Necrotizing Herpetic Retinitis (Acute Retinal Necrosis / Progressive Outer Retinal Necrosis)

Key Points at a Glance

Highlights of This Disease

• Necrotizing herpetic retinitis is a spectrum of rapidly progressive viral retinopathy consisting of acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN).
• Acute retinal necrosis was first reported in Japan in 1971 by Urayama et al. as “Kirisawa-type uveitis,” a disease concept originating from Japan.
• The most common cause of acute retinal necrosis is varicella-zoster virus (VZV), followed by herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2).
• This disease is an ophthalmic emergency; once the clinical diagnosis is confirmed, antiviral therapy must be initiated immediately.
• Standard treatment is induction therapy with intravenous acyclovir 10 mg/kg three times daily for 2 weeks, followed by switching to valacyclovir.
• Retinal detachment occurs in approximately 70% of untreated acute retinal necrosis cases, and two-thirds of affected eyes have visual acuity of 0.1 or worse.
• Progressive outer retinal necrosis occurs in immunocompromised individuals such as those with HIV infection, rapidly involving the posterior pole without significant vitritis.

1. What is Necrotizing Herpetic Retinitis?

Necrotizing herpetic retinitis is a spectrum of rapidly progressive viral retinopathy consisting of acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN).

Acute retinal necrosis was first reported in Japan in 1971 by Urayama et al. as “Kirisawa-type uveitis.” This disease, reported as a fulminant uveitis with an unprecedented course in six cases, represents the first description of acute retinal necrosis in Japan and worldwide.

Differences in clinical presentation depending on immune status are an essential feature of this disease.

• Acute retinal necrosis: Occurs mainly in immunocompetent patients. Presents as peripheral retinitis with vasculitis, iridocyclitis, and vitritis.
• Progressive outer retinal necrosis: Occurs in immunocompromised patients such as those with HIV infection. Rapidly involves the macula and peripheral retina without significant intraocular inflammation or vascular lesions.

This disease is a true ophthalmic emergency, and immediate treatment is essential to prevent permanent vision loss.

Q What is the difference between acute retinal necrosis and PORN?

A

Acute retinal necrosis primarily occurs in immunocompetent individuals and is characterized by severe inflammation (vitritis, anterior uveitis, arteritis) starting from the periphery. In contrast, PORN occurs in severely immunocompromised individuals such as those with HIV infection, and is characteristically different in that the retina, including the posterior pole, rapidly necrotizes without significant vitritis. Both require emergency treatment.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Patients with acute retinal necrosis typically present with the following symptoms.

• Floaters: Due to anterior vitritis and vitreous opacities.
• Photophobia (light sensitivity): Light sensitivity due to anterior segment inflammation.
• Decreased vision: Progressive and rapid visual impairment.
• Eye pain: May be a prominent feature but is often absent.

Without treatment, the fellow eye is affected within one month in one-third of patients. More than 85% of cases are unilateral at onset.

Clinical Findings

Acute Retinal Necrosis Findings

Anterior segment: Granulomatous or non-granulomatous anterior uveitis, mutton-fat keratic precipitates. In acute retinal necrosis caused by herpes simplex virus, elevated intraocular pressure (mean 35 mmHg) is frequently observed.

Retinal lesions: Yellow-white necrotic patchy lesions starting in the far periphery or mid-periphery. They enlarge, increase in number, and coalesce over time.

Retinal vasculitis: Primarily arteritis. Characteristic is stick-shaped hemorrhages along the veins.

Progressive outer retinal necrosis findings

Lack of inflammation: Characterized by the absence of significant vitritis.

Onset from the posterior pole: Unlike acute retinal necrosis, it affects the posterior pole and macula from the early stage.

Rapid progression: May show marked progression within 24 to 48 hours.

Bilaterality: Tends to be bilateral from the early course.

In the course of acute retinal necrosis, yellowish-white granular lesions (viral replication sites) seen in the peripheral retina expand circumferentially and posteriorly, but progression stops about one week after initiation of antiviral therapy. Subsequently, each granular lesion coalesces into dense, well-demarcated geographic white lesions (due to direct viral damage and occlusive vasculitis).

