Bilateral optic nerve infiltration and leukemic retinopathy as initial signs of leukemia relapse with central nervous system involvement in an adult: A case report

Bilateral optic nerve infiltration and leukemic retinopathy as initial signs of leukemia relapse with central nervous system involvement in an adult: 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 Bilateral optic nerve infiltration and leukemic retinopathy as initial signs of leukemia relapse with central nervous system involvement in an adult: A case report Yisai Wang, Ling Zhu, Hongtao Wang, Zhen Li, Ruomeng Bai, Qinghua Wei, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3791887/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background: We describe a case in which bilateral optic nerve infiltration and leukemic retinopathy were the initial signs of disease relapse in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + -ALL) with central nervous system (CNS) involvement. Case presentation: A 65-year-old Asian female with Ph + -ALL in complete remission presented at our institution with symptoms of visual disturbance, central scotoma and pain with eye movement in both eyes for a 1-month duration. Ophthalmic examination revealed remarkable optic disc swelling with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and retinal hemorrhages in both eyes. She was subsequently referred to the treating oncologist and diagnosed with Ph + -ALL relapse with multiple relapsed diseases involving the bone marrow and CNS. After intrathecal (IT) therapy, her visual acuity dramatically improved, and her leukemic infiltrates decreased. Conclusions: To the best of our knowledge, this is the first case report of ALL relapse with CNS involvement presenting as bilateral optic nerve infiltration and leukemic retinopathy in an adult. Hence, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting leukemia relapse. Case report Philadelphia chromosome-positive acute lymphoblastic leukemia Optic nerve infiltration Leukemic Retinopathy Relapse Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Leukaemia is a malignant haematologic disease caused by acquired clonal abnormalities of haematopoietic stem cells that replace normal bone marrow, and acute lymphoblastic leukaemia (ALL) accounts for approximately 70% of all cases of this disease [ 1 ] . Most adults with acute ALL who achieve complete remission (CR) will relapse, whatever their prior treatment, cannot be rescued using currently available therapies [ 2 ] . The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). There have been few studies among adult patients focused on CNS disease [ 3 ] , and prevention of recurrence is the best strategy for long-term survival in patients with this disease [ 4 ] . The Philadelphia (Ph) chromosome is the most common cytogenetic abnormality found in adult B-cell lineage ALL [ 5 ] and has been proven to be an adverse prognostic factor in ALL [ 6 ] . The clinical presentation of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + -ALL), similar to other forms of ALL, is largely nonspecific [ 7 ] . Although patients with leukemia classically present with fatigue, fever and bleeding, ocular manifestations occur in up to 90% of these patients [ 8 ] . All parts of the eye can be involved either prior to systemic diagnosis of leukemia or during the disease course [ 9 ] , with manifestations relating to direct leukemic infiltration or from secondary effects from hematologic abnormalities, CNS involvement or opportunistic infections [ 10 ] . In the literature, few reports of visual symptoms as the first sign of ALL relapse have been published. We describe a rare case in which an elderly female presented with bilateral blurry vision as the first sign of Ph + -ALL relapse. This is the first report of bilateral optic nerve infiltration and leukemic retinopathy as initial signs of ALL relapse with CNS involvement in an adult. Case presentation A 65-year-old Asian female with Ph + -ALL in complete remission presented at our institution with symptoms of visual disturbance, central scotoma and pain with eye movement in both eyes for a 1-month duration. Her past medical history included a diagnosis of Ph + -ALL initially presenting as fever 2 years previously, after which she started chemotherapy for 18 months. At the time of presentation, her ALL status was in complete remission, and her laboratory test results were normal for 6 months. Ocular examination revealed a best-corrected visual acuity (BCVA) of 20/40 in the right eye (RE) and 20/50 in the left eye (LE). The intraocular pressure (IOP) of both eyes was within normal limits. Both eyes had normal pupillary reflexes and normal ocular adnexa, a quiet anterior chamber, a clear lens