PEER REVIEWED

Infectious Viral Retinitides

ALLISON DUBLIN, MD ∙ ANNAL D. MELETH, MD, MS ∙ H. NIDA SEN, MD, MHS ∙ ROBERT B. NUSSENBLATT, MD

The infectious viral retinitides constitute a rare group of diseases with distinct clinical characteristics and challenging management dilemmas. This review will primarily focus on three viral retinitides associated with Herpesviridae: acute retinal necrosis, progressive outer retinal necrosis and cytomegalovirus retinitis.

ACUTE RETINAL NECROSIS

Acute retinal necrosis (ARN) is a rare, aggressive and potentially blinding disease associated with Herpesviridae that was first described in 1971 by Urayama et al. The disease typically manifests in an immunocompetent individual and is usually unilateral at onset. Bird et al. described the bilateral variant of ARN in 1978 in a group of four patients who presented initially with unilateral disease.¹ Fellow eye involvement can occur in approximately 10% to 36% of cases, usually within a time period of six weeks, though it has been described as far as 34 years removed from the initial episode.^2,3

Patients with ARN typically present complaining of mild to moderate eye pain, accompanied by decreased vision and floaters. The mean age of presentation is in the sixth decade, though the disease has been described at all age ranges. ARN is a clinical diagnosis; the American Uveitis Society's criteria for diagnosis include:

1. One or more foci of retinal necrosis with discrete borders in the peripheral retina.
2. Rapid circumferential progression of necrosis in the absence of treatment.
3. Evidence of occlusive vasculitis with arteriolar involvement.
4. Prominent inflammation in the anterior and posterior chambers.

The areas of peripheral retinal necrosis in ARN are typically full-thickness lesions that are white or cream colored, with associated vitritis and well-defined borders (Figure 1). Other findings associated with the presentation of ARN include optic neuritis, scleritis and episcleritis. The retinal atrophy often leads to full-thickness retinal breaks and secondary rhegmatogenous retinal detachment in up to 75% of cases. The vascular occlusive disease associated with ARN can result in neovascularization and vitreous hemorrhage.

Figure 1. Characteristic appearance of ARN. Note the large areas of white retinal necrosis with overlying vitritis. FA demonstrates significant occlusive vasculopathy and neovascularization.

The diagnosis of ARN is based on clinical appearance with concomitant demonstration of the virus by anterior-chamber paracentesis or pars plana vitreous biopsy with the detection of viral antibodies or the viral DNA by polymerase chain reaction (PCR). Although ocular antibody levels do rise above those of the serum, quantitative PCR has the highest sensitivity and specificity, providing definitive pathogen identification.

Implicated viruses in order of prevalence of causative agent are varicella zoster virus (VZV), herpes simplex viruses (HSV) type 1 and 2, Epstein-Barr virus (EBV) and cytomegalovirus.^4,5 The role of EBV in ARN was questioned in a recent series, due to the concurrent detection of VZV in the cases of ARN with EBV.⁴ In addition to a viral etiology, an immunogenetic predisposition may exist with regard to risk of developing ARN. Specific human leukocyte antigen (HLA) haplotypes, including HLA-DQw7 antigen and phenotypes -Bw62 and -DR4 in the Caucasian population and HLA-Aw33, -B44, and -DRw6 in the Japanese population, may result in a predisposition to ARN.^6,7

Treatment of ARN has classically included intravenous acyclovir (Zovirax, GlaxoSmithKline), with systemic corticosteroids and adjunctive vitrectomy for dense vitreous hemorrhage, vitreous opacification or secondary rhegmatogenous retinal detachment. Treatment with antivirals has been shown to reduce the risk of bilateral involvement and extension of the disease.^4,5,8 Antiviral therapy is known to decrease the virus propagation to the unaffected eye via chiasmal or transynaptic spread. Intravitreal injections of ganciclovir or foscarnet (Foscavir, AstraZeneca) and oral famciclovir (Famvir, Novartis) or valacyclovir (Valtrex, GlaxoSmithKline) with oral steroids in those who fail to respond to or who have contraindications to systemic acyclovir have also been used successfully.^9-12 Treatment with antivirals does not appear to reduce the risk of subsequent retinal detachment.^13,14

Prophylactic laser barricade applied posteriorly to areas of retinal necrosis has been suggested to reduce the incidence of secondary retinal detachment, though much debate remains regarding the effectiveness of this therapeutic modality.^4,5 The presence of vitritis hinders effective visualization and laser treatment in many cases of ARN.

