Varicella zoster virus associated non-necrotizing retinopathy:Three case reports and literature review

Varicella zoster virus associated non-necrotizing retinopathy:Three case reports and literature review | 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 Varicella zoster virus associated non-necrotizing retinopathy:Three case reports and literature review Zhe Li, Min Xu, Fang Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6966883/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 Purpose : To report the clinical features, diagnostic approaches, and therapeutic outcomes of three cases of varicella zoster virus (VZV)-associated non-necrotizing retinopathy (NNHR) and review the relevant literature. Methods : Clinical data were collected by reviewing the medical records of three patients diagnosed with NNHR. Results : All patients presented with unilateral vision loss, accompanied by anterior chamber and vitreous inflammation, but lacked peripheral retinal necrosis. Two patients were detected with VZV through aqueous humor PCR testing, while one patient was identified via metagenomic testing. Post-treatment, visual acuity improved significantly, with resolution of inflammation, absorption of retinal vascular sheathing, and no necrotic lesions during follow-up. Conclusion : NNHR should be suspected in cases of significant vitritis with concomitant retinal vasculitis to avoid misdiagnosis as idiopathic uveitis. Early PCR testing of intraocular fluid is critical for definitive diagnosis. Prompt systemic antiviral therapy effectively improves visual outcomes and mitigates inflammation. Figures Figure 1 Figure 2 Figure 3 Introduction Case 1 A 45-year-old male visited our hospital on May 14, 2021, presenting with a "20-day decline in left eye vision." The best corrected visual acuity (BCVA) was 0.5 of the left eye and the intraocular pressure was 12 mmHg (1 mmHg=0.133 kPa). Slit-lamp examination revealed mild congestion of the conjunctiva in the left eye, with mutton-fat keratic precipitates (KP) on the posterior corneal surface, aqueous cells (+), aqueous flare (+). The optic disc margins were indistinct due to inflammatory vitreous opacities with cells (+++), segmental white sheath changes of vascular, with no necrotic lesions in the peripheral retina (Figure 1-A). Ocular B-scan ultrasound revealed numerous punctate hyperechoic foci in the vitreous of the left eye (Figure 1-B). Fundus fluorescein angiography (FFA) of the left eye, hazy refractive media obscure fluorescence details. Early phases showed dilated capillaries on the optic disc with ill-defined margins, along with extensive retinal vascular leakage and segmental vascular hyper-fluorescence. Late phases revealed persistent optic disc leakage and blurred disc margins (Figure 1-C). Initial diagnosis: Panuveitis in the left eye. Admission tests include complete blood count, complete biochemical tests, autoantibody spectrum, C-reactive protein, erythrocyte sedimentation rate, tuberculosis, etc. showed no significant abnormalities. The results of polymerase chain reaction (PCR) detection in the aqueous humor of the left eye indicate strong positivity for Varicella zoster virus (VZV), 2.68x10 5 Copies/ml. Diagnosed with left eye varicella zoster virus infected non-necrotizing uveitis based on clinical manifestations and aqueous humor virus testing. Administer intravenous infusion of acyclovir at a dose of 10mg/kg per body weight, every 8 hours (three times a daily), for 10 days. Add oral Prednisone tablets (40 mg once daily) 24 hours after initiating antiviral therapy. Concurrently administer Ganciclovir 2 mg/0.1 ml via intravitreal injection every 3 days for a total of 2 doses. Upon discharge, switch to oral Acyclovir tablets (0.8 g per dose, five times daily) and taper Prednisone by reducing the dose by 10 mg weekly. Four months later, the patient's left eye visual acuity improved to 1.0, aqueous cells (-), aqueous flare (-), vitreous haze reduced, and retinal vascular white sheathing was largely resolved (Figure 1-D). Case 2 A 27-year-old male presented to our hospital on February 21, 2022, with a chief complaint of “decreased vision accompanied by eye swelling in left eye for 7days”. The BCVA was 0.4 and the intraocular pressure was 34 mmHg of the left eye. Ocular findings of the left eye: conjunctival congestion, mild corneal edema, mutton-fat KP (+), aqueous cells (++), aqueous flare (++), vitreous flocculent opacity with cells (+), white vascular sheathing observed, with no necrotic lesions in the peripheral retina (Figure 2-A). In the early phase, FFA shows dilation of the optic disc capillaries with blurred margins, and fluorescence leakage and staining of the retinal vascular; In the late phase, persistent fluorescence leakage from the optic disc (Figure 