Acute retinal necrosis is a viral syndrome characterized by a panuveitis with necrotizing retinitis that may be complicated by retinal detachment, vaso-occlusion, optic neuropathy, and other causes of decreased visual acuity. Polymerase chain reaction testing provides a rapid and sensitive method of identifying the viral etiology of acute retinal necrosis, which is most commonly caused by herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus. Prompt diagnosis and treatment are paramount to prevent further vision loss. We review the management of acute retinal necrosis including systemic, local intravitreal, and combination antiviral medications. We also discuss the appropriate and inappropriate use of corticosteroids, laser retinopexy, surgical therapy, and other adjunctive measures.
In recent years, herpes zoster has been recognized as a frequent infection in
individuals with human immunodeficiency virus (HIV) infection, occurring in 8-
11 percent of patients. Although the occurrence of cutaneous dissemination is
infrequent, complications such as VZV retinitis, acute retinal necrosis, and chronic,
progressive encephalitis have been reported.
How to Differential Diagnose Acute Retinal Necrosis Syndrome
- Progressive outer retinal necrosis
- CMV retinitis
- Toxoplasma chorioretinitis
- Acute multifocal hemorrhagic retinal vasculitis
- Intraocular lymphoma or leukemia
- Bacterial/Fungal retinitis or endophthalmitis
- Behcet disease
- Sympathetic ophthalmia
- Vogt-Koyanagi-Harada syndrome
- Commotio retinae
- Central or branch retinal artery occlusion
- Ocular ischemic syndrome
- Collagen-vascular disease
How to Diagnose Acute Retinal Necrosis Syndrome
The diagnosis of ARN is usually made based on clinical characteristics. However, it may be appropriate to analyze an aqueous or vitreous sample to test for the presence of members of the herpesvirus family, especially in atypical or difficult diagnostic cases. Rarely, diagnostic vitrectomy or endo-retinal biopsy may be necessary.
The following tests may be performed on aqueous or vitreous samples for further diagnostic certainty:
- Viral PCR
- Viral culture
- Use of direct or indirect immunofluorescence to identify viral antigens
- Measurement of viral antibodies
- Intraocular antibody titers with calculation of the Goldmann-Witmer coefficient
- Also, rule out immunocompromise in all cases of retinitis especially HIV
- Ultrawide field imagint (Optos) may be useful in documenting and following up the peripheral involvement in a single image.
- Fundus fluorescein angiogram for occlusive arteritis
- Optical coherence tomography to document cystoid macular edema, epiretinal membrane
clinical diagnostic criteria of ARN includes anterior and posterior uveitis, peripheral retinal necrosis, occlusive vasculopathy, and disease progression without therapeutic intervention. Histological analysis of the retina in ARN shows inflammatory cell (lymphocytes and plasma cells) infiltration of the retina and around vascular networks with eosinophilic intranuclear inclusions suggestive of herpes virus particles.
Historically, the diagnosis of ARN is made by clinical examination, but underdiagnosis or misdiagnosis of less typical presentations is a concern because the delay in diagnosis often leads to poor clinical and visual outcomes. When the clinical examination is suggestive of ARN, treatment should be initiated and laboratory confirmation may not be necessary. Laboratory methods that aid in diagnosis include serum or intraocular fluid antibody testing, viral culture, retinal biopsy, and immunocytochemistry, but routine use of these methods has been limited by poor sensitivity or specificity, lack of widespread availability for testing, and excessive risk to the patient
Polymerase chain reaction (PCR) analysis or local antibody analysis (i.e. calculation of Goldmann-Witmer coefficient) from anterior chamber fluid or vitreous fluid can identify the particular virus causing ARN. Prior studies support the utility of PCR analysis with a sensitivity and specificity of greater than 90% in detecting VZV, HSV, and CMV. Given the developments in PCR and its usefulness in the diagnosis of ARN, PCR is currently the preferred method of viral diagnosis. It has been proposed to include laboratory data in the diagnostic criteria for ARN.Both qualitative and quantitative real-time PCR testing may be used both to ascertain the etiology of ARN and potentially to assess the response of ARN to therapy.The differential diagnosis of ARN includes other infectious and inflammatory processes such as syphilis, toxoplasmosis, cytomegalovirus retinitis, Behcet’s disease, pars planitis, sarcoidosis, and intraocular lymphoma.
Risk factors for Acute Retinal Necrosis Syndrome
Genetics are believed to play a role in an individual’s risk for ARN with antigen expression of:
HLA-DQw7, HLA-Bw62, and HLA-DR4 in American Caucasian populations and
HLA-Aw33, HLA-B44, and HLA-DRw6 in Japanese populations.
Although ARN is most commonly seen in healthy, immunocompetent individuals, immunosuppression from corticosteroids, for example, may predispose patients. Immunocompromised patients, such as those with HIV, may develop progressive outer retinal necrosis (PORN), a more aggressive viral retinitis also caused by the Herpes family viruses. ARN may be seen in AIDS patients also.
