Necrotizing Herpetic Retinitis

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Article initiated by:

Debra A Goldstein, MD

All contributors:

Alexa Li, Russell W. Read, MD, PhD, Alex Kozak, Alan Palestine, MD, Jessica Shantha, MD, Marissa Larochelle, MD, Debra A Goldstein, MD

Assigned editor:

Marissa Larochelle, MD

Review:

Assigned status Update Pending

 by Marissa Larochelle, MD on December 22, 2022.

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Contributing Editors:	add

Acute retinal necrosis (ARN) and Progressive outer retinal necrosis (PORN) represent a spectrum of rapidly progressing necrotizing herpetic retinopathies. Viral necrotizing retinitis is a true ocular emergency and immediate initiation of treatment is essential in preventing permanent vision loss. Immunocompetent hosts develop peripheral retinitis accompanied by vasculitis, iridocyclitis, and vitritis (ARN). Immunocompromised persons, such as those infected with HIV or otherwise immunosuppressed, develop a necrotizing retinitis that may rapidly involve the macula as well as the peripheral retina, without significant intraocular inflammation or vasculopathy (PORN). The outcomes of both of these entities may be devastating and include blindness from complicated retinal detachment and optic atrophy. While potent specific and supportive drug therapy exists, early diagnosis and treatment remains the key to successful management while the prognosis for patients with severe immune dysfunction remains guarded.

Disease Entity

Acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN) comprise a spectrum of potentially devastating, rapidly progressive viral retinopathies. The clinical picture resulting from herpetic infection depends upon the host’s immune status. Necrotizing herpetic retinitis presents as ARN primarily in immunocompetent patients. This clinical entity must be differentiated from PORN, the necrotizing herpetic retinitis that develops exclusively in immunocompromised hosts.

Etiology

Acute retinal necrosis (ARN) was initially described in 1971 by Urayama et al in otherwise healthy young Japanese adults, and is caused by reactivation of latent viral infection. The most common cause of ARN syndrome is varicella zoster virus (VZV), followed by herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), and rarely cytomegalovirus (CMV). Patients with ARN due to HSV-1 and VZV tend to be older, while those with HSV-2 tend to be younger.

Risk Factors

Risk factors for acquiring a necrotizing viral retinitis include an active or past history of herpetic infection, which is found in up to 50% of patients. HSV-associated ARN in particular has been associated with a coexisting or prior history of viral encephalitis or meningitis. Retinitis due to VZV often occurs in the elderly population, as acquired cell-mediated immunity diminishes with age. While immunocompetent individuals are mainly affected by HSV and VZV, CMV retinitis typically occurs in immunocompromised individuals. Risk factors predisposing to CMV retinitis include immunosuppression such as HIV infection, diabetes mellitus, cancer, and the use of systemic corticosteroid or immunosuppressive therapy. Local corticosteroid use is also a rare risk factor and may be associated with fulminant, rapidly progressive ARN.

Pathophysiology

Infection of the retina with herpes simplex or herpes zoster and rarely CMV or Epstein-Barr virus (EBV) has been implicated in the pathogenesis of the disease . HSV-1 has been identified in chorioretinal tissue biopsies and the vitreous body. Furthermore, HSV-1 and HSV-2 DNA have been detected in intraocular fluids by PCR testing. 

History

ARN is equally common in men and women. While children and the elderly may be affected, ARN tends to be a disease of young adults. It may present without a prodrome, years after the primary infection, as well as following herpetic encephalitis.

Physical examination

Ocular examination of patients with ARN reveals inflammation in the anterior and posterior segments. Over 85% of cases present unilaterally.  Early in the course of the disease, an anterior granulomatous or nongranulomatous uveitis may present with keratic precipitates. Vitritis may be severe. The retinal lesions of ARN are white-yellow patches of necrotizing retinitis that usually first appear in the far- or midperiphery. With time, these patches become larger, increase in number, and coalesce. Without antiviral therapy, full-thickness necrosis of the entire peripheral retina will result. The posterior pole is usually spared until late in the disease course. Retinal vasculitis is common, usually primarily an arteritis. Disk edema and retrobulbar optic nerve disease are not uncommon early in the course of ARN. ARN may also present with diffuse scleritis; therefore it is imperative to perform a dilated funduscopic examination on every patient with scleritis. The retinitis in PORN is typically bilateral with a propensity to affect the posterior pole early in the disease course; significant vitritis is absent in these immunocompromised individuals.

Symptoms

Patients with ARN usually complain of floaters, photophobia, and decrease in visual acuity in one eye. Pain may be a prominent feature but is often absent. Left untreated, the fellow eye becomes involved within a month in one-third of patients; however, retinitis may appear several decades after the initial presentation.

Clinical diagnosis

The diagnosis of ARN is usually a clinical one as summarized by the diagnostic criteria established by the executive committee of the American Uveitis Society.

