Eye (1988) 2,496-505

Ocular Involvement in AIDS

ALLAN E. KREIGER, and GARY N. HOLLAND, Los Angeles, USA

The acquired syndrome roaneurysms, and intraretinal microvascular (AIDS) is no longer a rare disease afflicting abnormalities. Autopsy studies of AIDS only a small segment of the world popula­ patients indicate that capillary changes in the tion. It has been recognised to occur in most are almost always present. These countries of the world; and, as of October, include swelling of endothelial cells, thicken­ 1987, there had been over 1000 cases ing of the basal lamina, degeneration and loss reported in the United Kingdom. I Despite of pericytes, and narrowing of capillary scientific determination of the causitive lumens. IS The pathogenetic mechanisms agent, better understanding of the behind these changes are not known, how­ pathogenesis of the clinical disease, and ever HIV has recently been shown to be pre­ clarification of the risk factors involved, the sent in retinal tissue. IS Viral (HIV-l) antigen epidemic continues to spread. As physicians, was found in the internal and external nuc­ we are destined to have to deal with the rav­ lear layers and the external plexiform layer as ages of AIDS increasingly in the future. well as in the capillary endothelial cells. Pos­ The first case reports of what became sibly, the endothelial infection results in known as AIDS appeared in 1981.2 Ophthal­ capillary alterations and occlusions. Another mic lesions were noted in the UCLA patients possibility is the deposition of circulating from the very beginning; they were reported immune complexes, which have arisen from by Holland and his associates in 1982.3 Since systemic infections, in the retinal capillaries. then, clinical and autopsy studies have con­ firmed that clinically apparent ophthalmic Cotton-wool spots (CWS) disorders are common, occurring in 40% to Having a similar ophthalmoscopic apppear­ 94% of surveyed patients with AIDS.3-16 ance to those seen in other retinal capillary Often, they result in significant morbidity occlusive diseases, cotton-wool spots in and may lead to severe or AIDS patients are the result of obstruction of blindness. blood flow, ischaemia, and stasis of axoplas­ The ophthalmic complications of AIDS mic flow in the nerve fibre layer of the retina. sort naturally into four categories: the lesions The consequent accumulation of cellular of a primary retinal microvascular disease of organelles within the axon cause localised unknown cause; opportunistic infections of patches of swelling and opacification in the the eye; neoplasms of the eye and adnexa; superficial retina which give the lesions their and neuro ophthalmic abnormalities. typical appearance (Fig. 1). They occur in the posterior pole, usually along the major vas­ Retinal Vascular Disease cular arcades, and they may be single or mul­ Retinal microvascular disease is the most tiple. Their appearance is made even more common ophthalmic manifestation of striking by the absence of other extensive AIDS.ls.17 The clinical features include: cot­ vascular changes or retinal abnormalities. ton-wool spots, retinal haemorrhages, mic- The usual clinical course of CWP is to

Correspondence to: UCLA Medical Center, 10833 Le Conte Avenue. Los Angeles, California. 90024-1771. U.S.A.

Presented at the Annual Congress of the Ophthalmological Society of the United Kingdom. April 1988. OCULAR INVOLVEMENT IN AIDS 497 develop over a few days and then to regress evidence does not indicate that this organism over a period of 4 to 6 weeks. They are plays a direct aetiologic role in the develop­ asymptomatic and, because of their transient ment of these lesions. 19.20 nature, may only be found ophthalmoscopi­ cally with multiple examinations. Distin­ Other microvascular abnormalities. guishing CWP from early CMV Although less dramatic than the CWP, reti­ may be difficult. Serial observations, how­ nal haemorrhages, capillary mic­ ever, will clarify the diagnosis as CWP invari­ roaneurysms, and intraretinal microvascular ably will fade with time and CMV abnormalities (IRMA), are frequently seen retinopathy will worsen. ophthalmoscopically and on fluorescein Cotton-wool spots may also be seen in the angiography (Fig. 2). These changes are AIDS related complex (ARC) and do not often subtle and less easily appreciated than establish the diagnosis of AIDS in a patient CWP and have been reported in 15% to 40% with known HIV infection. Their prognostic of patients.9.14.21 They are also located significance is unclear at this time. Pathologi­ primarily in the posterior pole and are gener­ cally, CWP in AIDS patients are identical to ally asymptomatic and without known prog­ those seen in other diseases such as diabetes nostic implications. or hypertension. Although one case report related cotton-wool spots to the prescence of Ischaemic Pneumocystis carinii cysts in the adjacent Capillary occlusion may rarely involve the retina, the bulk of pathological and clinical perifoveolar capillaries resulting in visual loss. This has been observed pathologically and clinically and is characterised by retinal oedema and exudates surrounding the fovea in association with multiple CWP.15 We have observed one patient who developed perifoveal capillary occlusion and the forma­ tion of bilateral macular holes.