with increased density and no vitreous cells in the anterior vitreous face. Overall, the anterior segment examination was unremarkable. A fundus photo showed dramatic creamy-white optic nerve infiltration with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and tortuosity, and blot hemorrhages on the foveal area in the RE (Fig. 1A). The LE had a similar hemorrhagic fundal presentation as the RE, except that fewer peripapillary and retinal hemorrhages were located in the LE (Fig. 1B). Optical coherence tomography (OCT) revealed macular edema with irregularity in retinal layers and subretinal fluid around the optic disc in the RE (Fig. 2A). Serous macular detachments with subretinal hyperreflectivity and subretinal fluid around the optic disc were observed in LE (Fig. 2B). Neither neurologic nor dermatologic signs were present on physical examination. Based on the ocular findings and history of blood disease, the patient was referred to the treating oncologist for further management. Peripheral blood investigations (performed within 3 days of initial presentation) revealed a hemoglobin level of 11.6 g/dL, a white blood cell count of 3680/µL, and a platelet count of 129,000/µL. Bone marrow examination revealed an increase in blast cells. Lumbar puncture (LP) showed normal cerebrospinal fluid (CSF) open pressure (16 cm). Flow cytometry analysis of CSF samples revealed 1667/µL nucleated cells and 97% immature B cells with a phenotype similar to that of cells detected at initial diagnosis. Cerebral magnetic resonance imaging (MRI) showed no enhancement of the optic nerve top or bottom. She was managed as a case of ALL relapse with CNS involvement and the patient was subsequently treated with 12 cycles of intrathecal (IT) therapy (methotrexate, dexamethasone, and cytarabine) for 6 weeks. Cranial irradiation was scheduled but delayed for personal reasons. We followed up with the patient for a duration of 8 weeks, during which she experienced visual recovery, as revealed by a BCVA of 20/25 in the RE and 20/32 in the LE. However, complete resolution has not yet been achieved. Follow-up fundus examination (Fig. 3) along with OCT (Fig. 4) revealed that retinal hemorrhages were significantly reduced and that edema of the optic nerve decreased in both eyes. Discussion and conclusions The presence of specific ocular lesions was associated with a higher frequency of bone marrow relapses and CNS involvement, leading to a lower survival rate [ 11 ] . Leukemic retinopathy is the term most often used to denote the fundus manifestations of anaemia, thrombocytopenia and hyperviscosity observed in patients with leukaemia [ 12 ] . Experts believe that leukemic retinopathy is associated with abnormal hematologic parameters and coagulopathy [ 13 , 14 ] . Our patient presented with bilateral retinal vein dilatation and tortuosity, blot and flame-shaped retinal hemorrhages, and serous retinal detachment, features that were the result of both direct retinal leukemic infiltration and leukostasis secondary to hyperleukocytosis [ 15 ] . However, serous retinal detachment (SRD) in her LE has been reported less commonly in the setting of acute leukemia and may develop as a result of choroidal involvement by leukemic cells causing retinal pigment epithelial disturbances or due to incompetence of the outer blood‒retinal barrier (BRB), which induces retinal pigment epithelial changes [ 16 , 17 ] . Although they are more common in acute (vs. chronic) leukemia, they are less common in patients with the lymphoid (vs. myeloid) subtypes, females and older patients, making our patient an unlikely suspect [ 18 ] . Hyperreflective specks in the vitreous give the impression of vitreous seeding and considered as leukemic infiltrates. This may be caused by the leukaemic cells entering the vitreous from optic disk neovascularization, and vitreous haemorrhage allows neoplastic cells to enter the vitreous cavity, similar to the presentation in our case [ 19 ] . With the increase in survival of patients with leukemia, the incidence of CNS relapse is on the rise. The optic nerve can reveal leukemic involvement of the CNS [ 20 ] . However, optic nerve infiltration as an initial sign of relapse is quite rare. The eyes and optic nerves are identified as pharmacological sanctuaries for leukemia therapy because the BRB shields the CNS from any systemically administered chemotherapeutic drugs [ 21 ] . Thus, many adjuvant therapies are often required to achieve complete remission. In our patient, bone marrow and CSF aspiration showed massive leukemic cells, while the CSF open pressure was normal. Researchers have postulated that one does not have to suspect increased intracranial pressure to explain swelling of the optic nerve