2-B). Initial diagnosis: Panuveitis in the left eye. The PCR test results of the aqueous humor indicate strong positivity for VZV, 8.78 * 10 6 Copies/ml. Further diagnosed with varicella zoster virus infected non-necrotizing uveitis in the left eye. In addition to local intraocular pressure-lowering therapy, other treatments were the same as before. After a follow-up visit one month later, the patient's visual acuity improved to 1.0, with normal intraocular pressure, aqueous cells (-), aqueous flashes (-), vitreous haze reduced, retinal vascular white sheathing absorption, no necrotic lesions in the retina (Figure 2-C). Case 3 A 46-year-old male visited our hospital on April 17, 2024, with a chief complaint of “decreased vision in left eye for 14 days”. Diagnosed by the local hospital "Glaucomatocyclitic Crisis (Posner-Schlossman Syndrome", with the intraocular pressure 30mmHg measured. Presented to our hospital for further management. The BCVA was 0.02 and the intraocular pressure was 13 mmHg of the left eye. Ocular findings of the left eye: mild conjunctival congestion, transparent cornea, small KP (+), aqueous cells (+), aqueous flare (+), significant vitreous opacity, visible yellow-white mass lesions, and no necrotic lesions in the peripheral retina (Figure 3-A). A large number of punctate strong echoes can be detected in the vitreous body by ocular B-scan ultrasound (Figure 3-B). Admission diagnosis: Uveitis with high suspicion of infectious etiology. Diagnostic vitrectomy for the left eye was performed on April 19, 2024, and vitreous humor was collected for metagenomic testing. White vascular sheathing observed along peripheral retinal vessels, but no peripheral necrotic lesions were identified (Figure 3-C). Post-operation FFA findings: In the early phase, the capillaries on the surface of the optic disc dilated and the margins are blurred; In the late phase, fluorescence leakage from the optic disc, and the peripheral retinal vascular on the temporal side was stained (Figure 3-D, E). The metagenomic testing result of the left eye vitreous: VZV positive, PCR test result indicated VZV positive: 6.65 * 10 4 copies/ml. The revised diagnosis was: varicella zoster virus infected non-necrotizing uveitis. Oral administration of 0.8 g of acyclovir tablets was given, 5 times daily. After a follow-up visit one month later, the patient's visual acuity improved to 0.9, with aqueous cells (-), aqueous flare (-), vitreous clear, retinal vascular white sheathing absorption, and no necrotic lesions in the retina (Figure 3-F). Discussion Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and VZV are large double-stranded DNA viruses belonging to the Herpesviridae family，can establish latency in the trigeminal ganglia following primary infection. They may reactivate and spread along nerve axons to cutaneous or ocular tissues during periods of immune suppression. 1 Ocular infections can manifest as keratitis, scleritis, anterior uveitis, and acute retinal necrosis (ARN) . 2 ARN is one of the most serious complications of VZV infection, characterized by rapidly progressing peripheral retinal necrosis, occlusive vasculitis, and vitreous opacity, often leading to retinal detachment and vision loss. 3 In recent years, non-necrotizing herpetic retinopathy (NNHR) caused by VZV infection has gradually been recognized as an atypical manifestation of herpetic retinitis. So far, only a few NNHR case series have been reported. 4–10 In 2003, Bodaghi et al. 4 first reported five NNHR patients, demonstrating that herpesvirus can induce NNHR. The authors conducted aqueous humor analysis in 37 patients with corticosteroid-resistant posterior uveitis, identifying herpesvirus positivity in 5 cases (HSV in 2 cases, VZV in 3 cases). Viral detection was achieved through PCR in 4 cases and Goldman-Witmer coefficient analysis in 1 case. All five patients were immunocompetent with no prior history of viral anterior uveitis. These individuals had been previously diagnosed with birdshot chorioretinopathy, Behçet's disease, or idiopathic retinal vasculitis. Clinical manifestations included chronic posterior uveitis (hyaloiditis, retinal edema), mild anterior chamber inflammation, arteriolar sheathing, occlusive retinal vasculitis, and optic papillitis. Unlike ARN, NNHR lacks characteristic retinal necrotic lesions. It may present unilaterally or bilaterally and is primarily characterized by chronic inflammatory manifestations including hyaloiditis, retinal vasculitis and/or optic papillitis, or panuveitis, with retinal vascular involvement serving as a distinguishing feature. FFA shows diffuse vascular leakage and staining, which can involve arteries, veins, or both. Patients with NNHR typically exhibit mild anterior chamber reactions. The different clinical forms of herpetic viral retinitis may be associated with the intraocular viral load and the host's immune status. It is hypothesized that the underlying reason may be that NNHR patients exhibit better functional cellular immunity compared to ARN patients. 