Opportunistic Ocular Infections A number of organisms have been found to cause ocular infections which can involve the anterior segment, the posterior segment or the ocular adnexae.

Fig. 1. Cotton-wool patches in AIDS. Anterior Segment Infections Virus Infections Herpes simplex may produce corneal epithe­ lial lesions which can be prolonged and severe. Response to topical antivirals is good, but recurrence is common as it is in most AIDS related infections. CMV may infect the , but it is probably not a cause of significant morbidity. HIV has not yet been implicated in any ocular disease.

Other infections. Patients with compromised by viral infection or adnexal problems may develop Fig. 2. Fluorescein angiography demonstrating secondary bacterial infections. Corneal the retinal microvascular disease of AIDS. (Re­ ulcers caused by Candida albicans and Can­ printed with permission). dida parapsilosis have been reported.22,23 498 A. E. KREIGER ET AL.

Posterior Segment Infections fluid. There is no pain associated with the Cytomegalovirus (CMV) retinopathy infection and the anterior segment is usually By far the most commonest and most clini­ quiet with the exception of minimal aqueous cally significant opportunistic infection of the humour flare and cell reaction. Rarely, eye is that caused by CMV. CMV is a haemorrhage may extend into the vitreous ubiquitous virus; nearly 80% of adults in the and give rise to the sensation of "". United States have complement-fixing anti­ Retinal detatchment is attended with the body to it by the age of 40.24 Other than in usual symptom of visual field loss. fetuses, it is not known to cause retinal infec­ Pathologically, the retinal lesions are tion in the immunocompetent host. Prior to characterised by widespread, full-thickness the advent of AIDS, CMV retinopathy was necrosis.9 There is remarkably little accom­ seen only in immunocompromised patients panying inflammation except for occasional' and infants with cytomegalic inclusion dis­ lymphocytes and a few foci of acute inflam­ ease. In contrast, the frequency of the retinal matory cells; hence, the preferred name for infection in AIDS patients has been reported this entity is CMV retinopathy rather than to be as high as 46% .15.17 One can expect that . Scattered retinal haemorrhages may improvements in the general medical care of be noted and the adjacent vitreous humour is AIDS patients with extension of life-expec­ usually clear. The underlying does tancy will lead to a greater at-risk period and not appear to be invaded by the infection higher liklihood of acquiring this complica­ although there may be a few foci of inflam­ tion. It has been suggested that the retinal matory cells there. Chronic lesions show microvasculopathy of AIDS may predispose marked replacement of the retina with a thin patients to retinal infection with CMV.14.15 gliotic membrane. CMV retinopathy is characterised by single or multiple zones of yellowish-white retinal opacification with irregular, feathered bor­ ders (Fig. 3). Numerous, tiny white dots may be visible within the substance of the clouded regions giving it a mottled look. They are more evident at the edges of the lesions where the surrounding normal retina is trans­ parent. usually accom­ panies the infection and may occur at the edges of the lesions or within their substance. Vascular sheathing may also be seen. Lesions may occur anywhere in the fundus from the ora serrata to the posterior pole, but the reg­ ion of the vascular arcades is often where the infection is first noted. Typically, there is a centrifugal advance into the normal sur­ rounding retina, leaving behind necrotic, thin tissue which has a stippled appearance and which is prone to develop retinal breaks. Unchecked, the lesions will spread to involve all of the retina. The rate of advance depends on the virulence of the organism and the resi­ tance of the host. Diagnosis is rarely a prob­ lem because of the distinctive appearance of the lesions and their typical course. Patients are often asymptomatic until the Fig. 3. Cytomegalovirus retinopathy in AIDS. a. lesions affect the fovea or the Initial lesion. b. Later, showing centrifugal enlarge­ with direct infection or extension of oedema ment. OCULAR INVOLVEMENT IN AIDS 499