The previous history of herpetic infection including encephalitis may be present.
Clinical diagnosis of Acute Retinal Necrosis Syndrome
Most important characteristics are vitritis, occlusive retinal arteriolitis, and peripheral retinitis which becomes confluent in late stages. Compared to cytomegaloviral retinitis, the vitritis is extensive, retinitis is peripheral and hemorrhage is less
- One or more foci of retinal necrosis with discrete borders, located in the peripheral retina
- Rapid progression in absence of antiviral therapy
- Circumferential spread
- Occlusive vasculopathy, affecting arterioles
- Prominent vitritis and/or anterior chamber inflammation
How to Treat Acute Retinal Necrosis Syndrome
General treatment Acute Retinal Necrosis Syndrome
Without intervention, the active phase of the disease can last between 6-12 weeks, while treatment with antivirals and/or steroids may reduce the latency to 4-6 weeks. Treatment of ARN is complex and should be individualized based on the overall clinical picture and vitreoretinal findings. Prospective, randomized controlled trials have not been performed given the rarity of the disease; thus, treatment recommendations are based on case reports/series. Treatment modalities may include antiviral, anti-inflammatory, and antithrombotic therapy in cases with ischemic optic neuropathy, as well as laser photocoagulation for retinal detachment prophylaxis or surgery for retinal detachment repair.
Treatment with Intravenous Antivirals. Intravenous
antiviral therapy historically has been the standard treatment for
ARN, and several parameters have been used to follow the
response to treatment, including the time to initial and complete
regression of retinitis, visual outcomes, incidence of RD, and
fellow eye involvement.
Medical therapy for Acute Retinal Necrosis Syndrome
Antiviral therapy can be administered systemically (intravenously or orally) as well as via intravitreal injection. Prior to the mid-1990’s, intravenous (IV) administration of antiviral agents (usually acyclovir) was carried out for at least the first week after diagnosis of ARN because it was believed that higher serum and intraocular concentrations of the antiviral agent could be achieved; thereafter, it was considered appropriate to transition the patient to oral antivirals (acyclovir, famciclovir, valacyclovir, or valganciclovir) for an additional 4-12 weeks. With the advent of newer antiviral agents, many physicians now advocate the use of oral antiviral agents such as famciclovir, valacyclovir or valganciclovir as initial induction agents for the treatment of ARN. Renal function should be monitored while patients are on systemic antivirals. Intravitreal delivery of antiviral agents is also common practice. The use of steroids and antithrombotic therapy (i.e. Aspirin) is controversial and may be used at the treating physicians’ discretion. Steroids may be started under the cover of antivirals and should never be started alone in the stage of acute retinitis.
Commonly used systemic antiviral agents include the following which can be tapered slowly over months following resolution of the acute herpetic phase of ARN:
- Acyclovir (13 mg/kg/dose divided every 8 h IV for 7 days, followed by 800 mg five times daily orally for 3–4 months)
- Famciclovir (500 mg orally q8h)
- Valacyclovir (1000–2000 mg orally q8h for induction)
- Ganciclovir (500 mg IV q12h)
- Valganciclovir (900 mg twice daily orally for 3 weeks induction, then 450 mg twice daily for maintenance)
Aspirin, Heparin, and Warfarin
The pathogenesis of ARN involves vascular occlusion manifesting as retinal ischemia. Hyperaggregation of platelets is reported in ARN and has been treated successfully with corticosteroids and aspirin. Other therapies for anticoagulation include heparin and warfarin. Strong evidence does not currently exist, however, for the use of anticoagulation. In addition, the safety of these drugs in the context of other systemic diseases in each patient is an important consideration
Antiviral agents administered intravitreally can provide beneficial adjunctive therapy, especially if retinitis is threatening the macula or optic disc:
- Ganciclovir (200-2000 ug per 0.1 mL)
- Foscarnet (1.2-2.4 mg per 0.1 mL)
Steroids may have a beneficial therapeutic effects if initiated 24-48 hours after the start of antiviral therapy or once regression of retinal necrosis been demonstrated:
- Prednisone (0.5-2.0 mg/kg/day orally for up to 6-8 weeks)
Aspirin may minimize vascular thrombosis and propagation of further retinal ischemia and necrosis. Topical steroid drops and cycloplegics have also been shown to be beneficial, depending upon the degree of anterior segment inflammation. Topical antiviral therapy has been shown not to be efficacious in the treatment of ARN.
Medical follow-up for Acute Retinal Necrosis Syndrome
Patients with unilateral ARN should be closely followed with a dilated examination of both of their eyes. Approximately 50-75% of patients with ARN will go on to develop a retinal detachment. Reports of second eye involvement range from 3-35%, with variable involvement attributable to etiologic agent, the course of therapy, and immune status. The antiviral therapy reduces the duration of active disease and reduces the chance of involvement of the fellow eye. However, the retinal detachment may not be reduced by antiviral therapy.
