**6. Endogenous viral endophthalmitis (EVE)**

Viral infections represent a significant cause of posterior segment endogenous endophthalmitis due to their systemic spread, and viruses are more likely than other organisms to spread via a neuronal pathway. Viral infections can appear as isolated

ocular manifestations or as part of a systemic infection. For example, Herpes Simplex virus 1 (HSV-1) and Varicella Zoster virus (VZV) spread via transaxonal route while Cytomegalovirus (CMV) and Epstein Barr virus (EBV) spread via hematogenous route within lymphocytes [159]. Infections causing posterior segment infections can lead to manifestations of the choroid, retina, and vitreous due to their highly vascularized nature [160, 161]. Prompt recognition and treatment can lead to improved visual outcomes in patients, but EVE is often misdiagnosed as non-infectious uveitis, anterior uveitis, or conjunctivitis, leading to poorer outcomes [160].

Patients with EVE often have an underlying immunosuppressed condition, so they should be evaluated for underlying immunosuppression if not already known [65]. DM, corticosteroid use, diminished lymphocyte response, HIV/AIDS, and malignancy can all encourage viruses to proliferate [162]. Patients with a history of travel to endemic areas or close contact with farm animals (particularly swine herders) should be evaluated for EVE [161]. Cases of EVE following systemic Ebola and COVID-19 infections have also been documented [163, 164]. There have been cases of viral endophthalmitis following intravitreal steroid injections that are exogenous in nature [160]. Identifying the common clinical features can aid in the prompt diagnosis of EVE. Common features include photophobia, decreased visual acuity, and eye pain [161]. Other presenting ocular features include conjunctival hemorrhages, peripapillary hemorrhage, narrowing of the inferior retinal vessels, anterior segment inflammation, focal lesion of the posterior pole, vitreous inflammation, occlusive vasculitis, keratic precipitates, chorioretinal scarring, ocular hypertension, and neovascularization [160, 163, 164]. EVE frequently presents as unilateral disease on presentation but can become bilateral as it progresses [160, 165–167].

Successful treatment of EVE requires prompt diagnosis using fluid from a vitreous tap [160]. PCR is the main laboratory test that has been effective in establishing diagnosis of viral infection such as HSV, VZV and CMV [160]. One study examined aqueous and vitreous fluid samples for HSV-1, HSV-2, VZV, EBV, CMV, and Human Herpesvirus 6 found PCR to have sensitivity and specificity of 91.3% and 98.8%, respectively in detection of herpes viruses as well as toxoplasma and fungal elements [168]. Viral serology of the vitreous is effective in confirming the pathogen involved in 80–90% of cases [160, 169, 170] and frequently changes the working diagnosis (23%) or confirms an uncertain diagnosis (39%) [170]. Moreover, PCR sensitivity can be further improved when combined with the calculation of Goldmann-Witmer coefficient (GWC) and immunoblotting for ocular fluid and serum antibodies. The GWC is a comparison of specific antibodies levels to total immunoglobulin in both aqueous humor and serum samples. Multiplex PCR allows testing of several organisms from a single ocular sample; however, this process, similar to monoplex PCR, does require the knowledge of a particular virion's sequence information prior to testing in order to design the primer necessary to generate a PCR product [171]. Fundus photography, retinal imaging, and optical coherence tomography (OCT) are all useful in diagnosing and monitoring EVE [160, 172].

Treatment of EVE requires systemic antivirals, intravitreal antivirals (or intraocular antiviral implants), and systemic corticosteroids for inflammation [160]. In the 1990s, Peyman and many others noted improvement of cytomegalovirus (CMV) retinitis after treatment with intravitreal ganciclovir and systemic antivirals [76, 173–179]. Studies also confirm the efficacy of systemic valaciclovir for appropriate management of EVE [179]. The role of systemic and intravitreal acyclovir for treatment of herpes virus retinitis has also been documented [174, 178]. Management of both ocular and systemic complications is essential for a favorable prognosis [160]. Long-term preventative antiviral therapy may be considered if patients

*Endogenous Endophthalmitis: Etiology and Treatment DOI: http://dx.doi.org/10.5772/intechopen.96766*

present with recurrent inflammation. Patients may require anti-vascular endothelial growth factor agents for macular edema or neovascularization [160] and may also undergo vitrectomy for proper management**.** Vitrectomy should be considered when patients present with severe inflammation, retinal detachment, or traction that may create a detachment. Vitrectomy with silicone-oil tamponade and scleral buckle placement has been proven successful [179]. Caution should be taken in eyes of patients with a history of Ebola virus disease who present with evolving dark retinal regions, as these are characteristic of viable *Zaire ebolavirus* (EBOV) which poses a significant health risk during intraocular procedures [163]. Some eyes may experience neovascularization, for which they should undergo photocoagulation and/or retinal detachment surgery [160].

Several viruses have been implicated in the development of EVE. Most commonly, it is due to reactivation of the herpesvirus family, specifically varicella zoster virus (VZV), herpes simplex virus (HSV I and HSV II), CMV, and Epstein–Barr virus (EBV) [160, 180, 181]. The outcome of viral reactivation is influenced by multiple factors including strain virulence, human leukocyte antigen, and host immune response. HSV- EVE is generally well treated with systemic antiviral and corticosteroids with the resolution of symptoms [181]. However, as the virus remains latent in the trigeminal and dorsal root ganglion, recurrence is possible [181]. VZV-EVE may occur in adults with chickenpox but is rare in children [160]. It is more common in adults and may precede shingles in immunocompromised patients, but Acute Retinal Necrosis (ARN) can occur in patients with normal immune function; HSV I, HSV II, and VZV can cause ARN [182]. VZV generally has a poorer prognosis compared to HSV. EBV-EVE generally has a good prognosis and resolves rapidly with near-complete recovery [160]. Most people (90%) are CMV seropositive (it is thought to be latent in bone marrow) so it periodically actively replicates in both immunocompromised and normal patients. Therefore, culture of CMV shed in the patient's urine does not mean active systemic CMV infection to support the diagnosis of CMV retinitis. Patients can experience systemic symptoms, but ocular manifestations are more likely to be the initial finding [183]. CMV retinitis has historically had poor visual outcomes, although new antiretroviral therapies have decreased its incidence and improved outcomes [183]. Patients may experience reactivation of herpesvirus infections following other viral infections, such as COVID-19 [184].

Other causes implicated with EVE include pseudorabies, Zika virus, Dengue, Ebola, Chikungunya, and COVID-19 [163–165, 185]. Unlike herpesvirus infections, patients typically do not present with a history of immunosuppression. However, history is significant with respect to travel to endemic areas or known exposure to infected individuals [163–165, 185]. The posterior vitreous cavity may act as a reservoir for some viral infections. Zika and COVID-19 infections are notable for the presence of viral RNA in the tears [165]. In contrast, patients with Ebola Virus Disease (EBD) in the eye are negative for Ebola of the tears and conjunctiva [163]. However, virions have been recovered from the anterior chamber in eyes of recovered Ebola patients and poses a risk for cataract surgeons [163].

Patients with ocular viral infections are also at risk for reactivation of other bacterial or fungal agents in the eye. Cases of toxoplasmosis following Ebola infection have been documented in a small subset of patients [127]. Compared to more common causes, novel causes of EVE (Dengue and COVID) have no prospective, randomized therapeutic trials. As such, definitive therapies are not well established, and prognosis can range from full resolution to permanent vision loss [165, 185]. COVID-19 and Zika are more likely to cause poor visual outcomes compared to standard causes [164, 165]. Prompt diagnosis and early treatment are important for good visual outcomes of EVE.
