Infectious or noninfectious ocular disorders, some of which may lead to severe visual impairment, have been reported in 40 to 90% of patients with acquired immunodeficiency syndrome (AIDS) referred for formal ophthalmoscopy. In prospective observational cohort studies conducted prior to the clinical availability of the new, more potent generation of antiretroviral agents for the treatment of human immunodeficiency virus (HIV) disease, the incidence of cytomegalovirus (CMV) retinitis (the most common ophthalmologic complication of AIDS) was reported to be in the range of 20 to 40% in patients with an AIDS diagnosis. In the first 18 months since potent HIV protease inhibitors became widely available in the United States and Europe, the incidence of new CMV retinitis diagnoses decreased markedly. How sustained this decrease will be is unknown, but if new antiretroviral treatment strategies ultimately lead to extensive HIV cross resistance to these agents, the incidence of CMV retinitis may again increase.

The differential diagnosis of HIV-associated ocular disease is best considered by its anatomic location.

Diseases of the Choroid, Retina, and Vitreous

Retinal Microvascular Disease
The most common ophthalmologic complication observed in patients with HIV infection is retinal microvascular disease, which usually manifests as asymptomatic cotton-wool spots or small retinal hemorrhages. Cotton-wool spots have been reported in up to half of patients with advanced HIV disease. Histopathologically, these lesions represent areas of retinal ischemia. Both immune complex deposition and direct HIV retinal infection have been implicated in the pathogenesis of cotton-wool spot lesions. On funduscopic examination, they typically appear as white spots with feathered edges on the surface of the retina.

A common location is near major posterior retinal vessels, and these lesions can have small associated retinal hemorrhages. It may be difficult to differentiate between cotton-wool spots and early lesions of CMV retinitis, which can have a very similar appearance. Sometimes the distinction can be made only by serial ophthalmoscopic examination. Cotton-wool spots remain stationary or resolve, whereas the lesion of CMV retinitis increases in size. Because cotton-wool spots virtually never cause symptomatic loss of vision and often spontaneously resolve, no treatment is indicated.

Small retinal hemorrhages and other microvascular abnormalities have been reported in up to 40% of patients with AIDS. These lesions also are asymptomatic, except in the rare case where perifoveal involvement may result in visual blurring.

Cytomegalovirus Retinitis
CMV retinitis is the most common sight-threatening ocular opportunistic infection in patients with AIDS. It usually occurs only in patients with a history of an absolute CD4+ (T helper) lymphocyte count <50 cells/muL. The typical appearance is a white, cottage cheese-like retinal exudate, often associated with hemorrhage and frequently located adjacent to major retinal vessels. In tissue sections, full-thickness retinal necrosis and swollen retinal cells containing intranuclear and intracytoplasmic inclusions are observed.

Patients with CMV retinitis typically present with complaints of painless visual impairment-either “floaters,” blurred vision, decreased visual acuity, or visual field defects-almost always affecting one eye more than the other. Several studies of untreated CMV retinitis have demonstrated a natural history of progressive retinal destruction caused by new retinal lesions or increasing size of previous lesions usually evident within weeks by serial ophthalmoscopy.

CMV retinitis is diagnosed primarily by its typical clinical appearance. The differential diagnosis includes cotton-wool spots, retinal hemorrhages, choroidal granulomas, acute retinal necrosis syndrome, and toxoplasmic and syphilitic retinitis. Because differentiating between these entities may be difficult, and the therapy of CMV retinitis is expensive, time-consuming, and toxic, the diagnosis of CMV retinitis must be confirmed by an experienced ophthalmologist. Because of poor specificity and sensitivity, CMV cultures of blood or urine are not clinically useful diagnostic tests. However, recent studies of more sensitive techniques of detecting CMV viremia (e.g., CMV DNA amplification by polymerase chain reaction [PCR] or staining peripheral blood leukocytes for CMV antigen) appear to have better predictive value for identifying patients at high risk for developing CMV retinitis. It is not yet clear whether these more sensitive tests have clinical utility in screening.

