AIDS and the eye A 10-year experience

Reviews

AIDS and the eye A 10-year experience

Hector Maclean, FRCS(Ed), FRACO, FRCOphth, DO* Anthony JH Hall, FRACO, FRACSt Mark F McCombe, FRACO, FRACS,t A Murray Sandland, MB BS,$

Abstract

Background: The AIDS database at Fairfield Hospital, Melbourne, maintains information on eye pathology as identified by the three visiting ophthalmologists. Patients underwent an eye consulta- tion: if they had ocular symptoms; if signs were seen on direct ophthalmoscopy by physicians; or when their CD4+ve cell count fell below 50/vL. The first AIDS-associated eye signs were identified in mid-1984. In the subsequent decade, 3257 patients in Victoria tested positive for HIV, and 845 of the 1123 who developed AIDS were treated at Fairfield Hospital.

Methods: We undertook a retrospective review of the Fairfield Hospital database to identify the AIDS- associated ocular problems seen.

Results: Some 723 patients had an eye consulta- tion. In the earliest stage of HIV infection, minor non-specific ophthalmic involvement may occur. As the disease progresses, microvasculopathy (cottonwool spots and haemorrhages) appears. External disease also occurs such as molluscum contagiosum and Kaposi’s sarcoma of the con- junctiva. With more suppression of the immune system, opportunistic infections become common, and have a considerable visual morbidity. Cerebral

toxoplasmosis (1 17 patients) is only rarely associated with ocular involvement (three patients), but cytomegalovirus (CMV) commonly causes retinitis [204 patients (24%)]. It has been the AIDS-defining illness in 26 patients. A majority had the disease confined to one eye. Mean CD4 cell count at onset is 15+5 pL and it has been associated with a viraemia in all but two patients. Late complications of CMV retinitis include relapse in 41 (20%), spread to the other eye in 24 (12%), and retinal detachment in 30 (15%). Visual impairment follows from retinal destruction, optic nerve involvement, and retinal detachment.

Conclusion: The ophthalmic workload from late ocular complications of AIDS is increasing. Newer and more effective methods of treatment are being developed. Ophthalmologists are becoming more aware of the need for universal precautions to avoid risks from this and other blood-borne infections.

Key Words: AIDS, cytomegalovirus retinitis, eye infections, eye manifestations, ganciclovir, toxoplasmosis oculare.

AIDS has many manifestations in the eye (Figures 1- 12). Early American series reported that as many as 94% of patients showed ocular

*Melbourne University Department of Ophthalmology, 32 Gisborne Street, East Melbourne 3002, Victoria. f Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, East Melbourne 3002, Victoria. $ Fairfzeld Infectious Diseases Hospital, Yarrabend Road, Fairfeld 3078, Victoria. Reprints: Associate Professor H Maclean.

AIDS and the eye - A 10-year experience 61

features.' At first, ophthalmic symptoms and signs may be minimal. As the disease progresses, there is increasing suppression of the immune system (particularly of the CD4+ve subset of T-cell lymphocytes), many infective conditions become more common, and visual morbidity appears. The first eye involvement noted in Melbourne was confirmed, very early in the epidemic, in May 1984. This paper reviews our experience in the subsequent decade. In the ten years, 1123 Victorians have developed AIDS, a third of the 3257 known to be HIV positive? Eight hundred and forty-five of these patients have been cared for at Fairfield Hospital in Melbourne, and of these we have seen 723 patients.

External disease

Mild orbital pain of non-specific nature may be present in the acute lymphadenopathy stage, even before seroconversion. It resolves sponta- neously. Squamous blepharitis features in some reports, but is uncommon in our patients. Chlamydia1 disease can be difficult to distin- guish clinically from chronic allergic conjunc- tivitis (both being resistant to conventional treatments), but only two patients had positive cultures.

With increasing failure of the immune system, multiple molluscum contagiosum lesions can develop on the face and lids, but usually do not cause ocular problems. The dusky red, rounded lesions of Kaposi's sarcoma can appear on the eyelids, but are more likely to be found in the inferior fornix. It is worth pulling down the lower lid to look for them, but nonetheless they are rare in our patients (seven patients; 1 %). They are very sensitive to low- voltage x-rays or beta irradiation, though cryotherapy is also useful.

Although herpes zoster ophthalmicus is much more common in younger patients if they are HIV-positive,? it is still relatively rare, and only three patients were referred with it. No instance of varicella-zoster virus retinitis4 has been recognised. Herpes simplex keratitis can be intractable and dendritic ulcers have appeared even in patients who are taking oral acyclovir (two patients). However, topical acyclovir ointment does help, with topical adeno- sine arabinoside ointment as an alternative.

Internal disease

The commonest intraocular complication is HIV micro~asculopathy.~ The cause remains unknown. The usual form is retinal nerve fibre layer infarcts or cottonwool spots, and AIDS is now the foremost differential diagnosis for this sign. Over 50% of our patients show these.The appearances are usually classical. Sometimes there is blood adjacent, or there may be a haemorrhagic centre like a Roth spot. Blot haemorrhages, perhaps more likely if platelet production is depleted, and microaneurysms may occur also. The cottonwool spots are smaller than those of diabetes, for example, are transient, and do not cause visual symptoms. Some of the larger ones may resemble areas of retinitis caused by cytomegalovirus. The most useful differentiation has been to examine the fundi again in one to two weeks. Cottonwool spots have a lifespan of around six weeks and remain the same size, whereas an area of retinitis will enlarge.

