Epstein–Barr virus (EBV) infection belongs to herpes-virus groups, known as human herpesvirus 4, and occurs commonly and worldwide.1,2 The virus may be spread through the exchange of bodily fluids as with blood transfusion or sexual contact. Once the patient is infected, the virus persists for a lifetime. In the early stages of infection, patients may be asymptomatic as the virus is inactive or latent and exists within B cells with long-lasting memory. When it is reactivated, EBV infection can cause benign or malignant diseases, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma.3–6
The incidence of ocular involvement with EBV infection has been reported. However, retinal manifestation associated with EBV is still rare. To our knowledge, the case report of vasculitis associated with EBV infection in Indonesia has not been reported.
A 26-year-old woman came to AINI Eye Hospital, Jakarta, Indonesia, complaining of bilateral blurred vision. She denied having any fever, sore throat, and any chronic medical problems. The patient had no previous ocular history and did not wear eyeglasses. Her best-corrected visual acuity on the right side was 6/19, whereas her left eye was 6/30. Slit-lamp examination illustrated no abnormalities on the anterior part of the eyes. Fundus examination revealed prominent white sheathing retinal phlebitis in all quadrants, macular edema, exudates around the macula, peripheral hemorrhage dots, and irregular macular reflex (Figure 1). There were no abnormalities on her general physical examination. There were also no systemic signs and symptoms of Lyme disease, Behçet disease, sarcoidosis, and systemic lupus erythematosus. However, the examinations of fundus fluorescein angiogram and optical coherence tomography before and after therapy were not performed.
Laboratory results did not show any abnormalities. The test revealed normal results for all of the following tests: blood pressure, fasting blood glucose, complete blood cell count, prothrombin time, partial thromboplastin time, alkaline phosphate, erythrocyte sedimentation rate and C-reactive protein. Hepatitis, human immunodeficiency virus, herpes simplex virus, varicella zoster virus, tuberculosis, toxoplasmosis, and syphilis were excluded. The polymerase chain reaction (PCR) analysis of serum was negative for cytomegalovirus, varicella zoster virus, and herpes simplex virus, yet EBV in serum was positive. The patient denied having histories of EBV infection during her childhood. However, the PCR analysis of vitreous was not performed.
The patient was treated with systemic acyclovir (500 mg, 3 times daily) for 3 weeks by an internist, along with topical dexamethasone 1%, topical neomycin 3.5 mg, and topical polymyxin 6,000 IU 3 times a day from an ophthalmologist. After 1 month of treatment, the symptoms resolved. The white sheathing phlebitis and exudates slightly decreased. Two months later, his visual acuity recovered (right eye 6/7, left eye 6/9). The optic disk swelling also resolved with minimal exudates and macular edema (Figure 2).
Epstein–Barr virus infection can lead to ocular complications, such as conjunctivitis, dacryoadenitis, keratitis, and iritis.7,8 However, EBV infection involving the retina is still rare and presumptive. Some reports have described retinal manifestations associated with EBV infection, including retinochoroiditis,9,10 acute retinal necrosis,11 central nervous system vasculitis,12 and necrotizing retinitis with extensive hemorrhage coinfected with cytomegalovirus and human immunodeficiency virus.13 Kim et al14 found the appearance of coalescing, yellowish lesion in the macula and edematous optic disk in the patient with EBV infection.
However, our patient was different with these cases. The interesting finding from the funduscopy is the prominent appearance of white sheathing retinal phlebitis in all four retinal quadrants. According to the initial reports, this condition is similar with frosted branch angiitis.15,16 The first case was introduced by Ito et al17 in 1976 as abnormal white sheathing of veins in a Japanese child with panuveitis and retinal vasculitis. Throughout the year, the major cases of frosted branch angiitis are found in Japanese. Other reports are subsequently reported from the United States, Korea, Turkey, India, and Spain.15 Our patient is the first to be described in Indonesia. Frosted branch angiitis is mostly found in young healthy patients. Some infections and autoimmune diseases have also been associated with frosted branch angiitis.9,18 The presence of frosted branch angiitis was thought to emerge from the immune response caused by the infections.19
We performed PCR test to find the possible etiology of the retinitis. Many similar cases conducted PCR tests along with the other serology tests.20 Matos et al21 concluded that PCR examination in the vitreous was highly recommended to confirm the clinical diagnosis. However, the PCR test of serum has low sensitivity for some viruses, including EBV.21 In our case, the PCR test of serum for EBV was positive; however, PCR on the vitreous body was not performed.
Our patient did not show any history of systemic EBV infection. It has been known that the prevalence of EBV serology in healthy people is high in some countries.22–24 However, the seroprevalence of EBV infection in a healthy population of Indonesia is still unknown. This circumstance can indicate the possibility of a false-positive EBV serology in our study. Thus, PCR of vitreous may be essential in this case to determine the possible cause of retinitis.
In addition, frosted branch–like appearance has been found in some disorders, including Behçet disease,25 systemic lupus erythematosus,26 and Crohn disease.27 Nevertheless, in our patient, there were no systemic findings of Behçet disease, systemic lupus erythematosus, and Crohn disease. The clinical manifestations of this patient may not be due to disorders, yet the additional examination for syndromes, in this case, should always be considered.
According to the topics we have discussed, those phenomena have also been seen in a young male patient with vasculitis without evidence of EBV infection.12 He had retinal ischemia with multiple cotton-wool spots, intraretinal hemorrhages, and central nervous system vasculitis. The authors found negative results in repeated EBV PCR from blood, cerebrospinal fluid, and brain tissue samples. However, they confirmed a diagnosis of X-linked lymphoproliferative disease (XLP), and the EBV-encoded RNA test was positive in postmortem brain. They strongly suggested that a comprehensive workup should be performed, and immunologic disorders should be considered as differential diagnosis, when an abnormal event is found in a young patient's eyes.12
However, the benefits of antiviral with/without steroid treatment against ocular manifestations of EBV infection have been previously reported.2,28 Our patient relieved her symptoms after treated with valacyclovir. However, the direct benefit of topical steroid in treating our patient is debatable. Many studies described that ophthalmic steroids mainly treat the ocular inflammations in the anterior segment of the eye, including keratitis, anterior uveitis, and ocular allergies or injuries, yet its effect on the posterior part is still not clear.29 A pilot study demonstrated a resolve of macular edema in noninfectious uveitis after receiving topical dexamethasone.30 Our patient might get the similar effect, yet it is still uncertain because the posttreatment optical coherence tomography was not performed.
In conclusion, to our knowledge, this case of retinal vasculitis with a frosted branch–like appearance associated with EBV infection is the first report from Indonesia. In our opinion, it is suggested that PCR test from vitreous humor tap should be considered to find the direct correlations between eye lesions and EBV infection. A thorough workup is recommended to be performed in frosted branch–like vasculitis for investigating the differential diagnosis.
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