Acute Retinal Necrosis

Acute retinal necrosis (ARN) can lead to uveitis, retinal detachment, and blindness. Acute retinal necrosis was first described in the Japanese literature in 1971 and termed Kirisawa uveitis. During the past 3 decades, acute retinal necrosis syndrome has been a source of fear, frustration, and fascination for many ophthalmologists. Unfortunately, it can be a visually devastating condition for the patient.

A necrotic retina is shown in the image below.

Acute retinal necrosis may be a result of dormant herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), cytomegalovirus, or varicella-herpes zoster virus (VZV) viral reactivation in the retina. The exact etiology of this reactivation is still elusive; however, an immunogenetic predisposition to the disease is likely.

Frequency

United States

Acute retinal necrosis accounts for 5.5% of uveitis cases over a 10-year period.[1]

International

In Switzerland, acute retinal necrosis accounts for 1.7% of uveitic cases.

Mortality/Morbidity

Significant visual loss may occur. Retinal detachment is a frequent complication (~50%)[2, 3, 4] and is a cause of legal blindness in some bilateral cases of acute retinal necrosis.

Race

No clear racial predilection exists.

Sex

This condition appears to have a predilection for males; however, the extent is not clear.

Age

Acute retinal necrosis is a disease of young healthy individuals aged 20-50 years.

A bimodal age distribution possibly exists, peaking at approximately ages 20 and 50 years. This distribution may be related to differences in etiologic agents. When varicella-zoster virus or herpes simplex virus type 1 is involved, the median age is 57 and 47 years, respectively. When herpes simplex virus type 2 is involved, the median age is 20 years.

Typically, acute retinal necrosis is a disease of immunocompetent individuals. Initially, patients may complain of the following:

• Red eye

• Periorbital pain

• Hazy vision or decreased vision

• Appearance of floaters

• Decreased color vision

• Other areas of previous infections - Primary varicella infections, herpes zoster

Infection with herpes simplex virus (HSV-1 or HSV-2) and VZV can cause widely variable clinical manifestations, ranging from the typical severe acute retinal necrosis to more atypical, slowly progressing necrotizing and nonnecrotizing inflammation.[5]

In the era prior to the advent of antiviral therapy, bilateral involvement occurred in one third to three quarters of cases. The commencement of second eye infection ranged from 24 hours to 6 months months after the first eye’s involvement.[6]

Examination findings may include the following:

• Anterior uveitis (iritis)

• Panuveitis

• Episcleritis or scleritis

• Keratic precipitates - Fine or granulomatous

• Occlusive retinal vasculitis involving arteries and veins

• One or more focus of retinitis, resulting in necrosis with discrete borders located in the retinal periphery with circumferential spread

• Vitritis (shown in the image below)

• Optic neuropathy

  Severe vitritis with occlusive arteriolitis.

Most cases of acute retinal necrosis have been reported to be caused by the following[7] :

• Varicella-zoster virus

• Herpes simplex type 1

• Herpes simplex type 2[8]

Careful and complete ophthalmological examination should be undertaken in all patients with anterior uveitis. Fundoscopy following pupillary dilation should include examination of the peripheral retina to search for areas of retinal whitening or vasculitis.

Retinal detachment is the principal complication of ARN. Prompt diagnosis and early treatment decreases the risk of retinal detachment and improves visual acuity outcomes.[9]

Acute retinal necrosis (ARN) is a clinical diagnosis.[10, 11]

Laboratory tests are nondiagnostic and may not be conclusive.

Viral titers for the following may be helpful:

• Herpes simplex virus 1

• Herpes simplex virus 2

• Varicella-zoster virus

For baseline, obtain the following:

• Complete blood cell count

• Renal function tests

• Liver function tests

Fluorescein angiography is as follows:

• Not diagnostic

• Early decrease in choroidal perfusion

• May show delayed arterial filling

• Hypofluorescence in areas of active lesions

Ocular ultrasound is as follows:

• Can rule out retinal detachment in the presence of media opacity sufficient to obscure retinal examination

• May show enlarged optic nerve sheath[12]

CT scan may show optic nerve sheath enlargement.

MRI may demonstrate concurrent lesions of the optic tract and the lateral geniculate body, suggesting axonal spread.

Lumbar puncture may show cerebrospinal fluid pleocytosis.

Stage 1 is necrotizing retinitis, with the following substages:

• Stage 1a - Discrete areas of peripheral retinitis

• Stage 1b - Confluent areas of peripheral retinitis, papillitis, and macular edema

Stage 2 is vitreous opacification or organization.

Stage 3 is regression of retinal necrosis, with secondary pigmentation of the lesion with condensation of the vitreous base.