since leukemic infiltration through the central retinal vessels and vessels in the pial septa is sufficient to cause venous congestion and/or ischemia with edema [ 22 ] . Optic neuropathy in the context of leukemia can be diagnosed through a broad variety of methods, including infiltration, infections, compression, vasculitis, radiotherapy-induced complications or adverse effects of chemotherapeutic agents [ 23 – 25 ] . All these possibilities should be excluded through careful investigations. There were no signs of infection. Furthermore, the absence of neurologic and dermatologic signs, such as dysacusis, vitiligo, and poliosis, is not consistent with Harada's syndrome. A diagnosis of leukemic optic nerve infiltration was highly considered. An 8-week follow-up appointment at the ophthalmology clinic demonstrated functional and anatomic improvement in both eyes. In the present case, cerebral MRI showed no enhancement of the optic nerve top or bottom, which also explains that radiological features are neither specific nor sensitive for ocular leukemia [ 26 ] . A recent review illustrated the poor sensitivity of CSF cytology [ 27 ] . Of note, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting disease relapse. Progress in the research and therapy of adult ALL is accelerating [ 28 ] , and future studies should investigate better approaches for the early diagnosis of relapsed disease and more intensive strategies to improve patient survival. In summary, understanding ocular involvement in leukemia is crucial since the eye is the only organ where leukemic infiltration to nerves and blood vessels can be observed directly. Recognizing fundus changes in leukemia allows earlier diagnosis and prompt treatment. Ophthalmologists should be aware of these possible manifestations and possible etiologies in patients with ALL, even if they have achieved disease remission. In this report, we present an unusual case of bilateral optic nerve infiltration and leukemic retinopathy as initial signs of Ph + -ALL relapse with CNS involvement in an elderly female and explore the underlying proposed pathologic basis of these ocular manifestations in leukemia. Hence, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting disease relapse. Abbreviations Ph + -ALL Philadelphia chromosome-positive acute lymphoblastic leukemia CNS Central nervous system RE right eye LE left eye IOP Intraocular pressure OCT Optical coherence tomography MR Magnetic resonance CSF Cerebrospinal fluid BRB blood‒retinal barrier. Declarations Acknowledgements Not applicable. Authors’ contributions YW collected the patients’ medical records, fundus and OCT images, and wrote and revised the manuscript. LZ was the haematologist who contributed to the revision of manuscript. HC, ZL and HW was responsible for clinical evaluation and management of the patient’s ophthalmic manifestations and contributed to revision of the manuscript. RB, LH, YX, SL, QW are contributed to revision of the manuscript. All authors read and approved the final manuscript. Funding No funding or grant support. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent to publish the report was obtained from the subject and their legal guardians. Competing interests The authors declare that they have no competing interests. Author details 1 Department of Ophthalmology, Peking University Shougang Hospital, Beijing, China. 2 Department of haematology, Air Force Medical University, Beijing, China. References Nikaido H, Mishima H, Ono H, Choshi K, Dohy H. Leukemic involvement of the optic nerve. Am J Ophthalmol. 1988;105(3):294–8. https://doi.org/10.1016/0002-9394(88)90013-x . El Fakih R, Jabbour E, Ravandi F, Hassanein M, Anjum F, Ahmed S, et al. Current paradigms in the management of Philadelphia chromosome positive acute lymphoblastic leukemia in adults. 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Neurooncol Pract. 2017;4(1):60–6. https://doi.org/10.1093/nop/npw006 . Epub 2016 Dec 9. Culler AM. Fundus Changes in Leukemia. Trans Am Ophthalmol Soc. 1951;49:445–73. Gordon KB, Rugo HS, Duncan JL, Irvine AR, Howes EL Jr, O'Brien JM, et al. Ocular manifestations of leukemia: leukemic infiltration versus infectious process. Ophthalmology. 2001;108(12):2293–300. https://doi.org/10.1016/s0161-6420(01)00817-x . Kaikov Y. Optic nerve head infiltration in acute leukemia in children: an indication for emergency optic nerve radiation therapy. Med Pediatr Oncol. 1996;26(2):101–4. https://doi.org/10.1002/(SICI)1096-911X(199602)26:23.0.CO;2-P . Ho WL, Wong H, Yau T. The ophthalmological complications of targeted agents in cancer therapy: what do we need to know as ophthalmologists? Acta Ophthalmol. 