Treatment of CMV retinopathy is limited Untreated, blindness is the inevitable result to immunomodulating drugs and to antiviral of rhegmatogenous . therapy. Ganciclovir, a recently introduced Unfortunately, retinal detachment is often antiviral with activity against CMV, has been bilateral. In our series at UCLA, 81.5% of used with some success to halt progressive patients who developed retinal detachments CMV retinopathy,21.25-28 however it does not had these in both eyes.32 Even with successful eradicate the virus and CMV can be reco­ surgical reattachment, the visual prognosis is vered from the retina after treatment. 29 poor because of the continuing infection and Because the disease will recur inevitably relentless retinal necrosis. Nevertheless, if from the borders of the old lesions when the the infection can be controlled by the use of drug is withdrawn, it is necessary to keep antiviral medications and the retina is patients on long-term, low dose, mainte­ reatachable with modern vitreoretinal nance. This is complicated by the need for techniques, one should consider operating on intravenous administration of ganciclovir and those patients who would otherwise be blind the tendency of the drug to further supress without intervention. Limited, but useful vis­ bone marrow function.28 The commonest ion may be salvagable in a few patients and cause of theraputic failure with ganciclovir is provide some solace for the remaining drug induced, life-threatening neutropenia. months of their lives. Furthermore, some pateints continue to lose Rhegmatogenous retinal detachment in vision from progressive retinopathy despite AIDS patients are unique in that there are continued low-dose maintenance. This is usually large areas of retinal necrosis in undoubtedly due to the persistance of live which numerous retinal breaks may occur. virus in the retina despite favourable clinical Once these areas detach, they must be consi­ response to the initial treatment regimen. dered to be retinal breaks and be treated as Trisodium phosphonoformate hexahydrate such. Pneumatic retinopexy is rarely indi­ is another antiviral drug with activity against cated because of this phenenomenon. Scleral CMV that is being investigated for the treat­ buckling alone should be reserved for those ment of CMV retinopathy. 30 Its efficacy patients in which the pathology is limited. appears to be similar to that of ganciclovir Most often, vitrectomy, gas-fluid exchange, and it also must be given as maintenance internal drainage of subretinal fluid, internal therapy to prevent reactivation of infection. photocoagulation, and injection of long-last­ Its major toxicity is renal. ing gas or silicone oil. is needed to have any Intravitreous injection of ganciclovir has chance of achieving enduring retinal reat­ been used in an attempt to achieve the tachment. The late complications of silicone theraputic benefit without the side effect of oil are less of a concern in these patients with bone marrow suppression.3l The phar­ limited life-expectancy. macokinetics of the drug administered in this fashion are poorly understood and the ideal dosage regimes and indications are under investigation. Our experience at UCLA has been limited to a small number of patients in which there was no other option to attempt to salvage vision. Our impression, at this time, is that progression of the disease can be slowed somewhat, but that morbidity of the treatment is considerable. Rhegmatogenous retinal detachment is a severe complication of CMV retinopathy and other opportunistic necrotising (Fig. 4).32 Retinal breaks are likely to form in Fig. 4. Rhegmatogenous retinal detachment fol­ the regions of extreme retinal thinning even lowing necrotising opportunistic retinopathy in in the absence of vitreous traction. AIDS. 500 A. E. KREIGER ET AL.

