Clinical background

Acute retinal necrosis (ARN), which was first reported by Urayama and colleagues, occurs rarely but is a potentially blinding disorder. Most cases of ARN are unilateral, although approximately one-third of patients develop bilateral disease which may occur either coincident with involvement of the presenting eye, or weeks, months, or years later. ARN is observed most commonly in the immunocompetent host but occasionally occurs when there is immunocompromise. Although varicella-zoster virus (VZV) was associated with the initial description of ARN, subsequently herpes simplex virus (HSV) type 1 (HSV-1), HSV type 2 (HSV-2), Epstein–Barr virus (EBV), and, very rarely, cytomegalovirus (CMV) were also implicated in its pathogenesis ( Box 80.1 ). A member of the herpesvirus family is presumed to be the pathogenic agent in cases in which a close (usually) temporal relationship between clinical herpetic infection and the onset of the retinal infection is observed.

Patients with herpesvirus retinitis will commonly present with blurred vision caused by inflammatory debris in the vitreous humor. Some patients may also have ocular pain which is indicative of inflammation of the anterior segment of the eye. HSV retinitis is characterized by marked retinal edema, exudate, hemorrhage, and vascular occlusion ( Figures 80.1 and 80.2 ). The disease may start in the posterior pole, equator, or periphery and is commonly associated with swelling of the optic disc and rhegmatogenous retinal detachment that usually occurs after a period of several weeks. Unless recognized quickly, retinitis may progress to ARN.

Fundus photographs of acute retinal necrosis in a human patient showing active necrosis, hemorrhage, and an area of scarring (A) and a retinal vessel in an area of necrosis (B).

(Courtesy of the Department of Ophthalmology, Medical College of Georgia, Augusta, Georgia.)

Photomicrograph of hematoxylin and eosin-stained section of a retinal biopsy from a human patient with acute retinal necrosis. There is loss of the retinal architecture and extensive inflammation.

(Courtesy of the Department of Ophthalmology, Medical College of Georgia, Augusta, Georgia.)

As defined by the American Uveitis Society (AUS), the features of ARN are not disease-specific or immune status-specific but are rather determined by the clinical characteristics of the disease and its course. These features include: (1) one or more discrete foci of necrosis in the periphery of the retina; (2) rapid progression in the absence of treatment; (3) circumferential spread; (4) occlusive arteriolar vasculopathy; and (5) inflammation in the anterior chamber and/or in the vitreous ( Box 80.2 ). Additional features may include optic neuropathy, scleritis, and pain. ARN is commonly seen in those with normal to mildly depressed immune status. Another syndrome involving herpesvirus infection of the retina is progressive outer retinal necrosis (PORN), which is characterized by decreased vision, floaters, and loss of peripheral vision. However, in contrast to ARN, there are cottonwool spots and multifocal areas of retinal whitening with confluent necrosis are observed, but retinal vasculitis and intraretinal hemorrhages are rare. PORN is usually observed in patients with moderate-to-severe immunosuppression, such as those with acquired immunodeficiency syndrome (AIDS). The original definition of ARN included the requirement that patients be immunocompetent; however, as noted above, the immune status of the patient is not an important clinical criterion, so ARN may also be observed in immunosuppressed patients.

ARN is rare. A study to assess the incidence of ARN in the UK revealed an incidence of approximately 1 case per 1.6–2.0 million people per year ( Box 80.3 ). Because of the small number of individuals who develop ARN, large-scale genetic studies to determine whether there are genetic predilections toward ARN have not been done. However, in a study of 27 patients with ARN, the frequency of the HLA-DQw7 antigen was significantly increased in ARN patients compared with controls (55% versus 19%) and the BW62, DR4 was also more common in ARN patients (16% versus 2.6%). In another study, HLA-DR9 was associated with more severe ARN and 50% of the patients with fulminant ARN had the HLA-DR9 genotypes compared with none of the patients with milder disease. It has also been suggested that impaired control of latent HSV-1 is attributable to defects in the ability of plasmacytoid dendritic cells to produce type 1 interferons in response to herpesvirus infection. Therefore, in addition to the possibility of increased risk of ARN in patients with certain HLA phenotypes, other non-HLA-associated factors such as the ability of certain cells to produce interferon may also play a role in predisposition to development of ARN and/or its severity.

There appears to be a difference in age distribution between ARN caused by HSV-1 or VZV and ARN caused by HSV-2, but this distribution is not absolute. A review of 28 patients (30 eyes) with ARN suggested that patients with ARN resulting from HSV-1 or VZV are usually older (median age 47 and 57 years, respectively) whereas those patients with ARN resulting from HSV-2 are often younger (median age, 20 years). ARN is occasionally observed in patients coincident with or following encephalitis or meningitis; in the former, ARN is usually due to HSV-1 while in the latter, ARN is usually caused by HSV-2.

Diagnosis

The diagnosis of viral retinitis depends on the ocular and systemic manifestations as well as the clinical examination of the fundus of the eye. While comparison of local and systemic antiviral antibody titers as well as virus isolation have been used to diagnose the disease, the current standard for diagnosis of viral infection of the retina is polymerase chain reaction (PCR) of aqueous humor and/or vitreous samples to detect viral DNA. PCR is exquisitely sensitive and specific; for example, the sensitivity and specificity of PCR for diagnosis of VZV infection are 100% and 97%, respectively.