Emergency response required

Both acute retinal necrosis and progressive outer retinal necrosis are ophthalmic emergencies. If necrotizing retinitis, vitritis, or retinal vasculitis starting from the periphery is observed, antiviral therapy should be initiated immediately without waiting for laboratory results.

3. Causes and Risk Factors

Causative viruses

The most common cause of acute retinal necrosis is varicella-zoster virus, followed by herpes simplex virus type 1 and herpes simplex virus type 2. Cytomegalovirus is an important cause in immunocompromised individuals.

• Varicella-zoster virus: More common in older adults. Age-related decline in cell-mediated immunity is involved.
• Herpes simplex virus type 1: More common in adults and older adults. May be associated with a history of herpes encephalitis.
• Herpes simplex virus type 2: More common in younger individuals. Has been associated with meningitis.
• Cytomegalovirus: Primarily occurs in immunocompromised individuals (HIV infection, diabetes, cancer, users of immunosuppressive therapy).

Risk Factors

• Current or past history of herpes infection: Found in up to 50% of patients.
• Immunosuppressed state: HIV infection, diabetes, malignancy, systemic steroid/immunosuppressive therapy use.
• Topical steroid use: A rare risk factor that may be associated with fulminant acute retinal necrosis.
• Advanced age: Increased risk of acute retinal necrosis due to varicella-zoster virus.

From a prevention perspective

Herpes zoster vaccine (especially vaccination for shingles in those aged 50 and older) may reduce the risk of ocular complications (herpes zoster ophthalmicus) caused by varicella-zoster virus. If you are immunocompromised, it is important to ask your doctor for regular evaluation of eye symptoms.

4. Diagnosis and Testing Methods

The diagnosis of acute retinal necrosis is usually made clinically. The diagnostic criteria established by the SUN (Standardization of Uveitis Nomenclature) 2021 Working Group are used [2].

SUN 2021 Diagnostic Criteria for Acute Retinal Necrosis

Diagnosis is made by the following combination:

Required: Necrotizing retinitis involving the peripheral retina

And any of the following:

1. Positive PCR for herpes simplex virus or varicella-zoster virus from aqueous humor or vitreous sample
2. Characteristic clinical findings (circumferential or confluent retinitis + retinal vascular sheathing and/or occlusion + vitritis more than mild)

Diagnostic criteria in Japan

In Japan, the following diagnostic criteria are used (combination of initial ocular findings, clinical course, and intraocular fluid virus testing).

Initial ocular findings:

• Anterior chamber inflammatory cells or mutton-fat keratic precipitates
• Yellow-white lesions in the peripheral retina
• Retinal arteritis
• Optic disc hyperemia
• Inflammatory vitreous opacities
• Elevated intraocular pressure

Clinical course:

• Rapid circumferential expansion of retinal lesions
• Development of retinal tears or retinal detachment
• Retinal vascular occlusion
• Optic atrophy
• Response to antiviral drugs

Viral testing (PCR)

Detection of viral DNA by PCR of intraocular fluid (aqueous humor, vitreous fluid) is the most sensitive and specific diagnostic method. Quantitative PCR is also useful for evaluating viral load, disease activity, and treatment response.

Goldmann-Witmer coefficient (GW coefficient)

A test comparing antibody production in intraocular fluid and serum. A GW ratio greater than 4 indicates local antibody production and has diagnostic value. However, note that intraocular antibody production may be insufficient in the early stage (within 10 days) of onset.

5. Standard treatment

The treatment goals for acute retinal necrosis are: (1) to stop retinal necrosis, (2) to minimize secondary damage from inflammation and vascular occlusion, and (3) to protect the fellow eye. Antiviral therapy should be started immediately without waiting for laboratory results.

ASAP therapy (standard treatment in Japan)

Start the following four elements simultaneously as soon as possible.