Other viral retinitides. immunocompetent host, the retinitis is rarely Herpes simplex also causes retinal infection associated with preexisting retinochoroidal in AIDS patients, but it occurs with much scars, suggesting that is an acquired infection less frequency than CMV.15.33 Herpes or is disseminated from a non-ocular site. simplex virus has been found in the retina at Retinal lesions present a variable clinical autopsy and we have seen three patients with picture. They may be single, multiple, unilat­ widespread necrotising retinitis which were eral, bilateral, focal or diffuse. There may be presumed to be from this organism since the little vitreous reaction or there may be severe clinical picture was not similar to CMV vitritis and even anterior segment inflamma­ retinopathy and the patients all suffered from tion. It is unlikely that the lesions of toxop­ cutaneous herpes simplex infections.32 lasmosis would be confused with those of The retinal lesions appeared suddenly as CMV. They lack the grainy appearance and numerous grayish patches, 2 to 3 mm in associated haemorrhage and do not tend to diameter, located in the mid-periphery (Fig. spread in the characteristic "brush-fire" man­ 5). Over a span of 2 or 3 days these discontin­ ner as do those of the viral infection. When ous blotches coallesced rapidly into zones ocular toxoplasmosis is suspected, patients extending from the vascular arcades nearly to should be evaluated for central nervous sys­ the ora serrata. Retinal haemorrhages were tem involvement, especially if there are any seen, but were not extensive until late in the neurological signs or change in mentation course. The vitreous was clear. With time, (Fig. 6). the retinal lesions became more opaque and Antiparasitic therapy may be effective in then began to thin and appear to dissolve. limiting visual loss and in treating the With this development, numerous retinal neurologic manifestations, but continued holes formed and the retina detached. The disease was bilateral in all patients. Treat­ ment with acyclovir intravenously appeared to halt progression of the lesions acutely in one patient; however, as with CMV retinopathy, they would reactivate at their edges on cessation of intravenous therapy. In this individual, oral acyclovir seemed to inhibit spread of the infection slightly. Herpes zoster infection of the retina, produc­ ing a clinical appearance similar to the acute retinal necrosis syndrome, has been seen in a patient with AIDS.34 It is likely that other viral infections of the retina will be disco­ vered as our dealing with this disease increases. Although HIV has been found to infect the retina, there has been no specific correlation with clinical retinitis or retinopathy. The role of this virus in initiating or facillitating other infections is yet to be clarified.

Ocular toxoplasmosis Whereas toxoplasmosis is a common intrac­ ranial infection in AIDS patients, few reports of ocular involvement have appeared; they account for only 1-3% of ocular infection in patients with AIDS.34 In contrast to toxoplas­ Fig. 5. Herpes-associated retinopathy in AIDS. mIC occurring in an a. Initial lesion b. 48 hours later. OCULAR INVOLVEMENT IN AIDS 5()1 treatment is necessary to prevent reactivation deliniated. Effective treatment with standard of the disease. anti-microbial therapy may be limited to the extent of the infection and the severe Candida Chorioretinitis immunosuppression of AIDS. Although mucocutaneous candidiasis is very Retinal vasculitis has been reported common in patients with HIV infection, can­ primarily in patients in Africa. Vitreous dida chorioretinitis has been reported only inflammation, without retinal lesions, has rarely.35.36 Apparently, it does not occur in been seen.3.9,11,39 The causes of these disor­ the absence of other factors which favour ders are unknown, but it has been speculated endogenous spread of fungi to the eye, such that they are related to the presence of HIV as intravenous drug abuse or the presence of in the intraocular tissues. an indwelling intravenous catheter. Adnexal infections Syphilis Herpes zoster ophthalmicus In AIDS patients Treponema pallidum can Herpes zoster ophthalmicus occurs fre­ cause severe disease. Luetic retinitis and quently in patients with HIV infection.40,41 have been reported.37.38 The Although it alone does not establish the diag­ retinal lesions are yellowish in colour and are nosis of AIDS, it seems to be associated with located deeply within the tissue. They may be an increasing incidence of development of widespread and may result in significant reti­ the syndrome. Certainly, HIV infection nal necrosis and ultimate retinal break for­ should be suspected in any young individual mation and retinal detachment.32 Resolution with zoster ophthalmicus. with penicilin therapy is the rule, but recurr­ The skin lesions, , and anterior ence is common after treatment with doses may be extremely severe and dissemi­ felt to be adequate in the immunocompetent nated infections can occur. 5,6 Chronic host. dendriform keratitis, following skin envole­ ment has been reported.42 Other infections Treatment should include systemic acyc­ A number of infectious agents, including lovir to promote healing of the skin lesions Mycobacterium avium-intracellulare, Cryp­ and to limit the severity of the ocular lesions. tococcus neoformans, Histoplasma cap­ Systemic steroids should be avoided because sulatum, and Pneumocystis carin ii, have been of their suppression of the immune system. found in the eye at autopsy in patients with disseminated disease.34 The clinical manefes­ Other infections tations of these organisms have yet to be Molluscum contagiosum may cause extensive cutaneous lesions of the and face. When severe, they may result in ocular sur­ face irritation, trauma. or infection.43 Culture negative and keratitis has been reported in up to 10% of patients in some series.34 The cause is unknown.

