Toxoplasma gondii Retinochoroiditis associated with Epstein-Barr Virus-Induced Retinal Necrosis in an Immunocompetent Patient

Toxoplasma gondii Retinochoroiditis associated with Epstein-Barr Virus-Induced Retinal Necrosis in an Immunocompetent Patient | 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 Short Report Toxoplasma gondii Retinochoroiditis associated with Epstein-Barr Virus-Induced Retinal Necrosis in an Immunocompetent Patient Maria Carmela Saturno, Danilo Iannetta, Ngoc Chau Nguyen, Lorette Leon, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8893893/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Purpose: To describe a rare case of concomitant Toxoplasma gondii (Tg) retinochoroiditis and Epstein–Barr virus (EBV) retinal necrosis in an immunocompetent patient, successfully treated with a combined intravitreal and systemic therapeutic approach. Methods: A 52-year-old immunocompetent woman with recurrent bilateral Tg retinochoroiditis presented with reactivation in the left eye unresponsive to standard antiparasitic therapy. Comprehensive clinical examination, including vitreous polymerase chain reaction (PCR) testing, was performed. Results: PCR analysis of the vitreous sample confirmed the presence of both Tg and EBV. Intravitreal methotrexate (MTX) was initiated and administered over an 8-week period in combination with ongoing intravitreal clindamycin and systemic antiparasitic therapy, together with low-dose antiviral treatment. The patient demonstrated progressive clinical improvement, with stabilization of visual acuity and retinal morphology on optical coherence tomography (OCT). Serial vitreous PCR monitoring revealed a gradual decline in Tg and EBV loads until both pathogens became undetectable. No recurrence occurred during follow-up. Conclusion: This is the first reported case of Tg–EBV coinfection–related retinochoroiditis in an immunocompetent patient. The favorable outcome following intravitreal MTX supports a potential dual mechanism in EBV-associated retinal necrosis, combining immunomodulatory suppression of B-cell proliferation with a direct antiviral activity. This case underscores the importance of considering coinfection in atypical or treatment-refractory retinochoroiditis, even in immunocompetent hosts. retinochoroiditis retinal necrosis Toxoplasma gondii Epstein–Barr virus methotrexate intravitreal therapy Figures Figure 1 Figure 2 Figure 3 Introduction Toxoplasma gondii (Tg) is a ubiquitous intracellular parasite, with approximately one-third of the global human population estimated to have been exposed, representing one of the leading causes of posterior uveitis [1, 2]. The classic presentation is a unilateral, unifocal retinochoroiditis with overlying vitritis, although milder infections may manifest as multiple small outer retinal opacities, known as “punctate outer retinal toxoplasmosis”. Persistent or reactivated infection, particularly in immunocompromised hosts, may lead to extensive retinal necrosis mimicking other necrotizing retinitis, such as cytomegalovirus retinitis. Severe or atypical cases can also occur in elderly or immunocompetent patients infected with virulent strains [1–4]. The diagnosis of ocular toxoplasmosis (OT) is mainly clinical, but biological confirmation is crucial in atypical or treatment-resistant cases. Despite its incidence, the optimal therapy for OT is controversial and there is no consensus on which drugs must be used for prophylactic treatment of recurrences [1]. Coinfections with other pathogens, such as Epstein-Barr virus (EBV), have been reported in 7–8% of patients, regardless of immune status, complicating diagnosis and it is linked to a worse prognosis [4]. EBV is a ubiquitous DNA virus of the Herpesviridae family infecting over 90% of humans. It primarily targets B lymphocytes, establishing lifelong latency within these cells. Although usually asymptomatic, EBV can cause systemic and ocular diseases, including necrotizing retinitis, especially in immunocompromised individuals. In terms of treatment, antivirals or corticosteroids have shown variable benefits in isolated reports. In 2008, Frenkel et al. reported favorable outcomes describing a 10-year experience with intravitreal methotrexate (IVT MTX) for the treatment of vitreoretinal involvement in primary central nervous system lymphoma. As an antifolate antimetabolite, MTX inhibits DNA synthesis and suppresses the proliferation of activated B lymphocytes, the main reservoir of EBV. Based on this mechanism, IVT MTX has shown efficacy in EBV-related vitreoretinal lymphoma, and in few reported EBV-associated retinal necrosis, either alone or in combination with antiviral agents [5–9]. We hereby report a rare case of coinfection by EBV and Tg in an immunocompetent patient presenting with retinochoroiditis successfully treated by a combination of systemic antiviral and antiparasitic therapy, as well as IVT clindamycin and MTX. Case Presentation A 52-year-old immunocompetent woman with a history of depression, treated with venlafaxine, mirtazapine and pregabalin, had been followed at Helvetia Retina Associates, MIOS sa, Lausanne, Switzerland for bilateral Tg retinochoroiditis since 2009. The left eye (LE) experienced multiple recurrences from 2014 and underwent cataract surgery in 2023, achieving a postoperative best-corrected visual acuity (BCVA) of 20/20. In April 2024, a further recurrence in the LE was treated with oral azithromycin (500 mg on day 1, followed by 250 mg daily) and oral prednisone at a starting dose of 80 mg/day, which was gradually tapered. Given multiple risk factors for recurrence, including age over 40 years, bilateral disease, macular involvement and extensive lesion size, a six-month prophylactic regimen