• A (Aciclovir: antiviral therapy)
• S (Steroid: anti-inflammatory therapy)
• A (Aspirin: antithrombotic therapy)
• P (Prophylaxis for retinal detachment)

Pharmacotherapy

Antiviral therapy

Therapy	Drug/Dosage	Route	Duration
Induction therapy	Acyclovir 10 mg/kg 3 times/day	Intravenous infusion	2 weeks
Alternative induction therapy	Valtrex tablets (500 mg) 6 tablets divided into 3 doses	Oral	2 weeks
Maintenance therapy	Valtrex tablets (500 mg) 6 tablets divided into 3 doses	Oral	2 weeks after initial therapy

Recent findings have reported that induction therapy with oral valacyclovir (up to 2 g per dose, three times daily) shows comparable visual outcomes and retinal detachment rates to intravenous acyclovir [3].

Intravitreal Antiviral Injection

Patients receiving combination therapy of systemic administration and intravitreal foscarnet (2.4 mg/0.1 ml) have shown improved visual acuity and reduced retinal detachment rates compared to systemic therapy alone, and should be considered as induction therapy for patients with acute retinal necrosis [1,4].

For cytomegalovirus retinitis, ganciclovir (5 mg/kg twice daily) or valganciclovir (900 mg twice daily) is used.

Anti-inflammatory Therapy and Others

• Steroids: Initiated 24–48 hours after starting antiviral therapy (to minimize vitreous inflammation and formation of vitreous strands that can cause tractional retinal detachment). Caution is needed because local steroid therapy may promote rapid progression of retinitis and vision loss.
• Antithrombotic therapy: Aspirin (100 mg) 1 tablet once daily for 4 weeks. Prevents complications due to occlusive vasculitis.
• Mydriatics: Prevention of posterior synechiae.

In bilateral cases, the interval between onset in the right and left eyes is often within one month, so antiviral administration should be continued for an additional two weeks after the initial two-week therapy.

Surgical Treatment

Large retinal tears are prone to occur in areas of retinal necrosis, leading to retinal detachment.

• Prophylactic laser photocoagulation: Prophylactic barrier laser photocoagulation posterior to the necrotic lesion (preferably during the granular lesion stage) [7]. However, evidence is not yet established, and some studies have not shown a significant reduction in retinal detachment rates in eyes that received prophylactic laser treatment.
• Vitrectomy: A combination of silicone oil tamponade, endophotocoagulation, and encircling band is performed. Because multiple atrophic posterior tears exist in the thin, necrotic retina, vitrectomy is generally preferred over scleral buckling.
• Prophylactic vitrectomy: Prophylactic vitrectomy during the granular lesion stage is sometimes recommended, but evidence is currently insufficient as several studies have found no significant difference in retinal reattachment status between early surgery and observation [5].

Treatment Precautions

• Topical steroids are dangerous: Topical steroid therapy may promote rapid progression of retinitis and vision loss, so careful use is required.
• Hypotony after silicone oil tamponade: Hypotony can become a problem after oil removal, sometimes necessitating reinjection of oil. This is thought to be due to ciliary body dysfunction caused by severe inflammation.
• Contraction of residual lens capsule: Lens capsule contraction is inevitable after vitrectomy, and early laser capsulotomy is necessary.
• Prognosis of progressive outer retinal necrosis: In immunocompromised patients, especially HIV-infected individuals with markedly decreased CD4 counts, the prognosis of progressive outer retinal necrosis still requires a cautious outlook. Attention must also be paid to the emergence of acyclovir-resistant viruses.

Q Will vision definitely recover once treatment is started?

A

Although there are reports of good outcomes with aggressive intervention, the overall prognosis of acute retinal necrosis still requires a cautious outlook. The prognosis of untreated acute retinal necrosis is traditionally poor, with two-thirds of eyes having visual acuity of 0.1 (20/200) or worse. Early diagnosis and early initiation of treatment are the most important factors determining prognosis, and prompt referral to an ophthalmology specialist is essential.

6. Pathophysiology and Detailed Pathogenesis

Reactivation of latent virus plays a central role in the development of necrotizing herpetic retinitis.

