Chapter 164 – HIV-Related Uveitis
PRAVIN U. DUGEL
ALLEN B. THACH
• In individuals infected by human immunodeficiency virus, most of the ocular infections are caused by opportunistic organisms. The opportunistic infections include cytomegalovirus retinitis, progressive outer retinal necrosis, toxoplasmic retinochoroiditis, fungal chorioretinitis, infectious multifocal choroiditis, molluscum contagiosum, and microsporidia keratopathy.
• The features of the infection depend on the infectious agent and the site of infection.
• Retinal necrosis.
• Chorioretinal lesions.
• Multifocal choroidal lesions.
• Eyelid lesions.
• Epithelial keratopathy.
• Retinal microvasculopathy.
The ocular manifestations of acquired immunodeficiency syndrome (AIDS) are protean. They include various opportunistic infections of the retina, choroid, and ocular adnexa and neoplasms that involve the eyelids, conjunctiva, and other ocular and orbital structures. A number of anterior segment diseases, such as herpes simplex, herpes zoster, and ulcerative keratitis, are described in more detail in Chapter 162 . A separate class of anterior and posterior segment manifestations that concern ocular neoplasms and AIDS is described in Chapter 183 . In AIDS, even though anterior and posterior segments, including orbital tissue, are involved through various infections or neoplastic disorders, the most common visually disabling complications occur primarily in the posterior segment. Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with AIDS. This entry is described in detail in Chapter 163 . The introduction of highly active antiretroviral therapy (HAART) resulted in a dramatic decline in incidence of CMV retinitis and other opportunistic ocular infections.
PROGRESSIVE OUTER RETINAL NECROSIS
EPIDEMIOLOGY AND PATHOGENESIS
Even though progressive outer retinal necrosis (PORN) is less common than CMV retinitis, the former causes a more rapid destruction of the retina and carries a poor prognosis. Electron microscopy of a retinal biopsy specimen and polymerase chain reaction
Figure 164-1 Progressive outer retinal necrosis. A, Day 2. B, Day 6. Notice the deep, white outer retinal lesions that coalesce and progressively expand in a circumferential manner, with sparing of the perivascular retina and minimal overlying inflammation. (With permission from the American Journal of Ophthalmology.)
studies show herpes zoster as the causative agent of retinal necrosis.
In a patient with AIDS, PORN consists of deep outer retinal lesions in a circumferential pattern in the peripheral retina. These lesions tend to coalesce rapidly and progress to full-thickness retinal necrosis in a matter of days, and they continue to progress more posteriorly with a minimal amount of overlying inflammation ( Fig. 164-1 ). A unique feature that characterizes this condition is apparent sparing of the paravascular retina.  Within a matter of weeks, vision may deteriorate from 20/20 (6/6) to no light perception. Often the disease starts in one eye and the fellow eye becomes involved within weeks to months. In a variant of PORN
the retinitis begins in the posterior pole with little or no clinical evidence of vasculitis. 
The diagnosis of PORN is a clinical one in a patient who has human immunodeficiency virus (HIV) infection. A history of recent or concurrent herpes zoster infection in the skin or elsewhere is helpful in the diagnosis. Rapid progression and sparing of retinal vessels and adjacent retina are characteristic. Histopathological and immunohistochemical studies, in situ hybridization, and polymerase chain reaction that utilizes varicella-zoster virus primers may reveal a herpes zoster viral process.
Progressive outer retinal necrosis must be differentiated from peripheral CMV retinitis and ocular toxoplasmosis. The characteristic and differentiating features of PORN include rapid and relentless progression, circumferential involvement of the outer retina followed by full-thickness retinal necrosis, and initial sparing of the paravascular retina. In CMV retinitis all layers of the retina tend to be affected in a granular fashion in the periphery. The retinal vessels are not spared and, in fact, often have segmented vasculitis. Progression is usually toward the posterior pole in a radial fashion as opposed to a circumferential fashion. Toxoplasmosis tends to cause a vitritis and a significant necrotizing reaction in the retina. The vasculature is not spared and progression does not take place in a circumferential manner.
Several HIV-infected individuals who have PORN usually develop cutaneous zoster infection prior to its development. Occasionally, simultaneous development of cutaneous zoster and PORN occurs. Usually, the CD4+ lymphocyte count is low (peripheral CD4+ lymphocyte counts less than 50 cells/mm3 ).  Patients may also develop other manifestations of advanced HIV infection.
Histopathologically, advanced cases of PORN reveal total necrosis of the retina, with both inner and outer retina necrosis. However, sparing of the retinal venules also occurs in such cases. Retinal pigment epithelium may be involved.  Viral inclusions could be observed in the retinal cells. Immunohistochemical or in situ hybridization that utilizes varicella-zoster virus probes may show positive immunostaining or hybridization in the infected cells. Electron microscopic studies may disclose typical herpes viral particles in the infected cells.