with pyrimethamine 25 mg and folic acid 15 mg was initiated in August 2024. However, prophylaxis was interrupted during a hospital admission for severe depression and the patient presented in October 2024 with recurrent inflammation in the LE. On presentation, BCVA had decreased to 20/60 and slit-lamp examination revealed 3 + anterior chamber cells, 1 + flare, vitritis and IOP was 43 mmHg. She was treated with azithromycin (500 mg on day 1 and 250 mg daily), topical dexamethasone (Dexafree®) six times daily, topical brinzolamide-brimonidine (Simbrinza®) twice daily and oral acetazolamide 250 mg twice daily. Because of intolerance to systemic corticosteroids, causing insomnia and mood deterioration, a topical approach was preferred and an IVT implant of dexamethasone 700 µg (Ozurdex®) was administered in her LE, resulting in temporary control of inflammation and visual improvement. In January 2025, during a follow up visit, the patient referred blurred vision. The ophthalmological examination revealed BCVA declined to 20/33 and a large area of retinal infiltration with a sharp leading edge to the temporal side of the fovea. Sheathing of neighbouring veins and arterioles, as well as blot hemorrhages were also noted in the adjacent retina. (Fig. 1 ). Because the patient admitted discontinuing prophylactic treatment during Christmas holidays, a further reactivation of Tg was suspected, and oral trimethoprim–sulfamethoxazole (Bactrim forte®) twice daily was initiated. Despite the medical treatment, the clinical course worsened, with progressive visual decline and enlargement of the retinal lesion. Optical coherence tomography (OCT) revealed marked retinal thickening, retinal hyperreflectivity and loss of retinal stratification, without choroidal involvement, vitreous cells or preretinal deposits (Fig. 2 , T0). Given the atypical clinical and imaging features, and after failing to achieve disease control with a single intravitreal injection of clindamycin, a pars plana vitrectomy with vitreous biopsy and removal of the Ozurdex® implant was performed. Polymerase chain reaction (PCR) analysis of the vitreous sample was positive for both Tg and EBV. Based on these findings, IVT MTX 400 µg was initiated in combination with IVT clindamycin (1mg), systemic acyclovir (800 mg 3 times a day) and Bactrim forte® (twice daily). Nine injections spaced between 5 and 14 days were given, based on the clinical response and PCR data (Table 1 ). MTX injections were continued until the EBV titers were negative on two repeat measurements. Clindamycin was discontinued when the Tg lesion appeared clinically quiescent. Table 1 Treatment and response characteristics following the initiation of intravitreal methotrexate Days since IVT initiation Visual acuity Quantitative PCR Titers Intravitreal Therapy Systemic Therapy ** EBV Toxoplasmosis Methotrexate Clindamycin* Acyclovir Sulfamethoxazole + trimethoprim 0 0.12 28229 254757 x x x x 5 0.2 1211 20522 x x x x 12 0.2 1091 7937 x x x x 20 800 2177 x x x x 26 0.2 928 2620 x x x x 33 0.13 1022 1046 x x x x 41 0.2 0 485 x x x x 54 0.12 0 141 x x x 160 0.16 0 0 x 280 0.2 Symbol “x” indicates that treatment was administered EBV: Epstein-Barr virus IVT: intravitreal therapy * IVT Clindamycin was given once, prior to the IVT methotrexate one week prior at the end of the vitrectomy ** For systemic therapy, the “x” indicates that the therapy was continued until this day. Bactrim forte was switched to pyrimethamine and folic acid on day 160. Over subsequent weeks, intraocular inflammation progressively subsided, and no further extension of the retinal lesion was observed on widefield imaging or OCT (Fig. 2 , T280). Serial vitreous PCR demonstrated a gradual decline in both EBV DNA and Tg loads. BCVA improved to 20/25 and remained stable at the most recent follow-up. Nine months after treatment initiation, the area of EBV-associated paramacular retinitis evolved into retinal pigment epithelium atrophy with minimal pigmentation and localized fibrosis; a coexisting epiretinal membrane was surgically peeled in July 2025 (Fig. 3 ). Discussion To our knowledge, this is the first reported case of concomitant Tg and EBV retinochoroiditis occurring in an immunocompetent patient. A similar coinfection has been described for the first time by Mejìa-Salgado et al., in a pharmacologically immunosuppressed patient receiving corticosteroids, MTX and abatacept for rheumatoid arthritis. In their report, the patient developed bilateral granulomatous anterior chamber inflammation, vitritis and extensive retinal necrosis with macular involvement. The concomitant infection was confirmed by PCR analysis of vitreous samples and the patient was treated with combined oral antiviral and antiparasitic therapy [2]. In contrast, our patient achieved sustained remission within two months through a dual pathogen-directed strategy consisting of IVT MTX and low-dose systemic acyclovir for EBV, together with IVT clindamycin and oral trimethoprim–sulfamethoxazole for Tg . Moreover, our case underscores the diagnostic challenges posed by rare ocular coinfections, particularly in patients with a known history of recurrent Tg retinochoroiditis, in whom disease reactivation may be erroneously attributed to Tg alone. In this context, OCT plays a pivotal role in raising suspicion for an alternative or additional etiology. As described by Pichi et al., Tg retinochoroiditis typically presents with hyperreflective preretinal deposits with associated choroidal involvement, whereas viral retinitis predominantly affects only retinal layers without choroidal infiltration [10]. In our patient, the emergence of a new retinal lesion characterized by marked retinal thickness and hyperreflectivity on OCT, in the