The current treatment options for CMV retinitis include chronic intravenous treatment with ganciclovir or foscarnet, initial therapy with intravenous ganciclovir followed by chronic oral ganciclovir therapy, intermittent intravenous therapy with cidofovir, or surgical placement of an intraocular device that releases ganciclovir intravitreally for 6 to 8 months combined with chronic oral ganciclovir (

Table 415-1) . Ganciclovir is a nucleoside analogue prodrug that is preferentially phosphorylated within CMV-infected cells to an active drug, ganciclovir triphosphate, which inhibits CMV replication. Foscarnet is a pyrophosphate analogue that does not require phosphorylation for its anti-CMV activity.

Cidofovir is a very potent anti-CMV nucleotide analogue that does not require phosphorylation by CMV-encoded enzymes. In the absence of marked immune reconstitution, therapy must be given indefinitely to minimize further irreversible visual impairment. Both ganciclovir- and foscarnet-resistant strains of CMV have emerged and have been associated with therapeutic failure. In such cases, use of these agents in combination or of cidofovir may be effective in controlling retinitis progression.

Because atrophy occurs in areas of active CMV retinitis, patients are susceptible to rhegmatogenous retinal detachment (resulting from a scar in a thinned portion of the retina) even when active retinitis has been controlled with antiviral therapy. For such patients, surgical reattachment by removal of the vitreous and injection of silicone oil can be temporarily effective in restoring functional vision.

Toxoplasmic Chorioretinitis
Toxoplasmic chorioretinitis is rare compared to CMV retinitis, but may complicate up to 20% of cases of AIDS-associated toxoplasmic encephalitis. Unlike toxoplasmic retinitis in immunocompetent individuals, which typically results from reactivation of congenitally acquired cysts latent in the retina, AIDS-associated toxoplasmic chorioretinitis does not appear to originate in pre-existing retinochoroidal scars, but from dissemination of organisms from nonocular sites of disease.

Necrotizing retinal lesions are often bilateral and multifocal, and (as in CMV retinitis) may result in rhegmatogenous retinal detachment. Vitreous inflammation and anterior uveitis are more common and associated hemorrhage less common than in CMV retinitis. Because nearly all cases of toxoplasmic chorioretinitis are associated with toxoplasmic encephalitis, a computed tomographic (CT) or magnetic resonance (MR) scan of the brain should be done whenever this diagnosis is considered.

Specific antiparasitic therapy (pyramethamine and sulfadiazine, or pyramethamine and clindamycin, in the same doses used to treat toxoplasmic encephalitis) usually is effective in preventing further retinal necrosis, but chronic maintenance therapy must be continued indefinitely to prevent relapse.

Acute Retinal Necrosis Syndrome
Widespread, often bilateral, necrotizing retinitis caused by herpes simplex or varicella-zoster virus is now a well-characterized, although rare, AIDS-associated condition. Unlike CMV retinitis, this disease often is associated with ocular pain and concomittant keratitis or iritis. Many individuals have had recent or concurrent trigeminal zoster or orolabial herpes simplex infection, and evidence of concurrent viral meningoencephalitis may be present. On funduscopic examination, widespread, pale or gray, peripheral retinal lesions are noted. Although intravenous acyclovir is effective in preventing further retinal necrosis, subsequent retinal detachment is a frequent, sight-threatening complication.

Progressive Outer Retinal Necrosis Syndrome
Progressive outer retinal necrosis is a recently described clinical variant of varicella-zoster retinitis occurring in patients with CD4+ lymphocyte counts less than 100 cells/muL and characterized by multifocal, deep retinal lesions that rapidly progress to confluence. Less inflammatory cell response is observed in this condition than in acute retinal necrosis. The clinical response to available antiviral therapies is poor.