Neoplasms Kaposi sarcoma. Kaposi sarcoma is a muticentric malignant neoplasm thought to be derived from endothelial cells.9 It may involve the skin of the eyelids and lid margins, the conjunctiva, Fig. 6. Computerised axial tomography revealing and rarely the .7·9.14.15,44.45 Conjunctival cerebal toxoplasmic necrotising granuloma in involvement has been reported in 16-18% of AIDS patient with toxoplasmic retinochoroiditis. AIDS patients with Kaposi sarcoma.9.15 502 A. E. KREIGER ET AL.

Conjunctival Kaposi sarcoma lesions appear as bright red subepithelial masses (Fig. 7) usually, they are located in the inferior Cul-de-sac, but palpebral and bulbar lesions may occur.34 Small lesions may be mistaken for sub-conjunctival haemorrhages. Tumors may be overlooked unless the lids are everted during the ophthalmic examina­ tion. Since the conjunctiva may be the first sit� for development of the tumor, the con­ junctiva should be inspected even in the absence of other known systemic sarcomas. Rarely are the tumors symptomatic unless Fig. 7. Sub-conjunctival Kaposi sarcoma. (re­ they ulcerate or become bulky and interfere printed with permission). with lid function. Since they are radiosensi­ tive, treatment with irradiation will cause regression with little risk to the eye. lar findings, including visual field defects, Orbital lymphoma , and cranial nerve palsies, have Burkitt lympoma has been reported to occur been reported with these entitiesY in the orbit, manifestating as proptosis, lid The main non-viral opportunistic infec­ swelling and motility disturbance.46 This tions of the brain are toxoplasmosis and cryp­ lesion may respond to irradiation or tococcosis.48 Cerebal toxoplasmic lesions in . AIDS patients consist of necrotising granulomas. Headaches and alterations in Neuro ophthalmologic Abnormalities. conciousness are the commonest presenting A variety of neuro ophthalmologic signs and symptoms; ocular findings may be seen symptoms can result from manifestation of depending on the location of the granulomas. AIDS.34 Often, the is Antibiotic therapy is often effective in con­ involved with primary HIV infection, oppor­ trolling the infection, but recurrences off tunistic infections, and intracranial neop­ therapy are usual. In some series, cryptococ­ lasms. The frequency of neuro-ophthalmic cal meningitis is the commonest non-viral findings in AIDS is unknown, however cent­ opportunistic infection of the CNS in AIDS ral nervous system disease may present in patients.48 In contrast to toxoplas­ this manner and the clinician should be alert mosjs,which usually occurs in patients in to the diagnostic possibilities. whom AIDS has already been diagnosed, cryptococcal meningitis is often the initial Primary HIV infection opportunistic infection upon which the diag­ Primary HIV encephalopathy, characterised nosis of AIDS is made.48 The disease has an by progressive dementia, is the most com­ insidious onset and a subacute course. Ocular mon CNS illness associated with AIDSY findings are variable; cranial nerve palsies Visual disturbances, including gaze palsies and papilloedema have been noted.34 Treat­ and , were found in 5% of patients ment with antifungal medications may be in one series.47 has also been effective, but the treatment of this disease reported.34 has not yet been standardised. Other causes of CNS infection include Opportunistic infections Mycobacterium tuberculosis, Mycobacterium Opportunistic viral infections are rep­ avium-intracellulare, various fungi including resented mainly by JC virus, a papovavirus Histoplasma capsulatum and various bac­ which causes progressive multifocal teria.42 Neuro-ophthalmic manifestations leukoencephalopathy, and the herpes vir­ have not been characterised fully in these and uses, which mainly cause encephalitis. Ocu- other less common infections. OCULAR INVOLVEMENT IN AIDS 503

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