Mark L. Nelson

BASICS

DESCRIPTION

• HIV retinopathy and CMV retinitis are by far the most common ocular manifestations of HIV.

• Cytomegalovirus (CMV) retinitis is the most important AIDS-associated illness to affect the eyes. It is a full thickness retinal infection that can lead to necrosis and to retinal tears and detachments.

• Other ocular manifestations of HIV infection include HIV retinopathy, various opportunistic infections including toxoplasmosis, syphilis, pneumocystis carinii, cryptococcus, and herpes-family virus infections, especially CMV retinitis and progressive outer retinal necrosis. Kaposi Sarcoma, intraocular lymphoma, and conjunctival squamous cell carcinoma also occur.

Pediatric Considerations

Congenital CMV infection can cause significant neurological and developmental abnormalities.

Pregnancy Considerations

Mothers with CMV primary infections can pass the virus on to fetus transplacentally causing congenital CMV infection.

EPIDEMIOLOGY

Incidence

In the pre-HAART era, CMV retinitis had a cumulative lifetime incidence of 25–40%. The incidence has decreased considerably in recent years.

Prevalence

• HIV retinopathy occurs in 50–60% of patients infected with HIV.

• Historically, CMV retinitis occurred in up to 40% of patients with HIV and is an AIDS-defining illness; however, it is much less common in the HAART era.

RISK FACTORS

The main risk factor for development of CMV retinitis is a low CD4 count, typically below 50.

GENERAL PREVENTION

HAART therapy has shown great benefit for reduction in CMV retinitis, as it often maintains a CD4 count above 50.

PATHOPHYSIOLOGY

• CMV reaches the retina hematogenously. It then infects the retinal vascular endothelium.

• On histopathology, infected cells show pathognomonic cytomegalic inclusions with large eosinophilic intracellular bodies.

• Electron microscopy can show CMV particles within infected cells.

• Histopathology shows full thickness retinal necrosis, coagulative vasculitis, and choroiditis.

ETIOLOGY

• Cytomegalovirus (CMV) is a member of the herpes virus family.

• There is a high prevalence of CMV antibodies in the general population and most people are thought to have been infected at one time or another.

• In healthy people, CMV infection may manifest as a mild mono-like illness, or may be asymptomatic.

COMMONLY ASSOCIATED CONDITIONS

• Although CMV retinitis occurs most commonly in patients with AIDS, it can also occur in severely immunocompromised individuals, such as those receiving chemotherapy.

• Before HAART, a diagnosis of CMV retinitis was associated with a median survival time of 6 months.

DIAGNOSIS

HISTORY

• Patients may present with decreased visual acuity, flashing lights (photopsias), or blind spots (scotomata).

• One study found that 54% were asymptomatic.

PHYSICAL EXAM

• Physical exam shows yellow–white areas of retinal necrosis with some retinal hemorrhages that often start in the periphery and follow the vasculature centripetally.

• There may also be hard exudates, and mottling of the retinal pigment epithelium.

• Each lesion is most active at the borders.

• As most patients are severely immunocompromised, there is usually minimal vitreitis.

• Very early CMV may resemble cotton wool spots, but with lesions larger than 750 μm, CMV must be considered.

• Funduscopy may show a granular pattern, a fulminant/hemorrhagic appearance, or “frosted branch” angiitis.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• CD4 count and viral load are important lab tests to follow. It is not necessary to draw CMV blood serology as CMV has a high prevalence in the population.

• Aqueous sampling with PCR analysis can be used to identify CMV DNA.

Imaging

• Serial fundus photographs are helpful to document progression of disease.

• Fluorescein angiography is not usually helpful in diagnosis.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes cotton wool spots from other causes, herpetic retinitis syndrome such as ARN and PORN, and toxoplasmosis.

TREATMENT

MEDICATION

First Line

• In all FDA approved treatments of CMV retinitis, there is an initial period of high-dose antiviral induction followed by continuous maintenance. Initially, oral valganciclovir (the oral pro-drug of ganciclovir) 900 mg b.i.d for 21 days of induction followed by 900 mg q day for maintenance therapy can be used. The major side effect of valganciclovir/ ganciclovir is bone marrow suppression.

– However, in eyes with macula threatening disease, IV ganciclovir should still be considered.