Hillenkamp et al. compared early vitrectomy with intravitreal acyclovir lavage (40 μg/mL) in addition to standard therapy with intravenous acyclovir and oral prednisolone with IV acyclovir and oral prednisolone alone in a nonrandomized retrospective comparative case series. They found a reduced rate of secondary rhegmatogenous retinal detachment (RRD) with a reduced incidence of phthisis bulbi in the vitrectomy group, with four of 10 eyes developing RRD vs 18 out of 20 in the standard therapy group. Interestingly, the final visual outcome was unchanged, suggesting that the cause of visual loss in ARN is likely related to ischemic vasculopathy of the optic nerve or macula.

Intravenous antiviral therapy with acyclovir (10 mg/kg three times per day) is advocated over oral antivirals due to more consistent intraocular penetration with concurrent systemic corticosteroids (1 mg/kg/day tapered by 10 mg very five days) to decrease the host inflammatory response. Following initial induction, continued treatment with oral antivirals for a duration of three months is recommended. For VZV-related ARN, acyclovir 800 mg by mouth five times per day is suggested, while half the dose is considered efficacious in HSV-related ARN.

RRDs associated with ARN are best treated aggressively, as a higher rate of anatomical success has been achieved using vitrectomy techniques, long-acting gas, and silicone-oil tamponade vs scleral buckling alone.^15-17

PROGRESSIVE OUTER RETINAL NECROSIS

In contrast to ARN, progressive outer retinal necrosis (PORN) is found primarily in immunocompromised individuals, most often with advanced stages of HIV/AIDS (CD4 + T lymphocytes 50 cells/μL or less). PORN has also been described after allogeneic stem-cell transplantation¹⁸ and in an immunocompetent individual who did not show full-thickness retinal involvement.¹⁹

PORN also typically manifests with little or no inflammatory component, spares the retinal vasculature, and displays multiple patchy areas of outer retinal whitening (Figure 2). The progression of PORN to confluent full-thickness retinal necrosis occurs more rapidly than ARN, can involve the posterior pole early in the disease process, and is more likely to progress to bilateral involvement (71%). Poor visual outcomes are common in PORN. An initial series of 65 eyes found an eventual visual acuity of no light perception in 67% of eyes, despite antiviral treatment.²⁰

Figure 2. PORN. Note the peripheral areas of outer retinal whitening with confluent involvement of macula, and lack of vitritis or vasculitis.

Secondary RRD is a common sequelae of disease in PORN, with rates of up to 75% in involved eyes.^20,21 VZV is the virus most often implicated in PORN; however, cases of HSV have been observed. Quantitative polymerase chain reaction sampling of the aqueous humor or vitreous biopsy is indicated for pathogen identification and can provide an indication of disease activity.²²

A multipronged aggressive treatment approach is vital for successful management of PORN. Immune reconstitution with highly active antiretroviral therapy (HAART) with coadministration of systemic antiviral intravenous therapy and intravitreal therapy is indicated.^11,19,21-27

Per Yin et al., twice weekly intravitreal injections of ganciclovir (2 mg/0.05 mL) and foscarnet (1.2 mg/0.05 mL) for a total of 58 injections in conjunction with intravenous ganciclovir (5 mg/kg) and foscarnet (90 mg/kg) twice daily successfully retained central visual acuity of 20/20 in a Thai woman.²² Qualitative PCR was used to determine treatment efficacy and duration and was subsequently tapered when the viral load was undetectable and CD4 count increased to above 50 cells/mm³. If immune reconstitution with HAART is not attainable, long-term suppressive antiviral therapy is indicated.

Retinal detachments should be managed aggressively with vitrectomy and silicone oil tamponade.²¹ The ganciclovir implant has also been used as an adjunctive treatment in management of PORN.²⁶

CYTOMEGALOVIRUS RETINITIS

Cytomegalovirus (CMV), a member of the Herpesviridae family, is the most common ocular opportunistic infection in patients with AIDS. Systemic infection with CMV is common and a high seropositivity for CMV antibodies exists in the general population.