No treatment has been found to be universally successful. Treatment with more than one antiviral agent (i.e., ganciclovir and foscarnet, ganciclovir and acyclovir, foscarnet and acyclovir, or all three together) may improve the response and final visual outcome.  Sorivudine, an oral antiviral agent, may be effective. Intravitreal injection of ganciclovir and foscarnet has also been attempted with limited success. 
COURSE AND OUTCOME
The disease tends to progress rapidly and often results in a retinal detachment within days or weeks. The progression is usually toward the posterior pole in cases that present with peripheral retinitis. The retinal detachment appears to proceed via a rhegmatogenous process.
The incidence of ocular toxoplasmosis in HIV-infected certain individuals varies; it appears to be relatively more common in countries such as Brazil. Ocular toxoplasmosis in many patients who have AIDS is thought to result from an acquired infection by the parasite Toxoplasma gondii, which may be surmised from multifocality, bilaterality, and the lack of preexisting scars.   
Ocular toxoplasmosis associated with AIDS is often seen with no preexisting chorioretinal scar and is frequently bilateral and multifocal. Vitreous inflammation is a common clinical finding. In some patients the clinical picture is quite similar to that of ocular toxoplasmosis observed in immunocompetent individuals. However, some of the HIV patients present with diffuse retinitis that simulates CMV infection, but retinal hemorrhages are not observed in toxoplasmosis. The typical “headlight in a fog” funduscopic picture is also found. Surprisingly, a significant inflammatory reaction is normally present despite the immunosuppression. Almost 25% of patients who have ocular toxoplasmosis have intracranial involvement. In fact, toxoplasmosis is the most common cause of AIDS-associated, nonviral intracranial infection. Therefore, all AIDS patients who have ocular toxoplasmosis should undergo an intracranial imaging study (computed tomography or magnetic resonance imaging with contrast).
Usually, ocular toxoplasmosis is diagnosed on the basis of clinical findings. Serological tests and polymerase chain reaction performed with the intraocular fluids may be helpful, and occasionally a retinal or choroidal biopsy may be required to establish the tissue diagnosis.  Ocular toxoplasmosis must be distinguished from CMV retinitis and PORN. Characteristic features of the ocular toxoplasmosis in AIDS include significant inflammation despite immunocompromise, multifocal and sometimes bilateral lesions, and lack of preexisting chorioretinal scars. Unlike the finding in PORN, there is no circumferential pattern of progression with sparing of the paravascular retina. Unlike the finding in CMV retinitis, there is a significant amount of overlying inflammation with no significant retinal hemorrhage.
Histopathologically, several cysts of Toxoplasma are present at the site of retinitis. In addition, free forms of the organism may be found. The retina is almost always necrotic, and adjacent choroid often contains chronic inflammatory cell infiltration.
Antitoxoplasma therapy similar to that given to patients who are immunocompetent is effective in patients who have AIDS. This consists of a combination of pyrimethamine, sulfadiazine, and folinic acid. However, clindamycin, tetracycline, atovaquone, and spiramycin are also effective. Patients who have AIDS are not given high doses of systemic corticosteroids. Additional immunosuppression in an already immunocompromised patient may bring about severe opportunistic infections, which may be life threatening as well as sight threatening.
In individuals infected by HIV, various fungi may cause chorioretinitis and orbital cellulitis. These include Candida albicans, Aspergillus, Histoplasma capsulatum, and others. Candida ( Chapter 171 ) and Aspergillus result in similar intraocular infection.
Ocular histoplasmosis is an uncommon opportunistic infection in patients who have AIDS. It presents clinically as a creamy white, choroidal lesion with subretinal infiltrates that are approximately one fourth of a disc diameter; the lesions may be bilateral. Scattered intraretinal hemorrhages have been reported. All retinal infiltrates have distinct borders.
The diagnosis of ocular histoplasmosis is often made in the setting of a disseminated infection. The clinical picture is entirely nonspecific, but it does serve to initiate a full evaluation for a systemic infection. As a result of this systemic evaluation, other likely candidates, such as ocular toxoplasmosis, fungal endophthalmitis, and other opportunistic infections that cause a
Figure 164-2 Pneumocystic choroiditis. Multiple lesions occur in the choroid.
retinochoroiditis, can be ruled out. In the differential diagnosis of ocular histoplasmosis the following entities are considered: candidal retinitis, toxoplasmic retinochoroiditis, and mycobacterial and pneumocystic choroiditis.
