Retinal and choroidal disease
Cotton wool spots
Aside from its ability to cause retinal infection secondary to immunodeﬁciency, human immunodeficiency virus (HIV) is associated with a retinopathy in its own right. The retinopathy is characterised by transient nerve ﬁbre layer infarcts (cotton wool spots) and scattered small retinal haemorrhages that rarely cause visual morbidity. It is caused by a combination of local capillary endothelial cell changes (possibly cytomegalovirus induced) and rheological changes and is a sign of established immunodeﬁciency. It does not require treatment.
Cytomegalovirus (CMV) retinitis is the most important cause of visual loss in patients with acquired immune deficiency syndrome (AIDS) (Figure 1). The first clinical description of CMV retinitis was made in 1971 in a renal transplant recipient who had widespread systemic CMV disease and subsequently died. Before the AIDS pandemic, CMV retinitis was rare and the treatment of CMV retinitis was poor. None the less, it usually did not present a clinical problem because the immune deficit responsible for the retinitis was often reversible. The original report of CMV retinitis in patients with AIDS was made in 1983.
Patients with CMV retinitis usually present with floaters and mild to moderate visual loss. The degree of visual loss depends on the site in the retina of the CMV retinitis. On ophthalmoscopy CMV retinitis appears as conﬂuent areas of full thickness necrotising retinitis with haemorrhage. There are usually associated areas of old healed retinitis with a granular pigmentary change behind the leading border of active retinitis. It may be associated with an accompanying retinal vasculitis (which may be severe). There is generally only mild overlying vitritis and minimal anterior uveitis. The initial involvement can be at the posterior pole or in the peripheral retina. When the disease occurs in the periphery, it has a more granular appearance than when it occurs at the posterior pole. Occasionally patients with small focal areas of involvement present a diagnostic problem. Visual loss in CMV retinitis may arise from optic nerve or macular involvement with retinitis, rhegmatogenous retinal detachment, serous macular detachment or cystoid macular oedema. Of these causes, only serous or rhegmatogenous detachment are reversible. The degree of visual loss at presentation depends on the site of the retinitis. Peripheral retinitis can be associated with normal vision and no symptoms.
Figure 1. Cytomegalovirus retinitis. Source: Hall AJ. Ophthalmology Department, The Alfred Hospital, Melbourne VIC. Used with permission. Natural history of cytomegalovirus retinitis The prognosis of untreated CMV retinitis is poor. In patients whose CD4 T-lymphocyte (CD4) cell count remains low and who do not receive anti CMV treatment, there is gradual progression and eventual blindness.
CMV retinitis is usually diagnosed clinically without the need for conﬁrmatory tests. CMV retinitis is a disease of the severely immunodeﬁcient and, in patients with AIDS, it rarely occurs with a CD4 count of > 50cells/μL. At a given CD4 cell count, the risk of developing CMV retinitis is increased when other opportunistic infections occur, e.g. Pneumocystis jirovecii pneumonia strongly predicts the development of retinitis (relative risk = 5.8), as does Mycobacterium avium complex infection (relative risk = 5.3). CMV serology is of little use in the diagnosis of retinitis in patients with AIDS because of the high background degree of seropositivity among sexually-active homosexual men and the lack of a rise in titre of CMV antibody during the development of CMV retinitis. Negative CMV serology may occasionally be useful in excluding CMV as a cause of retinitis in non-homosexual patients with AIDS as these patients have a lower background incidence of positive CMV serology. In patients with CMV retinitis there is usually an associated CMV viraemia detectable by testing the plasma CMV viral load. In patients in whom the diagnosis is in doubt, the most sensitive and specific conﬁrmatory test is an anterior chamber or vitreous tap for detection of CMV DNA by a polymerase chain reaction (PCR) test. This test serves to exclude other non-CMV causes for retinitis such as infection by varicella zoster virus (VZV) or herpes simplex virus (HSV) or toxoplasmosis. The incidence of CMV retinitis has fallen dramatically since the widespread use of combination antiretroviral therapy (cART). However, there is still a persistent risk of visual loss in patients with HIV infection and CMV retinitis.
The mainstay of treatment for intra-ocular infections in patients with AIDS is restoration of pathogen-specific immune responses with cART. The principles of treatment of CMV retinitis are to induce remission with induction treatment, maintain remission with ongoing treatment, monitor for progression and complications, and treat these complications as and when they occur.