absence of choroidal or preretinal involvement (Fig. 2 , T0), together with a poor response to conventional antiparasitic therapy, raised suspicion for an additional infectious etiology. Subsequently, vitreous biopsy under air [11] and PCR played a crucial role to achieve a definitive diagnosis. Furthermore, quantitative PCR on serial vitreous samples proved valuable in guiding targeted therapy. monitoring treatment response and allowing discontinuation of IVT therapy in only two months, when the titers were at the level of detection or below [6, 7]. From a therapeutic standpoint, the management of EBV-related retinitis remains difficult and controversial [6–8]. In vitro studies have shown that anti-herpesvirus drugs such as nucleoside/nucleotide analogs (ganciclovir, cidofovir) or pyrophosphate analogs (foscarnet) inhibit EBV-DNA polymerase activity [9]. However, in most clinical cases a slow rate of response is observed, associated with a significant vision loss [2, 12]. In this context, there is emerging evidence of IVT MTX’s antiviral effects in EBV-associated retinal necrosis [6–8]. MTX inhibits purine and pyrimidine synthesis, suppressing T- and B-cell proliferation and downregulating inflammatory cytokines such as TNF-α, IFN-γ and IL-6 [6–8, 13]. Mashima et al. first described an 83-year-old immunosuppressed woman who developed PCR-confirmed EBV necrotizing retinitis unresponsive to systemic acyclovir and ganciclovir. After 15 IVT MTX injections, both inflammation and EBV DNA load decreased, leading to a clinical improvement [6]. Similarly, Cho et al. reported a renal transplant recipient with EBV-induced necrotizing retinitis confirmed by vitreous PCR. The disease progressed despite IVT ganciclovir and foscarnet, but the addition of IVT MTX resulted in a clinical improvement [8]. Mechanistically, the pathogenesis of EBV-related retinal disease remains poorly defined, particularly regarding how the virus’s established biology culminates in retinal necrosis. Beyond its well-established B-cell tropism, EBV has been implicated in neuroinflammatory and neurodegenerative disorders. Studies suggest that EBV may exert direct neurotropic effects or indirectly promote tissue injury through infected B cells, leading to neuroinflammation, demyelination, glial activation and neuronal degeneration [14, 15]. EBV has been observed within neurons and glial cells of patients affected by multiple sclerosis, with viral burden correlating with disease severity in postmortem brain tissue [16, 17]. By analogy, similar mechanisms are likely present in retinal neural tissue. Finally, this case also highlights the potential relevance of the patient’s chronic depressive disorder as a contributing factor. Chronic depression has been associated with reduced natural killer cell cytotoxicity, altered B-cell homeostasis, elevated proinflammatory cytokines resulting in an impairment of the innate immune responses and suggesting higher susceptibility to viral infections [18–20]. In conclusion, our report suggests that concomitant Tg and EBV infection may occur in immunocompetent individuals. Intravitreal therapy with MTX may lead to rapid decrease in intravitreal EBV titers and serial quantitative PCR can be useful in monitoring the therapeutical duration and efficacy. Abbreviations Toxoplasma gondii (Tg) Epstein–Barr virus (EBV) Polymerase chain reaction (PCR) Methotrexate (MTX) Optical coherence tomography (OCT) Ocular toxoplasmosis (OT) Intravitreal (IVT) Best-corrected visual acuity (BCVA) Left eye (LE) Declarations Ethics approval and consent to participate : This study was conducted in accordance with the tenets of the Declaration of Helsinki. Ethical approval was not required for this case report according to institutional policies, as it describes a single clinical case without experimental intervention. Written informed consent was obtained from the patient for participation and for publication of clinical data. Consent for publication : Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Availability of data and materials : All data generated or analyzed during this study are included in this published article. Additional information is available from the corresponding author upon reasonable request. Competing interests : The authors declare that they have no competing interests. Funding : The authors received no specific funding for this work. Authors' contributions: Maria Carmela Saturno managed the patient, conceptualized the case report, and drafted the manuscript. Danilo Iannetta contributed to data interpretation and critically revised the manuscript. Ngoc Chau Nguyen participated in clinical management and data collection. Lorette Leon contributed to clinical evaluation and manuscript revision. Marc D. de Smet supervised the case management, contributed to interpretation of findings, and critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript. Acknowledgements : Not applicable. References Standardization of Uveitis Nomenclature (SUN) Working Group. Classification Criteria for Toxoplasmic Retinitis. Am J Ophthalmol (2021) ; 228:134–141. 10.1016/j.ajo.2021.03.042 . Epub 2021 May 11. PMID: 33845002 Mejía-Salgado G, Cardozo-Pérez C, Cifuentes-González C, Durán-Merino C, de-la-Torre A (2024) Coinfection Suspicion is Imperative in Immunosuppressed Patients with Suspected Infectious Uveitis and Inadequate Treatment Response: A Case Report. Ocul Immunol Inflamm. ;32(10):2548–2552. doi: 10.1080/09273948.2024.2367656. Epub 2024 Jun 18. PMID: 38889439 Goh EJH, Putera I, La Distia Nora R, Mahendradas P, Biswas J, Chee SP et al (2022) Ocular toxoplasmosis. Ocul Immunol Inflamm. :1–20. doi: 10.1080/09273948.2022.2117705. Published online September 12. de-la-Torre A, Valdés-Camacho J, De Mesa CL, Uauy-Nazal A, Zuluaga JD, Ramírez-Páez LM et al (2019) Coinfections and differential diagnosis in immunocompetent patients with uveitis of infectious origin. BMC Infect Dis 19(1):91. 