Stage 4 is retinal detachment, with the following substages:

• Stage 4a - Acute tractional retinal tears or detachment with traction or proliferative vitreoretinopathy

• Stage 4b - Chronic retinal detachment

Retinal lesions regress a mean of 3.9 days after initiation of antiviral therapy. No new retinal lesions or progressive optic nerve involvement has been noted 48 hours or more after treatment is initiated.[13]

Timely clinical diagnosis hastens earlier antiviral therapy. Better initial visual acuity makes for better visual outcomes.[4]

Acute retinal necrosis (ARN) treatment consists of the following[14, 15, 16, 17] :

• Antiviral therapy, including intravenous acyclovir, oral valacyclovir, oral famciclovir, intravitreal foscarnet, intravitreal valacyclovir, or intravitreal famciclovir,[18, 13, 19, 20] or a combination of oral and intravitreal antiviral therapies: Given the evidence that most cases of ARN are due to varicella-zoster or herpes simplex viral infection, acyclovir therapy is recommended. Most clinicians have observed that acyclovir speeds the regression of ARN and prevents new lesion formation.[18]  There is a significant correlation between prompt treatment and outcomes.[21]

• Anti-inflammatory therapy

• Antithrombotic therapy

• Retinal detachment prophylaxis

For severe ARN, early vitrectomy with laser demarcation of areas of retinal necrosis together with intravenous antiviral agents should be considered.[22]

Surgical procedures, such as the following, are required when retinal detachment occurs:

• Vitrectomy

• Endolaser

• Possible scleral buckle

• Intraocular tamponade: Silicone oil is the usual choice due to the multiple necrotic/atrophic retinal holes (Swiss cheese appearance).

• C3 F8 (octafluoropropane/perfluoropropane) or other fluoridated gases for temporary absorbable intraocular tamponade

Consultations may be obtained from an infectious disease specialist or internist.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Class Summary

Antivirals reduce progression of virus in the affected eye as well as protection of the other eye.[21]

Acyclovir (Zovirax)

Has affinity for viral thymidine kinase and once phosphorylated causes DNA chain termination when acted on by DNA polymerase. Patients experience less pain and faster resolution of cutaneous lesions when used within 48 h from rash onset. May prevent recurrent outbreaks. Early initiation of therapy is imperative.

Ganciclovir (Cytovene)

Synthetic guanine derivative active against cytomegalovirus (CMV). An acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo.

Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly due to preferential phosphorylation of ganciclovir in virus-infected cells.

For patients who experience progression of CMV retinitis while receiving a maintenance treatment with either dosage form of ganciclovir, the re-induction regimen should be administered.

Valacyclovir (Valtrex)

Prodrug rapidly converted to the active drug acyclovir. More expensive but has a more convenient dosing regimen than acyclovir.

Famciclovir (Famvir)

After ingestion, drug is rapidly biotransformed into active compound penciclovir and phosphorylated by viral thymidine kinase. By competition with deoxyguanosine triphosphate, penciclovir triphosphate inhibits viral polymerase subsequently inhibiting viral DNA synthesis/replication.

Adjust dose in patients with renal insufficiency or hepatic disease.

Used against herpes simplex and varicella-zoster viruses.

Foscarnet (Foscavir)

Analog of pyrophosphate. Inhibits DNA polymerase of CMV and reverse transcriptase of HIV. Virostatic; renal excretion. As effective as ganciclovir. Median time to relapse on Rx is 53 d. Foscarnet/ganciclovir CMV retinitis trial: 234 newly diagnosed patients randomized. Same efficacy for controlling retinitis and preserving vision. Survival with foscarnet 12.6 mo versus 8.5 for ganciclovir group; mortality risk 1.79x. Controlling for antiretroviral use, still better survival with foscarnet. Foscarnet has anti-HIV activity but has more dose-limiting toxicity.

Class Summary

These agents systemically interfere with events leading to inflammation.

Prednisone (Rayos)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Prednisolone (FloPred, Millipred, Millipred DP, Prelone)

Elicits mild mineralocorticoid activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level

Class Summary

Antiplatelets inhibit the cyclooxygenase system, decreasing the level of thromboxane A2, which is a potent platelet activator.

Aspirin (Bayer Aspirin, Ascriptin, Aspirtab, Buffinol, Buffasal)

Treats mild to moderate pain and headache. Inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.

Observe patients for reactivation or retinal detachment and for development of retinitis in the fellow eye.

Check blood work.

Antivirals include acyclovir, valacyclovir, ganciclovir, famciclovir, and foscarnet.

An anti-inflammatory, such as prednisone, should be started 24-48 hours after antiviral therapy is initiated.

Antiplatelets (aspirin) should be started 24-48 hours after beginning antiviral therapy.

Prophylactic barrier laser to the peripheral retina posterior to the areas of retinal necrosis is required to reduce the risk of retinal detachment.

Complications of acute retinal necrosis may include the following:

• Retinal detachment (50%)

• Anterior ischemic neuropathy

• Central retinal artery occlusion

• Cataract - From inflammation or steroids

• Glaucoma - From inflammation or steroids

Visual prognosis is guarded if retinal detachment, anterior ischemic optic neuropathy, or central retinal artery occlusion occur.[1, 2]

Fortunately, in the era of treatment with antivirals, acute retinal necrosis is usually a unilateral disease. The risk of involvement of the fellow eye was as high as 75% prior to the modern institution of therapy with acyclovir. Recent studies report fellow-eye involvement rates of 3-13% in patients presenting with unilateral disease and receiving prompt and extended treatment.[4, 23]