In general, treatment should be commenced at diagnosis to limit the extent of progression of the disease, to prevent second eye involvement and to confer the beneﬁt of treatment of any associated systemic CMV infection (Table 1). In general the most effective treatment for the involved eye is local intravitreal injection of an antiviral agent. This treatment obviously does not protect the other (non-injected) eye or the rest of the body. In general systemic intravenous antiviral treatment (ganciclovir or foscarnet) is slightly better than oral antiviral treatment (valganciclovir). The ﬁrst-line intravenous treatments (ganciclovir or foscarnet) are equally eﬀective at treating the retinitis in the eye targeted for treatment. Where they vary is in the systemic side eﬀects, systemic beneﬁts, eﬀect on the second eye and practical diﬃculties involved in treatment.
In a well patient with reasonable blood counts and mild-to-moderate CMV retinitis, the most common induction regimen is oral valganciclovir 900 mg twice daily for 3 weeks (or until induction of remission) , followed by maintenance oral valganciclovir 450 mg twice daily. A patient with more aggressive vision threatening CMV retinitis may be treated initially with intravitreal foscarnet (2.4 mg twice weekly) and with oral valganciclovir.
Where induction treatment fails or has to be discontinued because of toxicity, the induction regimen can be changed or combinations used. Induction treatment is continued until there is ophthalmoscopic regression of the retinitis, usually between 2 to 4 weeks. Regression is diagnosed clinically by the absence of thickening or progression and the replacement of the active lesion with a lightly pigmented scar. The possibility of misdiagnosis should be considered in all patients who tolerate induction therapy but fail to achieve regression of lesions.
After treatment, the clinical appearance of the retinitis changes. Healed retinitis is easily recognised by a lack of retinal thickening (seen as a loss of retinal whitening) with disappearance of retinal haemorrhage and vasculitis and halting of progression of the retinitis. Occasionally there is an atypical healing response with persistence of a white ﬂat border of opaciﬁcation8 that does not advance for many weeks to months. The risk of progression to bilateral retinitis increases with time. Even on systemic treatment, the incidence of bilateral retinitis in patients who initially presented with unilateral disease is 10% at 6 months. The incidence of retinal detachment increases with increasing survival of patients with CMV retinitis and with extensive peripheral disease. Detachment occurs due to a combination of multiple small peripheral retinal holes and a mild degree of proliferative vitreoretinopathy.
All available anti-CMV treatments are virustatic rather than virucidal and, once remission is achieved, maintenance treatment must be used or recurrence will occur (at a median time of 16 days). Maintenance therapy can be discontinued when the CD4 count is > 100cells/μL for 3 months on cART. All patients should be screened regularly for recurrences and relapses but the frequency of screening should be increased in those at higher risk:
- Those who have missed or reduced their maintenance treatment
- Those with evidence of systemic CMV activation (including increased plasma CMV viral load)
- Those who have had frequent relapses in the past
- Those whose CD4 count remains < 50cells/μL.
The advantages, disadvantages and side effects of these regimens are largely the same as for when they are used as induction. Doses and routes of delivery of intravitreal maintenance therapy are listed in Table 2:
|Drug||Dose||Route of administration|
|Ganciclovir||200-400 μg once weekly||Intravitreal|
|Foscarnet||1200-2400 μg once weekly||Intravitreal|
Once the patient is in remission and on maintenance treatment, the eyes should be examined for detection of relapse according to the following schedule:
Four-weekly screening for: Standard maintenance patients Two-weekly screening if: Missed or reduced maintenance therapy CMV viraemia (or positive equivalent test e.g. CMV viral load).
Management of relapse of cytomegalovirus retinitis
Relapse of retinitis may take the form of an extension of existing areas of retinitis or the development of new areas of retinitis or the involvement of a previously uninvolved eye. The prevalence of viral resistance increases with time on treatment, but in spite of this there is usually a therapeutic response to re-induction (i.e. an increase in the dose to induction doses) with the same agent as has been used for maintenance treatment. If clinical relapse is accompanied by borderline tolerance of the original maintenance regimen, then re-induction with another regimen is recommended (e.g. a change from oral valganciclovir to intravenous ganciclovir or a change from intravenous ganciclovir to intravenous foscarnet). If the disease is severely vision-threatening or if the patient has relapsed more than once, then a change to intra-ocular therapy (regular intra-ocular injections of ganciclovir or foscarnet) is usually indicated. If that relapse occurs while on intra-ocular ganciclovir then a change to intra-ocular foscarnet or possibly a combination of ganciclovir and foscarnet is usually indicated. Usually re-induction treatment for relapse requires a shorter course of treatment than does normal induction and ophthalmoscopic monitoring is required to determine when maintenance should be recommenced.