10.1186/s12879-018-3613-8 Evans AS, Niederman JC (1989) Epstein-Barr virus. In: Evans AS (ed) Viral Infections of Humans, Epidemiology and Control. Plenum Publishing Corporation, New York, pp 265–292 Mashima A, Usui Y, Umazume K, Muramatsu D, Goto H (2020) Successful treatment of necrotizing retinitis with epstein-barr virus-positive ocular fluid by intravitreal methotrexate injection. Ocul Immunol Inflamm 28:552–555 Mushiga Y, Komoto T, Nagai N, Ozawa Y (2021) Effects of intraocular treatments for Epstein-Barr virus (EBV) retinitis: A case report. Medicine (Baltimore). ;100(48):e28101. 10.1097/MD.0000000000028101 . PMID: 35049237 Cho J, Bhavsar AR, Cho DH, Sattarova V, Abel AS, Zadroga R (2022) Successful Treatment of Epstein-Barr Virus-Induced Necrotizing Retinitis with Intravitreous Ganciclovir, Foscarnet, and Methotrexate. Case Rep Ophthalmol 13(1):116–123 eCollection 2022 Jan-Apr.PMID: 35431884 Gershburg E, Pagano JS (2005) Epstein-Barr virus infections: prospects for treatment. J Antimicrob Chemother 56(2):277–281. 10.1093/jac/dki240 Pichi F, Invernizzi A, Tucker WR, Munk MR (2020) Optical coherence tomography diagnostic signs in posterior uveitis. 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Curr Res Neurobiol. ; 3:100046. 10.1016/j.crneur.2022.100046 . eCollection 2022. PMID: 36685766 Orr N, Steinman L (2025) Epstein-Barr virus and the immune microenvironment in multiple sclerosis: Insights from high-dimensional brain tissue imaging. Proc Natl Acad Sci U S A. ;122(11): e2425670122. 10.1073/pnas.2425670122 . Epub 2025 Mar 10. PMID: 40063794 Magliozzi R, Serafini B, Rosicarelli B, Chiappetta G, Veroni C, Reynolds R, Aloisi F (2013) B-cell enrichment and Epstein-Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. J Neuropathol Exp Neurol 72(1):29–41. 10.1097/NEN.0b013e31827bfc62 PMID: 23242282 Blume J, Douglas SD, Evans DL (2011) Immune suppression and immune activation in depression. Brain Behav Immun. ;25(2):221-9. 10.1016/j.bbi.2010.10.008 . Epub 2010 Oct 16. PMID: 20955778 Beurel E, Toups M, Nemeroff CB (2020) The Bidirectional Relationship of Depression and Inflammation: Double Trouble. Neuron. ;107(2):234–256. 10.1016/j.neuron.2020.06.002 . Epub 2020 Jun 17. PMID: 32553197 Zhang HG, Wang B, Yang Y, Liu X, Wang J, Xin N, Li S, Miao Y, Wu Q, Guo T, Yuan Y, Zuo Y, Chen X, Ren T, Dong C, Wang J, Ruan H, Sun M, Xu X, Zheng H (2022) Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis. Cell Res. ;32(10):897–913. 10.1038/s41422-022-00689-9 . Epub 2022 Jul 12. PMID: 35821088 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 May, 2026 Reviews received at journal 20 Mar, 2026 Reviewers agreed at journal 13 Mar, 2026 Reviewers invited by journal 10 Mar, 2026 Editor assigned by journal 17 Feb, 2026 Submission checks completed at journal 17 Feb, 2026 First submitted to journal 16 Feb, 2026 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-8893893","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":604146479,"identity":"5a5bde6c-0078-4e32-af7c-232ff6f25ab4","order_by":0,"name":"Maria Carmela Saturno","email":"data:image/png;base64,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","orcid":"","institution":"Helvetia Retina Associates, MIOS sa","correspondingAuthor":true,"prefix":"","firstName":"Maria","middleName":"Carmela","lastName":"Saturno","suffix":""},{"id":604146482,"identity":"0debc939-054c-4a40-8f9d-6109bba6a17f","order_by":1,"name":"Danilo Iannetta","email":"","orcid":"","institution":"Sapienza University of Rome","correspondingAuthor":false,"prefix":"","firstName":"Danilo","middleName":"","lastName":"Iannetta","suffix":""},{"id":604146485,"identity":"966bcbaa-a7ac-46d1-81ba-43461a37314b","order_by":2,"name":"Ngoc Chau Nguyen","email":"","orcid":"","institution":"Helvetia Retina Associates, MIOS sa","correspondingAuthor":false,"prefix":"","firstName":"Ngoc","middleName":"Chau","lastName":"Nguyen","suffix":""},{"id":604146489,"identity":"8c3787de-1b9e-40d8-9c93-b360305b13d0","order_by":3,"name":"Lorette Leon","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lorette","middleName":"","lastName":"Leon","suffix":""},{"id":604146491,"identity":"bf24728a-a722-41d4-ae97-da3853f1aea6","order_by":4,"name":"Marc D. Smet","email":"","orcid":"","institution":"Helvetia Retina Associates, MIOS sa","correspondingAuthor":false,"prefix":"","firstName":"Marc","middleName":"D.","lastName":"Smet","suffix":""}],"badges":[],"createdAt":"2026-02-16 14:23:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8893893/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8893893/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104781832,"identity":"3bcd4bcc-f222-45cc-98e3-a28c8cfab4c4","added_by":"auto","created_at":"2026-03-17 07:56:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":405260,"visible":true,"origin":"","legend":"\u003cp\u003eWide-field color fundus photograph of the left eye showing a large area of retinal infiltration with a sharp leading edge extending temporally to the fovea. Perivascular sheathing of adjacent veins and arterioles is visible, along with scattered blot hemorrhages in the surrounding retina.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8893893/v1/e99f460e91193390672feef8.png"},{"id":104594047,"identity":"451c6674-eec9-4668-98b9-9a722d78b4f6","added_by":"auto","created_at":"2026-03-13 17:47:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":766017,"visible":true,"origin":"","legend":"\u003cp\u003eSerial spectral-domain optical coherence tomography (OCT) scans through the fovea obtained at different time points after initiation of therapy (t = 0, 7, 82, and 280 days). The sequence illustrates the evolution of the lesion, showing absence of further central progression and a gradual structural improvement at the margins of the fovea over time. The last image shows no epiretinal membrane, as it had been surgically peeled beforehand.