6 Following VZV reactivation, stronger cellular immunity might restrict the virus's direct cytolytic effects and instead trigger vasculitis and immune-mediated chronic inflammatory responses . All three cases in this study were young to middle-aged males without systemic immunosuppressive conditions, suggesting they may possess more robust cellular immune function. Early and definitive diagnosis is crucial for NNHR. With the development of intraocular fluid detection technology, aqueous humor PCR virus detection can provide reliable pathogenic evidence for NNHR. 6,11 In our study, among the three patients, two were detected with VZV through aqueous humor PCR testing, while one case was identified via metagenomic testing, which was later subsequently confirmed with PCR to determine its viral load. Wensing et al. reported several cases of non-ARN herpetic retinitis, with positive Goldmann Walter coefficient (GWC) and negative PCR result. Therefore, when PCR results are negative, GWC should be considered as a supplementary diagnostic method. 6 Antiviral therapy should be initiated immediately upon confirmation of viral infection. Multiple studies recommend oral acyclovir (800 mg five times daily) or oral valacyclovir (2-3 g/day), with the treatment course to be maintained for approximately 8 months to prevent recurrence. In cases of frequent relapses, long-term antiviral prophylaxis may be considered. Albert et al. 11 published the sole long-term follow-up report on NNHR, describing two cases with occlusive retinal vasculitis and incipient neovascularization diagnosed through aqueous humor PCR testing. Although both patients demonstrated good initial responses to antiviral therapy, they nevertheless experienced multiple recurrences during follow-up. While visual prognosis in NNHR is generally favorable, those presenting with occlusive vasculitis may ultimately result in suboptimal final visual acuity. All three patients in this study received systemic antiviral therapy following confirmed VZV infection. Patient 1 was additionally administered intravitreal ganciclovir injections as adjunctive treatment. Patients 1 and 2 received adjunctive oral corticosteroids at low-to-moderate doses post-antiviral therapy, while Patient 3 did not receive corticosteroids due to undergoing vitrectomy. Notably, all three cases demonstrated significant visual acuity improvement and marked ocular clinical improvement following antiviral treatment. In summary, NNHR represents an uncommon uveitis manifestation caused by HSV and VZV. This entity should be suspected in cases of severe vitritis with concomitant retinal vasculitis. Intraocular fluid analysis facilitates definitive diagnosis, where early detection and prompt antiviral intervention may improve visual outcomes in affected patients. Declarations Acknowledgements Not applicable. Authors' contributions Zhe Li and Min Xu wrote the main manuscript text and prepared all figures. Fang Chen have substantively revised it. Funding The author(s) reported that there is no funding associated with the work featured in this article. Ethics approval and consent to participate The study was approved by the Research Ethics Committee of the Northern Jiangsu People’s Hospital Affiliated to Yangzhou University. Written informed consent was obtained from the patient for publication of this case reports and accompanying images. Consent for publication The patient gave written informed consent of their personal details for the publication of this case report, including images and clinical data base. Availability of data and materials No datasets were generated or analysed during the current study. Competing interests The authors declare no competing interests. References Tugal-Tutkun I, Cimino L, Akova YA. Review for Disease of the Year: Varicella Zoster Virus-Induced Anterior Uveitis. Ocular Immunology and Inflammation . 2018;26(2):171-177. doi:10.1080/09273948.2017.1383447 Miserocchi E, Waheed NK, Dios E, et al. Visual outcome in herpes simplex virus and varicella zoster virus uveitis. Ophthalmology . 2002;109(8):1532-1537. doi:10.1016/S0161-6420(02)01113-2 Holland GN, Executive Committee of the American Uveitis Society. Standard Diagnostic Criteria for the Acute Retinal Necrosis Syndrome. American Journal of Ophthalmology . 1994;117(5):663-666. doi:10.1016/S0002-9394(14)70075-3 Bodaghi B, Rozenberg F, Cassoux N, Fardeau C, LeHoang P. Nonnecrotizing herpetic retinopathies masquerading as severe posterior uveitis. Ophthalmology . 