Cytomegalovirus (CMV) retinitis occurred in 24% of our patients (204 of 845), but in a higher proportion of those with low CD4 counts. It is the major cause of visual morbidity and blindness. Initially, patients were exam- ined by an ophthalmologist only when a lesion was noted during direct ophthalmoscopic view- ing through an undilated pupil. Subsequently, patients with CMV disease identified in other organs were screened. Since the importance of a low CD4 count was recognised, all patients with a CD4 count below 50/pL are now screened ophthalmologically. Some of the increase in earlier days was the result of this more intensive screening, but plotting the incidence of new cases over the decade shows a peak in 1991 and a decrease since (Figure 13): the reason is not clear.

Some patients have premonitory symptoms of photopsia, of decreased acuity, of floaters or even of field defects, but in most CMV retinitis is a silent lesion found at routine fundus examination. The indirect ophthalmoscope is needed, as in half of the patients the lesions are in the peripheral retina. The macula is usually spared until late. Usually only one eye is involved, the second eye becoming infected later in 25 (12%). In the acute phase of the chorioretinal infection, there are multiple white areas of infected retina that become confluent.

62 Australian and New Zealand Journal of Ophthalmology 1996; 24(1)

Figure 1 External disease: the lower lid is pulled down to Figure 4 C T scan showing typical ring enhancement of cerebral toxoplasmosis. The patient had a further lesion in

the cerebellum. reveal a Kaposi sarcoma in the lower fornix.

Figure 2 HIV microvasculopathy: cotton-wool spots in the first Melbourne patient to have these identified. Figure 5 Focal rounded choroidal lesions in a patient

recovered from Pneumocystis carinii pneumonia (PCP). The lesions are smaller than those usually described after

PCP and the aetiology is uncertain.

Figure 3 A thick, opalescent macular retinitis with defined granular edges: CMV was present in leukocytes but the lesion was unresponsive to ganciclovir. Retinal biopsy culture gave a pure growth ofToxoplasma gondi.

Figure 6 Pre-ganciclovir CMV retinitis. The lesion is slowly progressing with a ‘brush fire’ border.


Figure 7 Typical acute CMV retinitis in a typical location Figure 10 choroidal vessels in an area of successfully treated CMV

retinitis.

The thin glial scar with occluded retinal and - ‘cottage cheese and tomato ketchup retinopathy’.

Figure 8. CMV retinitis responding to ganciclovir. The retinal opalescence at the edge of the infected area

indicates incomplete suppression of the infection.

Figure 11 There is a linear retinal tear at the edge of an area of healed CMV retinitis with retinal detachment

above.

Figure 9 CMV retinitis responding to ganciclovir. Another typical appearance. The exudative/lipid material

eventually disappeared. Figure 12 A variant appearance of CMV retinitis - the

so-called ‘frosted branch angiopathy’.


There are associated retinal haemorrhages. These white-haemorrhagic lesions may distrib- ute along blood vessels. The clinical appearances have been well described as a ‘cottage cheese and tomato ketchup’ retinopathy because of the creamy swelling and the blood in the lesions. A striking feature is the lack of any reaction in the overlying vitreous. The lesions have no relationship to the sites of previous retinal microinfarcts.

Important risk factors are the presence of CMV in urine or leukocytes as well as a low CD4+ve lymphocyte count (15 k 5/pL)P Patients believe that they are much more likely to contract the disease in the colder months of winter, but we have found no evidence to sup- port this. Many patients had evidence of pre- existing CMV infection in other organs or in leukocytes. In 26 patients known to be HIV positive, it was the first opportunistic infection or AIDS-defining illness.

If untreated, CMV retinitis causes blindness by progressive retinal destruction, by optic nerve involvement, or by retinal detachment. Treatment is possible with the virustatic drugs ganciclovir or foscarnet, or even with a combination of both (at full doses) when the virus shows some resistance to ganciclovir. The pre- ferred initial treatment is a 14 to 21 day course of ganciclovir at 5 mg/kg twice daily intra- venously (induction treatment) with six having instead foscarnet at 100 mgkg twice daily intra- venously because of pre-existing leukopaenia.

Because the drugs are not virucidal, virus particles may remain in the retina so that a sup- pressing dose of the drugs has to be given con- tinually. We have found that rather than the usual five to seven day per week maintenance dosage regimen, ganciclovir may be given at 10 mg/kg over one hour three days a week, with no increase in relapse rates, but with considerable savings in medical and nursing time.7 Foscarnet is less toxic to the bone marrow, but is potentially nephrotoxic, and the need for concomitant rehydration is a disadvantage for many patients because of the attendant malaise and the time required. As an alternative, either drug may be given intravitreally. This is useful, especially if there is granulocytopaenia, because the antiretroviral drug AZT is being given also. The dosage is contr~versial>~ and the logistics of repeated intravitreal injections make them difficult to manage.‘O Intravitreal injection may

AIDS and the eye - A 10-year experience

also be disadvantageous because systemic CMV infection is not being treated concurrent- ly. Sustained-release devices have been developed for pars plana insertion” and may prove useful for patients who do not have CMV disease elsewhere. There is a potential risk of endophthalmitis when the wall of the eye is breached, but retinal detachment does not become more common.

