primarily caused by the human herpesvirus (HHV) family of viruses, including cytomegalovirus (CMV; HHV 5), varicella-zoster virus (VZV; HHV 3), herpes simplex virus (HSV; HHV 1 and 2), and Epstein–Barr virus (HHV 4) [1]. Host immunoregulation is critical in guarding against viral cytotoxicity and the ocular sequelae of herpetic disease [2]. HHVs are known opportunistic pathogens. They have a notable predilection toward retinal tissue, and the incidence of HHV infection is highest in immunocompromised hosts [3]. Since cancer patients are often both intrinsically immunocompromised because of the cancer itself and iatrogenically immunocompromised because of cancer treatment, they are particularly susceptible to opportunistic infections, including viral retinitis.

Presentations of viral retinitis can range from no symptoms to severe visual loss secondary to aggressive acute retinal necrosis (ARN). Due to this wide range of presentations, routine screening for viral retinitis in cancer patients is of utmost importance. This chapter will focus on CMV retinitis, ARN, and progressive outer retinal necrosis (PORN).

37.2 Epidemiology

The epidemiology of viral retinitis in cancer patients is complicated by the fact that infection can represent a primary infection, reactivation of a latent infection, or reinfection. Reactivation of a latent infection is the most common presentation because of high rates of seropositivity even in the general population, especially for CMV.

Although there has been only limited research on viral retinitis specifically in cancer patients, it is known that CMV is not only the most common opportunistic ocular infection occurring in all immunocompromised hosts but also the most common cause of viral retinitis [4]. Other common causes of viral retinitis include other members of the HHV family, including VZV and HSV. The literature includes case reports of viral retinitis due to rubella, coxsackie virus, Epstein–Barr virus, rubeola, subacute sclerosing panencephalitis virus, Rift Valley fever virus, influenza A virus, mumps virus, and hepatitis B virus in immunocompromised hosts, but not all of these causes have been reported specifically in cancer patients [5–8].

37.3 Clinical Features

37.3.1 CMV Retinitis

Patients with CMV retinitis may be asymptomatic or may present with new floaters, blurred vision, or flashes of light. Although more than 80% of patients present with visual acuity of better than 20/50 [4], central visual loss can occur secondary to retinal necrosis involving the fovea, serous macular exudation, optic nerve involvement, or rhegmatogenous retinal detachment involving the macula [9, 10]. There is an associated mild vitreous inflammation often described as being less than might

be expected for the degree of retinal damage. There may be fine, stellate keratic precipitates and posterior synechiae, but there is little overlying vitreous or anterior chamber inflammation [3, 4].

At one end of the spectrum of CMV retinitis is an indolent/granular retinitis, more often seen in the retinal periphery and associated with less dense retinal opacification and little or no hemorrhage or retinal vascular sheathing. At the other end of the spectrum is a fulminant/edematous retinitis, characterized by prominent necrosis and hemorrhage, often along blood vessels in the posterior pole (Fig. 37.1). A striking perivascular sheathing may be present [3]. Although CMV has been associated with ARN, this is not a common presentation [11].

Fig. 37.1 Fulminant retinitis characterized by prominent retinal necrosis and hemorrhage along blood vessels in the posterior pole

A “zone” system is used to classify retinal involvement in CMV retinitis. Zone 1 lesions are present within a circle around the fovea with a radius of 3000 μm or within 1500 μm of the edge of the optic nerve. Zone 2 lesions are located outside zone 1 but posterior to the ampullae of the vortex veins at the equatorial retina. Zone 3 lesions are present between zone 2 and the ora serrata.

CMV retinitis spreads at a rate of approximately 250 μm/week, and there are usually atrophic areas that appear as retinal pigment epithelial pigmentation. Reactivation may begin at the edge of these atrophic scars, expanding outward [3]. Although clinically any area of active retinitis ought to be considered as progression, research studies have defined progression of CMV retinitis as expansion extending from the edge of an atrophic scar by 750 μm along a border at least 750 μm in length, or the appearance of a new area of retinitis greater than one-fourth of the disc diameter [3].

Diagnosis is based on clinical findings, primarily on indirect ophthalmoscopy. Polymerase chain reaction testing of aqueous and/or vitreous samples for CMV is highly specific but rarely clinically necessary. Fundus photography can confirm ophthalmoscopy findings and may be a more sensitive way to monitor response to therapy than clinical examination alone [12]. Fluorescein angiography is not typically indicated but may reveal blocking defects from areas of hemorrhage and leaking or nonperfusion of vessels in involved retinal areas [3].

37.3.2 Acute Retinal Necrosis

ARN is a vaso-occlusive necrotizing retinitis that is usually secondary to herpes zoster or HSV. Even though ARN can result from HSV-1 or HSV-2, herpes zoster is the most frequent culprit, and ARN often develops concurrently with or after zoster dermatitis, ipsilateral facial nerve palsy (Ramsay Hunt syndrome), or herpes zoster ophthalmicus [13, 14]. A bimodal age distribution has been proposed, with HSV-2 affecting younger patients and HSV-1 and herpes zoster affecting older patients. ARN usually presents as unilateral disease, but may involve the second eye (bilateral acute retinal necrosis, BARN) in up to one-third of patients within several months after initial ocular involvement.

ARN is a specific syndrome that is defined by the Executive Committee of the American Uveitis Society [15] as (1) one or more foci of retinal necrosis with discrete borders in peripheral retina, (2) rapid progression of the disease, (3) circumferential spread of the disease, (4) occlusive vasculopathy with arteriolar involvement, and (5) prominent inflammatory reaction in the vitreous and anterior chamber.

ARN is characterized by prominent anterior uveitis with or without keratic precipitates, retinal and choroidal vasculitis, vitritis, and papillitis [4]. The acute phase of ARN lasts 4–12 weeks. ARN begins as a multifocal retinitis with yellowish-white peripheral lesions that gradually enlarge and coalesce 360◦, spreading peripherally. The acute phase of ARN may be further characterized by a prominent retinal vasculitis. The junction of necrotic and normal retina can be a site of vitreous traction leading to retinal breaks and subsequent rhegmatogenous retinal detachments, which occur in up to 75% of affected eyes [16].

Rapidly sloughed necrotic retinal debris in the vitreous cavity contributes to a pronounced vitritis that distinguishes ARN from CMV retinitis [3, 4]. ARN also has a more rapid progression and a reduced tendency to hemorrhage compared to CMV retinitis [3].

37.3.3 Progressive Outer Retinal Necrosis

PORN and ARN are considered by some authors to be the same disease process. The umbrella term necrotizing herpetic retinopathy has been used to describe a spectrum of infection that includes these two entities. PORN was initially described in patients with advanced HIV infection and typically occurs in immunocompromised patients secondary to herpes zoster [17].

PORN is characterized by primary involvement of the outer retina, minimal to no vitreous inflammation, and extremely rapid progression [4, 18]. Multifocal, peripheral, deep retinal lesions rapidly achieve confluence and posterior progression. A characteristic “cracked mud” perivascular pattern has been described, attributed to early removal of necrotic debris from perivascular retina. PORN can progress to involve the optic nerve, retinal pigment epithelium, and choriocapillaris.