Rare cause of left eye floaters and blurred vision in an immunocompromised patient: acute retinal necrosis (ARN)

Background

Acute retinal necrosis (ARN) was first described by Japanese doctors as acute unilateral panuveitis associated with retinal periarteritis and subsequent progression to diffuse necrotising retinitis and retinal detachment.1 ARN is rare with two UK nationwide surveys demonstrating the incidence of ARN at one case per 2 million people per year. ARN is usually caused by the herpes virus family including varicella zoster virus (VZV) or herpes simplex virus (HSV) in both healthy and immunocompromised adults. There have been very limited case reports linking the causes to either cytomegalovirus (CMV) infection or Epstein-Barr virus (EBV).2 ARN is rare with two UK nationwide surveys demonstrating the incidence of ARN at one case per 2 million people per year.3 4 ARN presents with typical symptoms of eye redness, periorbital pain, photophobia and vision loss.2 Classical examination features include anterior-segment findings of episcleritis, scleritis, keratitis and/or anterior chamber inflammation, which may be either nongranulomatous or granulomatous, and posterior-segment findings of vitreous inflammation, one or more areas of full-thickness necrotising retinitis, occlusive arteritis, signs of optic neuropathy being present when the optic disc is involved.2

We report a case of a man in his early 30s with ARN in the presence of atypical symptoms of left eye floaters and blurred vision 5 months after allogenic haematopoietic stem cell transplant (Allo-HSCT). The unusual symptoms and the rare cause of ARN in a post Allo-HSCT adult warrants sharing the case with our clinical colleagues.

Case presentation

A man in his early 30s first came to the outpatient department because of floaters and blurred vision in his left eye for the past week, associated with nonspecific general tiredness. The patient was diagnosed with T-cell ALL 1 year ago, and underwent chemotherapy and Allo-HSCT 5 months ago. In the preceding 5 months prior to his presentation, the patient received monthly intrathecal injection of 10 mg methotrexate and 10 mg dexamethasone as well as oral methylprednisolone.

His general physical examinations were unremarkable.

Eye examination: best-corrected visual acuity (BCVA) of right eye was 20/20, BCVA of left eye was 20/50, intraocular pressure of both eyes were normal.

Left eye ophthalmoscope and slit lamp examination: numerous dot-like keratic precipitates (KPs) were seen in corneal endothelial cells. We could also observe posterior synechia of iris (figure 1), vitreous opacities, patches of retinal haemorrhage, yellow white necrotic tissues in peripheral retina and occlusive peripheral blood vessels resembling white lines especially in the inferior nasal and temporal retina (figure 2). No abnormality was observed in the patient’s right eye.

Investigations

Blood test showed that CMV-IgM and CMV-IgG were all positive as well as a consistent lower ratio of CD4/CD8 (CD4/CD8 ratio <1), negative HSV1-IgG and negative HSV2-IgG. All other serology tests were negative with EBV serology, HHV-6 serology, HIV, venereal disease research laboratory test +fluorescent treponemal antibody absorption test (FTA-ABS), interferon-gamma release assays and toxoplasmosis. His VZV IgG serology was negative prior to transplant and he was given vaccination and returned positive serology 2 weeks prior to his allo-HSCT. However, CMV-IgM and CMV-IgG were positive throughout the treatment. Aqueous PCR DNA analysis for CMV, HSV, VZV, EBV and HHV-6 were unable to perform due to the clinical risk of the sampling procedure, which would be discussed in detail in the outcome section.

Full blood picture examination showed mildly reduced lymphocyte count and abnormal liver function with moderately raised ALT, GGT, AST and ALP, in keeping with most likely acute viral infection.

Fundus fluorescence angiography showed that there was no swelling of the optic disc but late hyperfluorescence was evident. In the nasal inferior retina of left eye, non-perfusion areas were seen in angiogram (figure 3). No abnormality of right eye vessels was observed.

Differential diagnosis

The patient’s anterior chamber inflammation, vitritis haze, retinal vasculitis and multifocal peripheral retinitis was consistent with the diagnosis of ARN. Besides, he was immunocompromised due to ongoing immunosuppressants and was positive for CMV IgG and IgM in association with lower CD4/CD8 ratio and negative viral serology screen for HSV, EBV, HHV-6 and unremarkable VZV (positive IgG due to vaccination). Therefore, it was very likely that CMV infection caused the ARN. The lower lymphocyte counts and abnormal liver function test certainly support acute CMV infection being the most likely cause of ARN diagnosis in this patient.

In this case, the ophthalmological differentials mainly include progressive outer retinal necrosis (PORN) and CMV retinitis being consistent with the reported case-based literature.5 Progressive outer renal necrosis affects the posterior pole, usually sparing the vitreous and anterior chamber but with early involvement of the posterior pole and outer retina. PORN is generally associated with minimal retinal haemorrhage and with clear paravascular areas.6 PORN is a form of VZV chorioretinitis, usually found in people with AIDS. It causes atrophic retinal holes and retinal detachments.7 Visual prognosis is poor with current evidence-based treatment.7 8 Another essential differential diagnosis is CMV retinitis, which is featured by minimal or absent vitritis (ie, clear media), haemorrhage, immunosuppression, early involvement of posterior pole. Unlike ARN, the posterior pole, including the optic disc and macular zone, is most frequently involved in CMV retinitis and PORN.1 Consequently, our case was on a clear path towards a diagnosis of ARN instead of CMV retinitis. In our case with the possible improvement of the immune system by the therapy, a low-grade CMV retinitis in retina periphery may ensue to cause an increased inflammatory response, leading to paradoxical uveitis due to immune reconstitution.