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8893893/v1/affb8eeb60ca302859cffeec.png"},{"id":104594045,"identity":"a236897d-a1f8-438e-a14d-17a15ebe5d5d","added_by":"auto","created_at":"2026-03-13 17:47:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":404814,"visible":true,"origin":"","legend":"\u003cp\u003eWide-field color fundus photograph obtained nine months after initiation of therapy showing the healed area of paramacular retinitis. The lesion is characterized by retinal pigment epithelium (RPE) atrophy with sparse pigmentation, distinct from the more pigmented toxoplasmosis scars. Mild fibrosis is visible along the superior and inferior borders of the scar. The epiretinal membrane previously present over the fovea had surgically peeled.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8893893/v1/46147cc0dc12a51ff74502b3.png"},{"id":104784650,"identity":"ae6b41b8-caa5-4ae7-bd19-91563789cfc0","added_by":"auto","created_at":"2026-03-17 08:08:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2573414,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8893893/v1/d7b78241-9f1d-4ea1-b8e0-b2641e1c2f8f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Toxoplasma gondii Retinochoroiditis associated with Epstein-Barr Virus-Induced Retinal Necrosis in an Immunocompetent Patient","fulltext":[{"header":"Introduction","content":"\u003cp\u003eToxoplasma gondii (Tg) is a ubiquitous intracellular parasite, with approximately one-third of the global human population estimated to have been exposed, representing one of the leading causes of posterior uveitis [1, 2]. The classic presentation is a unilateral, unifocal retinochoroiditis with overlying vitritis, although milder infections may manifest as multiple small outer retinal opacities, known as \u0026ldquo;punctate outer retinal toxoplasmosis\u0026rdquo;. Persistent or reactivated infection, particularly in immunocompromised hosts, may lead to extensive retinal necrosis mimicking other necrotizing retinitis, such as cytomegalovirus retinitis. Severe or atypical cases can also occur in elderly or immunocompetent patients infected with virulent strains [1\u0026ndash;4]. The diagnosis of ocular toxoplasmosis (OT) is mainly clinical, but biological confirmation is crucial in atypical or treatment-resistant cases. Despite its incidence, the optimal therapy for OT is controversial and there is no consensus on which drugs must be used for prophylactic treatment of recurrences [1]. Coinfections with other pathogens, such as Epstein-Barr virus (EBV), have been reported in 7\u0026ndash;8% of patients, regardless of immune status, complicating diagnosis and it is linked to a worse prognosis [4].\u003c/p\u003e \u003cp\u003eEBV is a ubiquitous DNA virus of the Herpesviridae family infecting over 90% of humans. It primarily targets B lymphocytes, establishing lifelong latency within these cells. Although usually asymptomatic, EBV can cause systemic and ocular diseases, including necrotizing retinitis, especially in immunocompromised individuals. In terms of treatment, antivirals or corticosteroids have shown variable benefits in isolated reports. In 2008, Frenkel et al. reported favorable outcomes describing a 10-year experience with intravitreal methotrexate (IVT MTX) for the treatment of vitreoretinal involvement in primary central nervous system lymphoma. As an antifolate antimetabolite, MTX inhibits DNA synthesis and suppresses the proliferation of activated B lymphocytes, the main reservoir of EBV. Based on this mechanism, IVT MTX has shown efficacy in EBV-related vitreoretinal lymphoma, and in few reported EBV-associated retinal necrosis, either alone or in combination with antiviral agents [5\u0026ndash;9].\u003c/p\u003e \u003cp\u003eWe hereby report a rare case of coinfection by EBV and Tg in an immunocompetent patient presenting with retinochoroiditis successfully treated by a combination of systemic antiviral and antiparasitic therapy, as well as IVT clindamycin and MTX.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 52-year-old immunocompetent woman with a history of depression, treated with venlafaxine, mirtazapine and pregabalin, had been followed at Helvetia Retina Associates, MIOS sa, Lausanne, Switzerland for bilateral Tg retinochoroiditis since 2009. The left eye (LE) experienced multiple recurrences from 2014 and underwent cataract surgery in 2023, achieving a postoperative best-corrected visual acuity (BCVA) of 20/20.\u003c/p\u003e \u003cp\u003eIn April 2024, a further recurrence in the LE was treated with oral azithromycin (500 mg on day 1, followed by 250 mg daily) and oral prednisone at a starting dose of 80 mg/day, which was gradually tapered. Given multiple risk factors for recurrence, including age over 40 years, bilateral disease, macular involvement and extensive lesion size, a six-month prophylactic regimen with pyrimethamine 25 mg and folic acid 15 mg was initiated in August 2024.\u003c/p\u003e \u003cp\u003eHowever, prophylaxis was interrupted during a hospital admission for severe depression and the patient presented in October 2024 with recurrent inflammation in the LE. On presentation, BCVA had decreased to 20/60 and slit-lamp examination revealed 3\u0026thinsp;+\u0026thinsp;anterior chamber cells, 1\u0026thinsp;+\u0026thinsp;flare, vitritis and IOP was 43 mmHg. She was treated with azithromycin (500 mg on day 1 and 250 mg daily), topical dexamethasone (Dexafree\u0026reg;) six times daily, topical brinzolamide-brimonidine (Simbrinza\u0026reg;) twice daily and oral acetazolamide 250 mg twice daily. Because of intolerance to systemic corticosteroids, causing insomnia and mood deterioration, a topical approach was preferred and an IVT implant of dexamethasone 700 \u0026micro;g (Ozurdex\u0026reg;) was administered in her LE, resulting in temporary control of inflammation and visual improvement.