Chapter 88 Acute Retinal Necrosis Syndrome
Definition
In 1971 Urayama and coworkers1 first reported six cases of an apparently new syndrome characterized by acute necrotizing retinitis, vitritis, retinal arteritis, choroiditis, and late-onset rhegmatogenous retinal detachment. Young and Bird2 described two similar cases in 1978 and gave the syndrome the acronym BARN (bilateral acute necrosis syndrome). With the subsequent recognition of unilateral and asynchronous bilateral cases, the disease has been termed simply acute retinal necrosis syndrome, or ARN syndrome. Acute retinal necrosis syndrome is characterized by the initial onset of episcleritis or scleritis, periorbital pain, and anterior uveitis, which may be granulomatous or stellate in appearance. This is followed by decreased vision resulting from vitreous opacification, necrotizing retinitis, and, in some cases, optic neuritis or neuropathy. The retinitis appears as deep, multifocal, yellow-white patches, typically beginning in the peripheral fundus (Figs 88.1, 88.2) and then becoming concentrically confluent and spreading toward the posterior pole (Figs 88.3–88.5); the macula frequently is spared. An active vasculitis is present, with perivascular hemorrhages, sheathing, and terminal obliteration of arterioles by thrombi. The phase of active retinitis usually lasts 4–6 weeks.3–8
With resolution, pigmentation of the peripheral lesions begins at their posterior margins, leaving a scalloped appearance (Fig. 88.6), frequently accompanied by retinal breaks at the junction of normal and necrotic retina. Giant retinal pigment epithelial tears may develop.9 A rhegmatogenous retinal detachment has been observed in approximately 75% of untreated eyes, generally within 1–2 months after the onset of the disease. Earlier exudative and rhegmatogenous detachments have been noted, particularly in cases associated with herpes simplex virus (HSV).3,6,8,10 Vitreous inflammation may lead to organization and proliferative vitreoretinopathy,11 adding a traction component to the retinal detachment (Fig. 88.7). Vision may suddenly decrease as a result of anterior ischemic optic neuropathy. Macular pucker also may occur.
Computed tomography12–14 and ultrasonography14 have revealed enlargement of the optic nerve sheath in ARN cases associated with prominent optic disc edema. Since ARN patients can develop meningoencephalitis, it is helpful to keep this possibility in mind, look for symptoms and signs of neurologic disease, and refer the patient for further investigation as appropriate.15 Even in ARN patients who are not immunocompromised and who have no clinical evidence of encephalitis, magnetic resonance imaging of selected cases has shown lesions of the lateral geniculate, optic tracts, and chiasm,16 suggesting viral spread through the central nervous system by axoplasmic transport from retinal ganglion cells. An explanation for this has been shown in mouse models, where there is evidence to show that HSV1 infection may progress through the optic chiasm from one eye to the other and along the visual pathways leading to meningoencephalitis.17
The contralateral eye is involved in approximately one-third of untreated ARN cases, usually within 6 weeks of the onset of disease in the first eye.9,18 However, the second eye can be affected as late as 34 years after involvement of the first eye,19 and the fellow eye has become involved even after acyclovir treatment for ARN in the first eye.20 Mild forms of ARN syndrome, characterized by patchy, peripheral retinal opacification, recently have been reported. These mild cases did not become rapidly confluent or lead to detachment.21 It is unclear whether this atypical presentation is a result of intense acyclovir and corticosteroid therapy or a reflection of a wide range of disease severity. In addition, less involved forms of ARN have been reported after primary varicella, without concomitant therapy.22
Patient population
ARN syndrome occurs most commonly in otherwise healthy patients of either sex and of any age; in general, patients are not immunocompromised or systemically ill. However, ARN patients may demonstrate subclinical immune dysfunction. In one review of 216 patients with ARN, impaired cellular immunity was noted in 16%.23 Skin testing of patients with ARN revealed anergy in five of seven tested cases and abnormal lymphocyte proliferative indices in one-third.24 The significance of cutaneous anergy is unclear, however, since patients with zoster infections frequently demonstrate anergy.25 Specific HLA haplotypes may increase the relative risk of developing ARN syndrome, such as the HLA-DQw7 antigen and phenotype Bw62, DR4 in white patients in the United States26 and HLA-Aw33, B44, and DRw6 in Japanese patients.27 Pleocytosis of the cerebrospinal fluid frequently accompanies the syndrome,9,13,28 and intrathecal production of antibodies against herpesviruses has been demonstrated in selected cases.4 Some patients present with ARN before, after, or at the same time as they show skin manifestations of varicella zoster infection29,30 (e.g., primary varicella, herpes zoster ophthalmicus, or Ramsay Hunt syndrome). Unilateral ARN also has been noted after herpes simplex keratitis.31 Diffuse cerebral atrophy and labyrinthine deafness have been reported following ARN,32 and some investigators have suggested that ARN be considered as one of the uveomeningeal syndromes.14
With the increase in intravitreal steroid injections for a variety of retinal diseases, there have been reports of ARN occurring in immunocompetent patients and other patients who have medical comorbidities. As a result, this increased risk has led some to increase their vigilance for the development of viral retinitis following intravitreal injection 33–35
Acute necrotizing retinitis that is clinically identical to ARN or shares many features with ARN has been reported in immunocompromised patients. ARN was first described in immunocompromised patients in 1985;36 a recent case series described 26 cases of ARN in AIDS patients, noting a generally fulminant course.37 The cause of the retinitis in these immunocompromised patients may be particularly diverse or multifactorial. For example, an AIDS patient died after an ARN-like syndrome with concurrent encephalitis, and herpes simplex viral antigens were localized in the central nervous system at postmortem examination.38 In contrast, several immunocompromised patients have presented with ARN in association with skin manifestations of zoster.39 Although ARN syndrome initially was defined as manifesting in otherwise healthy patients, many authorities have broadened the diagnostic criteria to include immunocompromised hosts.39–42 It is the evolution of clinical signs and symptoms, and not the specific pathogen or immune status of the patient, that serves as the sole basis by which ARN syndrome has been defined (see Differential Diagnosis, below).