If an indwelling catheter is placed, many patients can give their own infusions. Risk of relapse in our patients has been calculated as 3.46 within a month when leukocyte CMV culture is positive while on treatment, and rises to 7.9 if even one week of maintenance therapy is omitted.I2 If ganciclovir has had to be ceased because of leukopaenia, particularly if the antiretroviral drug azidothymidine (AZT) is being used at the same time, a change to foscarnet has regained control. Otherwise, colony-stimulating factors can be used. In three of the 204 patients where there has been coexisting systemic CMV disease and where neither drug alone con- rrolled the retinitis, a combination of both drugs’? did so. Intravitreal dosage has been used where there has been no evidence of systemic infection. Involvement of the fellow eye occurred in 24 patients (12%) at a mean time of 10 weeks from, and in spite of, the initial treatment.

Survival has steadily increased from a mean of 6.5 weeks to 8.5 months in a decade, and continues to increase in more recently diagnosed patients. The over-all survival curve is shown in Figure 14. A longer survival (mean 12 months) has been reported overseas for patients being treated with fo~carnet,’~ com- pared with those receiving ganciclovir. In our series, most patients have found the side effects of foscarnet so unpleasant that they prefer ganciclovir, even though their survival prospects may be shorter.

Rhegmatogenous retinal detachment is one of the most feared complications of CMV retinitis, and has happened to 30 of our patients (15%), often limited to small localised areas. Other series cite the risk as 18% to 29%” and with no increase if drugs are given intravitreally. The retinal tears are often multiple and occur in either an area of active CMV retinitis or in thin, necrotic, previously infected retina. Two patients have had argon laser photocoagu- lation to localise a detaching retina. Liquid sili-

65

50 ' 40

30

20

I0

/

'84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94(till Sep) Year of mesentatwn

Figure 13 Incidence of new cases of CMV retinitis over a decade.

cone is the most useful aid to reattachment of the retina, or occasionally gas (e.g., SF6), although long-term visual prognosis is guarded. Immediate visual prognosis after detachment repair is limited by pre-existing CMV-induced optic nerve damage. Like many, we have adopt- ed a policy of not offering operation if the fellow eye is not involved by CMV retinitis and if the acuity is already reduced in the affected eye. However, one cannot predict whether the fellow eye will remain free from infection, and the validity of such a policy has been ~ha1lenged.l~ Survival after the retina detaches is poor, the median time at present being 90 days, although one recent series reports a mean survival time of210 days.I6

Other opportunistic infections are much less frequent. Toxoplasma chorioretinitis (three patients) may mimic cytomegalovirus retinitis, but it tends to present before the immune system is so compromised. The lesions, which are usually at the macula, show a much denser, thicker creamy retinal opacification with smooth non-granular borders. l7 There is usually evidence of uveitis, although the vitreous may remain clear as in CMV retinitis. The lesions have no relationship to old chorioretinal scars, and serological tests are very variable. Cerebral toxoplasmosis is much more common (1 17 patients) and usually coexists, with typical ring enhancement being shown on C T scans. Treatment with pyrimethamine and sulphadi- azine is very effective, but long-term maintenance treatment must be used.

l - O 1 'i

0.41

0.0 4 I , . ,

0 200 400 600 800 1000 1200

Days

Figure 14 Kaplan-Meier survival curve from time of diagnosis of CMV retinitis till death for all patients until

September 1994.

Cryptococcal meningitis is treated with flu- conazole and amphotericin. The papilloedema may be gross and there are often intranuclear motility problems. The rounded choroidal lesions of Pneurnocystis choroiditis have been observed mimicking acute multifocal placoid pigment epitheliopathy18 in two presumed cases only.

Much more ophthalmic effort will be needed in the future. It has to be assumed that all HIV positive patients will develop AIDS. The majority will need ophthalmic examination and this will have to be repeated at shorter intervals as the immune system fails. As survival time improves, an increasing number will require ophthalmic treatment. Victoria now has 2000 HIV-positive individuals who do not yet have AIDS and 15 to 16 new cases are diagnosed per month.' Extrapolating these figures to the rest of Australia gives some idea of the case load we face. Adopting the concept of universal precautions prevents risks to ophthalmologists involved in this work, and also prevents spread of disease between patients.

Acknowledgement Anthony JH Hall was in receipt of

Commonwealth Aids Research Grant No. 90/01555 during part of this work. Our colleagues, DrwJ Heriot and DrW Campbell, and several Retina Fellows have shared the ophthalmic management of these patients. Numerous physician colleagues have been


involved in their general care. To all who have participated in this work over a decade, considerable gratitude is due.

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AIDS and the eye A 10-year experience

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