\u003c/p\u003e \u003cp\u003eIn January 2025, during a follow up visit, the patient referred blurred vision. The ophthalmological examination revealed BCVA declined to 20/33 and a large area of retinal infiltration with a sharp leading edge to the temporal side of the fovea. Sheathing of neighbouring veins and arterioles, as well as blot hemorrhages were also noted in the adjacent retina. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Because the patient admitted discontinuing prophylactic treatment during Christmas holidays, a further reactivation of Tg was suspected, and oral trimethoprim\u0026ndash;sulfamethoxazole (Bactrim forte\u0026reg;) twice daily was initiated. Despite the medical treatment, the clinical course worsened, with progressive visual decline and enlargement of the retinal lesion. Optical coherence tomography (OCT) revealed marked retinal thickening, retinal hyperreflectivity and loss of retinal stratification, without choroidal involvement, vitreous cells or preretinal deposits (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, T0). Given the atypical clinical and imaging features, and after failing to achieve disease control with a single intravitreal injection of clindamycin, a pars plana vitrectomy with vitreous biopsy and removal of the Ozurdex\u0026reg; implant was performed.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePolymerase chain reaction (PCR) analysis of the vitreous sample was positive for both Tg and EBV. Based on these findings, IVT MTX 400 \u0026micro;g was initiated in combination with IVT clindamycin (1mg), systemic acyclovir (800 mg 3 times a day) and Bactrim forte\u0026reg; (twice daily). Nine injections spaced between 5 and 14 days were given, based on the clinical response and PCR data (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). MTX injections were continued until the EBV titers were negative on two repeat measurements. Clindamycin was discontinued when the Tg lesion appeared clinically quiescent.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment and response characteristics following the initiation of intravitreal methotrexate\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDays since IVT initiation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVisual acuity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eQuantitative PCR Titers\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eIntravitreal Therapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eSystemic Therapy **\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEBV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eToxoplasmosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMethotrexate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eClindamycin*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAcyclovir\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSulfamethoxazole\u0026thinsp;+\u0026thinsp;trimethoprim\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28229\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e254757\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20522\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7937\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e800\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e26\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e928\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2620\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e33\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1046\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e41\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e485\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e54\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e160\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e280\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eSymbol \u0026ldquo;x\u0026rdquo; indicates that treatment was administered\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eEBV: Epstein-Barr virus\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eIVT: intravitreal therapy\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e* IVT Clindamycin was given once, prior to the IVT methotrexate one week prior at the end of the vitrectomy\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e** For systemic therapy, the \u0026ldquo;x\u0026rdquo; indicates that the therapy was continued until this day. Bactrim forte was switched to pyrimethamine and folic acid on day 160.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOver subsequent weeks, intraocular inflammation progressively subsided, and no further extension of the retinal lesion was observed on widefield imaging or OCT (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, T280). Serial vitreous PCR demonstrated a gradual decline in both EBV DNA and Tg loads. BCVA improved to 20/25 and remained stable at the most recent follow-up. Nine months after treatment initiation, the area of EBV-associated paramacular retinitis evolved into retinal pigment epithelium atrophy with minimal pigmentation and localized fibrosis; a coexisting epiretinal membrane was surgically peeled in July 2025 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first reported case of concomitant Tg and EBV retinochoroiditis occurring in an immunocompetent patient. A similar coinfection has been described for the first time by Mej\u0026igrave;a-Salgado et al., in a pharmacologically immunosuppressed patient receiving corticosteroids, MTX and abatacept for rheumatoid arthritis. In their report, the patient developed bilateral granulomatous anterior chamber inflammation, vitritis and extensive retinal necrosis with macular involvement. The concomitant infection was confirmed by PCR analysis of vitreous samples and the patient was treated with combined oral antiviral and antiparasitic therapy [2]. In contrast, our patient achieved sustained remission within two months through a dual pathogen-directed strategy consisting of IVT MTX and low-dose systemic acyclovir for EBV, together with IVT clindamycin and oral trimethoprim\u0026ndash;sulfamethoxazole for \u003cem\u003eTg\u003c/em\u003e.