2003;110(9):1737-1743. doi:10.1016/S0161-6420(03)00580-3 Wickremasinghe SS, Stawell R, Lim L, Pakrou N, Zamir E. Non-necrotizing herpetic vasculitis. Ophthalmology . 2009;116(2):361. doi:10.1016/j.ophtha.2008.09.043 Wensing B, de Groot-Mijnes JDF, Rothova A. Necrotizing and nonnecrotizing variants of herpetic uveitis with posterior segment involvement. Arch Ophthalmol . 2011;129(4):403-408. doi:10.1001/archophthalmol.2010.313 Albert K, Masset M, Bonnet S, Willermain F, Caspers L. Long-term follow-up of herpetic non-necrotizing retinopathy with occlusive retinal vasculitis and neovascularization. J Ophthalmic Inflamm Infect . 2015;5:6. doi:10.1186/s12348-015-0038-z Narayanan S, Gopalakrishnan M, Giridhar A, Anthony E. Varicella Zoster-related Occlusive Retinal Vasculopathy--A Rare Presentation. Ocul Immunol Inflamm . 2016;24(2):227-230. doi:10.3109/09273948.2014.938759 Hu F, Peng X, Wang H. Unilateral Acute Retinal Necrosis with Contralateral Non-necrotizing Herpetic Uveitis. Ocular Immunology and Inflammation . 2024;32(3):351-354. doi:10.1080/09273948.2020.1860232 Kumar A, Chatterji A, Sharma VK, Ambiya V, Kumar S, Tandel K. Bilateral non-necrotizing herpetic retinopathy: Unusual initial presentation of ocular HSV-1 infection. J Med Virol . 2024;96(5):e29633. doi:10.1002/jmv.29633 Albert K, Masset M, Bonnet S, Willermain F, Caspers L. Long-term follow-up of herpetic non-necrotizing retinopathy with occlusive retinal vasculitis and neovascularization. J Ophthal Inflamm Infect . 2015;5(1):6. doi:10.1186/s12348-015-0038-z 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6966883","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":492253191,"identity":"88e9bbee-6f24-4415-a800-7a5b5198ca25","order_by":0,"name":"Zhe Li","email":"","orcid":"","institution":"Northern Jiangsu People’s Hospital Affiliated to Yangzhou University","correspondingAuthor":false,"prefix":"","firstName":"Zhe","middleName":"","lastName":"Li","suffix":""},{"id":492253192,"identity":"3c5e7926-16eb-4243-807f-96509c0610c3","order_by":1,"name":"Min Xu","email":"","orcid":"","institution":"Northern Jiangsu People’s Hospital Affiliated to Yangzhou University","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Xu","suffix":""},{"id":492253193,"identity":"fc2eefbe-eac0-416f-a384-61eee3323d6c","order_by":2,"name":"Fang Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYDAC5gMMDIwNDAz8zMyHHxCnhS0BokWynS3NgDQtBud5FCSI0sHfxmP88eeOw4mbD/MwGDDU2EQT1CJxjMfAmPfM4cRth3kPPGA4lpbbQEiLgXyPQTJjG0gLX4IBY8NhIrSw8Rgc/AnUsrmZx0CCWC2GDbxALRuYidUicYytmJn3TLrxjMPAQE4gxi/8bcybgSFmLdvff/jwgw81NoS1MDBwgCKw2RGsMoGwchBgfwAk6uyJUzwKRsEoGAUjEgAAzoBBISTY7C8AAAAASUVORK5CYII=","orcid":"","institution":"Northern Jiangsu People’s Hospital Affiliated to Yangzhou University","correspondingAuthor":true,"prefix":"","firstName":"Fang","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2025-06-24 14:38:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6966883/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6966883/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87884087,"identity":"15aa7b2b-2eae-4904-933e-96826caf7d01","added_by":"auto","created_at":"2025-07-30 04:57:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":283793,"visible":true,"origin":"","legend":"\u003cp\u003eA: Fundus showed vitreous opacity, segmental white sheath changes of vascular, with no necrotic lesions in the peripheral retina. \u003cstrong\u003eB\u003c/strong\u003e: Ocular B-scan ultrasound revealed numerous punctate hyperechoic foci in the vitreous. \u003cstrong\u003eC\u003c/strong\u003e: FFA showed dilated capillaries on the optic disc with ill-defined margins, along with extensive retinal vascular leakage and segmental vascular hyper-fluorescence. \u003cstrong\u003eD\u003c/strong\u003e: Fundus showed vitreous haze was reduced, and vascular white sheathing was largely resolved four months later.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6966883/v1/7fccd887c6cf2b2643c116ce.png"},{"id":87884088,"identity":"d86aa45e-eab7-43e1-8257-9adbd0528880","added_by":"auto","created_at":"2025-07-30 04:57:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":353684,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e: Fundus showed\u003cstrong\u003e \u003c/strong\u003esegmental white vascular sheathing, with no necrotic lesions in the peripheral retina. \u003cstrong\u003eB\u003c/strong\u003e: FFA shows dilation of the optic disc capillaries with blurred margins, and fluorescence leakage and staining of the retinal veins. \u003cstrong\u003eC\u003c/strong\u003e: Fundus showed vitreous haze was reduced, retinal vascular white sheathing was absorbed, with no necrotic lesions one month later.