Etiology
Considerable evidence points to multiple members of the herpesvirus family in the etiology of ARN syndrome. In numerous studies, varicella zoster virus (VZV) has been the most frequent virus isolated,43 sometimes in up to two-thirds of patients.44 VZV was isolated in tissue culture from the vitreous of a blind eye enucleated early in the course of the disease, and specific varicella zoster antigens were identified in retinal tissue by immunocytologic staining45 (Fig. 88.8). VZV was identified by electron microscopy in necrotic retinal tissue (Fig. 88.9) in two other cases of ARN.46 Varicella zoster DNA in intraocular fluids of ARN cases has been confirmed by polymerase chain reaction (PCR),47 and Witmer quotients of paired serum to intraocular fluid antibody levels have been diagnostic of varicella zoster in numerous cases.48,49 Varicella zoster antigens have been demonstrated in vitreous aspirates of patients with ARN syndrome.50
Fig. 88.8 Varicella zoster antigens (brown) are seen in cells scattered in all layers of a necrotic retina.
Restriction endonuclease patterns of the ARN virus isolate were similar to those of typical varicella zoster strains and showed similar sensitivities to a panel of antiviral drugs.51 Although strain heterogeneity has been observed in the varicella zoster viruses associated with ARN syndrome,52 these data thus do not support the notion that the ARN virus represents a mutant strain of VZV with significant alterations in either the viral thymidine kinase or DNA polymerase genes. It therefore remains enigmatic why an “old virus” should give rise to a “new” syndrome.
Some reports have suggested that other members of the herpesvirus family may cause ARN, in about 20% of cases according to one study.44 A number of studies have implicated HSV because of concurrent herpes simplex skin lesions,53 the detection of herpes simplex antigens on vitreous cells,7 the presence of immune complexes containing herpes simplex antigens in aqueous or serum,54 the documentation of intraocular antibody synthesis directed against HSV,49 diagnostic changes in serum antibody levels to herpes simplex, polymerase chain reaction detection of herpes simplex,55 or the culture of herpes simplex from vitreous humor.3,8,45 Several cases have been described of ARN caused by reactivation of HSV type 2.47,55,56 Interestingly, patients with herpes simplex type 2 appear to be much younger (mean 21 years) than those with either herpes simplex type 1 or varicella zoster (mean age 40 years).49,57,58 The proportion of ARN syndrome patients with disease caused by HSV-2 may be higher in Japan than in the United States, perhaps coincident with changing epidemiologic distributions of HSV-1 versus HSV-2 in this population.59, 60 Patients with ARN syndrome caused by herpes simplex type 1 appear to have a higher risk of encephalitis or meningitis than those with disease caused by VZV.57,61–65
In one study of a case of ARN,66 cytomegalovirus (CMV) was cultured and CMV antigens were demonstrated in retinal tissue, but megalic cells or electron-dense cytoplasmic inclusions, which have uniformly typified CMV infection of the retina, were not identified. In another case the polymerase chain reaction yielded positive results for CMV in one immunocompetent individual, whose vitreous was negative for VZV and HSV types 1 and 2.67 Epstein–Barr virus has also been postulated in some cases of ARN syndrome,68,69 but definitive linkage of this nearly ubiquitous virus to disease remains problematic. Indeed, EBV has been found in 20% of normal cadaveric eyes,70 and while one study found EBV by PCR in about one-sixth of their ARN cases, each case was also positive for VZV by PCR.44
Pathologic features
Studies of blind eyes enucleated early in the course of ARN have demonstrated retinal necrosis, hemorrhage, and considerable vitreous debris. The retinal necrosis is full-thickness, and an underlying choroiditis is present that may be granulomatous (Fig. 88.10). VZV DNA and antigens have been identified in lymphoid cells within choroidal infiltrates in an eye enucleated in the late stage of disease.71 Eosinophilic intranuclear inclusions within cells of all layers of retina and retinal pigment epithelium were the first clues suggesting a possible viral etiology by a member of the herpes group.46 There is histologic evidence of retinal arteritis (Fig. 88.11), although no virus particles have been detected in vascular endothelium. Deposits of immune complexes containing varicella zoster viral antigens have been demonstrated in retinal vessel walls by immunocytologic methods and may play a role in the vasculitis seen during active stages. The perivasculitis is not restricted to retinal vessels alone and can involve the extraocular muscles (Fig. 88.12). Immune complexes with herpes simplex also have been identified in intraocular fluids in ARN cases.
Fig. 88.11 Histologic evidence of retinal vasculitis (arrows) in acute retinal necrosis.
(Courtesy of Robert Y. Foos.)
Ultrastructural studies of retinal tissue have revealed 180 nanometer virions containing icosahedral capsids, consistent with particles of the herpes group46 (see Fig. 88.8). The optic nerve may be largely necrotic and heavily infiltrated with plasma cells, but no virus particles or antigens have been seen in the optic nerve. It is possible that the absence of viral antigens or particles reflects more the time point in the course of the disease when enucleation was performed in these rare cases than conclusive evidence regarding acute optic nerve infection. The multifocal, deep retinitis observed early in the course of ARN is compatible with either blood-borne spread of virus or transmission to the eye through a bilateral nerve pathway. An animal model of ARN using herpes simplex virus suggests that spread to the contralateral eye occurs by retrograde axonal transport between the suprachiasmatic nucleus of the hypothalamus and the contralateral retina.72