2013;91(7):604-9. https://doi.org/10.1111/j.1755-3768.2012.02518.x . Epub 2012 Sep 12. Fadilah SA, Raymond AA, Cheong SK, Faridah A. Relapsed Acute Lymphoblastic Leukemia Presenting as Optic Neuritis. Hematology. 2001;6(4):267–9. https://doi.org/10.1080/10245332.2001.11752124 . Janetos TM, Volpe NJ, Simon SS. Neuro-ophthalmic manifestations of cancer: a narrative review. Chin Clin Oncol. 2022;11(3):25. https://doi.org/10.21037/cco-21-137 . Jabbour E, Short NJ, Jain N, Haddad FG, Welch MA, Ravandi F, et al. The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades. J Hematol Oncol. 2023;16(1):22. https://doi.org/10.1186/s13045-023-01409-5 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 11 Apr, 2024 Reviews received at journal 23 Mar, 2024 Reviews received at journal 14 Mar, 2024 Reviewers agreed at journal 14 Mar, 2024 Reviewers agreed at journal 04 Mar, 2024 Reviewers agreed at journal 27 Feb, 2024 Reviewers invited by journal 22 Feb, 2024 Editor invited by journal 28 Dec, 2023 Editor assigned by journal 26 Dec, 2023 Submission checks completed at journal 26 Dec, 2023 First submitted to journal 22 Dec, 2023 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. We do this by developing innovative software and high quality services for the global research community. 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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-3791887","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":264047893,"identity":"b93cc046-4682-42c5-ab9e-c1a44cb42a6d","order_by":0,"name":"Yisai Wang","email":"","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yisai","middleName":"","lastName":"Wang","suffix":""},{"id":264047894,"identity":"9f6e82ad-6153-4bbd-84dd-b051402e240c","order_by":1,"name":"Ling Zhu","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ling","middleName":"","lastName":"Zhu","suffix":""},{"id":264047895,"identity":"3ec6cbd4-e627-42aa-b434-bb8e561aea87","order_by":2,"name":"Hongtao Wang","email":"","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongtao","middleName":"","lastName":"Wang","suffix":""},{"id":264047896,"identity":"32e2fadf-7b3f-4b61-85ea-e5abc54a61f0","order_by":3,"name":"Zhen Li","email":"","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhen","middleName":"","lastName":"Li","suffix":""},{"id":264047897,"identity":"62fc3b99-8add-454c-97ee-9fa17ce2de5d","order_by":4,"name":"Ruomeng Bai","email":"","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ruomeng","middleName":"","lastName":"Bai","suffix":""},{"id":264047898,"identity":"ab07b5fc-4134-48e3-a6a7-3cae24825891","order_by":5,"name":"Qinghua Wei","email":"","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qinghua","middleName":"","lastName":"Wei","suffix":""},{"id":264047899,"identity":"82d91b61-a50f-40f0-b560-60c03a22ab09","order_by":6,"name":"Lin Huang","email":"","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Huang","suffix":""},{"id":264047900,"identity":"f7244d0c-8669-4692-9dca-dbdd235a3fe1","order_by":7,"name":"Ying Xu","email":"","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Xu","suffix":""},{"id":264047901,"identity":"fdef47aa-b4e0-4a80-8776-cb868d49357d","order_by":8,"name":"Songguo Li","email":"","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Songguo","middleName":"","lastName":"Li","suffix":""},{"id":264047902,"identity":"33e55463-34f2-49e3-bfa6-dcd713307456","order_by":9,"name":"Hui Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYDACCRBhYCNn397Y+PADCVrSjA14DjcbSxCvheFw4gaJ9DYBHmJ08M9uPvaYp+Aw43bJh21A/XZyug2ELLlzLN2YxyCd2XJ2YtuDAoZkY7MDBLQYSOSYSfMYWLMx3E5sN5BgOJC4jbCW/G9ALcw8DDcPtknwEKclhw2oxVnC4AYjkVokbqSZSc4xSDOQ7EkEBrIBEX7hn5H8TOLNH5v6fvbjDx9+qLCTI6gF3Z2kKR8Fo2AUjIJRgAMAAMrqPQl+nR30AAAAAElFTkSuQmCC","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hui","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2023-12-22 12:14:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3791887/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3791887/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49083126,"identity":"3330dbb1-45bd-4a9a-9085-9e6be42a7980","added_by":"auto","created_at":"2024-01-02 20:18:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2202791,"visible":true,"origin":"","legend":"\u003cp\u003eFundus photos of both eyes at the presentation. (\u003cstrong\u003eA\u003c/strong\u003e) Fundus photo of the RE showed a dramatic creamy-white optic nerve infiltration with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and tortuosity, and blot hemorrhages on the foveal area. (\u003cstrong\u003eB\u003c/strong\u003e) Fundus photo of the LE with optic disc edema, with peripapillary hemorrhages, retinal venous dilation and tortuosity, less pronounced than RE.