Surgical Approach for Acute Retinal Necrosis Syndrome
Some retina specialists advocate the use of prophylactic laser along the posterior margin of the junction of the necrotic and non-necrotic retina to prevent the incidence of retinal detachment. The rates of success in preventing retinal detachment are variable, and consensus does not exist on whether laser demarcation should be employed. This may be due to the confounding fact that eyes in which laser can be successfully performed typically have optically clearer vitreous, less inflammation, and thereby less risk for developing retinal detachment.
Vitrectomy with or without the use of scleral buckle, with either gas or silicone oil tamponade, is usually reserved for those cases in which traction-rhegmatogenous retinal detachment occurs.
One of the most common complications in ARN is the development of atrophic retinal holes and rhegmatogenous retinal detachments (RRD) that develop secondary to retinal necrosis leading to retinal atrophy and vitreoretinal traction. Because of the resultant visual loss that may ensue following this complication, measures to prevent RD including laser retinopexy and early vitrectomy prior to RD development have been discussed as therapeutic options.
Prophylactic laser photocoagulation
Prophylactic laser photocoagulation has been used to prevent retinal detachment by creating strong chorioretinal adhesions posterior to the area of the involved retina. Meghpara et al. noted in their retrospective chart review that the 6 patients treated with prophylactic laser did not develop retinal detachments. Lau et al. demonstrated in their cohort of 22 patients that prophylactic laser retinopexy decreased the incidence of retinal detachment from 80% to 35.3% in the treatment group. While some cases series note decreased reports of retinal detachment others report minimal benefit. Factors that prevent laser photocoagulation in ARN patients are vitreous inflammation and the view of the posterior pole. This may bias the results of retrospective reviews where patients receiving laser therapy have less retinal involvement and vitreous inflammation which would favor better outcomes.
Pars plana vitrectomy
Prophylactic vitrectomy has also been described for the prevention of RRD. Cases reports show variable outcomes with prevention in some series but of the failure to prevent RRD in others. In one retrospective review of 104 patients in which 48 eyes received a prophylactic vitrectomy at final follow up 52% of the retinas were attached in the vitrectomy group and 75% of the retinas were attached in the non-vitrectomy group.
What are the Complications of Acute Retinal Necrosis Syndrome
Many cases finally have less than 20/200 due to
- Retinal holes and tears
- Retinal detachment
- Proliferative vitreoretinopathy
- Vitreous hemorrhage
- Macular pucker
- Optic neuropathy- pallor of the optic disc
Intravenous versus Oral Antivirals for Acute Retinal Necrosis Syndrome
There are no studies that directly compare oral with intravenous therapy for ARN. Comparisons across studies are difficult because of the retrospective nature of the studies, differences in baseline characteristics, variable outcome measures, and different time periods being studied (intravenous therapies in the 1980s and 1990s; oral therapy in the 2000s). Despite these limitations, the body of evidence suggests that the time to initial and complete regression of retinitis appears comparable to oral or intravenous therapies. In addition, the development of contralateral eye involvement was low with both modes of therapy.
Future Research for Acute Retinal Necrosis Syndrome
Future studies should compare oral versus intravenous antiviral therapy in the initial management of ARN. In addition, studies should compare systemic antiviral therapy
alone versus systemic with adjunctive intravitreal antiviral treatment. Prospective, randomized, controlled, doublemasked studies are the gold standard for determining the effect of treatment. However, these studies are difficult in the setting of ARN because of its rarity, and therefore properly conducted retrospective studies are more feasible. Multicenter studies will likely be necessary to generate an adequate sample size. Detailed analysis of intravitreal drug levels of acyclovir after intravenous acyclovir and oral
valacyclovir may provide useful information about drug penetration and comparative therapeutic efficacy. One limitation of the studies in the literature is the lack of
uniform reporting of outcome measures. Treatment success may be defined by several modalities, including time to initial and complete regression of retinitis, visual and
anatomic outcomes, and contralateral eye involvement. A clear description of the severity of disease is necessary, including VA, extent, and location of retinitis (preferably
using fundus photography), and degree of intraocular inflammation. Subsequent studies should focus on standardized definitions of outcomes to better assess responses
and to allow for improved cross-trial comparison.
Prognosis of Acute Retinal Necrosis Syndrome
The visual outcome of eyes affected by ARN is variable and largely depends upon vision at the time of presentation as well as whether or not secondary retinal detachment or ischemic optic neuropathy occurs. Development of retinal detachment depends upon the extent of retinal necrosis present at the time of diagnosis, the amount of vitritis overlying areas of retinal necrosis (with more vitritis associated with a higher risk of RD), and varying response to treatment regimens.