Our clinical assessment was consistent with the diagnoses of ARN in an early 30-year-old man 5 months after allo-HSCT. His ARN was most likely caused by an acute CMV infection evidenced by his positive CMV IgG and IgM in association with lower CD4/CD8 ratio and negative viral serology screen for HSV, EBV, HHV-6 and unremarkable VZV (positive IgG due to vaccination). The count of CD3 +CD4+cells was 34.9/µl (normal range 441–2156/µl), and the ratio was 3.8% (normal range 28.2%–62.8%). The count of CD3 +CD8+cell was 576.73/µl (normal range 125–1312/µl), and the ratio was 62.85% (normal range 10.2%–40.1%). His allo-HSCT 5 months ago with his ongoing immunosuppressants of methotrexate and dexamethasone might have contributed to his immune dysfunction, shown by lowered CD4/CD8 ratio. It has been well documented that a lower CD4/CD8 ratio is not only associated with HIV overall immune dysfunction serving as a biomarker for HIV disease progression, response to treatment, morbidity and mortality,9 but also significantly impacted by CMV infection through the expansion of CMV-specific CD8 cells. The accumulation of CMV-specific CD8 cells lowers CD4/CD8 ratios, leading to the immune risk phenotype.10 The consensus diagnosis would be ARN most likely caused by acute CMV infection associated with very low CD4/CD8 ratio in the absence of positive viral serology screen for HSV, EBV, VZV and HHV-6. However, we are unable to make a definitive etiological diagnosis of acute CMV infection without aqueous PCR DNA analysis.11 12

Treatment

There have not been any consensus guidelines on the treatment of ARN due to its rarity, and most clinicians combined systemic and topical use of antiviral medication, corticosteroid, prophylactic laser in treating ARN. Systemic therapy has been shown to be effective in stopping disease progression and preventing involvement of unaffected eye.13 On confirmation of the diagnosis, the patient was treated with topical ganciclovir ophthalmic gel, anti-inflammatory and pupil-dilation eye-drops in conjunction with oral and intravenous ganciclovir. We used ganciclovir instead of acyclovir because ganciclovir is more effective in treating CMV infection in comparison with acyclovir and is more suitable for immune-suppressed patients.14

In addition to antiviral medication, corticosteroid is very important due to its effects in relieving intense inflammatory response. Therefore, methylprednisolone was also given to the patient and he continued his routine anti-rejection medications. His clinical improvement was demonstrated in the raised visual acuity of his left eye and resolution to the left eye KP (figure 4) with less opaque vitreous body.

In view of his left retina showing ischaemic necrosis in the peripheral vessels of the temporal retina (figure 5), we performed retinal laser photocoagulation (figure 6) of his left eye to prevent possible complications including retinal hole or retinal detachment.

Outcome and follow-up

The patient continued 3 months of 532 nm laser and returned to outpatient for review. The post-treatment condition of left eye remained stable (figure 7) showing no inflammation in the aqueous humour or vitreous and only few remaining KP. His left eye visual acuity was slightly reduced as his cataract worsened (figure 8) due to the use of high-dose oral methylprednisolone. Phacoemulsification and intraocular lens transplantation were performed 5 months after his first hospitalisation and the visual acuity of left eye increased to 20/32 postoperatively. Additionally, 532nm laser treatment was performed on the left retina to maintain its structural and functional stability. Meanwhile, we also monitored treatment efficacy with post allo-HSCT haematological biomarkers showing unremarkable results of CD4 count, CD8 count and its ratio. The patient has also used oral valacyclovir as a long-term prophylactic antiviral to prevent recurrence.

The quantitative PCR of aqueous humour for CMV DNA was not performed immediately after the clinical and serological confirmation of the diagnosis, because both the patient and treating clinicians were concerned about the risk of intravitreal infection by the invasive diagnostic procedure in the setting of his immunocompromised status despite of the proven clinical diagnostic value and the relatively low risk of infection about this procedure.11 12 However, in view of the need to monitor treatment response, we performed the quantitative PCR of aqueous humour for CMV DNA 6 months after the initial diagnosis when phacoemulsification and intraocular implantation were performed. After 6 months of systemic and local use of antiviral medications, quantitative PCR viral load of CMV and all other virus including HSV, EBV, VZV and HHV-6 were not detected in aqueous humour. The lower lymphocyte counts and abnormal liver function tests also returned to normal range. Therefore, we could conclude at least that viral replication, most likely CMV, was successfully suppressed and cleared with the 6 months of antiviral treatments. Finally, a long-term follow-up plan in this case is designed with regular ophthalmology monitor of potential retinal complications like viral retinitis or recurrent ARN in light of the patient being on lifelong immunosuppressive therapy.