• IV ganciclovir can be administered 5 mg/kg IV b.i.d for 2 weeks followed by 5 mg/kg IV for maintenance therapy. The major toxicity of ganciclovir is myelosuppression. Granulocyte-macrophage colony stimulating factor should be used concomitantly to avoid myelosuppression.

• Oral ganciclovir can be used as maintenance therapy, but recurrence is more frequent than with valganciclovir or IV ganciclovir, and the fellow eye is at greater risk of developing CMV retinitis.

• IV foscarnet at 90 mg/kg b.i.d for 2 weeks followed by 90–120 mg/kg daily for maintenance is another option. The principle toxicity of foscarnet is renal dysfunction, electrolyte abnormalities, and possibly seizures.

• Institution of HAART therapy is critical. It has raised the survival time from 0.65 years to >1 year, it has reduced the odds of CMV progression, and the number of new CMV cases has declined.

• Maintenance therapy may be discontinued in patients with CD4 >100 cells/μL who show no signs of progression AND who are on HAART.

Second Line

• Intravitreal administration of ganciclovir 200 μg–2 mg weekly and foscarnet 2.4 mg weekly. Induction with intravitreal injections is twice a week for 2–3 weeks. Intravitreal injection to one eye obviously does not protect the other eye from developing CMV retinitis.

• A ganciclovir intravitreal implant (Vitrasert) may be considered in patients who do not tolerate systemic treatment, but it does not provide systemic protection against CMV nor does it protect the other eye from CMV. It typically lasts 2 years if CMV resistance to ganciclovir does not develop.

• The risks of intravitreal injections include cataract, vitreous hemorrhage, retinal detachment, and infectious endophthalmitis.

• IV cidofovir at 5 mg/kg weekly for 2 weeks, then 5 mg/kg every other week for maintenance. Cidofovir may cause hypotony and anterior uveitis.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patients should be followed closely, especially if they have discontinued therapy as CMV retinitis has a high recurrence rate in patients with a CD4 count <100.

PROGNOSIS

• The prognosis was almost uniformly fatal prior to the advent of HAART.

• Now it carries a much better prognosis, but even with HAART, and anti-CMV therapy, mortality is still increased after CMV retinitis develops.

COMPLICATIONS

• Immune Recovery Uveitis (IRU) is a potential complication of recovery from low CD4 counts. Patients who had CMV retinitis, who then have reconstitution of their immune system, may develop anterior or intermediate uveitis, cystoid macular edema, and epiretinal membranes. Patients complain of vision loss, pain, photophobia, and floaters.

• Other complications of IRU include posterior subcapsular cataracts, proliferative vitreoretinopathy, and optic nerve neovascularization.

• CMV retinitis can cause retinal detachments. Regular monitoring is needed.

ADDITIONAL READING

• Martin DF, Sierra-Madero J, Walmsley S, et al; Valganciclovir Study Group. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med. 2002;346(15):1119–1126. Erratum in: N Engl J Med 2002;347(11):862.

• Goldberg DE, Smithen LM, Angelilli A, et al. HIV-associated retinopathy in the HAART Era. Retina 2005;25(5):633–649.

• Thorne JE, Jabs DA, Kempen JH, et al; Studies of Ocular Complications of AIDS Research Group. Incidence of and risk factors for visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology 2006 Aug;113 (8):1432–1440.

• Holland GN. AIDS and Ophthalmology: The first quarter century. Am J Ophthalmol 2008;145(3):397–408.

• Musch DC, Martin DF, Gordon JF, et al. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. The Ganciclovir Implant Study Group. N Engl J Med. 1997;337(2):83–90.

CODES

ICD9

• 078.5 Cytomegaloviral disease

• 363.20 Chorioretinitis, unspecified

CLINICAL PEARLS

• After HIV retinopathy, CMV retinitis is the most common ocular manifestation of AIDS. It is an AIDS defining illness.

• Patients may be asymptomatic or may have vision loss, floaters, flashes, or blind spots. Retinal findings of vascular angiitis, yellow–white retinitis with a granular appearance, and hemorrhage can be seen.

• Treatment is usually started with oral valganciclovir and HAART treatment is necessary to achieve any lasting remission.

• Prognosis is improved since HAART, but is still poor.

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