Most patients who have ocular histoplasmosis present with sepsis, and, therefore, the ocular findings occur relatively late in the course of this life-threatening disease. However, if the ocular findings occur earlier, the ophthalmologist must obtain a full systemic evaluation for an opportunistic infection to make this diagnosis.
On pathological evaluation, the retina contains multiple, white-tan lesions that may measure up to 1?mm in diameter—many are surrounded by a light tan halo. These lesions are located superficially and deep in the retina, are often perivascular, and contain histoplasmic organisms in all layers. The organisms are free or phagocytosed within histiocytic cells that occur with or without surrounding lymphocytes.
The ocular histoplasmosis is usually treated sufficiently by the intravenous antifungal medications required to treat the systemic infection. However, if necessary, supplemental intravitreal injections may be given concurrently.
INFECTIOUS MULTIFOCAL CHOROIDITIS
About 8–10% of terminally ill patients who have acquired immunodeficiency syndrome develop multifocal choroidal lesions that result from various infectious agents, which include Pneumocystis carinii ( Fig. 164-2 ), Cryptococcus ( Fig. 164-3 ), mycobacteria, and others.   
Infectious multifocal choroiditis presents as deep, creamy white to gray lesions below the retinal pigment epithelial layer. These are in a multifocal pattern in the posterior pole and midperiphery and tend to be more elongated in the far periphery, with very little, if any, overlying inflammation, and the retina may not be involved. These lesions may be caused by Cryptococcus neoformans, atypical mycobacteria, Pneumocystis carinii, or other infectious agents.
Diagnosis is a clinical one, but the specific diagnosis requires systemic evaluation, which includes imaging studies, blood cultures, biopsy, and histological examination of the affected visceral organs (such as lungs). The differential diagnosis of infectious multifocal choroiditis includes ocular toxoplasmosis and ocular histoplasmosis. These two disorders present with significant intraocular inflammation and lesions that tend to involve the outer retinal layers. Although these lesions may be multifocal, they are usually not arranged in a regular
Figure 164-3 Infectious multifocal choroiditis. This is secondary to infection with Cryptococcus neoformans.
Figure 164-4 Molluscum contagiosum. Typically has raised, 2–3?mm diameter eyelid lesions with umbiculated centers.
multifocal pattern that reflects the choroidal angioarchitecture. Rarely, deep outer retinal lesions of early PORN may be confused with infectious multifocal choroiditis. However, no progression toward coalescence of these lesions occurs in infectious multifocal choroiditis.
The clinical picture of infectious multifocal choroiditis is entirely nonspecific for a causative organism. Unlike patients who have ocular histoplasmosis, patients who have infectious multifocal choroiditis may be completely asymptomatic, other than the occasional patient who presents with symptoms of blurred vision. Indeed, this may be the first clinical sign of a systemic infection. Therefore, a full systemic evaluation is imperative and must be carried out immediately.
Histopathologically, the causative organisms can be seen vividly using special stains. Usually, the inflammatory cell infiltration is minimal or absent in the choroid. However, individuals receiving HAART may show morbid inflammatory reaction. Treatment of infectious multifocal choroiditis depends on the causative agent. As systemic involvement is the rule, intravenous therapy is required. Over a period of 1–3 months, the multifocal lesions may fade gradually, with minimal overlying retinal pigment epithelial changes.
Molluscum contagiosum ( Fig. 164-4 ) consists of raised lesions in the ocular adnexa that are 2–3?mm in diameter and typically have an umbiculated center. These lesions often shed viral particles
Figure 164-5 Molluscum contagiosum. Intracytoplasmic, small eosinophilic molluscum bodies occur in the deep layers of epidermis. The bodies become enormous and basophilic near the surface. The bodies may be shed into the tear film, where they cause a secondary, irritative, follicular conjunctivitis. (From Yanoff M, Fine BS. Ocular pathology, ed 5. St. Louis: Mosby; 2002.)
in the conjunctival cul-de-sac, which results in a follicular conjunctivitis. In patients who have AIDS these lesions tend to be multiple and bilateral. In immunocompromised patients, the molluscum virus, a DNA virus that belongs to the poxvirus family, tends to spread aggressively to the head and neck areas. Therefore, these lesions can be progressive as well as persistent.
The differential diagnosis of molluscum contagiosum includes ocular neoplasms typically associated with AIDS patients ( Chapter 183 ). Molluscum contagiosum is characterized by an umbiculated center, a lack of vasculature, and a lack of necrosis that differentiates it from a more aggressive neoplastic lesion, such as squamous cell carcinoma, Kaposi’s sarcoma, and lymphoma.
