Epstein–Barr virus (EBV) is a ubiquitous DNA virus of the herpes family and is the primary agent of infectious mononucleosis. Although 90 to 95 percent of adults are EBV-seropositive, the majority of primary infections are subclinical. Ocular manifestations of EBV infection are diverse and include dacryoadenitis, Parinaud oculoglandular syndrome, follicular conjunctivitis, stromal keratitis, anterior and posterior uveitis, chorioretinitis, optic neuritis, and ophthalmoplegia (1). Optic nerve involvement is particularly rare and has been documented primarily in immunocompetent patients after contracting mononucleosis (2–7). In solid organ transplant patients, EBV is most commonly associated with posttransplant lymphoproliferative disorder (PTLD), a potentially fatal complication due to lymphoid proliferation in the setting of immunosuppression (8). We report a unique case of an adult patient who developed severe bilateral EBV neuroretinitis after lung transplantation from primary EBV infection of the central nervous system.
A 57-year-old woman reported headache, malaise, and acute vision loss in her left eye. Medical history was significant for systemic scleroderma leading to lung transplantation 6 years previously. Medications included prednisone (7.5 mg daily), sirolimus (1 mg daily), and prophylactic trimethoprim/sulfamethoxazole (1 double-strength tablet 3 times weekly), and valganciclovir (450 mg 3 times weekly). Social history was unremarkable. She was married and retired, and denied recent travel or sick contact.
On examination, the visual acuity (VA) was 20/20, right eye, and 20/400, left eye, with a left relative afferent pupillary defect (RAPD). Intraocular pressure was 19 mm Hg in both eyes. Extraocular movements were full without pain on eye movement. Automated visual field testing revealed an enlarged blind spot in the right eye and dense generalized field loss in the left eye (Fig. 1). The fundus examination was notable for bilateral optic disc edema with nerve fiber layer hemorrhages, more severe in the left eye.
Given the history of lung transplantation and immunosuppression, a broad work-up was initiated, which included PTLD, plus inflammatory, infectious, and toxic etiologies. Postcontrast orbital and brain magnetic resonance imaging (MRI) showed pachymeningeal enhancement, as well as enlargement of the retrobulbar left optic nerve and sheath with subtle nerve enhancement, but no infiltrative mass (Fig. 2). Serum testing for Lyme disease, Bartonella species, Toxoplasma gondii, neuromyelitis optica, syphilis, and antineutrophil cytoplasmic antibody was negative. Random and trough levels of sirolimus were within therapeutic ranges. Lumbar puncture revealed normal opening pressure and cerebrospinal fluid (CSF) analysis showed mild lymphocytic pleocytosis (11 white blood cells, 93% lymphocytes), protein of 67 mg/dL (normal: 15–45 mg/dL), normal glucose, and negative cytology. With additional CSF studies pending, the patient's vision stabilized for 2 weeks on empiric high-dose systemic corticosteroids (1 g of intravenous methylprednisolone for 3 days followed by 60 mg of oral prednisone for 11 d). However, 1 week after resuming her regular daily dose of prednisone (7.5 mg), acuity in the right eye abruptly decreased to 20/150, dropping further to counting fingers (CF) at 1 foot within 1 week. Repeat visual field testing revealed new paracentral scotoma and superonasal field defect in the right eye (Fig. 3). A RAPD was now detected in the right eye where the disc edema worsened with cystoid macular edema and subretinal fluid now present. In the left eye, there was stable vision with evolution of optic disc pallor and a partial macular star (Fig. 4). Repeat brain MRI was stable and whole body positron emission tomography/computed tomography was unremarkable, arguing against PTLD.
CSF polymerase chain reaction (PCR) analysis (Viracor IBT Laboratories, Lee's Summit, MO) from the initial work-up returned, showing 10,400 copies/mL of EBV DNA in the CSF but none in serum. Cytomegalovirus, herpes simplex virus, and varicella zoster virus DNA were all absent from the CSF and serum. Serum EBV immunoglobulins M and G, and Epstein–Barr nuclear antigen had been negative at the time of her lung transplant and remain so to date. EBV DNA appeared in the serum at low levels after the right eye lost central vision (<1,000 copies/mL, real-time PCR using primers to a segment of LMP2 gene, UCSF Clinical Laboratories). The patient was diagnosed with bilateral EBV neuroretinitis.