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3791887/v1/19754e029c5dc7a0d22639cd.jpg"},{"id":49081902,"identity":"97c6dc8b-8828-4ed3-a834-cac6e697df3e","added_by":"auto","created_at":"2024-01-02 20:10:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1520748,"visible":true,"origin":"","legend":"\u003cp\u003eOptical coherence tomography (OCT) at the presentation. (\u003cstrong\u003eA\u003c/strong\u003e) OCT of the RE revealed macular edema with irregularity in retinal layers, dense cellular infiltrate in the retro-hyaloid space and vitreous cortex and subretinal fluid around the optic disc. (\u003cstrong\u003eB\u003c/strong\u003e) OCT of the LE showed serous macular detachments with subretinal hyperreflectivity and subretinal fluid around the optic disc.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3791887/v1/873d20cb0af19bbd0db7d013.jpg"},{"id":49081899,"identity":"7e8d59a7-5b97-46f1-be7e-3b5aa86bdb4f","added_by":"auto","created_at":"2024-01-02 20:10:18","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2123576,"visible":true,"origin":"","legend":"\u003cp\u003eFundus photos of both eyes taken 8 weeks after the initial presentation. (\u003cstrong\u003eA\u003c/strong\u003e) Fundus photo of the RE showed an absorption in macular and peripheral hemorrhage. (\u003cstrong\u003eB\u003c/strong\u003e) The disc margins were slightly blurry and vascular tortuosity was less pronounced in the LE.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3791887/v1/1f4b734a8fd43262254aa1dd.jpg"},{"id":49081903,"identity":"d9cafa83-b26f-41e2-a882-950174fdd65d","added_by":"auto","created_at":"2024-01-02 20:10:18","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1537827,"visible":true,"origin":"","legend":"\u003cp\u003eOCT taken 8 weeks after the initial presentation. (\u003cstrong\u003eA\u003c/strong\u003e) OCT of the RE revealed the persistent rupture of IS/OS. (\u003cstrong\u003eB\u003c/strong\u003e) OCT of the LE showed subretinal fluid disappeared basically.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3791887/v1/b4e001b1a1e2a6e0b0606f92.jpg"},{"id":49083347,"identity":"4542982c-c2ec-44d6-b125-b987a430c390","added_by":"auto","created_at":"2024-01-02 20:26:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":618859,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3791887/v1/ced921b4-e412-45cc-9363-929b47db74dc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Bilateral optic nerve infiltration and leukemic retinopathy as initial signs of leukemia relapse with central nervous system involvement in an adult: A case report","fulltext":[{"header":"Background","content":"\u003cp\u003eLeukaemia is a malignant haematologic disease caused by acquired clonal abnormalities of haematopoietic stem cells that replace normal bone marrow, and acute lymphoblastic leukaemia (ALL) accounts for approximately 70% of all cases of this disease\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Most adults with acute ALL who achieve complete remission (CR) will relapse, whatever their prior treatment, cannot be rescued using currently available therapies\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). There have been few studies among adult patients focused on CNS disease\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e, and prevention of recurrence is the best strategy for long-term survival in patients with this disease\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. The Philadelphia (Ph) chromosome is the most common cytogenetic abnormality found in adult B-cell lineage ALL\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e and has been proven to be an adverse prognostic factor in ALL\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. The clinical presentation of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph\u003csup\u003e+\u003c/sup\u003e-ALL), similar to other forms of ALL, is largely nonspecific\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Although patients with leukemia classically present with fatigue, fever and bleeding, ocular manifestations occur in up to 90% of these patients\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. All parts of the eye can be involved either prior to systemic diagnosis of leukemia or during the disease course\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e, with manifestations relating to direct leukemic infiltration or from secondary effects from hematologic abnormalities, CNS involvement or opportunistic infections\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the literature, few reports of visual symptoms as the first sign of ALL relapse have been published. We describe a rare case in which an elderly female presented with bilateral blurry vision as the first sign of Ph\u003csup\u003e+\u003c/sup\u003e-ALL relapse. This is the first report of bilateral optic nerve infiltration and leukemic retinopathy as initial signs of ALL relapse with CNS involvement in an adult.