Histopathologically, the lesions show multiple, round or oval, eosinophilic and basophilic bodies in the cytoplasmic inclusions. These inclusions are present in the epithelium, and larger basophilic inclusions usually displace the nucleus toward the periphery of the cell ( Fig. 164-5 ). Electron microscopy of these inclusions reveals viral particles that are somewhat rectangular and contain electron-dense nucleoid.
If patients have significant functional difficulties, such as persistent conjunctivitis, that cause irritation or visual symptoms, surgical excision, cautery, or cryotherapy is often effective.
Microsporidia are intracellular obligate parasitic protozoa that can cause punctate epithelial keratopathy in individuals infected by HIV. The patient may develop mild conjunctivitis. CD4+ lymphocyte counts in such patients are usually below 50 cells/ml3 . Gram staining of the conjunctival and corneal epithelial cells reveals organisms. Some patients respond well to topical fumagillin.
HUMAN IMMUNODEFICIENCY VIRUS MICROVASCULOPATHY
Approximately 75% of individuals infected by HIV develop microvascular abnormalities that involve the conjunctiva and retina. Hematological abnormalities, such as increased red blood cell aggregation, high fibrinogen levels, and above normal levels of plasma viscosity and quantitative immunoglobulin G, have been noted in most HIV-positive patients. Such hematological abnormalities may contribute to vascular damage and ocular ischemic lesions in the conjunctiva and retina. However, the possibility exists that this is a manifestation of an infectious microvasculopathy, perhaps as a result of HIV itself. An increased prevalence of retinopathy was observed in patients coinfected with HIV and hepatitis C compared with patients infected with HIV alone, which may indicate that immune complex deposition may cause vascular occlusion. Hepatitis C infection has a known association with hypergammaglobulinemia and cryoglobulinemia. 
Clinically, HIV microvasculopathy may be seen in the anterior segment or the posterior segment of the eye. The conjunctiva may show dilated, short segments of vessels, often in a corkscrew-like, tortuous pattern. In the posterior segment, intraretinal hemorrhage, retinal telangiectasia, cotton-wool spots, retinal vascular tortuosity, and vein or artery occlusions have been described. No known treatment exists for HIV microvasculopathy.
1. Foster DJ, Dugel PU, Frangieh GT, et al. Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol. 1990;110:341–8.
2. Margolis TP, Lowder CY, Holland GN, et al. Varicella zoster retinitis in patients with the acquired immune deficiency syndrome. Am J Ophthalmol. 1991;112:119–31.
3. Engstrom RE Jr, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis syndrome. A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology. 1994;101:1488–502.
4. Kuppermann BD, Quiceno JI, Wiley C, et al. Clinical and histopathologic study of varicella zoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol. 1994;118:589–600.
5. Chulla TA, Rutledge BK, Morley MG, Duker JS. The progressive outer retinal necrosis syndrome: successful treatment with combination antiviral therapy. Ophthalmic Surg Lasers. 1998;29:198–206.
6. Pinnolis MK, Foxworthy D, Kemp B. Treatment and progressive outer retinal necrosis with sorivudine. Am J Ophthalmol. 1995;119:516–17.
7. Morley MG, Duker JS, Zacks C. Successful treatment of rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol. 1994;117:264–5.
8. Holland GN, Engstrom RE Jr, Glasgow B, et al. Ocular toxoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol. 1988;106:653–67.
9. Cochereau-Massin I, LeHoang P, Lautier-Frau M, et al. Ocular toxoplasmosis in human immunodeficiency virus–infected patients. Am J Ophthalmol. 1992; 114:130–5.
10. Moorthy RS, Smith RE, Rao NA. Progressive ocular toxoplasmosis in patients with acquired immunodeficiency syndrome. Am J Ophthalmol. 1993;115:742–7.
11. Fardeau C, Romand S, Rao NA, et al. Diagnosis of toxoplasmic retinochoroiditis with atypical clinical features. Am J Ophthalmol. 2002;134:196–203.
12. Morinelli EN, Dugel PU, Riffenburgh R, Rao NA. Infectious multifocal choroiditis in patients with acquired immune deficiency syndrome. Ophthalmology. 1993;100:1014–21.
13. Zamir E, Hudson H, Ober R, et al. Massive mycobacterial choroiditis during highly active antiretroviral therapy: another immune-recovery uveitis? Ophthalmology. 2002;109:2144–8.
14. Dugel PU, Rao NA, Forster DT, et al. Pneumocystis carinii choroiditis after long-term aerosolized pentamidine therapy. Am J Ophthalmol. 1990;110:113–17.
15. Dugel PU, Rao NA. Ocular infections in the acquired immunodeficiency syndrome. Int Ophthalmol Clin. 1993;33:103–27.