Prior to the emergence of the AIDS pandemic, CMV retinitis was described in immunosuppressed patients after renal transplantation or patients with primary immune deficiencies.^28-30 A dramatic increase in the incidence of CMV retinitis was noted with the rise of HIV, with up to 40% of patients with AIDS affected. The primary risk factor for development of retinitis is degree of immune compromise, with CD4 counts of less than 50 cells/µL associated with an odds ratio of 4.2, compared with patients with CD4 counts greater than 100 cells/µL.³¹

The initiation of HAART therapy has resulted in a dramatic reduction in the incidence of CMV retinitis, though the rate of CMV retinitis in developing countries remains high, and the disease is thought to be underdiagnosed and undertreated in these populations.^32,33

The diagnosis of CMV retinitis is made on clinical grounds, though vitreous or aqueous sampling with PCR can be a useful adjunct in questionable cases. There are two classical clinical appearances to CMV retinitis (Figure 3):

1. Perivascular inflammation with irregular patches of fluffy white retinal edema and necrosis with associated scattered hemorrhages.
2. Granular lesion with central clearing and stippled retinal pigment epithelium.

Figure 3. CMV retinitis. Note the perivascular involvement with frosted branch angiitis appearance, areas of retinal whitening and hemorrhage at advancing edge of lesion with central clearing and granularity.

Additional features may include frosted branch angiitis, chronic vitritis or cystoid macular edema. Most commonly, retinitis progresses via expansion of previous retinal lesions, which can advance at a rate of up to 250 µm per week, typically faster anteriorly than posteriorly.³⁴ Autofluorescence imaging can be a useful adjunctive method with which to monitor activity, with the advancing border often displaying hyperautofluorescence.³⁵

Retinitis can also progress via the appearance of new lesions in separate locations. Vision loss occurs via macular or optic nerve involvement with primary retinitis or secondarily with macular edema associated with paramacular involvement. RRDs are also an important cause of vision loss in patients with CMV retinitis, developing in approximately 20% of patients.³⁶

There are five FDA-approved drugs for treatment of CMV retinitis: ganciclovir, foscarnet, cidofovir (Vistide, Gilead), fomivirsen (Vitravene, Novartis) and valganciclovir (Valcyte, Roche).

The previous standard of care for treatment for CMV retinitis involves intravenous ganciclovir (5 mg/kg twice daily) for an induction period of two weeks, followed by long-term maintenance daily. In sight-threatening cases or in patients unable to tolerate oral therapy, supplementary therapy with intravitreal injections of ganciclovir (2 mg/0.05 mL) or foscarne (1.2 mg/0.05 mL) may be indicated. Oral valganciclovir, a ganciclovir prodrug, has similar efficacy and is now the drug of choice due to ease of administration and equivalent efficacy in both induction and maintenance.³⁷

The gancyclovir intravitreal implant delivers gancyclovir for six to eight months at four times higher than the concentration of intravitreal injection and may be a good option in patients in whom systemic therapy is contraindicated.³⁸ Phenotypic and genotypic resistance to gancyclovir can occur, often secondary to mutations in the CMV UL97 gene.³⁹ The rate of resistance has declined dramatically with the widespread adoption of HAART therapy, from approximately 28% in the pre-HAART era to ~9% in the HAART era.⁴⁰

Administration of HAART therapy with subsequent immune recovery arrests CMV retinitis progression.⁴¹ Coadministration of HAART therapy to reconstitute the immune system is vital, as without HAART, 50% of patients will experience reactivation on the maintenance dose of CMV therapy, and close to 100% will relapse upon withdrawal of CMV therapy. Disease progression is typically halted within four to six weeks of initiating treatment. With adjunctive HAART therapy, CMV therapy may be halted with an increase in CD4 count along with close monitoring for reactivation.^42,43

The immune reconstitution associated with HAART can result in an immune recovery uveitis (IRU), manifested primarily by vitritis, possibly accompanied by anterior uveitis, cataract, macular edema or optic disc edema. Estimates of prevalence of IRU among CMV retinitis patients undergoing immune reconstitution vary widely, from 20% to 90%.^42,44,45 IRU may represent the recovery of specific anti-CMV immunity.

The risk of IRU appears to increase with large areas of previous retinitis. Primary sequelae and causes of vision loss among patients with IRU include the development of epiretinal membranes and or cystoid macular edema.^44,45 Treatment IRU may require courses of topical, periocular, or oral steroids. However, CMV retinitis can reactivate during management of IRU and must be watched for carefully.

CONCLUSION

The infectious viral retinitides constitute a demanding group of diseases in terms of diagnosis, treatment and management of long-term complications. In particular, the treatment approaches for ARN and PORN remain curtailed due to the rarity of these diseases and the subsequent deficiency of large prospective studies to further delineate management. Due to the potential visual implications of these diseases, a vigilant approach and long-term follow-up are essential. RP

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