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 65-year-old Asian female with Ph\u003csup\u003e+\u003c/sup\u003e-ALL in complete remission presented at our institution with symptoms of visual disturbance, central scotoma and pain with eye movement in both eyes for a 1-month duration. Her past medical history included a diagnosis of Ph\u003csup\u003e+\u003c/sup\u003e-ALL initially presenting as fever 2 years previously, after which she started chemotherapy for 18 months. At the time of presentation, her ALL status was in complete remission, and her laboratory test results were normal for 6 months. Ocular examination revealed a best-corrected visual acuity (BCVA) of 20/40 in the right eye (RE) and 20/50 in the left eye (LE). The intraocular pressure (IOP) of both eyes was within normal limits. Both eyes had normal pupillary reflexes and normal ocular adnexa, a quiet anterior chamber, a clear lens with increased density and no vitreous cells in the anterior vitreous face. Overall, the anterior segment examination was unremarkable. A fundus photo showed dramatic creamy-white optic nerve infiltration with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and tortuosity, and blot hemorrhages on the foveal area in the RE (Fig.\u0026nbsp;1A). The LE had a similar hemorrhagic fundal presentation as the RE, except that fewer peripapillary and retinal hemorrhages were located in the LE (Fig.\u0026nbsp;1B). Optical coherence tomography (OCT) revealed macular edema with irregularity in retinal layers and subretinal fluid around the optic disc in the RE (Fig.\u0026nbsp;2A). Serous macular detachments with subretinal hyperreflectivity and subretinal fluid around the optic disc were observed in LE (Fig.\u0026nbsp;2B). Neither neurologic nor dermatologic signs were present on physical examination. Based on the ocular findings and history of blood disease, the patient was referred to the treating oncologist for further management. Peripheral blood investigations (performed within 3 days of initial presentation) revealed a hemoglobin level of 11.6 g/dL, a white blood cell count of 3680/\u0026micro;L, and a platelet count of 129,000/\u0026micro;L. Bone marrow examination revealed an increase in blast cells. Lumbar puncture (LP) showed normal cerebrospinal fluid (CSF) open pressure (16 cm). Flow cytometry analysis of CSF samples revealed 1667/\u0026micro;L nucleated cells and 97% immature B cells with a phenotype similar to that of cells detected at initial diagnosis. Cerebral magnetic resonance imaging (MRI) showed no enhancement of the optic nerve top or bottom. She was managed as a case of ALL relapse with CNS involvement and the patient was subsequently treated with 12 cycles of intrathecal (IT) therapy (methotrexate, dexamethasone, and cytarabine) for 6 weeks. Cranial irradiation was scheduled but delayed for personal reasons. We followed up with the patient for a duration of 8 weeks, during which she experienced visual recovery, as revealed by a BCVA of 20/25 in the RE and 20/32 in the LE. However, complete resolution has not yet been achieved. Follow-up fundus examination (Fig.\u0026nbsp;3) along with OCT (Fig.\u0026nbsp;4) revealed that retinal hemorrhages were significantly reduced and that edema of the optic nerve decreased in both eyes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion and conclusions","content":"\u003cp\u003eThe presence of specific ocular lesions was associated with a higher frequency of bone marrow relapses and CNS involvement, leading to a lower survival rate\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Leukemic retinopathy is the term most often used to denote the fundus manifestations of anaemia, thrombocytopenia and hyperviscosity observed in patients with leukaemia\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Experts believe that leukemic retinopathy is associated with abnormal hematologic parameters and coagulopathy\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Our patient presented with bilateral retinal vein dilatation and tortuosity, blot and flame-shaped retinal hemorrhages, and serous retinal detachment, features that were the result of both direct retinal leukemic infiltration and leukostasis secondary to hyperleukocytosis\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. However, serous retinal detachment (SRD) in her LE has been reported less commonly in the setting of acute leukemia and may develop as a result of choroidal involvement by leukemic cells causing retinal pigment epithelial disturbances or due to incompetence of the outer blood‒retinal barrier (BRB), which induces