AUS criteria

• Single or multiple areas of retinal necrosis with distinct borders
• Necrotic foci usually located in peripheral retina
• Rapid disease progression if antiherpetic treatment not instituted.
• Extension of foci of retinal necrosis in a circumferential fashion
• Presence of occlusive vasculopathy with arteriolar involvement
• Prominent anterior chamber and vitreous inflammation.
• Characteristics that support but are not required for diagnosis:
  • Optic neuropathy or atrophy, scleritis, pain

Diagnostic procedures

The diagnosis of ARN is usually a clinical one. However, laboratory testing of aqueous and vitreous samples with polymerase chain reaction (PCR) is now widely utilized.  In particular, in atypical cases or in patients who fail to respond to treatment, intraocular fluid analysis of the aqueous and or vitreous samples or retinal biopsy may be employed to reach a definitive diagnosis. Polymerase chain reaction (PCR) analysis of intraocular fluids may detect minute quantities of herpetic DNA, making it the most sensitive, specific, and rapid diagnostic method. PCR has classically been performed on vitreous samples, but aqueous samples may also be used for diagnosis.This assay has largely supplanted viral culture, intraocular antibody titers, and serology. Quantitative PCR-based tests may provide additional information with respect to viral load, disease activity, and response to therapy.
The Goldmann-Witmer (GW) coefficient is a test that compares the levels of intraocular antibody production to that of serum, as measured by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay. The coefficient is defined as GW = X/Y; where GW = Goldmann-Witmer coefficient; X = specific antibody in aqueous or vitreous divided by total IgG in aqueous or vitreous; and Y = specific antibody in serum divided by total IgG in serum. A GW ratio > 4 is diagnostic of local antibody production to a specific microbial pathogen. This is a very useful test, that is not performed by most labs in the United States.

Laboratory test

See above

Differential diagnosis

The differential diagnosis of ARN includes infectious and noninfectious entities. Most of these conditions, with the exception of Behçet disease, atypical toxoplasmosis, and bacterial endophthalmitis, progress at a much slower pace than ARN, but should be included in the differential diagnosis.

The retinitis of Behcet’s disease may be indistinguishable from ARN. Behcet disease is most common in patients of Japanese, Middle-Eastern, or Mediterranean origin, but occurs in patients of all ethnic origins. Patients often have a history of oral aphthous ulcers, genital ulcers or skin lesions.

Management

The goals of treatment of ARN are (1) to stop the retinal necrosis in order to avoid the late consequences of the disease (retinal detachment and optic atrophy); (2) to minimize the collateral damage caused by severe inflammation and vascular occlusions; and (3) to protect the fellow eye. Antiviral therapy should begin immediately after the clinical diagnosis is made, rather than waiting for results of laboratory testing.

Medical therapy

Because most cases of ARN are thought to be caused by VZV and HSV, the standard therapy was induction with intravenous acyclovir for 10 to 14 days, followed by maintenance therapy with oral acyclovir, famciclovir, or valacyclovir. However, more recent data supports induction with oral therapy, such as valacyclovir up to 2g three times a day. Several studies have demonstrated that oral valacyclovir achieves comparable visual outcomes and retinal detachment rates when compared to intravenous acyclovir. Maintenance therapy for ARN is usually employed for 3 months, in order to reduce the risk of the disease in the fellow eye; it may be used longer in the setting of immunosuppression or multiple recurrences.

Intravitreal antiviral therapy should also be considered in the initial treatment regimen in conjunction with systemic antiviral therapy. Studies have shown that patients receiving combination systemic antiviral and intravitreal foscarnet injections (2.4 mg/0.1 ml) demonstrated improved visual acuity and reduced incidence of retinal detachment compared to the group receiving systemic treatment alone.  This data suggests that combination intravitreal and systemic antiviral therapy may lead to improved visual and anatomic outcomes and should be considered for induction therapy in ARN patients. 

After the first 24 to 48 hours of antiviral therapy, systemic corticosteroids may be introduced to minimize vitritis and the development of vitreous bands which may contribute to the development of tractional retinal detachment. However, caution is advised when using corticosteroids to decrease the inflammatory response associated with ARN, as local corticosteroid therapy may potentiate rapid progression of retinitis and vision loss.

Surgery

Large retinal breaks frequently develop in areas of retinal necrosis, and may lead to retinal detachment. Prophylactic laser photocoagulation posterior to the area of retinitis may prevent the extension of retinal detachment into the posterior pole, and 360°-barrier retinal photocoagulation has been recommended by some physicians as soon as the view permits. Others prefer to delay laser until retinal detachment necessitates surgery, preserving "retinal real estate". The evidence regarding the role of prophylactic laser retinopexy is not well-established at this time, as several studies did not find a significant reduction in the rate of retinal detachment in eyes treated with prophylactic laser.

Prophylactic vitrectomy and endolaser have also been recommended. However, there is currently insufficient evidence to support the role of early vitrectomy to prevent severe vision loss and retinal detachment, as several studies did not find a significant difference in retinal attachment status between eyes that underwent early vitrectomy and those that were observed. However, close monitoring of ARN patients is advised given the high risk of multiple, necrotic retinal breaks and potential for severe vision loss following retinal detachment.

In patients who have already developed a retinal detachment, pars plana vitrectomy with endolaser and silicone oil is usually preferred to scleral buckling procedures, given the multiplicity of atrophic posterior breaks in thin necrotic retina.

Complications

Without therapy, inflammation typically subsides within 2 to 3 months of onset. The eye is frequently left with 360° of peripheral retinal atrophy, with multiple posterior retinal breaks secondary to retinal necrosis. A combination of rhegmatogenous and tractional retinal detachment may develop secondary to retinal breaks and contraction of vitreoretinal traction bands that arise as a consequence of severe vitritis. Optic atrophy frequently develops in patients who suffered from disc edema earlier in the disease.

Prognosis

The prognosis of untreated ARN has traditionally been poor, with two-thirds of eyes having visual acuity of 20/200 or worse due to retinal detachment, optic atrophy, or retinal pathology. While there are reports of aggressive intervention resulting in better outcomes, overall the prognosis for patients with ARN remains guarded.