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6966883/v1/debca8e5ae3c32b1bd68e076.png"},{"id":87886018,"identity":"dfe1393c-9a52-4d87-9c01-497a743478ac","added_by":"auto","created_at":"2025-07-30 05:13:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":636835,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e: Fundus showed blurred datails due to significant vitreous opacity, with visible yellow-white mass lesions. \u003cstrong\u003eB\u003c/strong\u003e: A large number of punctate strong echoes was detected in the vitreous body by ocular B-scan ultrasound. \u003cstrong\u003eC\u003c/strong\u003e: Segmental white vascular sheathing was observed, but no peripheral necrotic lesions were identified on the post-operation fundus. \u003cstrong\u003eD \u003c/strong\u003eand \u003cstrong\u003eE\u003c/strong\u003e: Post-operation FFA showed the capillaries on the surface of the optic disc dilated and the margin was blurred, and the peripheral retinal vascular on the temporal side was stained. \u003cstrong\u003eF\u003c/strong\u003e: After a follow-up visit one month later, fundus showed vascular white sheathing absorption, and no necrotic lesions in the retina.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6966883/v1/44385780ead4b39e44b74071.png"},{"id":94728027,"identity":"bd869ac9-f2e1-4887-8776-ca325af7fab8","added_by":"auto","created_at":"2025-10-30 07:02:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2011244,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6966883/v1/0b669600-e2a3-48ba-a740-46debb3959c1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Varicella zoster virus associated non-necrotizing retinopathy:Three case reports and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCase 1\u0026nbsp;A 45-year-old male visited our hospital on May 14, 2021, presenting with a \u0026quot;20-day decline in left eye vision.\u0026quot; The best corrected visual acuity (BCVA) was 0.5 of the left eye and the intraocular pressure was 12 mmHg (1 mmHg=0.133 kPa). \u0026nbsp;Slit-lamp examination revealed mild congestion of the conjunctiva in the left eye, with mutton-fat keratic precipitates (KP) on the posterior corneal surface, aqueous cells (+), aqueous flare (+). The optic disc margins were indistinct due to inflammatory vitreous opacities with cells (+++), segmental white sheath changes of vascular, with no necrotic lesions in the peripheral retina (Figure 1-A). Ocular B-scan ultrasound revealed numerous punctate hyperechoic foci in the vitreous of the left eye (Figure 1-B). Fundus fluorescein angiography (FFA) of the left eye, hazy refractive media obscure fluorescence details. Early phases showed dilated capillaries on the optic disc with ill-defined margins, along with extensive retinal vascular leakage and segmental vascular hyper-fluorescence. Late phases revealed persistent optic disc leakage and blurred disc margins (Figure 1-C). Initial diagnosis: Panuveitis in the left eye. Admission tests include complete blood count, complete biochemical tests, autoantibody spectrum, C-reactive protein, erythrocyte sedimentation rate, tuberculosis, etc. showed no significant abnormalities. The results of polymerase chain reaction (PCR) detection in the aqueous humor of the left eye indicate strong positivity for Varicella zoster virus (VZV), 2.68x10\u003csup\u003e5\u0026nbsp;\u003c/sup\u003eCopies/ml. Diagnosed with left eye varicella zoster virus infected non-necrotizing uveitis based on clinical manifestations and aqueous humor virus testing. Administer intravenous infusion of acyclovir at a dose of 10mg/kg per body weight, every 8 hours (three times a daily), for 10 days. Add oral Prednisone tablets (40 mg once daily) 24 hours after initiating antiviral therapy. Concurrently administer Ganciclovir 2 mg/0.1 ml via intravitreal injection every 3 days for a total of 2 doses. Upon discharge, switch to oral Acyclovir tablets (0.8 g per dose, five times daily) and taper Prednisone by reducing the dose by 10 mg weekly. Four months later, the patient\u0026apos;s left eye visual acuity improved to 1.0, aqueous cells (-), aqueous flare (-), vitreous haze reduced, and retinal vascular white sheathing was largely resolved (Figure 1-D).\u003c/p\u003e\n\u003cp\u003eCase 2 A 27-year-old male presented to our hospital on February 21, 2022, with a chief complaint of \u0026ldquo;decreased vision accompanied by eye swelling in left eye for 7days\u0026rdquo;. \u0026nbsp;The BCVA was 0.4 and the intraocular pressure was 34 mmHg of the left eye. Ocular findings of the left eye: conjunctival congestion, mild corneal edema, mutton-fat KP (+), aqueous cells (++), aqueous flare (++), vitreous flocculent opacity with cells (+), white vascular sheathing observed, with no necrotic lesions in the peripheral retina (Figure 2-A). In the early phase, FFA shows dilation of the optic disc capillaries with blurred margins, and fluorescence leakage and staining of the retinal vascular; In the late