mild COVID-19\u003c/strong\u003e. \u003cem\u003eTherapeutic advances in neurological disorders \u003c/em\u003e2021, \u003cstrong\u003e14\u003c/strong\u003e:17562864211033521.\u003c/li\u003e\n\u003cli\u003ePostuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eMDS clinical diagnostic criteria for Parkinson\u0026apos;s disease\u003c/strong\u003e. \u003cem\u003eMovement disorders : official journal of the Movement Disorder Society \u003c/em\u003e2015, \u003cstrong\u003e30\u003c/strong\u003e(12):1591-1601.\u003c/li\u003e\n\u003cli\u003eMatsuura K, Ii Y, Maeda M, Tabei KI, Satoh M, Umino M, Miyashita K, Ishikawa H, Shindo A, Tomimoto H: \u003cstrong\u003eNeuromelanin-sensitive magnetic resonance imaging in disease differentiation for parkinsonism or neurodegenerative disease affecting the basal ganglia\u003c/strong\u003e. \u003cem\u003eParkinsonism \u0026amp; related disorders \u003c/em\u003e2021, \u003cstrong\u003e87\u003c/strong\u003e:75-81.\u003c/li\u003e\n\u003cli\u003eBond KM, Krings T, Lanzino G, Brinjikji W: \u003cstrong\u003eIntracranial dissections: A pictorial review of pathophysiology, imaging features, and natural history\u003c/strong\u003e. \u003cem\u003eJ Neuroradiol \u003c/em\u003e2021, \u003cstrong\u003e48\u003c/strong\u003e(3):176-188.\u003c/li\u003e\n\u003cli\u003eLehman LL, Gilbert DL, Leach JL, Wu SW, Standridge SM: \u003cstrong\u003eVertebral artery dissection leading to stroke caused by violent neck tics of Tourette syndrome\u003c/strong\u003e. \u003cem\u003eNeurology \u003c/em\u003e2011, \u003cstrong\u003e77\u003c/strong\u003e(18):1706-1708.\u003c/li\u003e\n\u003cli\u003eZubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S: \u003cstrong\u003eNeuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review\u003c/strong\u003e. \u003cem\u003eJAMA Neurol \u003c/em\u003e2020, \u003cstrong\u003e77\u003c/strong\u003e(8):1018-1027.\u003c/li\u003e\n\u003cli\u003ePaniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM, Fowkes M: \u003cstrong\u003eCentral nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)\u003c/strong\u003e. \u003cem\u003eJ Med Virol \u003c/em\u003e2020, \u003cstrong\u003e92\u003c/strong\u003e(7):699-702.\u003c/li\u003e\n\u003cli\u003eKwon DK, Kwatra M, Wang J, Ko HS: \u003cstrong\u003eLevodopa-Induced Dyskinesia in Parkinson\u0026apos;s Disease: Pathogenesis and Emerging Treatment Strategies\u003c/strong\u003e. \u003cem\u003eCells \u003c/em\u003e2022, \u003cstrong\u003e11\u003c/strong\u003e(23).\u003c/li\u003e\n\u003cli\u003eTueth LE, Duncan RP: \u003cstrong\u003eMusculoskeletal pain in Parkinson\u0026apos;s disease: a narrative review\u003c/strong\u003e. \u003cem\u003eNeurodegener Dis Manag \u003c/em\u003e2021, \u003cstrong\u003e11\u003c/strong\u003e(5):373-385.\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":"Internal carotid artery dissection, COVID-19, Parkinson’s disease, dyskinesia, stroke","lastPublishedDoi":"10.21203/rs.3.rs-4407014/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4407014/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eInternal carotid artery (ICA) dissection is a relatively rare cause of acute ischemic stroke. Stretching and compression of the ICA owing to sudden acceleration, deceleration, and rotational forces are risk factors for ICA dissection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to trigger an inflammatory response exacerbating endothelial dysfunction leading to arterial dissection. Although levodopa-induced cervical dyskinesia in Parkinson\u0026rsquo;s disease often manifests as choreiform movement, dissection has not been reported in such patients.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eA 51-year-old man with Parkinson\u0026rsquo;s disease (PD) presented with gradually worsening neck pain and transient aphasia one week after mild coronavirus disease 2019 (COVID-19) infection. The patient presented with levodopa-induced cervical dyskinesia. Magnetic resonance imaging revealed acute ischemic stroke in the left parietal lobe and an intramural hematoma with an area of stenosis in the left ICA. The patient was diagnosed with a left ICA artery dissection.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe quick cervical movement under COVID-19-related vessel wall vulnerability may cause ICA dissection. Although patients with PD often have neck pain, ICA dissection should be included as a differential diagnosis if the patient has COVID-19.\u003c/p\u003e","manuscriptTitle":"Internal carotid artery dissection in a patient with Parkinson’s disease after COVID-19 infection","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-30 20:52:22","doi":"10.21203/rs.3.rs-4407014/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":"0d06bd06-3369-4be1-8f5e-ad60eea17f29","owner":[],"postedDate":"May 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-06T20:53:26+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-30 20:52:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4407014","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4407014","identity":"rs-4407014","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}