Other Causes of Chorioretinitis and Vitritis
Cases of syphilitic retinitis have been reported in individuals with AIDS, AIDS-related complex (ARC) and asymptomatic HIV infection. There is no characteristic ophthalmologic appearance, but nearly all reported cases have had markedly positive serologic tests for active syphilis and dermatologic or central nervous system (CNS) manifestations of secondary syphilis. Generally, response to intravenous penicillin therapy has been good. Disseminated pneumocystosis (associated with use of inhaled pentamidine prophylaxis against Pneumocystis carinii pneumonia), Mycobacterium tuberculosis, and Mycobacterium avium complex infection with choroidal infiltrates have been described, but these lesions generally have not been sight-threatening. Rare cases of indolently progressive retinitis have been attributed to endogenous bacterial infection on the basis of retinal histopathology and response to broad-spectrum antibiotics. Also, vitritis (i.e., endophthalmitis) due to disseminated candidiasis may occur in parenteral drug users who are HIV infected or AIDS patients with indwelling central venous catheters.

OPTIC NEUROPATHY
Opportunistic infectious diseases affecting the optic nerve of patients with ARC or AIDS may result in visual impairment or blindness. The most common cause of optic neuropathy is CMV infection. When CMV retinitis involves the optic disc, swelling of the optic nerve head (papillitis) leads to decreased visual acuity. This may occur in the presence or absence of other areas of retinitis and may affect the intraorbital optic nerve (optic neuritis) or retrobulbar nerve (retrobulbar neuritis). The acute retinal necrosis syndrome caused by herpes simplex or varicella zoster virus infection may cause papillitis; syphilis may cause papillitis, optic neuritis, or retrobulbar neuritis in patients at any stage of HIV disease. The most serious ocular complication of crytococcal meningitis is an arachnoiditis that compresses the retrobulbar optic nerve, occassionally causing blindness. The cause of optic neuropathy usually can be established by seeking the other characteristic features of the specific infection. However, specific antimicrobial therapy for the cause of optic neuropathy often fails to improve vision once significant visual loss has occurred.

ANTERIOR UVEITIS
Severe anterior uveitis is uncommon in patients with HIV disease, but when such cases occur, syphilis or varicella-zoster virus infection are the most common causes. Mild, asymptomatic anterior uveitis commonly is observed in patients with CMV retinitis, but inflammation severe enough to cause symptoms is extremely rare (with the exception of patients receiving cidofovir therapy, which can cause severe, persistant uveitis). Occasional cases of toxoplasmic anterior uveitis also have been reported.

KERATITIS
Inflammatory disease of cornea (keratitis) is most frequently caused by varicella zoster or herpes simplex virus, and the clinical features usually make diagnosis relatively simple. Patients with advanced HIV disease who develop this complication may require intravenous acyclovir therapy in addition to topical trifluridine. Microsporida infection has also been reported to cause keratitis in HIV-infected patients.

DISEASES OF THE CONJUNCTIVA AND ADNEXA
Kaposi’s sarcoma (KS) has a predilection to involve ocular structures. Conjunctival Kaposi’s lesions appear as bright red subepithelial nodules, and small lesions may be mistaken for subconjunctival hemorrhages. Periorbital edema may be caused by lymphangitic KS, even in the absence of apparent ocular or cutaneous lesions. Most ocular lesions respond to local irradiation.

Nonspecific, nonprurulent conjunctivitis that often is self-limited has been reported in up to 10% of AIDS patients. Topical steroid and sulfa therapy may be beneficial for this condition. Other rare causes of conjunctivitis include syphilis and molluscum contagiosum infection. Orbital KS or Burkitt’s lymphoma may present with ptosis and diplopia.

References:
_{de Smet MD, Nussenblatt RB: Ocular manifestation of AIDS. JAMA 266:3019, 1991. Detailed review, with references, of non-CMV ocular complications of AIDS.}

Jacobson MA: Treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. N Engl J Med 337:105, 1997. Reviews and compares advantages and disadvantages of available treatments for CMV retinitis.

Margolis TP, Lowder CY, Holland GN, et al: Varicella-zoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthal 112:119, 1991. Detailed description of unique clinical characteristics of varicella-zoster virus retinitis.

Mark A. Jacobson M.D.