phase, persistent fluorescence leakage from the optic disc (Figure 2-B). Initial diagnosis: Panuveitis in the left eye. The PCR test results of the aqueous humor indicate strong positivity for VZV, 8.78 * 10\u003csup\u003e6\u0026nbsp;\u003c/sup\u003eCopies/ml. Further diagnosed with varicella zoster virus infected non-necrotizing uveitis in the left eye. In addition to local intraocular pressure-lowering therapy, other treatments were the same as before. After a follow-up visit one month later, the patient\u0026apos;s visual acuity improved to 1.0, with normal intraocular pressure, aqueous cells (-), aqueous flashes (-), vitreous haze reduced, retinal vascular white sheathing absorption, no necrotic lesions in the retina (Figure 2-C).\u003c/p\u003e\n\u003cp\u003eCase 3 A 46-year-old male visited our hospital on April 17, 2024, with a chief complaint of \u0026ldquo;decreased vision in left eye for 14 days\u0026rdquo;. Diagnosed by the local hospital \u0026quot;Glaucomatocyclitic Crisis (Posner-Schlossman Syndrome\u0026quot;, with the intraocular pressure 30mmHg measured. Presented to our hospital for further management. The BCVA was 0.02 and the intraocular pressure was 13 mmHg of the left eye. Ocular findings of the left eye: mild conjunctival congestion, transparent cornea, small KP (+), aqueous cells (+), aqueous flare (+), significant vitreous opacity, visible yellow-white mass lesions, and no necrotic lesions in the peripheral retina (Figure 3-A). A large number of punctate strong echoes can be detected in the vitreous body by ocular B-scan ultrasound (Figure 3-B). Admission diagnosis: Uveitis with high suspicion of infectious etiology. Diagnostic vitrectomy for the left eye was performed on April 19, 2024, and vitreous humor was collected for metagenomic testing. White vascular sheathing observed along peripheral retinal vessels, but no peripheral necrotic lesions were identified (Figure 3-C). Post-operation FFA findings: In the early phase, the capillaries on the surface of the optic disc dilated and the margins are blurred; In the late phase, fluorescence leakage from the optic disc, and the peripheral retinal vascular on the temporal side was stained (Figure 3-D, E). The metagenomic testing result of the left eye vitreous: VZV positive, PCR test result indicated VZV positive: 6.65 * 10\u003csup\u003e4\u003c/sup\u003e copies/ml. The revised diagnosis was: varicella zoster virus infected non-necrotizing uveitis. Oral administration of 0.8 g of acyclovir tablets was given, 5 times daily. After a follow-up visit one month later, the patient\u0026apos;s visual acuity improved to 0.9, with aqueous cells (-), aqueous flare (-), vitreous clear, retinal vascular white sheathing absorption, and no necrotic lesions in the retina (Figure 3-F).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHerpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and VZV are large double-stranded DNA viruses belonging to the Herpesviridae family，can establish latency in the trigeminal ganglia following primary infection. They may reactivate and spread along nerve axons to cutaneous or ocular tissues during periods of immune suppression.\u003csup\u003e1\u003c/sup\u003e Ocular infections can manifest as keratitis, scleritis, anterior uveitis, and acute retinal necrosis (ARN) .\u0026nbsp;\u003csup\u003e2\u003c/sup\u003e ARN is one of the most serious complications of VZV infection, characterized by rapidly progressing peripheral retinal necrosis, occlusive vasculitis, and vitreous opacity, often leading to retinal detachment and vision loss.\u003csup\u003e3\u003c/sup\u003e In recent years, non-necrotizing herpetic retinopathy (NNHR) caused by VZV infection has gradually been recognized as an atypical manifestation of herpetic retinitis. So far, only a few NNHR case series have been reported.\u0026nbsp;\u003csup\u003e4\u0026ndash;10\u003c/sup\u003e In 2003, Bodaghi et al.\u0026nbsp;\u003csup\u003e4\u003c/sup\u003efirst reported five NNHR patients, demonstrating that herpesvirus can induce NNHR. The authors conducted aqueous humor analysis in 37 patients with corticosteroid-resistant posterior uveitis, identifying herpesvirus positivity in 5 cases (HSV in 2 cases, VZV in 3 cases). Viral detection was achieved through PCR in 4 cases and Goldman-Witmer coefficient analysis in 1 case. All five patients were immunocompetent with no prior history of viral anterior uveitis. These individuals had been previously diagnosed with birdshot chorioretinopathy, Beh\u0026ccedil;et\u0026apos;s disease, or idiopathic retinal vasculitis. Clinical manifestations included chronic posterior uveitis (hyaloiditis, retinal edema), mild anterior chamber inflammation, arteriolar sheathing, occlusive retinal vasculitis, and optic papillitis. Unlike ARN, NNHR lacks characteristic