Immune reconstitution uveitis
Immune reconstitution uveitis usually occurs in patients with previously recognised and treated CMV retinitis (or occasionally in patients with unrecognised and untreated CMV retinitis) who have recently commenced eﬀective cART and who have had a subsequent improvement in their immune function. Patients generally present with a short-lived and benign uveitis. Occasionally the uveitis is accompanied by more severe vision-threatening complications such as macular oedema, neovascularisation or epiretinal membrane formation. Generally the disease is treatable with a simple short (four weeks) course of topical steroids (1% prednisolone acetate 1-2 hourly), occasionally more aggressive treatment with injected orbital steroids (triamcinolone acetonide or methylprednisolone acetate) or oral prednisolone is required. With time, the disease generally burns out of its own accord. Long-term treatment is rarely required. Generally, when the immune reconstitution uveitis is quiet and the CD4 count has been > 100cells/μL for 6 months, it is possible to stop all speciﬁc anti-CMV treatment.
Treatment of retinal detachment
The visual results of detachment surgery for retinitis-related retinal detachment depend on the degree of involvement with retinitis prior to the surgery and the pre-operative acuity. Eyes with extensive macular or disc involvement and those with acuity of less than counting fingers will do worse post-operatively. When surgery is undertaken, it usually entails a vitrectomy, membrane peel, internal drainage, fluid-gas exchange and injection of silicon oil. The silicon oil should not be removed and hence the eye is rendered variably hypermetropic postoperatively and binocularity is often not achievable if the other eye has normal vision. Some patients with small peripheral detachments can be successfully managed with laser barrage anterior to the detachment. The decision on whether or not to operate depends on the condition of the eye with the detachment, the patient’s vision in the other eye and the general health of the patient. The poor median survival of patients post detachment repair cannot be generally extrapolated to all retinitis patients with detachments and treatment decisions should be individualised for all patients.
Acute retinal necrosis
Acute retinal necrosis is characterised by rapidly progressive peripheral retinitis. Initially there is minimal vitritis but after just a few days the vitreous inﬁltrate increases dramatically. There are larger areas of retinal whitening than are seen with CMV retinitis and the disease has a much faster tempo (Figure 2).There is early development of bilateral involvement and early retinal detachment.
Figure 2. Acute retinal necrosis Source: Hall AJ. Ophthalmology Department, The Alfred Hospital, Melbourne VIC. Used with permission
The disease may occur at any level of immunosuppression and does occur in immunocompetent hosts. Acute retinal necrosis is usually caused by VZV but may also be caused by HSV and rarely by CMV. The diagnosis is usually made clinically but may be conﬁrmed by anterior chamber or vitreous tap for detection of viral DNA by PCR. In particular, this allows diﬀerentiation between acute retinal necrosis and CMV retinitis as the treatment of the two is quite diﬀerent.
Acute retinal necrosis has a worse prognosis than CMV retinitis. Acute retinal necrosis may follow an attack of shingles either in the ophthalmic division of the trigeminal nerve or elsewhere.
Treatment of acute retinal necrosis is usually with high-dose intravenous aciclovir (10 mg/kg / 8 hourly) or with intravitreal foscarnet (1200 μg) or a combination of the two. Induction treatment is generally continued for 2 to 3 weeks until the retinitis appears quiet. After successful induction, maintenance treatment is instituted with oral aciclovir 800 mg ﬁve times daily. In immunocompetent patients, maintenance treatment is usually for 3 to 6 months but in patients with HIV infection with a low CD4cell count maintenance treatment is lifelong.
Progressive outer retinal necrosis
Progressive outer retinal necrosis is a more virulent form of acute retinal necrosis, again caused by VZV. Patients present with visual loss from posterior pole involvement. Generally there is minimal vitritis and rapidly progressive multifocal posterior pole retinitis. This is followed by rapid peripheral enlargement of the retinitis and coalescence of the lesions. Again, there is early development of bilateral involvement and early retinal detachment. The untreated prognosis is very poor with almost universal blindness. The disease occurs in patients who are severely immune-suppressed (CD4 count < 20cells/μL). The diagnosis may be conﬁrmed by an anterior chamber or vitreous tap for detection of VZV DNA.
Treatment is diﬃcult. Generally combination treatment is required with at least one intravenous agent (aciclovir, ganciclovir or foscarnet) and at least one intravitreal agent (usually foscarnet). After induction treatment, long-term combination maintenance treatment is required.
