Acute Retinal Necrosis

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Background

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.



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The white area is necrotic retina.

Pathophysiology

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.

Epidemiology

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.

History

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

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 later.[6]

Physical

Examination findings may include the following:

Causes

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

Physical Examination

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

Complications

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]

Approach Considerations

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

Laboratory Studies

Laboratory tests are nondiagnostic and may not be conclusive.

Viral titers for the following may be helpful:

For baseline, obtain the following:

Imaging Studies

Fluorescein angiography is as follows:

Ocular ultrasound is as follows:

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.

Procedures

Lumbar puncture may show cerebrospinal fluid pleocytosis.

Staging

Stage 1 is necrotizing retinitis, with the following substages:

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:

Approach Considerations

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]

Medical Care

Acute retinal necrosis (ARN) treatment consists of the following[14] :

For severe ARN, early vitrectomy with laser demarcation of areas of retinal necrosis together with intravenous antiviral agents should be considered.[19]

Surgical Care

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

Consultations

Infectious disease specialist or internist

Medication Summary

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

Acyclovir (Zovirax)

Clinical Context:  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)

Clinical Context:  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)

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

Famciclovir (Famvir)

Clinical Context:  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)

Clinical Context:  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

Antivirals reduce progression of virus in the affected eye as well as protection of the other eye.[18]

Prednisone (Rayos)

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

Prednisolone (FloPred, Millipred, Millipred DP, Prelone)

Clinical Context:  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

These agents systemically interfere with events leading to inflammation.

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

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

Class Summary

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

Further Outpatient Care

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

Further Inpatient Care

Check blood work.

Inpatient & Outpatient Medications

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.

Deterrence/Prevention

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

Complications

Complications of acute retinal necrosis may include the following:

Prognosis

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, 20]

Author

Andrew A Dahl, MD, FACS, Assistant Professor of Surgery (Ophthalmology), New York College of Medicine (NYCOM); Director of Residency Ophthalmology Training, The Institute for Family Health and Mid-Hudson Family Practice Residency Program; Staff Ophthalmologist, Telluride Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

David T Wong, MD, FRCSC, Associate Professor of Ophthalmology and Vision Sciences, Department of Ophthalmology and Vision Sciences, University of Toronto Faculty of Medicine; Ophthalmologist-in-Chief, St Michael's Hospital, Canada

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Novartis, Alcon, Bayer<br/>Received research grant from: Novartis, Alcon, Bayer, Genetech<br/>Received consulting fee from Alcon for consulting; Received consulting fee from Novartis for consulting; Received consulting fee from Bayer for consulting; Received consulting fee from Allergan for consulting; Received consulting fee from B & L for consulting.

Saad Waheeb, MB, BCh, FRCSC, Consulting Staff, Department of Ophthalmology, King Abdulaziz University Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Steve Charles, MD, Founder and CEO of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine

Disclosure: Received royalty and consulting fees for: Alcon Laboratories.

Chief Editor

C Stephen Foster, MD, FACS, FACR, FAAO, FARVO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Aldeyra Therapeutics (Lexington, MA); Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA); Eyegate Pharma (Waltham, MA); Novartis (Cambridge, MA); pSivida (Watertown, MA); Xoma (Berkeley, CA); Allakos (Redwood City, CA)<br/>Serve(d) as a speaker or a member of a speakers bureau for: Alcon (Geneva, Switzerland); Allergan (Dublin, Ireland); Mallinckrodt (Staines-upon-Thames, United Kingdom)<br/>Received research grant from: Alcon; Aldeyra Therapeutics; Allakos Pharmaceuticals; Allergan; Bausch & Lomb; Clearside Biomedical; Dompé pharmaceutical; Eyegate Pharma; Mallinckrodt pharmaceuticals; Novartis; pSivida; Santen; Aciont.

Additional Contributors

Brian A Phillpotts, MD,

Disclosure: Nothing to disclose.

References

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The white area is necrotic retina.

Severe vitritis with occlusive arteriolitis.

The white area is necrotic retina.

Severe vitritis with occlusive arteriolitis.