retinal necrotic lesions. It may present unilaterally or bilaterally and is primarily characterized by chronic inflammatory manifestations including hyaloiditis, retinal vasculitis and/or optic papillitis, or panuveitis, with retinal vascular involvement serving as a distinguishing feature. FFA shows diffuse vascular leakage and staining, which can involve arteries, veins, or both. Patients with NNHR typically exhibit mild anterior chamber reactions. The different clinical forms of herpetic viral retinitis may be associated with the intraocular viral load and the host\u0026apos;s immune status. It is hypothesized that the underlying reason may be that NNHR patients exhibit better functional cellular immunity compared to ARN patients.\u003csup\u003e6\u003c/sup\u003e Following VZV reactivation, stronger cellular immunity might restrict the virus\u0026apos;s direct cytolytic effects and instead trigger vasculitis and immune-mediated chronic inflammatory responses . All three cases in this study were young to middle-aged males without systemic immunosuppressive conditions, suggesting they may possess more robust cellular immune function.\u003c/p\u003e\n\u003cp\u003eEarly and definitive diagnosis is crucial for NNHR. With the development of intraocular fluid detection technology, aqueous humor PCR virus detection can provide reliable pathogenic evidence for NNHR.\u003csup\u003e6,11\u003c/sup\u003e In our study, among the three patients, two were detected with VZV through aqueous humor PCR testing, while one case was identified via metagenomic testing, which was later subsequently confirmed with PCR to determine its viral load. Wensing et al. reported several cases of non-ARN herpetic retinitis, with positive Goldmann Walter coefficient (GWC) and negative PCR result. Therefore, when PCR results are negative, GWC should be considered as a supplementary diagnostic method.\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAntiviral therapy should be initiated immediately upon confirmation of viral infection. Multiple studies recommend oral acyclovir (800 mg five times daily) or oral valacyclovir (2-3 g/day), with the treatment course to be maintained for approximately 8 months to prevent recurrence. In cases of frequent relapses, long-term antiviral prophylaxis may be considered. Albert et al.\u0026nbsp;\u003csup\u003e11\u003c/sup\u003epublished the sole long-term follow-up report on NNHR, describing two cases with occlusive retinal vasculitis and incipient neovascularization diagnosed through aqueous humor PCR testing. Although both patients demonstrated good initial responses to antiviral therapy, they nevertheless experienced multiple recurrences during follow-up. While visual prognosis in NNHR is generally favorable, those presenting with occlusive vasculitis may ultimately result in suboptimal final visual acuity. All three patients in this study received systemic antiviral therapy following confirmed VZV infection. Patient 1 was additionally administered intravitreal ganciclovir injections as adjunctive treatment. Patients 1 and 2 received adjunctive oral corticosteroids at low-to-moderate doses post-antiviral therapy, while Patient 3 did not receive corticosteroids due to undergoing vitrectomy. Notably, all three cases demonstrated significant visual acuity improvement and marked ocular clinical improvement following antiviral treatment.\u003c/p\u003e\n\u003cp\u003eIn summary, NNHR represents an uncommon uveitis manifestation caused by HSV and VZV. This entity should be suspected in cases of severe vitritis with concomitant retinal vasculitis. Intraocular fluid analysis facilitates definitive diagnosis, where early detection and prompt antiviral intervention may improve visual outcomes in affected patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhe Li and Min Xu wrote the main manuscript text and prepared all figures. Fang Chen have substantively revised it.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) reported that there is no funding associated with the work featured in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Research Ethics Committee of the\u0026nbsp;Northern Jiangsu People\u0026rsquo;s Hospital Affiliated to Yangzhou University. Written informed consent was obtained from the patient for publication of this case reports and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient gave written informed consent of their personal details for the publication of this case report, including images and clinical data base.