retinal pigment epithelial changes\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Although they are more common in acute (vs. chronic) leukemia, they are less common in patients with the lymphoid (vs. myeloid) subtypes, females and older patients, making our patient an unlikely suspect \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Hyperreflective specks in the vitreous give the impression of vitreous seeding and considered as leukemic infiltrates. This may be caused by the leukaemic cells entering the vitreous from optic disk neovascularization, and vitreous haemorrhage allows neoplastic cells to enter the vitreous cavity, similar to the presentation in our case\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWith the increase in survival of patients with leukemia, the incidence of CNS relapse is on the rise. The optic nerve can reveal leukemic involvement of the CNS\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. However, optic nerve infiltration as an initial sign of relapse is quite rare. The eyes and optic nerves are identified as pharmacological sanctuaries for leukemia therapy because the BRB shields the CNS from any systemically administered chemotherapeutic drugs\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Thus, many adjuvant therapies are often required to achieve complete remission. In our patient, bone marrow and CSF aspiration showed massive leukemic cells, while the CSF open pressure was normal. Researchers have postulated that one does not have to suspect increased intracranial pressure to explain swelling of the optic nerve since leukemic infiltration through the central retinal vessels and vessels in the pial septa is sufficient to cause venous congestion and/or ischemia with edema\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Optic neuropathy in the context of leukemia can be diagnosed through a broad variety of methods, including infiltration, infections, compression, vasculitis, radiotherapy-induced complications or adverse effects of chemotherapeutic agents\u003csup\u003e[\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. All these possibilities should be excluded through careful investigations. There were no signs of infection. Furthermore, the absence of neurologic and dermatologic signs, such as dysacusis, vitiligo, and poliosis, is not consistent with Harada's syndrome. A diagnosis of leukemic optic nerve infiltration was highly considered. An 8-week follow-up appointment at the ophthalmology clinic demonstrated functional and anatomic improvement in both eyes. In the present case, cerebral MRI showed no enhancement of the optic nerve top or bottom, which also explains that radiological features are neither specific nor sensitive for ocular leukemia\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. A recent review illustrated the poor sensitivity of CSF cytology\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. Of note, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting disease relapse. Progress in the research and therapy of adult ALL is accelerating\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e, and future studies should investigate better approaches for the early diagnosis of relapsed disease and more intensive strategies to improve patient survival.\u003c/p\u003e \u003cp\u003eIn summary, understanding ocular involvement in leukemia is crucial since the eye is the only organ where leukemic infiltration to nerves and blood vessels can be observed directly. Recognizing fundus changes in leukemia allows earlier diagnosis and prompt treatment. Ophthalmologists should be aware of these possible manifestations and possible etiologies in patients with ALL, even if they have achieved disease remission. In this report, we present an unusual case of bilateral optic nerve infiltration and leukemic retinopathy as initial signs of Ph\u003csup\u003e+\u003c/sup\u003e-ALL relapse with CNS involvement in an elderly female and explore the underlying proposed pathologic basis of these ocular manifestations in leukemia. Hence, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting disease relapse.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePh\u003csup\u003e+\u003c/sup\u003e-ALL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePhiladelphia chromosome-positive acute lymphoblastic leukemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCentral nervous system\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eright eye\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eleft eye\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIOP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntraocular pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOptical coherence tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebrospinal fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBRB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eblood‒retinal barrier.