The patient was treated with 6 weeks of intravenous acyclovir and experienced modest improvement in vision in the left eye and resolution of her headache. She was transitioned to long-term oral valacyclovir at treatment dosage (3 g daily). After initiating targeted therapy, CSF EBV titer gradually decreased from 10,400 to 6,500 (1 mo), to 4,700 (2 mo), to 2,600 (8 mo), to 1,700 copies per milliliter (14 mo). At 9 months after symptom onset, VA was CF, right eye, and, 20/100, left eye. MRI showed resolution of the left optic nerve sheath enhancement.
EBV-associated optic neuropathy is rare, seen mostly in immunocompetent adults in the setting of infectious mononucleosis (2–7). We evaluated an immunosuppressed patient who developed bilateral EBV neuroretinitis, with subacute swelling of the optic discs, accumulation of intraretinal and subretinal fluid originating from the disc leakage, and finally precipitation of lipid within the neurosensory retina once the fluid resorbed several weeks later (9). The thickening and enhancement of the left retrobulbar optic nerve seen on MRI in this patient has been previously reported in the setting of neuroretinitis (10,11). The absence of right optic nerve enhancement on repeat MRI could be explained by the course of high-dose steroids that the patient had just received or a more localized involvement of the optic nerve head on the right compared with the left side.
In this posttransplant patient, the presence of EBV in the CSF raised immediate concern for PTLD. However, the patient's imaging was not consistent with malignancy. Nonetheless, she is being serially monitored with neuroimaging, as EBV optic neuritis may be a precursor for future development of PTLD (12). The patient was an EBV-seronegative recipient of bilateral lung transplants from a donor whose EBV status was unknown. EBV IgM and IgG titers were negative posttransplantation and on admission, suggesting primary infection rather than reactivation. One previous report described EBV optic neuritis in a patient after solid organ transplant, but that case differed in that it was a pediatric patient who was EBV IgG seropositive before liver transplant (12).
It is notable that initially EBV DNA PCR was positive in CSF but not in the serum. This discrepancy between CSF and serum has been encountered previously in cases of EBV-associated PTLD, optic neuritis, and encephalitis (3,13–15). Potential explanations include the use of 2 different PCR assays for CSF and serum samples, preferential replication of the virus in the CNS, or presence of PCR inhibitor in the peripheral blood.
The diagnosis of EBV neuroretinitis was strongly supported by a high CSF EBV titer and the resolution of systemic symptoms, stabilization of vision loss, and a decline in CSF EBV viral load on initiation of high-dose acyclovir, all in the context of an otherwise unremarkable work-up. The required duration of oral antiviral treatment is unclear, although the patient's slowly improving CSF EBV titers suggest a need for prolonged therapy in order to clear the infection. One important strategy for all opportunistic infections is to reduce immunosuppression whenever feasible, although that was not possible in this case. In contrast to our patient's outcome, the prognosis of EBV optic neuropathy appears to be more favorable in immunocompetent patients, with nearly complete recovery achieved in most individuals without antiviral treatment (6,7). It is noteworthy that clinical deterioration was slowed in our patient during a course of high-dose systemic steroids. We cannot fully exclude the possibility that an inflammatory neuroretinitis was caused by vasculitis related to the patient's underlying scleroderma. However, this seems unlikely given the patient's baseline immunosuppressed status. The steroid responsiveness was also consistent with a viral etiology.
Our case illustrates the need to consider EBV infection in the differential diagnosis among immunosuppressed individuals with atypical optic neuritis or neuroretinitis. As EBV optic nerve infection may present exclusively with CSF abnormalities, negative blood EBV DNA PCR tests do not necessarily rule out this cause. Prolonged systemic antiviral therapy that target herpes viruses should be considered, particularly in immunocompromised patients with EBV-associated optic neuropathy.
STATEMENT OF AUTHORSHIP
Category 1: a. Conception and design: Y. C. Hsia and M. H. Levin; b. Acquisition of data: Y. C. Hsia and M. H. Levin; c. Analysis and interpretation of data: Y. C. Hsia. Category 2: a. Drafting the manuscript: Y. C. Hsia; b. Revising it for intellectual content: M. H. Levin and P. V. Ching-Hong. Category 3: a. Final approval of the completed manuscript: M. H. Levin.
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