Retinal or chorioretinal involvement by toxoplasmosis is far less common in HIV patients than is central nervous system involvement (the converse is true in immunocompetent patients). Chorioretinal toxoplasmosis in patients with AIDS generally manifests as single or multifocal areas of dense white chorioretinal inﬂammation: it is less common to have large areas of conﬂuent retinitis. There is usually an associated vitritis. Whether single or multifocal there is usually no adjacent pigmented scar. There is often associated central nervous system disease. The diagnosis may be made clinically if there is associated, conﬁrmed central nervous system toxoplasmosis. The disease may be conﬁrmed by toxoplasmosis serology or by anterior chamber or vitreous tap and PCR for toxoplasma DNA. Treatment is with oral sulphadiazine (4 mg daily) (or clindamycin 300 to 600 mg four times daily), pyrimethamine (50 mg daily) and folinic acid (15 mg daily). If the patient is allergic to sulfa- based antibiotics, then atovaquone may be substituted. For patients who are intolerant of all systemic therapies intravitreal clindamycin may be used. For chorioretinal toxoplasmosis without cerebral involvement, oral steroids are usually not required.
Patients with AIDS with multifocal choroiditis generally have only mild, if any, visual disturbance. Multifocal choroiditis may be seen in patients with cryptococcal meningitis, especially with associated widespread non-central nervous system cryptococcal disease. In this case, the association with signs and symptoms of cryptococcal meningitis may aid in making the diagnosis. Multifocal choroiditis may also be seen in patients with widespread pneumocystis infection, especially in patients having inhaled pentamidine as prophylaxis for Pneumocystis jirovecii pneumonia. Less commonly, multifocal or unifocal choroiditis is seen in patients with disseminated Mycobacterium avium complex infection. In each case the clinical features are very similar with small (500 to 1500 mm) creamy white/yellow outer retinal/choroidal lesions. There is rarely associated haemorrhage and the associated vitritis is minimal.
Patients do not require speciﬁc ocular treatment but respond to systemic treatment of the associated systemic infection. The visual prognosis is good unless there is subfoveal involvement of the choroiditis.
Other ocular conditions
Uveitis without retinitis or choroiditis
Patients with AIDS with intra-ocular inﬂammation generally have an associated retinitis or choroiditis. Sometimes patients present with intra-ocular inﬂammation (uveitis or vitritis) without any focal areas of retinitis or choroiditis. In such cases there is a small number of possible underlying causes (Table 3). It is necessary to fully investigate these patients before making appropriate treatment decisions. It is unwise to treat these patients with steroids without determining the underlying cause.
Optic neuropathy in patients with AIDS rarely occurs as an isolated phenomenon. CMV optic neuritis is usually seen with adjacent CMV retinitis. Cryptococcal optic neuropathy is usually seen with associated cryptococcal meningitis. Syphilitic optic neuropathy is usually seen with secondary syphilis and associated syphilitic uveitis. Optic nerve swelling with good optic nerve function may be seen from any central nervous system space occupying lesion in patients with AIDS but the most common causes of papilloedema in patients with AIDS are toxoplasmosis and central nervous system lymphoma.
External infections and tumours
Blepharitis and sicca syndromes
Surface ocular irritation and dryness is common but usually not visually signiﬁcant. Blepharitis may be associated with facial seborrhoeic dermatitis. Treatment with simple topical lubricants or eyelid hygiene is generally suﬃcient. Occasionally, long-term, low-dose topical steroids (ﬂuoromethalone) may be needed.
Eyelid molluscum may cause a chronic conjunctivitis or simply be of cosmetic concern. It can be treated with local anaesthetic and curettage or cryotherapy.
Herpes simplex virus keratitis
Herpes simplex virus keratitis in patients with AIDS may be peripheral and prolonged. Even so, treatment with a simple longer-term topical aciclovir is generally sufficient. Aciclovir resistance may occur. Systemic therapy is rarely warranted.
Herpes zoster ophthalmicus
Herpes zoster ophthalmicus may be the presenting feature of HIV infection in young people in at-risk groups. Standard therapy with oral or intravenous aciclovir, valaciclovir or famciclovir is generally eﬀective. Long-term suppressive aciclovir may be required.
Lid and conjunctival Kaposi’s sarcoma
Lid or conjunctival Kaposi’s sarcomas are deep red/purple lesions which may be ﬂat or only slightly raised. They may look like a subconjunctival haemorrhage. Lid or conjunctival Kaposi’s sarcomas are treated with local anaesthetic and cryotherapy.
Microsporidial keratoconjunctivitis presents with a chronic conjunctivitis with characteristic ﬁne superﬁcial punctate keratopathy and subepithelial inﬁltrates. The diagnosis is usually made on corneal scrapes or biopsy. The patients usually respond to topical voriconazole or fumagillin.