\u003c/p\u003e \u003cp\u003eMoreover, our case underscores the diagnostic challenges posed by rare ocular coinfections, particularly in patients with a known history of recurrent Tg retinochoroiditis, in whom disease reactivation may be erroneously attributed to Tg alone. In this context, OCT plays a pivotal role in raising suspicion for an alternative or additional etiology. As described by Pichi et al., Tg retinochoroiditis typically presents with hyperreflective preretinal deposits with associated choroidal involvement, whereas viral retinitis predominantly affects only retinal layers without choroidal infiltration [10]. In our patient, the emergence of a new retinal lesion characterized by marked retinal thickness and hyperreflectivity on OCT, in the absence of choroidal or preretinal involvement (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, T0), together with a poor response to conventional antiparasitic therapy, raised suspicion for an additional infectious etiology. Subsequently, vitreous biopsy under air [11] and PCR played a crucial role to achieve a definitive diagnosis.\u003c/p\u003e \u003cp\u003eFurthermore, quantitative PCR on serial vitreous samples proved valuable in guiding targeted therapy. monitoring treatment response and allowing discontinuation of IVT therapy in only two months, when the titers were at the level of detection or below [6, 7].\u003c/p\u003e \u003cp\u003eFrom a therapeutic standpoint, the management of EBV-related retinitis remains difficult and controversial [6\u0026ndash;8]. In vitro studies have shown that anti-herpesvirus drugs such as nucleoside/nucleotide analogs (ganciclovir, cidofovir) or pyrophosphate analogs (foscarnet) inhibit EBV-DNA polymerase activity [9]. However, in most clinical cases a slow rate of response is observed, associated with a significant vision loss [2, 12].\u003c/p\u003e \u003cp\u003eIn this context, there is emerging evidence of IVT MTX\u0026rsquo;s antiviral effects in EBV-associated retinal necrosis [6\u0026ndash;8]. MTX inhibits purine and pyrimidine synthesis, suppressing T- and B-cell proliferation and downregulating inflammatory cytokines such as TNF-α, IFN-γ and IL-6 [6\u0026ndash;8, 13]. Mashima et al. first described an 83-year-old immunosuppressed woman who developed PCR-confirmed EBV necrotizing retinitis unresponsive to systemic acyclovir and ganciclovir. After 15 IVT MTX injections, both inflammation and EBV DNA load decreased, leading to a clinical improvement [6]. Similarly, Cho et al. reported a renal transplant recipient with EBV-induced necrotizing retinitis confirmed by vitreous PCR. The disease progressed despite IVT ganciclovir and foscarnet, but the addition of IVT MTX resulted in a clinical improvement [8].\u003c/p\u003e \u003cp\u003eMechanistically, the pathogenesis of EBV-related retinal disease remains poorly defined, particularly regarding how the virus\u0026rsquo;s established biology culminates in retinal necrosis. Beyond its well-established B-cell tropism, EBV has been implicated in neuroinflammatory and neurodegenerative disorders. Studies suggest that EBV may exert direct neurotropic effects or indirectly promote tissue injury through infected B cells, leading to neuroinflammation, demyelination, glial activation and neuronal degeneration [14, 15]. EBV has been observed within neurons and glial cells of patients affected by multiple sclerosis, with viral burden correlating with disease severity in postmortem brain tissue [16, 17]. By analogy, similar mechanisms are likely present in retinal neural tissue.\u003c/p\u003e \u003cp\u003eFinally, this case also highlights the potential relevance of the patient\u0026rsquo;s chronic depressive disorder as a contributing factor. Chronic depression has been associated with reduced natural killer cell cytotoxicity, altered B-cell homeostasis, elevated proinflammatory cytokines resulting in an impairment of the innate immune responses and suggesting higher susceptibility to viral infections [18\u0026ndash;20].\u003c/p\u003e \u003cp\u003eIn conclusion, our report suggests that concomitant Tg and EBV infection may occur in immunocompetent individuals. Intravitreal therapy with MTX may lead to rapid decrease in intravitreal EBV titers and serial quantitative PCR can be useful in monitoring the therapeutical duration and efficacy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eToxoplasma gondii (Tg)\u003c/p\u003e\n\u003cp\u003eEpstein–Barr virus (EBV)\u003c/p\u003e\n\u003cp\u003ePolymerase chain reaction (PCR)\u003c/p\u003e\n\u003cp\u003eMethotrexate (MTX)\u003c/p\u003e\n\u003cp\u003eOptical coherence tomography (OCT)\u003c/p\u003e\n\u003cp\u003eOcular toxoplasmosis (OT)\u003c/p\u003e\n\u003cp\u003eIntravitreal (IVT)\u003c/p\u003e\n\u003cp\u003eBest-corrected visual acuity (BCVA)\u003c/p\u003e\n\u003cp\u003eLeft eye (LE)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: This study was conducted in accordance with the tenets of the Declaration of Helsinki. Ethical approval was not required for this case report according to institutional policies, as it describes a single clinical case without experimental intervention. Written informed consent was obtained from the patient for participation and for publication of clinical data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: All data generated or analyzed during this study are included in this published article. Additional information is available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: The authors received no specific funding for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Maria Carmela Saturno managed the patient, conceptualized the case report, and drafted the manuscript.