A number of diseases may result in retinitis and, even if viral, not all of these diseases are caused by a member of the herpesvirus family. The differential diagnosis of herpesvirus retinitis should include Behçet’s disease, CMV retinitis, HSV-1 and 2 retinitis, lymphocytic choriomeningitis virus retinitis, primary intraocular lymphoma, sarcoidosis, syphilis, toxoplasmosis, and VZV-induced retinitis ( Box 80.4 ). In infants with apparent congenital chorioretinitis, the diagnostic workup should include lymphocytic choriomeningitis virus serology, especially if antibody titers for Toxoplasma gondii , rubella virus, CMV, and HSV are negative.

Treatment

The usual treatment of ARN is intravenous aciclovir, corticosteroids, and aspirin, followed by oral aciclovir. Intravitreal injections of foscarnet and oral aciclovir have been used in mild cases that have been detected early. VZV has also been successfully treated with brivuldine (not currently available in the USA) and valganciclovir. In general, retinal necrosis which progresses rapidly to the posterior pole is associated with a poor visual outcome. Eyes with less than grade II necrosis extension are good candidates for prophylactic peripheral retinal photocoagulation. Not surprisingly, early detection, prompt treatment with aciclovir, and rapid repair of retinal detachments seem to improve the final visual outcome. The issue of long-term prophylactic antiviral therapy to prevent ARN in an uninvolved fellow eye or to prevent ARN in a patient with a history of meningitis or encephalitis caused by a member of the herpesvirus family has not been resolved. However, since there is currently no way to predict who among patients with unilateral ARN will develop ARN in the fellow eye, long-term prophylactic antiviral therapy appears to be warranted.

If the diagnosis of ARN is not made quickly or if appropriate antiviral and anti-inflammatory therapies are delayed, retinitis caused by any of the three neurotropic herpesviruses (i.e., HSV-1, HSV-2, VZV) will usually progress quickly to ARN. Therefore, the prognosis for many patients with herpesvirus infections of the retina is poor because of the rapid and destructive nature of the disease. Although there are several antiviral agents that can be administered intravenously, intraocularly, and/or orally, many patients still experience significant vision loss because of optic neuritis, necrosis of the retina in or near the macula, or rhegmatogenous retinal detachment. Therefore, preventing/reducing vision loss in patients with ARN requires early detection (usually by PCR of aqueous or vitreous samples) and prompt treatment with the appropriate therapeutic regimen.

Pathology

The characteristics of ARN are focal, well-demarcated areas of retinal necrosis in the peripheral retina, circumferential progression of necrosis (which occurs rapidly in the absence of antiviral therapy), occlusive vasculopathy, and inflammation in both the anterior chamber and the vitreous humor. Optic neuritis and late retinal detachments are also observed in association with the disease, and, as noted above, even with treatment, severe visual impairment and/or blindness may result.

Etiology

Although bacteria, fungi, and parasites may all infect the posterior segment of the eye, members of the herpesvirus family are among the most common causes of infection involving the eye. The ubiquitous nature of the human herpesviruses together with the permissiveness in the human neuronal system for herpesvirus infection and transmission have conspired to make several of the herpesviruses the most common agents of chorioretinitis. Five of the eight members of the human herpesvirus family have the ability to cause retinitis. The first herpesvirus virus to be identified as a cause of ARN was VZV, and this virus remains the most common cause of ARN (accounting for 50–80% of cases) followed by HSV-1 and HSV-2. Rare cases of ARN caused by EBV and CMV (in immunocompetent patients) have been reported. However, given the ubiquitous nature of the human herpesviruses and the constant development of increasingly sensitive identification methodology, perhaps it would not be too surprising if other members of the herpesviruses are also identified as causative agents of retinal infections.

In infants, herpes simplex retinitis can result from congenital infection or from acute infection acquired during passage through an infected birth canal. Congenital HSV retinitis is defined as disease transmitted during gestation, before initiation of labor and delivery. In most cases of congenital HSV retinitis, the mothers have a history of newly acquired genital herpes infection which usually occurs during the second trimester. Active genital infection in the mothers at delivery is extremely rare compared with the neonatal acquired herpes retinitis, but sometimes it is difficult to differentiate congenital HSV retinitis from neonatally acquired HSV retinitis. Neonatal ocular infection with HSV is usually bilateral and is observed in infants from 2 days to several weeks of age; however, retinal findings may not be apparent until 3 weeks of age or after. Most cases of neonatal HSV retinitis occur concomitantly with HSV infection of the central nervous system (CNS) with only about 20% of cases of HSV retinitis associated with HSV conjunctivitis, keratitis, or disseminated dermatitis. ARN has also been described in children, and HSV-2 is the most common cause of ARN in children.

In adults, herpesvirus retinitis may result from acute virus infection or from reactivation of latent virus. A history of neonatal herpes infection is a risk factor for HSV-2 retinitis, as is a history of viral meningitis. The fact that HSV-2 retinitis has been observed following triggering events such as neurosurgery, periocular trauma, and administration of high-dose corticosteroids supports the idea that, at least for HSV-2 retinitis, most cases in adults are due to reactivation rather than acute infection.

In summary, ARN is most commonly caused by VZV, followed by HSV-1 and HSV-2 with only rare cases of ARN attributable to EBV or to CMV. Management of patients with ARN should include prompt diagnosis as well as prompt initiation of appropriate antiviral therapy. Prophylactic laser barrier treatment has been shown to lower the incidence of retinal detachment and administration of systemic corticosteroids (in addition to antiviral therapy) helps to limit damage caused by the severe inflammation associated with ARN. Retinal detachment may occur acutely or several months after onset of symptoms; vitrectomy and prompt repair of retinal detachments may result in improved acuity.