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTugal-Tutkun I, Cimino L, Akova YA. Review for Disease of the Year: Varicella Zoster Virus-Induced Anterior Uveitis. \u003cem\u003eOcular Immunology and Inflammation\u003c/em\u003e. 2018;26(2):171-177. doi:10.1080/09273948.2017.1383447\u003c/li\u003e\n\u003cli\u003eMiserocchi E, Waheed NK, Dios E, et al. Visual outcome in herpes simplex virus and varicella zoster virus uveitis. \u003cem\u003eOphthalmology\u003c/em\u003e. 2002;109(8):1532-1537. doi:10.1016/S0161-6420(02)01113-2\u003c/li\u003e\n\u003cli\u003eHolland GN, Executive Committee of the American Uveitis Society. Standard Diagnostic Criteria for the Acute Retinal Necrosis Syndrome. \u003cem\u003eAmerican Journal of Ophthalmology\u003c/em\u003e. 1994;117(5):663-666. doi:10.1016/S0002-9394(14)70075-3\u003c/li\u003e\n\u003cli\u003eBodaghi B, Rozenberg F, Cassoux N, Fardeau C, LeHoang P. Nonnecrotizing herpetic retinopathies masquerading as severe posterior uveitis. \u003cem\u003eOphthalmology\u003c/em\u003e. 2003;110(9):1737-1743. doi:10.1016/S0161-6420(03)00580-3\u003c/li\u003e\n\u003cli\u003eWickremasinghe SS, Stawell R, Lim L, Pakrou N, Zamir E. Non-necrotizing herpetic vasculitis. \u003cem\u003eOphthalmology\u003c/em\u003e. 2009;116(2):361. doi:10.1016/j.ophtha.2008.09.043\u003c/li\u003e\n\u003cli\u003eWensing B, de Groot-Mijnes JDF, Rothova A. Necrotizing and nonnecrotizing variants of herpetic uveitis with posterior segment involvement. \u003cem\u003eArch Ophthalmol\u003c/em\u003e. 2011;129(4):403-408. doi:10.1001/archophthalmol.2010.313\u003c/li\u003e\n\u003cli\u003eAlbert K, Masset M, Bonnet S, Willermain F, Caspers L. Long-term follow-up of herpetic non-necrotizing retinopathy with occlusive retinal vasculitis and neovascularization. \u003cem\u003eJ Ophthalmic Inflamm Infect\u003c/em\u003e. 2015;5:6. doi:10.1186/s12348-015-0038-z\u003c/li\u003e\n\u003cli\u003eNarayanan S, Gopalakrishnan M, Giridhar A, Anthony E. Varicella Zoster-related Occlusive Retinal Vasculopathy--A Rare Presentation. \u003cem\u003eOcul Immunol Inflamm\u003c/em\u003e. 2016;24(2):227-230. doi:10.3109/09273948.2014.938759\u003c/li\u003e\n\u003cli\u003eHu F, Peng X, Wang H. Unilateral Acute Retinal Necrosis with Contralateral Non-necrotizing Herpetic Uveitis. \u003cem\u003eOcular Immunology and Inflammation\u003c/em\u003e. 2024;32(3):351-354. doi:10.1080/09273948.2020.1860232\u003c/li\u003e\n\u003cli\u003eKumar A, Chatterji A, Sharma VK, Ambiya V, Kumar S, Tandel K. Bilateral non-necrotizing herpetic retinopathy: Unusual initial presentation of ocular HSV-1 infection. \u003cem\u003eJ Med Virol\u003c/em\u003e. 2024;96(5):e29633. doi:10.1002/jmv.29633\u003c/li\u003e\n\u003cli\u003eAlbert K, Masset M, Bonnet S, Willermain F, Caspers L. Long-term follow-up of herpetic non-necrotizing retinopathy with occlusive retinal vasculitis and neovascularization. \u003cem\u003eJ Ophthal Inflamm Infect\u003c/em\u003e. 2015;5(1):6. doi:10.1186/s12348-015-0038-z\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":"","lastPublishedDoi":"10.21203/rs.3.rs-6966883/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6966883/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: To report the clinical features, diagnostic approaches, and therapeutic outcomes of three cases of varicella zoster virus (VZV)-associated non-necrotizing retinopathy (NNHR) and review the relevant literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Clinical data were collected by reviewing the medical records of three patients diagnosed with NNHR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: All patients presented with unilateral vision loss, accompanied by anterior chamber and vitreous inflammation, but lacked peripheral retinal necrosis. Two patients were detected with VZV through aqueous humor PCR testing, while one patient was identified via metagenomic testing. Post-treatment, visual acuity improved significantly, with resolution of inflammation, absorption of retinal vascular sheathing, and no necrotic lesions during follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: NNHR should be suspected in cases of significant vitritis with concomitant retinal vasculitis to avoid misdiagnosis as idiopathic uveitis. Early PCR testing of intraocular fluid is critical for definitive diagnosis. Prompt systemic antiviral therapy effectively improves visual outcomes and mitigates inflammation.\u003c/p\u003e","manuscriptTitle":"Varicella zoster virus associated non-necrotizing retinopathy:Three case reports and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-30 04:57:03","doi":"10.21203/rs.3.rs-6966883/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":"3ede9947-0429-43f7-93a7-c6545d84e7e2","owner":[],"postedDate":"July 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-29T08:38:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-30 04:57:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6966883","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6966883","identity":"rs-6966883","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}