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYW collected the patients\u0026rsquo; medical records, fundus and OCT images, and wrote and revised the manuscript. LZ was the haematologist who contributed to the revision of manuscript. HC, ZL and HW was responsible for clinical evaluation and management of the patient\u0026rsquo;s ophthalmic manifestations and contributed to revision of the manuscript. RB, LH, YX, SL, QW are contributed to revision of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding or grant support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWritten\u0026nbsp;informed\u0026nbsp;consent to publish the report was obtained from the subject and their legal guardians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e Department of Ophthalmology, Peking University Shougang Hospital, Beijing, China. \u003csup\u003e2\u003c/sup\u003eDepartment of haematology, Air Force Medical University, Beijing, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNikaido H, Mishima H, Ono H, Choshi K, Dohy H. 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J Hematol Oncol. 2023;16(1):22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13045-023-01409-5\u003c/span\u003e\u003cspan address=\"10.1186/s13045-023-01409-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Case report, Philadelphia chromosome-positive acute lymphoblastic leukemia, Optic nerve infiltration, Leukemic Retinopathy, Relapse","lastPublishedDoi":"10.21203/rs.3.rs-3791887/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3791887/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eWe describe a case in which bilateral optic nerve infiltration and leukemic retinopathy were the initial signs of disease relapse in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph\u003csup\u003e+\u003c/sup\u003e-ALL) with central nervous system (CNS) involvement.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eA 65-year-old Asian female with Ph\u003csup\u003e+\u003c/sup\u003e-ALL in complete remission presented at our institution with symptoms of visual disturbance, central scotoma and pain with eye movement in both eyes for a 1-month duration. Ophthalmic examination revealed remarkable optic disc swelling with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and retinal hemorrhages in both eyes. She was subsequently referred to the treating oncologist and diagnosed with Ph\u003csup\u003e+\u003c/sup\u003e-ALL relapse with multiple relapsed diseases involving the bone marrow and CNS. After intrathecal (IT) therapy, her visual acuity dramatically improved, and her leukemic infiltrates decreased.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003eTo the best of our knowledge, this is the first case report of ALL relapse with CNS involvement presenting as bilateral optic nerve infiltration and leukemic retinopathy in an adult. Hence, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting leukemia relapse.\u003c/p\u003e","manuscriptTitle":"Bilateral optic nerve infiltration and leukemic retinopathy as initial signs of leukemia relapse with central nervous system involvement in an adult: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-02 20:10:13","doi":"10.21203/rs.3.rs-3791887/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-11T04:06:46+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-23T04:16:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-14T09:40:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"e2c1956a-2c25-4e9d-8a74-61b9f34396e6_SNPRID","date":"2024-03-14T09:31:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3499703b-60c2-48d4-943b-f9a51aaf2715","date":"2024-03-04T14:59:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5c262f9a-b5e1-4346-8af6-bd86ae104f1c","date":"2024-02-27T19:30:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-22T17:52:06+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-12-28T10:20:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-26T12:47:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-26T12:47:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2023-12-22T12:11:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d25f2cbe-e0b8-4ac0-a3b5-43bb10f003d2","owner":[],"postedDate":"January 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-05-17T03:10:09+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-02 20:10:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3791887","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3791887","identity":"rs-3791887","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}