\u003cbr\u003e\u0026nbsp;Danilo Iannetta contributed to data interpretation and critically revised the manuscript.\u003cbr\u003e\u0026nbsp;Ngoc Chau Nguyen participated in clinical management and data collection.\u003cbr\u003e\u0026nbsp;Lorette Leon contributed to clinical evaluation and manuscript revision.\u003cbr\u003e\u0026nbsp;Marc D. de Smet supervised the case management, contributed to interpretation of findings, and critically revised the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStandardization of Uveitis Nomenclature (SUN) Working Group. 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PMID: 35821088\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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-ophthalmic-inflammation-and-infection","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joii","sideBox":"Learn more about [Journal of Ophthalmic Inflammation and Infection](http://joii-journal.springeropen.com)","snPcode":"12348","submissionUrl":"https://submission.nature.com/new-submission/12348/3","title":"Journal of Ophthalmic Inflammation and Infection","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"retinochoroiditis, retinal necrosis, Toxoplasma gondii, Epstein–Barr virus, methotrexate, intravitreal therapy","lastPublishedDoi":"10.21203/rs.3.rs-8893893/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8893893/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose:\u003c/h2\u003e \u003cp\u003eTo describe a rare case of concomitant Toxoplasma gondii (Tg) retinochoroiditis and Epstein\u0026ndash;Barr virus (EBV) retinal necrosis in an immunocompetent patient, successfully treated with a combined intravitreal and systemic therapeutic approach.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eA 52-year-old immunocompetent woman with recurrent bilateral Tg retinochoroiditis presented with reactivation in the left eye unresponsive to standard antiparasitic therapy. Comprehensive clinical examination, including vitreous polymerase chain reaction (PCR) testing, was performed.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003ePCR analysis of the vitreous sample confirmed the presence of both Tg and EBV. Intravitreal methotrexate (MTX) was initiated and administered over an 8-week period in combination with ongoing intravitreal clindamycin and systemic antiparasitic therapy, together with low-dose antiviral treatment. The patient demonstrated progressive clinical improvement, with stabilization of visual acuity and retinal morphology on optical coherence tomography (OCT). Serial vitreous PCR monitoring revealed a gradual decline in Tg and EBV loads until both pathogens became undetectable. No recurrence occurred during follow-up.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThis is the first reported case of Tg\u0026ndash;EBV coinfection\u0026ndash;related retinochoroiditis in an immunocompetent patient. The favorable outcome following intravitreal MTX supports a potential dual mechanism in EBV-associated retinal necrosis, combining immunomodulatory suppression of B-cell proliferation with a direct antiviral activity. This case underscores the importance of considering coinfection in atypical or treatment-refractory retinochoroiditis, even in immunocompetent hosts.\u003c/p\u003e","manuscriptTitle":"Toxoplasma gondii Retinochoroiditis associated with Epstein-Barr Virus-Induced Retinal Necrosis in an Immunocompetent Patient","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-13 17:47:21","doi":"10.21203/rs.3.rs-8893893/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-16T10:58:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-20T06:00:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"215978510896346597726218955411460737351","date":"2026-03-13T05:18:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-11T03:38:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-17T08:57:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-17T08:57:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Ophthalmic Inflammation and Infection","date":"2026-02-16T14:13:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-ophthalmic-inflammation-and-infection","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joii","sideBox":"Learn more about [Journal of Ophthalmic Inflammation and Infection](http://joii-journal.springeropen.com)","snPcode":"12348","submissionUrl":"https://submission.nature.com/new-submission/12348/3","title":"Journal of Ophthalmic Inflammation and Infection","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"800897c5-5b14-4413-b6f6-89415fd05e6e","owner":[],"postedDate":"March 13th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-16T10:58:21+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-17T12:23:10+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-13 17:47:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8893893","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8893893","identity":"rs-8893893","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}