• Viral latency and reactivation: Herpes viruses such as herpes simplex virus, varicella-zoster virus, and cytomegalovirus establish latent infection in ganglia. They reactivate due to some trigger (immunosuppression, aging, stress, etc.) and reach the eye via nerves.
• Pathogenesis of acute retinal necrosis: Herpes simplex virus type 1 has been identified from chorioretinal tissue and vitreous, and DNA of herpes simplex virus type 1 and type 2 has been detected in intraocular fluid by PCR testing.
• Routes of infection: Acute retinal necrosis due to herpes simplex virus type 1 tends to occur in patients with a history or complication of herpes encephalitis, while acute retinal necrosis due to herpes simplex virus type 2 has been associated with meningitis. Acute retinal necrosis due to varicella-zoster virus has also been reported to be complicated by meningitis.
• Occlusive vasculitis: During the peak of inflammation, vasculitis occurs not only in retinal veins but also in arteries, leading to occlusive vasculitis with club-shaped hemorrhages along veins (characteristic of acute retinal necrosis) and occlusion of major arteries.
• Mechanism of retinal detachment: Approximately 3 to 4 weeks after starting treatment, incomplete posterior vitreous detachment occurs due to vitreous organization. Around this time, strong traction from the vitreous on the extremely thinned and fragile necrotic retina creates multiple breaks, leading to retinal detachment in about 70% of cases.
• Specificity of progressive outer retinal necrosis: Many cases of progressive outer retinal necrosis are likely to have developed acyclovir resistance due to long-term treatment for herpes zoster, and foscarnet should be considered [6]. Human herpesvirus 6 lacks thymidine kinase, so acyclovir is ineffective.

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7. Latest Research and Future Prospects (Investigational Reports)

For Patients: Please Read Carefully

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Oral Valacyclovir Induction Therapy

Conventional standard treatment involved hospitalization with intravenous acyclovir. However, recent studies have shown that induction therapy with oral valacyclovir (up to 2 g per dose, three times daily) achieves visual outcomes and retinal detachment rates equivalent to intravenous acyclovir. This finding is notable as it opens the possibility of initiating treatment on an outpatient basis.

Widespread Use of Intravitreal Antiviral Therapy

Combination therapy with systemic administration and intravitreal foscarnet injection (2.4 mg/0.1 ml) has shown better outcomes compared to systemic therapy alone, making standardization of induction therapy including intravitreal injection a research topic. Direct intraocular administration of antiviral drugs may achieve high local concentrations while minimizing systemic toxicity.

Utilization of Quantitative PCR

Research is accumulating that monitoring viral load using quantitative PCR testing is useful for assessing disease activity, determining treatment response, and optimizing treatment duration. Standardization of quantitative PCR and establishment of its clinical application remain future challenges.

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8. References

1. Schoenberger SD, Kim SJ, Thorne JE, et al. Diagnosis and Treatment of Acute Retinal Necrosis: A Report by the American Academy of Ophthalmology. Ophthalmology. 2017;124(3):382-392. PMID: 28094044

2. Standardization of Uveitis Nomenclature (SUN) Working Group. Classification Criteria for Acute Retinal Necrosis Syndrome. Am J Ophthalmol. 2021;228:237-244. PMID: 33845012

3. Baltinas J, Lightman S, Tomkins-Netzer O. Comparing Treatment of Acute Retinal Necrosis With Either Oral Valacyclovir or Intravenous Acyclovir. Am J Ophthalmol. 2018;188:173-180. PMID: 29447915

4. Botsford BW, Nguyen VQ, Eller AW. Acute Retinal Necrosis: Difference in Outcome by Viral Type and Options for Antiviral Therapy. Retina. 2021;41(11):2317-2322. PMID: 34137387

5. Fan S, Lin D, Wang Y. Role of Prophylactic Vitrectomy in Acute Retinal Necrosis in Preventing Rhegmatogenous Retinal Detachment: Systematic Review and Meta-analysis. Ocul Immunol Inflamm. 2022;30(2):515-519. PMID: 32966153

6. Ciulla TA, Rutledge BK, Morley MG, Duker JS. The progressive outer retinal necrosis syndrome: successful treatment with combination antiviral therapy. Ophthalmic Surg Lasers. 1998;29(3):198-206. PMID: 9547773

7. Lau CH, Missotten T, Salzmann J, Lightman SL. Acute retinal necrosis features, management, and outcomes. Ophthalmology. 2007;114(4):756-762. PMID: 17184841